WO2023274256A1 - 噻唑并内酰胺并螺杂环类化合物及其应用 - Google Patents
噻唑并内酰胺并螺杂环类化合物及其应用 Download PDFInfo
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- WO2023274256A1 WO2023274256A1 PCT/CN2022/102031 CN2022102031W WO2023274256A1 WO 2023274256 A1 WO2023274256 A1 WO 2023274256A1 CN 2022102031 W CN2022102031 W CN 2022102031W WO 2023274256 A1 WO2023274256 A1 WO 2023274256A1
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- acceptable salt
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
- C07D513/20—Spiro-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further 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
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- the invention relates to a class of thiazolactam spiroheterocyclic compounds and their application in the preparation of medicines for treating related diseases. It specifically relates to the compound represented by formula (I) and pharmaceutically acceptable salts thereof.
- Ras/Raf/MEK/ERK pathway is a classic mitogen activated protein kinase (MAPK) signaling cascade pathway, which is involved in the activation of various growth factors, cytokines, mitogens and hormone receptors Transduction is one of the most important signal transduction pathways controlling cell growth, differentiation and survival.
- MAPK mitogen activated protein kinase
- Extracellular regulated protein kinases are the main players and downstream key nodes of the Ras/Raf/MEK/ERK pathway, and they can be found in many human cancers overactivation.
- ERK Extracellular regulated protein kinases
- the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
- R and R are independently selected from H and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1 , 2 or 3 R a ;
- R 4 , R 5 , R 6 and R 7 are independently selected from H, F, Cl, Br, I and C 1-3 alkyl, and the C 1-3 alkyl is optionally replaced by 1, 2 or 3 R c substitution;
- n 0 or 1
- n 1 or 2;
- Ring A is selected from pyrazolyl and tetrahydropyranyl optionally substituted with 1, 2 or 3 R;
- R and R are independently selected from D, F, Cl, Br and I;
- R d is selected from F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and said C 1-3 alkyl and C 1-3 alkoxy are optionally replaced by 1, 2 or 3 R substitutions;
- R is selected from F, Cl, Br and I.
- the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
- R and R are independently selected from H and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1 , 2 or 3 R a ;
- R 4 , R 5 , R 6 and R 7 are independently selected from H, F, Cl, Br, I and C 1-3 alkyl, and the C 1-3 alkyl is optionally replaced by 1, 2 or 3 R c substitution;
- n 0 or 1
- n 1 or 2;
- Ring A is selected from pyrazolyl and tetrahydropyranyl optionally substituted with 1, 2 or 3 R;
- R and R are independently selected from D, F, Cl, Br and I;
- R d is selected from F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and said C 1-3 alkyl and C 1-3 alkoxy are optionally replaced by 1, 2 or 3 R substitutions;
- R is selected from F, Cl and Br.
- R 1 and R 2 are independently selected from H, CH 3 and CH 2 CH 3 , and the CH 3 and CH 2 CH 3 are optionally substituted by 1, 2 or 3 R a , Other variables are as defined herein.
- R 1 and R 2 are independently selected from H, CH 3 , CHF 2 , CD 3 and CH 2 CH 3 , and other variables are as defined in the present invention.
- R 4 , R 5 , R 6 and R 7 are independently selected from H, F, Cl, Br, I and CH 3 , and the CH 3 is optionally replaced by 1, 2 or 3 R c is substituted, and other variables are as defined herein.
- R 4 , R 5 , R 6 and R 7 are independently selected from H, F, Cl, Br, I and CH 3 , and other variables are as defined in the present invention.
- R d is selected from F, Cl, Br, I, CH 3 and OCH 3 , and the CH 3 and OCH 3 are optionally substituted by 1, 2 or 3 R, and other variables are as in the present invention defined.
- R d is selected from CH 3 and OCH 3 , and other variables are as defined in the present invention.
- the above-mentioned ring A is selected from said Optionally substituted with 1, 2 or 3 Rd , other variables are as defined herein.
- the above-mentioned ring A is selected from Other variables are as defined herein.
- the above compound or a pharmaceutically acceptable salt thereof is selected from:
- R 2 , R 6 and R 7 are as defined in the present invention.
- the present invention also provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof,
- the present invention also provides the application of the compound or the pharmaceutically acceptable salt thereof in the preparation of medicine for treating solid tumors.
- the present invention provides crystal form A of WX001, which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 10.2080 ⁇ 0.2000°, 18.8429 ⁇ 0.2000°, 20.6217 ⁇ 0.2000°;
- the above-mentioned crystal form A in its X-ray powder diffraction pattern, expressed by 2 ⁇ angle, contains at least 4 or 5 diffraction peaks selected from the following: 10.2080 ⁇ 0.2000°, 18.8429 ⁇ 0.2000° , 20.6217 ⁇ 0.2000°, 25.0767 ⁇ 0.2000°, 25.4797 ⁇ 0.2000°.
- the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 10.2080 ⁇ 0.2000°, 18.8429 ⁇ 0.2000°, 20.6217 ⁇ 0.2000°, 25.0767 ⁇ 0.2000°, 25.4797 ⁇ 0.2000°.
- the above-mentioned crystal form A in its X-ray powder diffraction pattern, expressed by 2 ⁇ angle, contains at least 6, 7 or 8 diffraction peaks selected from the following: 10.2080 ⁇ 0.2000°, 15.2687 ⁇ 0.2000°, 17.6747 ⁇ 0.2000°, 18.8429 ⁇ 0.2000°, 20.6217 ⁇ 0.2000°, 21.0531 ⁇ 0.2000°, 25.0767 ⁇ 0.2000°, 25.4797 ⁇ 0.2000°.
- the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 10.2080 ⁇ 0.2000°, 15.2687 ⁇ 0.2000°, 17.6747 ⁇ 0.2000°, 18.8429 ⁇ 0.2000°, 20.6217 ⁇ 0.2000°, 21.0531 ⁇ 0.2000°, 25.0767 ⁇ 0.2000°, 25.4797 ⁇ 0.2000°.
- the above-mentioned crystal form A in its X-ray powder diffraction pattern, expressed by 2 ⁇ angle, contains at least 9, 10, 11 or 12 diffraction peaks selected from the following: 10.2080 ⁇ 0.2000°, 14.4684 ⁇ 0.2000°,15.2687 ⁇ 0.2000°,17.6747 ⁇ 0.2000°,18.8429 ⁇ 0.2000°,20.6217 ⁇ 0.2000°,21.0531 ⁇ 0.2000°,21.5713 ⁇ 0.2000°,22.0420 ⁇ 0.2000°,22.4540 ⁇ 0.2000°,25.0767 ⁇ 0.2000°, 25.4797 ⁇ 0.2000°.
- the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 10.2080 ⁇ 0.2000°, 14.4684 ⁇ 0.2000°, 15.2687 ⁇ 0.2000°, 17.6747 ⁇ 0.2000°, 18.8429 ⁇ 0.2000°, 20.6217 ⁇ 0.2000°, 21.0531 ⁇ 0.2000°, 21.5713 ⁇ 0.2000°, 22.0420 ⁇ 0.2000°, 22.4540 ⁇ 0.2000°, 25.0767 ⁇ 0.2000°, 25.4797 ⁇ 0.2000°.
- the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 10.2080 ⁇ 0.2000°, 18.8429 ⁇ 0.2000°, and/or 20.6217 ⁇ 0.2000°, and/or 9.4003 ⁇ 0.2000°, and/or 10.4856 ⁇ 0.2000°, and/or 14.4684 ⁇ 0.2000°, and/or 15.0133 ⁇ 0.2000°, and/or 15.2687 ⁇ 0.2000°, and/or 15.6003 ⁇ 0.2000°, and/or 15.9518 ⁇ 0.2000° , and/or 16.6214 ⁇ 0.2000°, and/or 17.6747 ⁇ 0.2000°, and/or 17.9514 ⁇ 0.2000°, and/or 18.4703 ⁇ 0.2000°, and/or 19.1531 ⁇ 0.2000°, and/or 19.6571 ⁇ 0.2000°, and /or 21.0531 ⁇ 0.2000°, and/or 21.2894 ⁇ 0.2000°, and/or 21.5713 ⁇ 0.2000°, and/or 22.0420
- the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 10.2080°, 10.4856°, 14.4684°, 15.0133°, 15.2687°, 15.9518°, 16.6214°, 17.6747 °, 17.9514°, 18.4703°, 18.8429°, 19.1531°, 20.6217°, 21.0531°, 21.2894°, 21.5713°, 22.0420°, 22.4540°, 25.0767°, 25.4797°, 26.3255°, 26.954
- the XRPD pattern of the above-mentioned crystal form A is basically as shown in FIG. 1 .
- the differential scanning calorimetry curve of the above crystal form A has an onset point of an endothermic peak at 241.0 ⁇ 3.0°C.
- the DSC spectrum of the above crystal form A is shown in FIG. 2 .
- thermogravimetric analysis curve of the above-mentioned crystal form A reaches a weight loss of 0.83% at 150.0 ⁇ 3.0°C.
- the TGA spectrum of the above-mentioned crystal form A is shown in FIG. 3 .
- the present invention also provides the application of the above-mentioned crystal form A in the preparation of a medicament for treating solid tumors.
- the compound of the present invention shows better inhibitory activity to ERK1 and ERK2 enzymes;
- the compound of the present invention shows better inhibitory activity to HT29 cell proliferation;
- the compound of the present invention has better solubility under different pH conditions;
- the compound of the present invention has excellent Pharmacokinetic properties and antitumor effect.
- pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with human and animal tissues within the scope of sound medical judgment , without undue toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.
- pharmaceutically acceptable salt refers to a salt of a compound of the present invention, which is prepared from a compound having a specific substituent found in the present invention and a relatively non-toxic acid or base.
- base addition salts can be obtained by contacting such compounds with a sufficient amount of base, either neat solution or in a suitable inert solvent.
- acid addition salts can be obtained by contacting such compounds with a sufficient amount of the acid, either neat solution or in a suitable inert solvent.
- Certain specific compounds of the present invention contain basic and acidic functional groups and can thus be converted into either base or acid addition salts.
- the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid groups or bases by conventional chemical methods.
- 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 both.
- the compounds of the invention may exist in particular 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 their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are subject to the present within the scope of the invention.
- Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
- enantiomer or “optical isomer” refer to stereoisomers that are mirror images of each other.
- cis-trans isomers or “geometric isomers” arise from the inability to rotate freely due to the double bond or the single bond of the carbon atoms forming the ring.
- diastereoisomer refers to stereoisomers whose molecules have two or more chiral centers and which are not mirror images of the molecules.
- keys with wedge-shaped solid lines and dotted wedge keys Indicates the absolute configuration of a stereocenter, with a straight solid-line bond and straight dashed keys Indicates the relative configuration of the stereocenter, with a wavy line Indicates wedge-shaped solid-line bond or dotted wedge key or with tilde Indicates a straight solid line key or straight dotted key
- tautomer or “tautomeric form” means that isomers with different functional groups are in dynamic equilibrium at room temperature and are rapidly interconvertible. If tautomerism is possible (eg, in solution), then chemical equilibrium of the tautomers can be achieved.
- proton tautomers also called prototropic tautomers
- prototropic tautomers include interconversions via migration of a proton, such as keto-enol isomerization and imine-ene Amine isomerization.
- Valence isomers (valence tautomers) involve interconversions by recombination 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 an isomer”, “enriched in an isomer”, “enriched in an enantiomer” or “enantiomerically enriched” refer to one of the isomers or enantiomers
- the content of the 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 terms “isomer excess” or “enantiomeric excess” refer 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 other isomer or enantiomer is 10%, then the isomer or enantiomeric excess (ee value) is 80% .
- Optically active (R)- and (S)-isomers as well as 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 invention is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
- a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then a diastereomeric salt is formed by a conventional method known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. 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 compounds.
- compounds may be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
- radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
- heavy hydrogen can be used to replace hydrogen to form deuterated drugs.
- the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
- 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 changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
- 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 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 realizable basis.
- any variable eg, R
- its definition is independent at each occurrence.
- said group may optionally be substituted with up to two R, with independent options for each occurrence of R.
- substituents and/or variations 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.
- a substituent can be bonded to any atom on a ring when the bond of a substituent can cross-link two or more atoms on the ring, e.g., structural unit It means that the substituent R can be substituted at any position on cyclohexyl or cyclohexadiene. When the enumerated substituent does not indicate which atom it is connected to the substituted group, this substituent can be bonded through any atom, for example, pyridyl as a substituent can be connected to any atom on the pyridine ring. The carbon atom is attached to the group being substituted.
- linking group listed does not indicate its linking direction
- its linking direction is arbitrary, for example,
- the connecting 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 to form It can also be formed by connecting loop A and loop B in the opposite direction to the reading order from left to right
- any one or more sites of the group can be linked to other groups through chemical bonds.
- connection method of the chemical bond is not positioned, and there is an H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will decrease correspondingly with the number of chemical bonds connected to become the corresponding valence group.
- the chemical bonds that the site connects with other groups can use straight solid line bonds Straight dotted key or tilde express.
- the straight-shaped solid-line bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group;
- the straight dotted line bond indicates that the two ends of the nitrogen atom in the group are connected to other groups;
- the wavy lines in indicate that the 1 and 2 carbon atoms in the phenyl group are connected to other groups;
- the number of atoms in a ring is generally defined as the number of ring members, eg, "5-7 membered ring” means a “ring” with 5-7 atoms arranged around it.
- 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 (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
- Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
- C 1-3 alkoxy denotes those alkyl groups containing 1 to 3 carbon atoms attached to the rest 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 groups and the like.
- Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
- 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 combining them with other chemical synthesis methods, and the methods well known to those skilled in the art Equivalent alternatives, preferred embodiments include but are not limited to the examples of the present invention.
- references throughout this specification to "an embodiment” or “an embodiment” or “in another embodiment” or “in certain embodiments” mean that in at least one embodiment the Relevant specific reference elements, structures or features described above. Thus, appearances of the phrases “in one embodiment” or “in an embodiment” or “in another embodiment” or “in certain embodiments” in various places throughout the specification are not necessarily all referring to the same embodiment. Furthermore, particular elements, structures or characteristics may be combined in any suitable manner in one or more embodiments.
- 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 involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, in single crystal X-ray diffraction (SXRD), the cultured single crystal is collected with a Bruker D8 venture diffractometer to collect diffraction intensity data, the light source is CuK ⁇ radiation, and the scanning method is: After scanning and collecting relevant data, the absolute configuration can be confirmed by further analyzing the crystal structure by direct method (Shelxs97).
- SXRD single crystal X-ray diffraction
- the solvent used in the present invention is commercially available.
- aq stands for water; eq stands for equivalent, equivalent; DCM stands for dichloromethane; PE stands for petroleum ether; DMSO stands for dimethyl sulfoxide; EtOAc stands for ethyl acetate; EtOH stands for ethanol; MeOH stands for Methanol; BOC stands for tert-butoxycarbonyl, an amine protecting group; rt stands for room temperature; O/N stands for overnight; THF stands for tetrahydrofuran; Boc2O stands for di-tert-butyldicarbonate; TFA stands for trifluoroacetic acid; DIPEA stands for Diisopropylethylamine; iPrOH represents 2-propanol; mp represents melting point.
- Test method About 10 mg of sample is used for XRPD detection.
- the present invention 's differential thermal analysis (Differential Scanning Calorimeter, DSC) method
- Thermogravimetric Analysis (Thermal Gravimetric Analyzer, TGA) method of the present invention
- Dynamic moisture sorption (DVS) curves were collected on DVS Intrinsic plus from SMS (Surface Measurement Systems). The relative humidity at 25°C was corrected for the deliquescence points of LiCl, Mg( NO3 ) 2 and KCl.
- ⁇ W% represents the moisture absorption weight gain of the test product at 25 ⁇ 1°C and 80 ⁇ 2%RH.
- Figure 5 Tumor growth curves of human melanoma A375 model animals after administration of solvent and WX001 respectively;
- Figure 6 Body weight change rate of human melanoma A375 model animals during administration.
- Step 1 Synthesis of Compound A-1-2.
- A-1-1 150 g, 635.36 mmol, 1 eq
- calcium chloride 70.51 g, 635.36 mmol, 1 eq
- tetrahydrofuran 500 mL
- ethanol 1000 mL
- sodium borohydride 48.07g, 1.27mol, 2eq
- the reaction solution was concentrated under reduced pressure, the concentrate was diluted with 15% aqueous citric acid (4000 mL), and extracted with ethyl acetate (4000 mL x 3).
- A-1-2 (102 g, 525.64 mmol, 1 eq) and 2-methyltetrahydrofuran (1000 mL) were added to the reaction flask. After the nitrogen was replaced, the temperature was lowered to -70°C, and lithium diisopropylamide (2M, 525.64mL, 2.0eq) was slowly added dropwise. Stir at -70°C for 30 minutes, then slowly drop into a solution of A-1-3 (138.18g, 788.46mmol, 1.5eq) in 2-methyltetrahydrofuran (400mL) and continue the reaction at -70°C for 1 hour.
- reaction solution was quenched with saturated ammonium chloride aqueous solution (2000 mL), extracted with ethyl acetate (2000 mL x 4), separated and combined to obtain an organic phase.
- the organic phase was washed with saturated brine (1000 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product.
- the crude product was separated and purified by column first, and then purified by beating with methyl tert-butyl ether to obtain A-1-4.
- Step 3 Synthesis of Compound A-1-5.
- A-1-4 50 g, 135.39 mmol, 1 eq
- azodicarbonyldipiperidine 40.99 g, 162.47 mmol, 1.2 eq
- tetrahydrofuran 500 mL
- the temperature was lowered to 0°C
- a solution of tributylphosphine 32.87g, 162.47mmol, 40.09mL, 1.2eq
- tetrahydrofuran 100mL
- Step 4 Synthesis of Compound A-1-6.
- Step 7 Synthesis of Compound A-1.
- A-1-8 (10g, 27.68mmol, 1eq) and dichloromethane (100mL) were added to a dry reaction flask, and trifluoroacetic acid (41.04g, 359.90mmol, 26.65mL, 13eq) was added at 0°C, followed by The reaction was carried out at 0°C for 0.5 hours. After the reaction was completed, the reaction solution was slowly poured into saturated aqueous sodium bicarbonate solution (1000 mL), and the pH was adjusted to 7-8. Extracted with dichloromethane (1000mL x 3), separated and combined to obtain an organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain A-1.
- reaction solution 1 To the dry reaction flask was added WX001-3 (60 mg, 208.81 ⁇ mol, 1 eq), tetrahydrofuran (1 mL), zinc chloride solution (0.7M, 298.31 ⁇ L, 1 eq). Cool down to -78°C and add lithium hexamethyldisilazide (1M, 417.63 ⁇ L, 2eq), and react at 20°C for 1 hour to obtain reaction solution 1.
- WX001-3 60 mg, 208.81 ⁇ mol, 1 eq
- tetrahydrofuran 1 mL
- zinc chloride solution 0.7M, 298.31 ⁇ L, 1 eq
- the crude product was added into a mixed solvent of tert-methyl ether and n-hexane (total 1098 mL, the volume ratio of the two was 1:5), stirred for 1 hour, filtered, and the filter cake was collected and dried. Add water (5400 mL) to the filter cake, stir for 1 hour, filter, collect the filter cake, and dry to obtain I-1.
- reaction solution 1 Slowly drip the reaction solution 1 into the reaction solution 2, and react the mixed solution for 1 hour at 50° C. After the reaction is completed, quench the reaction with 0.1M ethylenediaminetetraacetic acid disodium salt (10800 mL), Stir for 30min. Add n-heptane (4800mL), stir for 0.5 hours. Filter, collect filter cake, dry to obtain crude product. Crude product is beaten with ethanol (7200mL) at 20 °C for 2 hours, filter, collect filter cake, and filter cake is dried to obtain I -3.
- Step 7 Synthesis of Form A of WX001.
- the filter cake was stirred with deionized water (1000 mL) at room temperature for 30 minutes. The filter cake was collected by filtration. The filter cake was stirred with acetonitrile (1000 mL) at room temperature for 30 min, and the filter cake was collected by filtration to obtain Form A of WX001.
- the hygroscopic weight gain of Form A of WX001 at 25°C and 80% RH is 0.1134%, almost no hygroscopicity.
- Embodiment 5 Stability test of WX001 crystal form A
- Test compounds were dissolved in 100% DMSO to prepare stock solutions of specific concentrations. Compounds were serially diluted in DMSO solution using an Integra Viaflo Assist smart pipette.
- ERK1 (or ERK2) kinase activity is the ratio of the remaining kinase activity in the test sample to the kinase activity of the control group (DMSO treatment). Curve fitting was performed using Prism (GraphPad software) and IC50 values were calculated.
- the compound of the present invention shows better inhibitory activity on ERK1 enzyme.
- the compound of the present invention shows better inhibitory activity on ERK2 enzyme.
- Test compounds were dissolved in 100% DMSO to make 10 mM stock solutions.
- the compound of the present invention exhibits better inhibitory activity on HT29 cell proliferation.
- mice Female BALB/c mice were used as experimental animals, and the blood concentration of the compound was measured after a single administration and the pharmacokinetic behavior was evaluated.
- the solvent of the intravenous injection group was 5% DMSO+95% (20% HP- ⁇ -CD)
- the compound to be tested was mixed with an appropriate amount of intravenous injection solvent, vortexed and sonicated to prepare a 0.5mg/mL clear solution, and filtered through a microporous membrane For future use;
- the vehicle for the oral group is 5% DMSO+95% (20% HP- ⁇ -CD). After mixing the compound to be tested with the vehicle, vortex and sonicate, a 0.3 mg/mL solution is prepared.
- C max is the maximum concentration
- F% is the oral bioavailability
- DNAUC AUC PO /Dose
- AUC PO is the oral exposure
- Dose is the drug dose
- Vd ss is the volume of distribution
- Cl is the clearance rate
- T 1/2 is the half-life
- NA is not tested.
- the compounds of the present invention exhibit excellent oral exposure and bioavailability.
- UV standard solutions of 1 ⁇ M, 20 ⁇ M and 200 ⁇ M are used as standard solutions for solubility experiments.
- the compound of the present invention has better solubility under different pH conditions.
- the anti-tumor effect of WX001 was evaluated using human melanoma A375 cell subcutaneous xenograft tumor nude mouse model.
- Cage made of polycarbonate, volume 375mm x 215mm x 180mm, bedding is corn cob, replaced once a week;
- Experimental animals are free to eat during the whole experimental period (irradiation sterilization, dry granular food);
- the animal information card for each cage should indicate the number of animals in the cage, sex, strain, date of receipt, test number of the dosing regimen, group and start date of the test;
- Animal identification Experimental animals were identified with ear tags.
- Tumor tissue inoculation and grouping 0.1 mL (5 ⁇ 10 5 cells) of A375 cells were inoculated subcutaneously in the right axilla of each mouse, and when the average volume of the tumor reached 170 mm 3 , the animals were randomly divided into 4 groups, and began to give medicine. See Table 22 for the experimental grouping and dosing regimen:
- Vehicle group 5% DMSO+95% (20% HP- ⁇ -CD).
- Test compound group Weigh the quantitative test compound in the dispensing bottle, add the corresponding volume of DMSO and vortex to obtain a clear solution, add the corresponding volume of 20% HP- ⁇ -CD and vortex to obtain a uniform suspension.
- Tumor diameter was measured twice a week with a vernier caliper.
- TGI (%) The antitumor efficacy of the compound is evaluated by TGI (%).
- WX001 can dose-dependently inhibit tumor growth after oral administration until the 21st day, at 12.5mg/kg , 25mg/kg and 50mg/kg three doses, TGI were 45%, 58% and 102%.
- the body weight of the experimental animals is used as a reference index for indirect determination of drug toxicity. As shown in Figure 6, the body weight of all the animals in the solvent control group and WX001 group did not decrease significantly when the drug was administered to the 21st day, and the tolerance was good.
- WX001 can inhibit tumor growth in a dose-dependent manner at three doses of 12.5mg/kg, 25mg/kg and 50mg/kg; the body weight of the animals did not decrease significantly during the administration process, and the tolerance was good.
- the solvent of the intravenous injection group was 5% DMSO+95% (20% HP- ⁇ -CD)
- the compound to be tested was mixed with an appropriate amount of intravenous injection solvent, vortexed and sonicated to prepare a 0.2mg/mL clear solution, and filtered through a microporous membrane For future use;
- the vehicle for the oral group is 5% DMSO+95% (20% HP- ⁇ -CD). After mixing the compound to be tested with the vehicle, vortex and sonicate, a 1 mg/mL solution is prepared.
- DMSO dimethyl sulfoxide
- HP- ⁇ -CD hydroxypropyl- ⁇ -cyclodextrin.
- C max is the maximum concentration
- F% is the oral bioavailability
- DNAUC AUC PO /Dose
- AUC PO is the oral exposure
- Dose is the drug dose
- Vd ss is the volume of distribution
- Cl is the clearance rate
- T 1/2 is the half-life.
- the compounds of the present invention exhibit excellent oral exposure and bioavailability.
- the solvent in the intravenous injection group was 5% DMSO+95% (20% HP- ⁇ -CD).
- the compound to be tested was mixed with an appropriate amount of intravenous injection solvent, stirred and dissolved to prepare a 0.4 mg/mL clear solution, which was filtered through a microporous membrane for use
- the vehicle of the oral group is 5% DMSO+95% (20% HP- ⁇ -CD). After the compound to be tested is mixed with the vehicle, it is stirred and dissolved to prepare a 0.3 mg/mL solution.
- DMSO dimethyl sulfoxide
- HP- ⁇ -CD hydroxypropyl- ⁇ -cyclodextrin.
- C max is the maximum concentration
- F% is the oral bioavailability
- DNAUC AUC PO /Dose
- AUC PO is the oral exposure
- Dose is the drug dose
- Vd ss is the volume of distribution
- Cl is the clearance rate
- T 1/2 is the half-life.
- the compounds of the present invention exhibit excellent oral exposure and bioavailability.
- the solvent in the intravenous injection group was 5% DMSO+95% (20% HP- ⁇ -CD).
- the compound to be tested was mixed with an appropriate amount of intravenous injection solvent, stirred and dissolved to prepare a 0.4 mg/mL clear solution, which was filtered through a microporous membrane for use
- the vehicle of the oral group is 5% DMSO+95% (20% HP- ⁇ -CD). After the compound to be tested is mixed with the vehicle, it is stirred and dissolved to prepare a 0.3 mg/mL solution.
- DMSO dimethyl sulfoxide
- HP- ⁇ -CD hydroxypropyl- ⁇ -cyclodextrin.
- C max is the maximum concentration
- F% is the oral bioavailability
- DNAUC AUC PO /Dose
- AUC PO is the oral exposure
- Dose is the drug dose
- Vd ss is the volume of distribution
- Cl is the clearance rate
- T 1/2 is the half-life.
- the compounds of the present invention exhibit excellent oral exposure and bioavailability.
- CHO-hERG cells were cultured in a 175cm 2 culture flask, and when the cell density grew to 60-80%, the culture medium was removed, washed with 7mL PBS (Phosphate Buffered Saline), and then digested by adding 3mL Detachin. After the digestion is complete, add 7 mL of culture medium to neutralize, then centrifuge, absorb the supernatant, and then add 5 mL of culture medium to resuspend to ensure that the cell density is 2-5 ⁇ 10 6 /mL.
- PBS Phosphate Buffered Saline
- Extracellular solution 140 NaCl, 5 KCl, 1 CaCl 2 , 1.25 MgCl 2 , 10HEPES and 10 Glucose, adjust the pH to 7.4 with NaOH.
- Intracellular fluid formulation 140 KCl, 1 MgCl 2 , 1 CaCl 2 , 10 EGTA and 10 HEPES, adjust the pH to 7.2 with KOH.
- the single-cell high-impedance sealing and whole-cell pattern formation processes are all automatically completed by the Qpatch instrument.
- the cell After obtaining the whole-cell recording pattern, the cell is clamped at -80 mV, before giving a 5-second +40 mV depolarization stimulus , give a pre-voltage of -50 mV for 50 milliseconds, then repolarize to -50 mV for 5 seconds, and then return to -80 mV. Apply this voltage stimulus every 15 seconds, record for 2 minutes, give extracellular fluid for 5 minutes, and then start the administration process.
- the compound concentration starts from the lowest test concentration, and each test concentration is given for 2.5 minutes. After all concentrations are given continuously, give Positive control compound 3 M Cisapride. At least 3 cells (n ⁇ 3) were tested for each concentration.
- the compound 20.00mM mother solution was diluted with DMSO, and 10 ⁇ L of the compound mother solution was added to 20 ⁇ L DMSO solution, and serially diluted 3 times to 6 DMSO concentrations. Take 4 ⁇ L of compounds with 6 DMSO concentrations, add them to 396 ⁇ L of extracellular fluid, dilute 100 times to 6 intermediate concentrations, then take 80 ⁇ L of compounds with 6 intermediate concentrations, add them to 320 ⁇ L of extracellular fluid, 5 times Dilute to the final concentration to be tested. The highest test concentration is 40 ⁇ M, and there are 6 concentrations in total of 40, 13.3, 4.4, 1.48, 0.494 and 0.165 ⁇ M respectively. The DMSO content in the final test concentration did not exceed 0.2%, and this concentration of DMSO had no effect on the hERG potassium channel. Compound preparation is done by Bravo Instruments throughout the dilution process.
- the experimental data were analyzed by GraphPad Prism 5.0 software.
- the experimental reagents used were purchased from Sigma, with a purity of >98%
- the compound of the present invention has weak inhibitory effect on hERG potassium channel current, lower risk of cardiotoxicity and higher safety.
- test compound To study the binding degree of test compound to human/mouse/rat/dog/monkey plasma albumin.
- test compound was dissolved in dimethyl sulfoxide (DMSO) to prepare stock solutions with concentrations of 10 mM and 2 mM, respectively.
- DMSO dimethyl sulfoxide
- a 40 ⁇ M working solution was prepared by diluting 2 ⁇ L of the stock solution (2 mM) with 98 ⁇ L of DMSO.
- a 400 ⁇ M working solution of the control compound was prepared by diluting 10 ⁇ L of the stock solution with 240 ⁇ L DMSO.
- the working solution of the compound (5 ⁇ L) was mixed with the blank matrix (995 ⁇ L) at a ratio of 1:200 to prepare the loaded matrix.
- test samples an additional matrix-containing sample was transferred to a separate 96-well plate (sample incubation plate) and incubated at 37° C. for 4 h.
- the compounds of the present invention have moderate plasma protein binding.
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Abstract
Description
参数 | 设定值 |
方法 | 线性升温 |
样品盘 | 铝盘,压盖/不压盖 |
温度范围 | 25℃-设置终点温度 |
扫描速率(℃/分钟) | 10 |
保护气体 | 氮气 |
参数 | 设定值 |
方法 | 线性升温 |
样品盘 | 铝盘,敞开 |
温度范围 | 室温-设置终点温度 |
扫描速率(℃/分钟) | 10 |
保护气体 | 氮气 |
吸湿性分类 | ΔW% |
潮解 | 吸收足量水分形成液体 |
极具吸湿性 | ΔW%≥15% |
有吸湿性 | 15%>ΔW%≥2% |
略有吸湿性 | 2%>ΔW%≥0.2% |
无或几乎无吸湿性 | ΔW%<0.2% |
溶剂 | 试验结果 |
MeOH | 晶型A |
丙酮 | 晶型A |
EtOAc | 晶型A |
MTBE | 晶型A |
ACN | 晶型A |
甲苯 | 晶型A |
1,4-二氧六环 | 晶型A |
H 2O | 晶型A |
溶剂(v/v) | 试验结果 |
MeOH/DCM(1∶1) | 晶型A |
THF/H 2O(1∶1) | 晶型A |
CHCl 3 | 晶型A |
1,4-二氧六环 | 晶型A |
溶剂(v/v) | 试验结果 |
CHCl 3 | 晶型A* |
THF/H 2O(1∶1) | 晶型A* |
ACN/H 2O(1∶1) | 晶型A* |
溶剂(v/v) | 试验结果 |
MeOH | 晶型A |
MIBK | 晶型A |
EtOAc | 晶型A |
THF/H 2O(1∶1) | 晶型A |
ACN/H 2O(1∶1) | 晶型A |
DMAc/H 2O(1∶1) | 晶型A |
溶剂(v/v) | 试验结果 |
EtOH | 晶型A |
EtOAc | 晶型A |
THF | 晶型A |
DCM | 晶型A |
正庚烷 | 晶型A |
H 2O | 晶型A |
EtOH/H 2O(0.97∶0.03,a w~0.2) | 晶型A |
EtOH/H 2O(0.93∶0.07,a w~0.4) | 晶型A |
EtOH/H 2O(0.86∶0.14,a w~0.6) | 晶型A |
EtOH/H 2O(0.71∶0.29,a w~0.8) | 晶型A |
ACN | 晶型A |
溶剂(v/v) | 试验结果 |
IPA | 晶型A |
丙酮/H 2O(1∶1) | 晶型A |
IPAc | 晶型A |
MTBE | 晶型A |
2-MeTHF | 晶型A |
1,4-二氧六环 | 晶型A |
CHCl 3/正庚烷(1∶1) | 晶型A |
甲苯 | 晶型A |
DMSO/H 2O(1∶1) | 晶型A |
ACN | 晶型A |
药物 | TGI |
WX001(12.5mg/kg,PO,BID) | 45% |
WX001(25mg/kg,PO,BID) | 58% |
WX001(50mg/kg,PO,BID) | 102% |
化合物 | IC50(μM) |
WX001 | >40 |
Claims (23)
- 式(I)所示化合物或其药学上可接受的盐,其中,R 1和R 2分别独立地选自H和C 1-3烷基,所述C 1-3烷基任选被1、2或3个R a取代;R 4、R 5、R 6和R 7分别独立地选自H、F、Cl、Br、I和C 1-3烷基,所述C 1-3烷基任选被1、2或3个R c取代;n为0或1;m为1或2;环A选自吡唑基和四氢吡喃基,所述吡唑基和四氢吡喃基任选被1、2或3个R d取代;R a和R c分别独立地选自D、F、Cl、Br和I;R d选自F、Cl、Br、I、C 1-3烷基和C 1-3烷氧基,所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个R取代;R选自F、Cl、Br和I。
- 根据权利要求1所述化合物或其药学上可接受的盐,其中,R 1和R 2分别独立地选自H、CH 3和CH 2CH 3,所述CH 3和CH 2CH 3任选被1、2或3个R a取代。
- 根据权利要求2所述化合物或其药学上可接受的盐,其中,R 1和R 2分别独立地选自H、CH 3、CHF 2、CD 3和CH 2CH 3。
- 根据权利要求1所述化合物或其药学上可接受的盐,其中,R 4、R 5、R 6和R 7分别独立地选自H、F、Cl、Br、I和CH 3,所述CH 3任选被1、2或3个R c取代。
- 根据权利要求4所述化合物或其药学上可接受的盐,其中,R 4、R 5、R 6和R 7分别独立地选自H、F、Cl、Br、I和CH 3。
- 根据权利要求1所述化合物或其药学上可接受的盐,其中,R d选自F、Cl、Br、I、CH 3和OCH 3,所述CH 3和OCH 3任选被1、2或3个R取代。
- 根据权利要求6所述化合物或其药学上可接受的盐,其中,R d选自CH 3和OCH 3。
- 根据权利要求13所述的晶型A,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:10.2080±0.2000°,18.8429±0.2000°,20.6217±0.2000°,25.0767±0.2000°,25.4797±0.2000°。
- 根据权利要求14所述的晶型A,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:10.2080±0.2000°,15.2687±0.2000°,17.6747±0.2000°,18.8429±0.2000°,20.6217±0.2000°,21.0531±0.2000°,25.0767±0.2000°,25.4797±0.2000°。
- 根据权利要求15所述的晶型A,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:10.2080±0.2000°,14.4684±0.2000°,15.2687±0.2000°,17.6747±0.2000°,18.8429±0.2000°,20.6217±0.2000°,21.0531±0.2000°,21.5713±0.2000°,22.0420±0.2000°,22.4540±0.2000°,25.0767±0.2000°,25.4797±0.2000°。
- 根据权利要求16所述的晶型A,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:10.2080°,10.4856°,14.4684°,15.0133°,15.2687°,15.9518°,16.6214°,17.6747°,17.9514°,18.4703°,18.8429°,19.1531°,20.6217°,21.0531°,21.2894°,21.5713°,22.0420°,22.4540°,25.0767°,25.4797°,26.3255°,26.9544°。
- 根据权利要求17所述的晶型A,其XRPD图谱基本上如图1所示。
- 根据权利要求13~18任意一项所述的晶型A,其差示扫描量热曲线在241.0±3.0℃处有一个吸热的起始点。
- 根据权利要求19所述的晶型A,其DSC图谱如图2所示。
- 根据权利要求13~18任意一项所述的晶型A,其热重分析曲线在150.0±3.0℃时失重达0.83%。
- 根据权利要求21所述的晶型A,其TGA图谱如图3所示。
- 根据权利要求1~12任意一项所述化合物或其药学上可接受的盐或根据权利要求13~22任意一项所述的晶型A在制备治疗实体瘤的药物中的应用。
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AU2022303965A AU2022303965A1 (en) | 2021-06-28 | 2022-06-28 | Thiazole-lactam-spiroheterocyclic compounds and applications thereof |
JP2023580482A JP2024526242A (ja) | 2021-06-28 | 2022-06-28 | チアゾール-ラクタム-スピロ複素環化合物及びその適用 |
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KR1020247002361A KR20240024963A (ko) | 2021-06-28 | 2022-06-28 | 티아졸-락탐-스피로헤테로사이클릭 화합물 및 이의 적용 |
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WO2021110169A1 (zh) * | 2019-12-06 | 2021-06-10 | 南京明德新药研发有限公司 | 作为erk抑制剂的噻唑并内酰胺类化合物及其应用 |
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