WO2022199587A1 - 嘧啶并杂环类化合物及其应用 - Google Patents
嘧啶并杂环类化合物及其应用 Download PDFInfo
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- WO2022199587A1 WO2022199587A1 PCT/CN2022/082328 CN2022082328W WO2022199587A1 WO 2022199587 A1 WO2022199587 A1 WO 2022199587A1 CN 2022082328 W CN2022082328 W CN 2022082328W WO 2022199587 A1 WO2022199587 A1 WO 2022199587A1
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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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/14—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
Definitions
- the present invention relates to a series of pyrimido-heterocyclic compounds and their applications, in particular to the compounds represented by formula (II) and their pharmaceutically acceptable salts.
- the KRAS gene is one of the most frequently mutated oncogenes in human cancers. In addition to directly promoting the proliferation and survival of tumor cells, KRAS gene mutations can also have an impact on the tumor microenvironment. In human cancers, the mutation occurs in nearly 90% of pancreatic cancers, 30%-40% of colon cancers, and 15%-20% of lung cancers. Additionally, 80% of oncogenic mutations occurred at codon 12, with the most common mutations including: p.G12D (41%), p.G12V (28%) and p.G12C (14%).
- KRAS G12C inhibitors such as Amgen's AMG510 and Mirati Therapeutics' MRTX849, herald the arrival of a new era of precision oncology.
- KRAS G12D small molecule has entered the clinical research stage, and KRAS G12D- mutated tumor patients have not benefited from precision medicine. Therefore, research in the field of KRAS G12D small molecules is urgently needed.
- the present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
- Ring A is selected from
- T 1 is selected from CH 2 , NH and O;
- T 2 is selected from CH and N;
- T 3 and T 4 are independently selected from CH 2 and NH;
- n, p and x are each independently selected from 0, 1 or 2;
- r, v and w are each independently selected from 1 or 2;
- q and u are independently selected from 1, 2 or 3;
- each R 1 is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 and CF 3 ;
- E 1 and E 3 are each independently selected from a bond, O, S, Se, NH and CH 2 , each independently optionally substituted with 1 or 2 Ra ;
- E 2 is selected from -C(O)-, -C(O)-(CH 2 ) g - and -(CH 2 ) h -, when g and h are not selected from 0, the -C(O)- (CH 2 ) g - and -(CH 2 ) h - are each independently optionally substituted with 1, 2 or 3 R b ;
- X 1 and X 2 are each independently selected from N and CR 4 ;
- L 1 is selected from a bond and CH 2 optionally substituted with 1 or 2 R c ;
- R 2 is selected from 5-10 membered heterocycloalkyl optionally substituted with 1, 2 or 3 R d ;
- R 3 is selected from C 6-10 aryl and 5-10 membered heteroaryl, said C 6-10 aryl and 5-10 membered heteroaryl respectively independently optionally replaced by 1, 2, 3, 4 or 5 R e substitutions;
- e is selected from 0, 1, 2 and 3;
- f, g and h are independently selected from 0, 1 and 2;
- each R a is independently selected from H and CH 3 ;
- each of R b and R c is independently selected from H, F, Cl, Br, I, OH, NH 2 and CN;
- Each R d is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and -OCO-C 1-3 alkylamino;
- each Rf is independently selected from H, F, Cl, Br, I, OH, NH2 , CN and CH3 ;
- Each R is independently selected from H, F, Cl, Br, I and CH3 .
- the ring A is selected from Other variables are as defined in the present invention.
- the ring A is selected from Other variables are as defined in the present invention.
- the structural fragment selected from R 1 , e and other variables are as defined herein.
- the structural fragment selected from Other variables are as defined in the present invention.
- the E 2 is selected from C(O), C(O)CH 2 , CH 2 and CH 2 CH 2 , and other variables are as defined herein.
- said R4 is selected from H, F, CH3 and CF3 , and other variables are as defined herein.
- the X 1 is selected from N, CH and C(CF 3 ), and other variables are as defined herein.
- the X 2 is selected from N, CH and CF, and other variables are as defined herein.
- the R d is selected from F, and other variables are as defined herein.
- the R 2 is selected from tetrahydropyrrolyl and hexahydro-1H-pyrrolizinyl, and said tetrahydropyrrolyl and hexahydro-1H-pyrrolizinyl are optionally separated by 1, 2 or 3 R d substitutions, R d and other variables are as defined herein.
- the R 2 is selected from Other variables are as defined in the present invention.
- the R 2 is selected from Other variables are as defined in the present invention.
- the Re is selected from H, F, Cl, Br, I, OH, NH2 , CN, CH3 , CH2CH3 , CH( CH3 ) 2 , OCH3 , OCH 2CH3 , OCH( CH3 ) 2 , NCH3 , NCH2CH3 , N( CH3 ) 2 , SCH3 , SCH2CH3 , SCH (CH3)2 , -C ⁇ CH , cyclopropyl and Cyclobutyl, the CH3 , CH2CH3 , CH( CH3 ) 2 , OCH3 , OCH2CH3 , OCH( CH3 ) 2 , NCH3 , NCH2CH3 , N ( CH3 ) 2 , SCH3 , SCH2CH3, SCH( CH3 ) 2 , -C ⁇ CH, cyclopropyl and cyclobutyl are optionally substituted with 1, 2 or 3 R, R and other variables as defined
- the Re is selected from H, F, Cl, OH, CF 3 , CH 2 CH 3 , CH(CH 3 ) 2 , OCF 3 , SCH 3 , -C ⁇ CH, Other variables are as defined in the present invention.
- the Re is selected from H, F, Cl , OH, NH2 , CH3 , CF3 , CH2CH3 , CH( CH3 ) 2 , OCH3 , OCF3, SCH 3 , SCF 3 , -C ⁇ CH,
- Other variables are as defined in the present invention.
- the R is selected from phenyl, naphthyl, and indazolyl, optionally surrounded by 1, 2, 3, 4, or 5 R e Substitution, Re and other variables are as defined herein.
- the R 3 is selected from Other variables are as defined in the present invention.
- the R 3 is selected from Other variables are as defined in the present invention.
- the R 3 is selected from Other variables are as defined in the present invention.
- the R 3 is selected from Other variables are as defined in the present invention.
- the structural unit selected from R4 and other variables are as defined in the present invention .
- the structural unit selected from R4 is selected from H, F, CH3 and CF3 , other variables are as defined in the present invention.
- the compound or a pharmaceutically acceptable salt thereof is selected from,
- R 2 and R 3 are as defined in the present invention.
- the compound or a pharmaceutically acceptable salt thereof is selected from,
- R 3 and R d are as defined in the present invention.
- the compound or a pharmaceutically acceptable salt thereof is selected from,
- R d is selected from F, Cl, Br, I, OH, NH 2 , CN and -OCO-C 1-3 alkylamino;
- R 3 is as defined in the present invention.
- the compound or a pharmaceutically acceptable salt thereof is selected from,
- R d is selected from F, Cl, Br, I, OH, NH 2 , CN and -OCO-C 1-3 alkylamino;
- R is as defined in the present invention.
- the carbon atoms with "*" and “#” are chiral carbon atoms and exist as (R) or (S) single enantiomer or enriched in one enantiomer.
- the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
- Ring A is selected from
- T 1 is selected from CH 2 , NH and O;
- T 2 is selected from CH and N;
- T 3 and T 4 are independently selected from CH 2 and NH;
- n, p and x are each independently selected from 0, 1 or 2;
- r, v and w are each independently selected from 1 or 2;
- q, s and u are each independently selected from 1, 2 or 3;
- each R 1 is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 and CF 3 ;
- E 1 and E 3 are each independently selected from a bond, O, S, Se, NR a and CH 2 , said CH 2 being optionally substituted with 1 or 2 Ra ;
- E 2 is selected from -C(O)-, -C(O)-(CH 2 ) g - and -(CH 2 ) h -, when g and h are not selected from 0, the -C(O)- (CH 2 ) g - and -(CH 2 ) h - are optionally substituted with 1, 2 or 3 R b ;
- X 1 and X 2 are each independently selected from N and CR 4 ;
- L 1 is selected from a bond and CH 2 optionally substituted with 1 or 2 R c ;
- R 2 is selected from 5-10 membered heterocycloalkyl optionally substituted with 1, 2 or 3 R d ;
- R 3 is selected from C 6-10 aryl and 5-10 membered heteroaryl, the C 6-10 aryl and 5-10 membered heteroaryl are optionally replaced by 1, 2, 3, 4 or 5 R e replace;
- e is selected from 0, 1, 2 and 3;
- f, g and h are independently selected from 0, 1 and 2;
- each R a is independently selected from H and CH 3 ;
- each of R b and R c is independently selected from H, F, Cl, Br, I, OH, NH 2 and CN;
- Each R d is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and -OCO-C 1-3 alkylamino;
- each Rf is independently selected from H, F, Cl, Br, I, OH, NH2 , CN and CH3 ;
- Each R is independently selected from H, F, Cl, Br, I and CH3 .
- the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof, which compound is selected from,
- the compound or a pharmaceutically acceptable salt thereof is selected from,
- the compound or a pharmaceutically acceptable salt thereof is selected from,
- the present invention also provides following synthetic method:
- R 3p is selected from
- R 3 is selected from
- R 3p is selected from
- R 3 is selected from
- the present invention also provides the following test methods:
- control compound stock solution 1 mM
- concentration of the test compound stock solution 10 mM.
- Test Method 2 Anticellular Proliferative Effects of Compounds in Tumor Cell Lines AsPC-1 and GP2D
- RPMI 1640 fetal bovine serum
- FBS fetal bovine serum
- Antibiotic-antimycotic antibiotic-antifungal
- L-glutamine L-glutamine
- DMSO dimethyl sulfoxide
- the tumor cell lines were cultured in a 37°C, 5% CO2 incubator according to the culture conditions indicated in the culture method. Periodically passaged, cells in logarithmic growth phase were taken for plating.
- the ULA plates were centrifuged at 1000 rpm for 10 minutes at room temperature. NOTE: After centrifugation, be careful not to cause unnecessary shaking. The plates were incubated overnight in an incubator at 37°C, 5% CO2 , and 100% relative humidity.
- Preparation of 10X compound working solution and compound treatment of cells (the first day): After preparing 10X compound working solution (DMSO 10X working solution), add 15 ⁇ L of 10X compound working solution to ULA culture plate respectively, and add 15 ⁇ L of 10X compound working solution to the vehicle control and blank control. Add 15 ⁇ L of DMSO-cell culture medium mixture to it. Return the 96-well cell plate to the incubator for 120 hours. Cell spheroidization was observed every day until the end of the experiment.
- CellTiter-Glo Luminescence Cell Viability Assay Day 5: The following steps were performed according to the instructions of Promega CellTiter-Glo 3D Luminescence Cell Viability Assay Kit (Promega#G9683). Add 150 ⁇ L (equivalent to the volume of cell culture medium in each well) of CellTiter-Glo 3D reagent to each well. Wrap the cell plate in aluminum foil to protect from light. Shake the plate on an orbital shaker for 5 minutes. Mix the air mixture carefully by pipetting up and down 10 times. Make sure the spheroids are sufficiently detached before proceeding to the next step. The solution in the ULA plate was then transferred to a black bottom plate (#655090) and left at room temperature for 25 minutes to stabilize the luminescent signal. Luminescent signals were detected on a 2104EnVision plate reader.
- IR(%) (1 ⁇ (RLU compound ⁇ RLU blank control)/(RLU vehicle control ⁇ RLU blank control)*100%.
- the inhibition rates of different concentrations of compounds were calculated in Excel, and then the GraphPad Prism software was used to plot the inhibition curves and calculate the relevant parameters, including the minimum inhibition rate, the maximum inhibition rate and IC 50 .
- the compound of the present invention has a good binding effect with KRAS G12D protein, can effectively inhibit p-ERK of GP2D cells, and has significant cell proliferation inhibitory activity on KRAS G12D mutant cells.
- the compounds of the present invention have good in vivo pharmacokinetic properties and significant antitumor effects.
- salts refers to salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases.
- base addition salts can be obtained by contacting the neutral forms of such compounds with a sufficient amount of base in neat solution or in 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 the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
- Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, and methanesulfonic acids; also include salts of amino acids such as arginine, etc. , and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base
- the pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
- the compounds provided herein also exist in prodrug forms.
- Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the present invention.
- prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.
- 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 isomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to within the scope of the present invention.
- Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
- enantiomers or “optical isomers” refer to stereoisomers that are mirror images of each other.
- cis-trans isomer or “geometric isomer” result from the inability to rotate freely due to double bonds or single bonds to ring carbon atoms.
- diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirror-image relationship.
- tautomer or “tautomeric form” refers to isomers of different functional groups that are in dynamic equilibrium and are rapidly interconverted at room temperature.
- a chemical equilibrium of tautomers can be achieved if tautomers are possible (eg, in solution).
- proton tautomers also called prototropic tautomers
- prototropic tautomers include interconversions by migration of protons, such as keto-enol isomerization and imine-ene Amine isomerization.
- Valence tautomers include interconversions by recombination of some bonding electrons.
- keto-enol tautomerization is the interconversion between two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
- the terms “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in one enantiomer” refer to one of the isomers or pairs
- the enantiomer content is less than 100%, and the isomer or enantiomer content 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%.
- isomeric excess or “enantiomeric excess” refer to the difference between two isomers or relative percentages of 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 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 mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
- a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art
- the diastereoisomers were resolved and the pure enantiomers recovered.
- separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).
- the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
- compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
- deuterated drugs can be formed by replacing hydrogen with deuterium, and the bonds formed by deuterium and carbon are stronger than those formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention. "Optional" or “optionally” means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
- substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable.
- oxygen it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on aromatic groups.
- optionally substituted means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically achievable basis.
- any variable eg, R
- its definition in each case is independent.
- the group may optionally be substituted with up to two Rs, with independent options for R in each case.
- combinations of substituents and/or variants thereof are permissible 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.
- substituents 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 substituents do not indicate through which atom it is attached to the substituted group, such substituents may be bonded through any of its atoms, for example, pyridyl as a substituent may be through any one of the pyridine ring The carbon atom is attached to the substituted group.
- the direction of attachment is arbitrary, for example,
- the linking group L in the middle is -MW-, at this time -MW- can connect ring A and ring B in the same direction as the reading order from left to right. It is also possible to connect ring A and ring B in the opposite direction to the reading order from left to right.
- Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
- aromatic ring is a cyclic group having a conjugated pi-electron system, the atoms of which are covered by a cloud of delocalized pi-electrons.
- the structural formula when it conforms to the valence state and covalent bonding rules, it can be written in the form of alternating single and double bonds, or it can be written as represents the delocalized ⁇ electron cloud.
- the structural formula The structures represented are all the same, the structural formula The structures represented are all the same. It can be a monocyclic or fused polycyclic ring system, wherein each ring is aromatic. Unless otherwise specified, the ring optionally contains 0, 1 or more heteroatoms independently selected from O, S and N.
- Cn-n+m or Cn - Cn+m includes any particular instance of n to n+ m carbons, eg C1-12 includes C1 , C2 , C3, C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also including any range from n to n+ m , eg C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 , etc.; in the same way, n yuan to n +m-membered means that the number of atoms in the ring is from n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membere
- C 1-6 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms.
- the C 1-6 alkyl includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl and the like; it can be Is monovalent (eg methyl), divalent (eg methylene) or polyvalent (eg methine).
- C 1-6 alkyl examples 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), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.
- C 1-3 alkyl is used to denote a straight or branched chain 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 (eg methyl), divalent (eg methylene) or multivalent (eg methine) .
- Examples of C1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
- C1-3alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an oxygen atom.
- the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy and the like.
- Examples of C 1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
- C 1-3 alkylamino refers to those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an amino group.
- the C 1-3 alkylamino groups include C 1-2 , C 3 and C 2 alkylamino groups and the like.
- Examples of C 1-3 alkylamino include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -NHCH 2 CH 2 CH 3 , - NHCH 2 (CH 3 ) 2 and the like.
- C 1-3 alkylthio refers to those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through a sulfur atom.
- the C 1-3 alkylthio group includes C 1-3 , C 1-2 and C 3 alkylthio groups and the like. Examples of C1-3 alkylthio groups include, but are not limited to, -SCH3 , -SCH2CH3 , -SCH2CH2CH3 , -SCH2 ( CH3 ) 2 , and the like.
- C 2-4 alkenyl is used to denote a straight or branched chain hydrocarbon group consisting of 2 to 4 carbon atoms containing at least one carbon-carbon double bond, a carbon-carbon double bond can be located anywhere in the group.
- the C 2-4 alkenyl group includes C 2-3 , C 4 , C 3 and C 2 alkenyl groups, etc.; the C 2-4 alkenyl group may be monovalent, divalent or multivalent.
- Examples of C 2-4 alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, butadienyl, and the like.
- C 2-4 alkynyl is used to denote a straight or branched chain hydrocarbon group consisting of 2 to 4 carbon atoms containing at least one carbon-carbon triple bond, a carbon-carbon triple bond can be located anywhere in the group.
- the C 2-4 alkynyl groups include C 2-3 , C 4 , C 3 and C 2 alkynyl groups and the like. It can be monovalent, bivalent or multivalent. Examples of C2-4alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, and the like.
- C 3-5 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 3 to 5 carbon atoms, which is a monocyclic ring system, said C 3-5 cycloalkyl including C 3 -4 and C 4-5 cycloalkyl, etc.; it may be monovalent, divalent or polyvalent.
- Examples of C3-5 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like.
- the term "5-10 membered heterocycloalkyl" by itself or in combination with other terms denotes a saturated cyclic group consisting of 5 to 10 ring atoms, respectively, of which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, where the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (ie, NO and S(O) p , p is 1 or 2). It includes monocyclic, bicyclic and tricyclic rings, wherein bicyclic and tricyclic rings include spiro, paracyclic and bridged rings.
- a heteroatom may occupy the position of attachment of the heterocycloalkyl to the remainder of the molecule.
- the 5-10-membered heterocycloalkyl includes 5-6-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, and the like.
- Examples of 5-10 membered heterocycloalkyl include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.) , tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1 -piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazole Alkyl, 1,2-oxazinyl, 1,2-thiazinyl, he
- C 6-10 aryl ring and “C 6-10 aryl group” can be used interchangeably in the present invention
- C 6-10 aryl ring” or C 6-10 aryl group means by A cyclic hydrocarbon group composed of 6 to 10 carbon atoms with a conjugated ⁇ -electron system, which may be a monocyclic, fused bicyclic or fused tricyclic system, wherein each ring is aromatic. It may be monovalent, divalent or polyvalent, and C6-10 aryl groups include C6-9 , C9 , C10 and C6 aryl groups and the like. Examples of C6-10 aryl groups include, but are not limited to, phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, and the like).
- 5-10-membered heteroaryl ring and “5-10-membered heteroaryl” can be used interchangeably in the present invention, and the term “5-10-membered heteroaryl” refers to a ring consisting of 5 to 10 rings.
- a cyclic group composed of atoms with a conjugated ⁇ -electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. It can be a monocyclic, fused bicyclic or fused tricyclic ring system, wherein each ring is aromatic.
- the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , p is 1 or 2).
- a 5-10 membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom.
- the 5-10-membered heteroaryl groups include 5-8-membered, 5-7-membered, 5-6-membered, 5- and 6-membered, 7-membered, 8-membered, 9-membered, 10-membered and other heteroaryl groups.
- Examples of the 5-10 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl, etc.) azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (
- protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
- amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
- Representative amino protecting groups include, but are not limited to: formyl; acyl groups, such as alkanoyl groups (eg, acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl groups, such as tert-butoxycarbonyl (Boc) ; Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); Arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
- hydroxy protecting group refers to a protecting group suitable for preventing hydroxyl side reactions.
- Representative hydroxy protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (eg acetyl); arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
- alkyl groups such as methyl, ethyl and tert-butyl
- acyl groups such as alkanoyl (eg acetyl)
- arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenyl
- the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction method (SXRD), the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuK ⁇ radiation, and the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
- SXRD single crystal X-ray diffraction method
- the cultured single crystal is collected by Bruker D8 venture diffractometer
- the light source is CuK ⁇ radiation
- the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
- TBDPS tert-butyltriphenylsilyl
- MOM methoxymethyl
- TIPS tri-tert-butylsilyl
- hr hours
- min minutes.
- 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 enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
- the solvent used in the present invention is commercially available.
- Compounds are named according to conventional nomenclature in the art or are used Software naming, commercially available compounds use supplier catalog names.
- the present invention will be described in detail by the following examples, but it does not mean any unfavorable limitation of the present invention.
- 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 enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, 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 modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the invention.
- the molecular docking process was performed by using Maestro ( Glide SP [1] and default options in version 2020-2).
- Maestro Glide SP [1] and default options in version 2020-2).
- For the preparation of the protein model select the crystal structure PDB: 5V6S of KRAS_G12C in the PDB database, mutate Cys12 to Asp12, use the protein preparation wizard module of Maestro [2] to add hydrogen atoms, and use the OPLS3 force field after energy optimization, as Docking template.
- the three-dimensional structure of the molecule was generated using LigPrep and energy minimization was performed [3] , and the small molecule conformation was sampled using the confgen module.
- the side length of the docking template was generated as The cube docking grid of , and the related molecules were docked using this grid file. Then, according to the calculated docking scrore and binding mode, a reasonable docking conformation was selected and saved, and Pymol was used to generate a binding mode map. Binding patterns of compounds A to J to KRAS G12D protein are shown in Figures 1 to 10 .
- the compound of the present invention has good binding with KRAS G12D .
- Lithium aluminum hydride (12.5 g, 329.38 mmol, 6.16 eq) was added to the reaction solution of compound A-4 (9.85 g, 53.48 mmol, 1 eq) in anhydrous tetrahydrofuran (200 mL) at 0 °C, and gradually warmed to room temperature (20 °C) stirring for 16hr. After the reaction, water (12.5 mL) was added dropwise with stirring at low temperature, 15% sodium hydroxide solution (12.5 mL) was added dropwise, and then water (25 mL) was added dropwise.
- reaction solution was washed with saturated ammonium chloride (100 mL*3), the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried.
- Triethylamine (16.54g, 163.43mmol, 22.75mL, 5eq) and di-tert-butyl carbonate (6.42g, 29.42mmol, 6.76mL, 0.9eq) were added to compound A-6 (12.44g, 32.69mmol) at 0°C , 1 eq) in anhydrous DCM (150 mL), stirred at 0 °C for 2 hr. After the reaction was completed, saturated ammonium chloride solution (80mL*3) was added to the reaction solution to quench the reaction, the layers were separated, the organic phase was taken, washed with saturated brine (80mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was Spin dry.
- the concentrate was prepared by high performance liquid chromatography (HPLC) (column: Phenomenex C18150*40mm*5 ⁇ m; mobile phase: [water (0.1% formic acid)-acetonitrile]; gradient: acetonitrile %: 1%-30%, 8min) Purified, and then subjected to supercritical fluid chromatography (SFC) (chiral column: DAICEL Chiralcel OD-3 100*4.6mm I.D., 3 ⁇ m); mobile phase: [A: carbon dioxide, B: ethanol (0.05% diethylamine)]; Elution gradient: B: 40%; flow rate: 2.8 mL/min) separation to give compound 1a and compound 1b.
- HPLC high performance liquid chromatography
- SFC supercritical fluid chromatography
- the purpose of this experiment is to verify the proliferation inhibitory effect of the compounds of the present invention on KRAS G12D mutant GP2D human colon cancer cells.
- cell line GP2D cell line GP2D, DMEM medium, penicillin/streptomycin antibiotics were purchased from Vicente, and fetal bovine serum was purchased from Biosera.
- 3D Cell Viability Assay (3D Cell Viability Chemiluminescence Detection Reagent) reagent was purchased from Promega.
- GP2D cells were seeded in a 96-well U-bottom cell culture plate, 80 ⁇ L of cell suspension per well, which contained 2000 GP2D cells. Cell plates were incubated overnight in a carbon dioxide incubator. The compounds to be tested were diluted 5-fold to the 8th concentration, that is, from 200 ⁇ M to 2.56 nM, and a double-well experiment was set up. Add 78 ⁇ L of medium to the middle plate, and then transfer 2 ⁇ L of each well of the compound to the middle plate according to the corresponding position. After mixing, transfer 20 ⁇ L of each well to the cell plate. Compound concentrations transferred to the cell plate ranged from 1 ⁇ M to 0.0128 nM. The cell plates were placed in a carbon dioxide incubator for 5 days.
- the IC 50 value can be obtained by curve fitting with four parameters ("log(inhibitor) vs. response--Variable slope" mode).
- the compound of the present invention has a significant inhibitory effect on the proliferation of GP2D cells.
- GP2D cells were seeded in a transparent 96-well cell culture plate, 80 ⁇ L of cell suspension per well, each well containing 8000 cells, the cell plate was placed in a carbon dioxide incubator, and incubated at 37°C overnight;
- the compounds of the present invention have a significant inhibitory effect on p-ERK in GP2D cells.
- the purpose of this experiment is to verify the inhibitory effect of the compounds of the present invention on the proliferation of AsPC-1 cells with KRAS G12D mutation.
- RPMI-1640 medium penicillin/streptomycin antibiotics were purchased from Vicente, and fetal bovine serum was purchased from Biosera.
- CellTiter-Glo Cell Viability Chemiluminescence Detection Reagent
- the AsPC-1 cell line was purchased from Nanjing Kebai Biotechnology Co., Ltd. Nivo Multilabel Analyzer (PerkinElmer).
- AsPC-1 cells were seeded in white 96-well plates, 80 ⁇ L of cell suspension per well, which contained 3000 AsPC-1 cells. Cell plates were incubated overnight in a carbon dioxide incubator.
- the compounds to be tested were diluted 5-fold to the 8th concentration with a spray gun, that is, from 2 mM to 25.6 nM, and a double-well experiment was set up.
- Compound concentrations transferred to cell plates ranged from 10 [mu]M to 0.128 nM.
- the cell plates were placed in a carbon dioxide incubator for 6 days. Another cell plate was prepared, and the signal value was read on the day of drug addition as the maximum value (Max value in the following equation) to participate in data analysis.
- the IC 50 value can be obtained by curve fitting with four parameters ("log(inhibitor) vs. response--Variable slope" mode).
- the compounds of the present invention have a significant inhibitory effect on the proliferation of AsPC-1 cells.
- the purpose of this experiment is to verify the proliferation inhibitory effect of the compounds of the present invention on KRAS G12D mutant PANC0403 cells
- Cell line PANC0403 was purchased from Nanjing Kebai, RPMI1640 medium was purchased from BI, penicillin/streptomycin antibiotics were purchased from Yuanbi, and fetal bovine serum was purchased from Gibco.
- 3D Cell Viability Assay (3D Cell Viability Chemiluminescence Detection Reagent) reagent was purchased from Promega. experimental method:
- the PANC0403 cells were seeded in a 96-well U-bottom cell culture plate, 80 ⁇ L of cell suspension per well, which contained 4000 PANC0403 cells. Cell plates were incubated overnight in a carbon dioxide incubator. The compounds to be tested were diluted 5-fold to the 8th concentration, that is, from 2000 ⁇ M to 25.6 nM, and a double-well experiment was set up. Add 78 ⁇ L of medium to the middle plate, and then transfer 2 ⁇ L of each well of the compound to the middle plate according to the corresponding position. After mixing, transfer 20 ⁇ L of each well to the cell plate. Compound concentrations transferred to cell plates ranged from 10 [mu]M to 0.128 nM.
- the cell plates were placed in a carbon dioxide incubator for 5 days. After the incubation of the cell plate with the compound added, 100 ⁇ L of cell viability chemiluminescence detection reagent was added to the cell plate, and incubated at room temperature for 10 minutes to stabilize the luminescence signal. Read using a multi-label analyzer.
- the IC 50 value can be obtained by curve fitting with four parameters ("log(inhibitor) vs. response--Variable slope" mode).
- the compound of the present invention has a significant inhibitory effect on the proliferation of PANC0403 cells.
- IP intraperitoneal injection
- C max the highest blood drug concentration after administration
- T max the time required to reach the peak drug concentration after administration
- T 1/2 the time required for the blood drug concentration to drop by half
- AUC 0-last the area under the drug-time curve, which refers to the area enclosed by the blood drug concentration curve versus the time axis.
- the compounds of the present invention exhibit higher drug exposure, longer half-life, and have good in vivo pharmacokinetic properties.
- mice Female Balb/c nude mice were inoculated subcutaneously with the PANC0403 human pancreatic cancer cell line and randomly divided into vehicle control and compound groups (6 animals per group) according to tumor volume and body weight on day 23 after inoculation, and administered as described below.
- Drug treatment 6 animals per group
- Group 1 vehicle control group: administration started in the afternoon on the day of grouping (the day of administration was the 0th day of administration), and the vehicle was administered by intraperitoneal injection at a dose of 0.1 mL/10 g body weight twice a day.
- Group 2 compound group: administration started in the afternoon on the day of grouping (the day of administration was the 0th day of administration), and the compound was administered by intraperitoneal injection at a dose of 5 mg/kg body weight twice a day.
- the vehicle was 10% Sulfobutylcyclodextrin in 50 mM pH 5.0 citric acid buffer, Sulfobutylcyclodextrin Supplier: CyDex Pharmaceuticals, KS.
- T tumor volume
- TGI tumor inhibition rate
- T/C tumor proliferation rate
- the compounds of the present invention have significant antitumor effect on human pancreatic cancer PANC0403 xenograft tumor model.
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Abstract
Description
细胞系 | 肿瘤类型 | 生长特点 | 培养方法 |
AsPC-1 | 胰腺癌 | 贴壁生长 | RPMI 1640+10%FBS |
GP2D | 结肠癌 | 贴壁生长 | DMEM+10%FBS+2mM L-glutamine |
供试品 | GP2D CTG IC 50(nM) |
化合物1b | 8.92 |
供试品 | GP2D p-ERK抑制活性IC 50(nM) |
化合物1b | 2.11 |
供试品 | AsPC-1 CTG IC 50(nM) |
化合物1b | 45.8 |
供试品 | PANC0403 CTG抑制活性IC 50(nM) |
化合物1b | 54 |
Claims (25)
- 式(II)所示化合物或其药学上可接受的盐,其中,T 1选自CH 2、NH和O;T 2选自CH和N;T 3和T 4分别独立地选自CH 2和NH;m、n、p和x分别独立地选自0、1或2;r、v和w分别独立地选自1或2;q和u分别独立地选自1、2或3;各R 1分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3和CF 3;E 1和E 3分别独立地选自键、O、S、Se、NH和CH 2,所述NH和CH 2分别独立地任选被1或2个R a取代;E 2选自-C(O)-、-C(O)-(CH 2) g-和-(CH 2) h-,当g和h不选自0时,所述-C(O)-(CH 2) g-和-(CH 2) h-分别独立地任选被1、2或3个R b取代;X 1和X 2分别独立地选自N和CR 4;L 1选自键和CH 2,所述CH 2任选被1或2个R c取代;R 2选自5-10元杂环烷基,所述5-10元杂环烷基任选被1、2或3个R d取代;R 3选自C 6-10芳基和5-10元杂芳基,所述C 6-10芳基和5-10元杂芳基分别独立地任选被1、2、3、4或5个R e取代;R 4选自H、F、Cl、Br、I、OH、NH 2、CN、COOH、C(=O)NH 2、C 1-3烷基、C 1-3烷氧基、C 2-4烯基和C 2-4炔基,所述C(=O)NH 2、C 1-3烷基、C 1-3烷氧基、C 2-4烯基和C 2-4炔基分别独立地任选被1、2或3个R f取代;e选自0、1、2和3;f、g和h分别独立地选自0、1和2;各R a分别独立地选自H和CH 3;各R b和R c分别独立地选自H、F、Cl、Br、I、OH、NH 2和CN;各R d分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和-OCO-C 1-3烷氨基;各R e分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、COOH、C(=O)NH 2、C 1-6烷基、C 1-3烷氧基、C 1- 3烷氨基、C 1-3烷硫基、C 2-4烯基、C 2-4炔基和C 3-5环烷基,所述C(=O)NH 2、C 1-6烷基、C 1-3烷氧基、C 1-3烷氨基、C 1-3烷硫基、C 2-4烯基、C 2-4炔基和C 3-5环烷基分别独立地任选被1、2或3个R取代;各R f分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和CH 3;各R分别独立地选自H、F、Cl、Br、I和CH 3。
- 根据权利要求1所述的化合物或其药学上可接受的盐,其中,R d选自H、F和-O-C(=O)-N(CH 3) 2。
- 根据权利要求1所述的化合物或其药学上可接受的盐,其中,X 1选自N、CH和C(CF 3)。
- 根据权利要求1所述的化合物或其药学上可接受的盐,其中,X 2选自N、CH和CF。
- 根据权利要求1所述的化合物或其药学上可接受的盐,其中,R 2选自四氢吡咯基和六氢-1H-吡咯里嗪基,所述四氢吡咯基和六氢-1H-吡咯里嗪基任选被1、2或3个R d取代。
- 根据权利要求1所述的化合物或其药学上可接受的盐,其中,R 3选自苯基、萘基和吲唑基,所述苯基、萘基和吲唑基任选被1、2、3、4或5个R e取代。
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