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WO2022170802A1 - Dérivé de pyrimido-pyridone en tant qu'inhibiteur de sos1, son procédé de préparation et son utilisation - Google Patents

Dérivé de pyrimido-pyridone en tant qu'inhibiteur de sos1, son procédé de préparation et son utilisation Download PDF

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WO2022170802A1
WO2022170802A1 PCT/CN2021/131012 CN2021131012W WO2022170802A1 WO 2022170802 A1 WO2022170802 A1 WO 2022170802A1 CN 2021131012 W CN2021131012 W CN 2021131012W WO 2022170802 A1 WO2022170802 A1 WO 2022170802A1
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compound
membered
reaction
mmol
kras
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Chinese (zh)
Inventor
谢成英
郑苏欣
陆晓杰
郑明月
乔刚
叶阳亮
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Suzhou Alphama Biotechnology Co Ltd
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Suzhou Alphama Biotechnology Co Ltd
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Priority to CN202180076242.7A priority Critical patent/CN116669738A/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—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
    • 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 invention belongs to the technical field of pyrimidopyridone derivatives, in particular to a pyrimidopyridone derivative as an SOS1 inhibitor, a preparation method and uses thereof.
  • the RAS family proteins belong to a small GTPase that includes three subfamilies, KRAS, NRAS, and HRAS.
  • the mutated RAS gene is an important oncogene, and RAS gene mutations are found in 20-30% of human tumors, especially pancreatic, colorectal, and lung cancers.
  • Various isoforms of RAS proteins have a balance between the activated state of GTP binding and the inactive state of GDP binding.
  • GTPase-activating proteins GAPs
  • GAPs can promote the conversion of GTP to GDP, thereby making RAS proteins inactive.
  • guanine nucleotide exchange factors can promote the release of GDP and the binding of GTP, thereby turning the RAS protein into the active state.
  • Activation of RAS protein can promote cell proliferation, apoptosis evasion and metabolic reorganization through the RAS-RAF-MEK-ERK and RAS-PI3K-PDK1-AKT signaling pathways, thereby promoting the occurrence and development of tumors.
  • SOS1 (son of sevenless 1) is a key guanine nucleotide exchange factor (GEF) that can bind to RAS protein, promote the binding of RAS protein to GTP, and turn RAS protein into an active state.
  • GEF guanine nucleotide exchange factor
  • Recent studies have found that SOS1 inhibitors alone can inhibit the growth of various RAS mutant cells, and can also synergize with MEK inhibitors, resulting in significant inhibition of KRAS-driven tumors 1-2 .
  • the development of SOS1 inhibitors has become a research hotspot.
  • SOS1 inhibitors of different structural types such as WO2018172250, WO2019201848, WO2018115380, WO2019122129, WO2020173935, WO2020180768 and WO2020180770, etc.
  • the object of the present invention is to provide a pyrimidopyridone derivative, its pharmaceutically acceptable salt, its tautomer or its stereoisomer, so as to screen out the Compounds with excellent properties in terms of efficacy, safety and selectivity as SOS1 inhibitors.
  • Another object of the present invention is to provide a method for the preparation of the derivatives, their pharmaceutically acceptable salts, their tautomers or their stereoisomers.
  • the present invention provides a pyrimidopyridone derivative, a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof, wherein the structure of the pyrimidopyridone derivative is as follows Formula (I) shows:
  • R 1 is selected from hydrogen or C 1 -C 3 alkyl; preferably hydrogen or methyl;
  • R 2 is selected from hydrogen or C 1 -C 3 alkyl, 3-7 membered cycloalkyl, 4-7 membered heterocyclyl, wherein C 1 -C 3 alkyl, 3-7 membered cycloalkyl, 4-7 membered cycloalkyl A membered heterocyclyl group is optionally substituted with 1-3 R 21 ;
  • L may be absent or selected from O, NH or N-(C 1 -C 3 alkyl);
  • R 3 is selected from H, C 1 -C 3 alkyl, 3-7 membered cycloalkyl, 4-7 membered heterocyclyl, wherein C 1 -C 3 alkyl, 3-7 membered cycloalkyl, 4-7 membered cycloalkyl A membered heterocyclyl group is optionally substituted with 1-3 R 31 ;
  • R a is selected from H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or 3-6 membered cycloalkyl;
  • R b is selected from H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or 3-6 membered cycloalkyl;
  • R 32 is selected from C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, 3-6 membered cycloalkyl or 4-7 membered heterocyclyl;
  • AR is selected from 6-10-membered aryl or 5-10-membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted by 1-4 R 4 ;
  • R 4 is selected from H, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, hydroxy-C 1 -C 3 alkyl, hydroxy-C 1 -C 3 haloalkyl, 3-6 membered cycloalkane base, 4-7 membered heterocyclic group, -OR a , -NR a R b , 6-10 membered aryl group or 5-10 membered heteroaryl group, of which 6-10 membered aryl group or 5-10 membered aryl group The heteroaryl group is optionally substituted by 1-4 R c ;
  • R c is selected from H, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, hydroxy-C 1 -C 3 alkyl, hydroxy-C 1 -C 3 haloalkyl, 3-6 membered cycloalkane base, 4-7 membered heterocyclic group, -OR a , -NR a R b , NR a R b -C 1 -C 4 alkyl, NR a R b -C 1 -C 4 haloalkyl; the formula ( The heteroatoms in the heterocyclic group or heteroaryl group in I) are 1-3 and are selected from one or more of oxygen, nitrogen and sulfur.
  • the phenyl group is optionally substituted by 1-4 R 4 , when the number of the R 4 is 2-4, the R 4 can be the same or different;
  • R 4 when the R 4 is a C 1 -C 3 haloalkyl group, the R 4 is 1-3, and when there are two or more R 4 , the R 4 can be the same or different;
  • the halogen atom therein is fluorine
  • the R 4 when the R 4 is halogen, the R 4 is 1-3, and when there are two or more R 4 , the R 4 can be the same or different;
  • the halogen atom is fluorine
  • R 4 when the R 4 is -NR a R b , the R 4 is 1-3, and when there are two or more R 4 , the R 4 can be the same or different;
  • the R 4 when the R 4 is -NR a R b , the R a and R b can be the same or different;
  • R 3 is H, C 1 -C 3 alkyl, 3-7 membered cycloalkyl, 4-7 membered heterocyclyl, wherein the 4-7 membered heterocyclyl is optionally surrounded by 1-3 R 31 replaced;
  • R 3 is a 4-7-membered heterocyclic group optionally substituted by 1-3 R 31 , and when said R 31 is 2-3, R 31 is the same or different;
  • the heterocyclic group contains 1-2 heteroatoms
  • the heteroatom of the heterocyclic group is nitrogen and/or oxygen;
  • R 3 is a 4-7-membered heterocyclic group optionally substituted by 1-3 R 31 , when the heteroatoms of the heterocyclic group are two, the two hetero atoms are the same or different;
  • the R 3 is a 4-7-membered heterocyclic group optionally substituted by 1-3 R 31
  • R a is selected from H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or 3-6 membered cycloalkyl;
  • R b is selected from H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or 3-6 membered cycloalkyl;
  • R 32 is selected from C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, 3-6 membered cycloalkyl or 4-7 membered heterocyclyl.
  • the phenyl group is optionally substituted by 1-4 R 4 , when the number of the R 4 is 2-4, the R 4 can be the same or different;
  • R 4 when the R 4 is a C 1 -C 3 haloalkyl group, the R 4 is 1-3, and when there are two or more R 4 , the R 4 can be the same or different;
  • the halogen atom therein is fluorine
  • the R 4 when the R 4 is halogen, the R 4 is 1-2, and when there are more than two R 4 , the R 4 can be the same or different;
  • the halogen atom is fluorine
  • R 4 when the R 4 is -NR a R b , the R 4 is 1-3, and when there are more than two R 4 , the R 4 can be the same or different;
  • the R 4 when the R 4 is -NR a R b , the R a and R b can be the same or different;
  • R 3 is H, C 1 -C 3 alkyl, 3-7 membered cycloalkyl, 4-7 membered heterocyclyl, wherein the 4-7 membered heterocyclyl is optionally surrounded by 1-3 R 31 replaced;
  • R 3 is a 4-7-membered heterocyclic group optionally substituted by 1-3 R 31 , and when said R 31 is 2-3, R 31 is the same or different;
  • the heterocyclic group contains 1-2 heteroatoms
  • the heteroatom of the heterocyclic group is nitrogen and/or oxygen;
  • R 3 is a 4-7-membered heterocyclic group optionally substituted by 1-3 R 31 , when the heteroatoms of the heterocyclic group are two, the two hetero atoms are the same or different;
  • the R 3 is a 4-7-membered heterocyclic group optionally substituted by 1-3 R 31
  • R a is selected from H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or 3-6 membered cycloalkyl;
  • R b is selected from H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or 3-6 membered cycloalkyl;
  • R 32 is selected from C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, 3-6 membered cycloalkyl or 4-7 membered heterocyclyl.
  • pyrimidopyridone derivatives are selected from any one of the following structures:
  • the present invention provides a preparation method of the pyrimidopyridone derivative, its pharmaceutically acceptable salt, its tautomer or its stereoisomer as described in the first aspect, which is selected from from one of the following two options:
  • the preparation method of the compound described in the general formula (I) of the present invention or its stereoisomer, tautomer or its pharmaceutically acceptable salt comprises the following steps:
  • the aromatic compound of general formula (I-1) is subjected to metal-catalyzed cross-coupling to obtain the compound of general formula (I-2);
  • the compound of the general formula (I-2) is reacted under catalyst conditions to obtain a chiral sulfonimide compound of the general formula (I-3);
  • the compound of general formula (I-3) is reduced by a metal reducing agent to obtain a chiral compound of general formula (I-4);
  • the compound of general formula (I-4) is cleaved by sulfonamide under acidic conditions to obtain a chiral benzylamine compound of general formula (I-A).
  • the compound of general formula (I-5) and tert-butyl bromoacetate are subjected to substitution reaction under basic conditions to obtain the compound of general formula (I-6);
  • the compound of general formula (I-6) is removed tert-butyl under acidic conditions to obtain the compound of general formula (I-7);
  • the 3rd step the compound of general formula (I-7) obtains the compound of general formula (I-8) through esterification reaction with alcohol under acidic conditions;
  • the compound of the general formula (I-9) and the amine of the general formula (I-10) are subjected to substitution reaction to obtain the compound of the general formula (I-11);
  • the 5th step the compound of general formula (I-11) obtains the compound of general formula (I-12) through halogenation reaction;
  • the 6th step the compound of general formula (I-12) and boronic acid or boron ester compound obtain the compound of general formula (I-13) through Suzuki reaction under basic conditions, in the presence of metal catalyst and ligand;
  • the compound of the general formula (I-15) and the amine of the general formula (I-10) are subjected to substitution reaction to obtain the compound of the general formula (I-16);
  • the compound of the general formula (I-16) and the compound of the general formula (I-8) are obtained under basic conditions to obtain the compound of the general formula (I-B).
  • the compound of general formula (I-B) and the compound of general formula (I-A) are subjected to substitution reaction to obtain the compound of general formula (I).
  • X, X 1 , X 2 and X 3 are halogen; X is preferably bromine; X 1 and X 2 are preferably chlorine; X 3 is preferably iodine; R 1 , R 2 , R 3 , AR and L have the same the same limits.
  • the preparation method of the compound described in the general formula (I) of the present invention or its stereoisomer, tautomer or its pharmaceutically acceptable salt comprises the following steps:
  • the compound of general formula (I-12) and methyl acrylate are subjected to Heck reaction to obtain the compound of general formula (I-17) under the adjustment and reduction of basicity and metal catalyst;
  • the compound of the general formula (I-17) is formed into an amide in the molecule under basic conditions to obtain the compound of the general formula (I-18);
  • the compound of the general formula (I-18) is subjected to halogenation to obtain the compound of the general formula (I-19);
  • the seventh step the compound of general formula (I-22) and the compound of general formula (I-23) are obtained by Suzuki reaction under basic conditions, in the presence of a metal catalyst and a ligand, to obtain the compound of general formula (I) .
  • X 1 , X 3 and X 4 are halogen; X 1 is preferably chlorine; X 3 is preferably iodine; X 4 is preferably bromine; X 5 is halogen or W is R 1 , R 2 , R 3 , AR and L have the same defined ranges as above.
  • the reagents that provide alkaline conditions are selected from organic bases or inorganic bases, and the organic bases are triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, bismuth One or more of lithium trimethylsilylamide, sodium tert-butoxide, sodium methoxide and potassium tert-butoxide, and the inorganic bases are sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, potassium acetate , one or more of cesium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate and lithium hydroxide;
  • the reagent for providing acidic conditions is one or more of hydrogen chloride, hydrogen chloride solution in 1,4-dioxane, hydrogen chloride solution in methanol, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid and phosphoric acid kind;
  • the metal catalyst is palladium/carbon, Raney nickel, tetrakis-triphenylphosphine palladium, palladium dichloride, palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride ( Pd(dppf)Cl 2 ), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, bistriphenylphosphonium palladium dichloride (Pd(PPh) 3 ) one or more of Cl 2 ) and tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 );
  • the ligands are 2-dicyclohexylphosphine-2,6'-dimethoxybiphenyl (SPhos), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (XantPhos), 2- Dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (XPhos), 2-dicyclohexylphosphino-2'-(N,N-dimethylamine)-biphenyl (DavePhos), 1, One or more of 1'-bis(diphenylphosphino)ferrocene (Dppf) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (BINAP), preferably 1,1 '-Binaphthalene-2,2'-bisdiphenylphosphine (BINAP);
  • the reducing agent is one or more of sodium borohydride, potassium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium aluminum tetrahydrogen;
  • the oxidant is one or more of potassium permanganate, manganese dioxide, potassium dichromate, sodium dichromate and potassium osmate;
  • the above reaction is preferably carried out in a solvent, and the solvent used is N,N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, 1,4-dioxane, water, tetrahydrofuran, dichloromethane, One or more of 1,2-dichloroethane, methanol, ethanol, toluene, petroleum ether, ethyl acetate, n-hexane and acetone.
  • the solvent used is N,N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, 1,4-dioxane, water, tetrahydrofuran, dichloromethane, One or more of 1,2-dichloroethane, methanol, ethanol, toluene, petroleum ether, ethyl acetate, n-hexane and acetone.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the pyrimidopyridone derivatives and/or stereoisomers, tautomers, pharmaceutically acceptable pyrimidopyridone derivatives as described in the first aspect salts; and pharmaceutically acceptable carriers and/or excipients and/or sustained release agents.
  • the term “comprising” means that the various ingredients can be used together in the mixture or composition of the present invention.
  • the terms “consisting essentially of” and “consisting of” are encompassed by the term “comprising”.
  • a "pharmaceutically acceptable” ingredient is one that is suitable for use in humans and/or animals without undue adverse side effects (eg, toxicity, irritation, and allergy), ie, with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier is a pharmaceutically acceptable solvent, suspending agent or excipient for delivering the active substance of the present invention or a physiologically acceptable salt thereof to animals or humans.
  • the carrier can be liquid or solid.
  • the pharmaceutical composition contains a safe and effective amount (such as 0.001-99.9 parts by weight, more preferably 0.01-99 parts by weight, more preferably 0.1-90 parts by weight) of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or excipient, wherein the total weight of the composition is 100 parts by weight.
  • a safe and effective amount such as 0.001-99.9 parts by weight, more preferably 0.01-99 parts by weight, more preferably 0.1-90 parts by weight
  • a pharmaceutically acceptable carrier or excipient wherein the total weight of the composition is 100 parts by weight.
  • the pharmaceutical composition of the present invention contains 0.001-99.9 wt %, more preferably 0.01-99 wt %, more preferably 0.1-90 wt % of the total weight of the compound represented by formula (I) or its pharmacy an acceptable salt; and a pharmaceutically acceptable carrier or excipient, wherein the total weight of the composition is 100% by weight.
  • the preferred ratio of the compound of formula (I) to a pharmaceutically acceptable carrier, excipient or sustained-release agent is that formula (I) as an active ingredient accounts for more than 65% of the total weight, and the rest accounts for The total weight ratio is 0.5-40%, or more preferably 1-20%, or more preferably 1-10%.
  • the unit dose of each dose comprises 0.05mg-500mg, preferably 0.5mg-200mg, more preferably 0.1mg-100mg of the compound of formula (I), enantiomer, external Racemates, pharmaceutically acceptable salts or mixtures thereof.
  • the amount of the active ingredients can generally be the conventional amount or lower in the prior art.
  • compositions of the present invention may be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, etc., wherein the compound of formula (I) may be present in a suitable solid or liquid carrier or diluent middle.
  • the pharmaceutical compositions of the present invention may also be stored in a suitable sterile device for injection or instillation.
  • the pharmaceutical composition may also contain odorants, flavoring agents, and the like.
  • the compound of formula (I) or the pharmaceutical composition comprising the compound of formula (I) of the present invention can be clinically used in mammals (including humans) by oral, nasal, dermal, pulmonary or gastrointestinal routes of administration.
  • the preferred route of administration is oral.
  • the preferred daily dose is 0.5 mg to 200 mg/kg body weight, taken in one or divided doses. Regardless of the method of administration, the optimal dose for an individual should depend on the specific treatment. It is common to start with a small dose and gradually increase the dose until the most suitable dose is found.
  • the effective dose of active ingredient employed may vary with the compound employed, the mode of administration, and the severity of the disease to be treated. Generally, however, satisfactory results are obtained when the compounds of the present invention are administered in doses of about 1-300 mg/kg of animal body weight per day, preferably in 1-3 divided doses per day, or in sustained release form Dosing. For most large mammals, the total daily dose is about 5-1000 mg, preferably about 10-500 mg.
  • Dosage forms suitable for oral administration contain about 1-200 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen can be adjusted to provide optimal therapeutic response. For example, several divided doses may be administered daily, or the dose may be proportionally reduced, as dictated by the exigencies of the therapeutic situation.
  • the compounds or pharmaceutically acceptable salts and compositions thereof can be administered orally as well as intravenously, intramuscularly or subcutaneously.
  • the preferred pharmaceutical compositions are solid compositions, especially tablets and solid- or liquid-filled capsules. Oral administration of the pharmaceutical composition is preferred.
  • Solid carriers include: starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include: sterile water, polyethylene glycols, nonionic surfactants and edible oils (eg corn oil, peanut oil and sesame oil) as appropriate to the characteristics of the active ingredient and the particular mode of administration desired.
  • Adjuvants commonly used in the preparation of pharmaceutical compositions may also advantageously be included, such as flavors, colors, preservatives and antioxidants such as vitamin E, vitamin C, BHT and BHA.
  • the active compounds or pharmaceutically acceptable salts thereof and compositions thereof may also be administered parenterally or intraperitoneally.
  • Solutions or suspensions of these active compounds can also be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquids, polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, these forms must be sterile and must be fluid for easy syringe expelling. It must be stable under the conditions of manufacture and storage and must be resistant to the contaminating influence of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, alcohol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • the compound represented by formula (I) or its pharmaceutically acceptable salt and its composition can also be administered in combination with other active ingredients or drugs for treating or preventing chronic pain diseases.
  • other active ingredients or drugs for treating or preventing chronic pain diseases.
  • two or more drugs are administered in combination, they generally have better effects than when the two drugs are administered separately.
  • the present invention provides a pyrimidopyridone derivative as described in the first aspect, its stereoisomer, tautomer, pharmaceutically acceptable salt or the pharmaceutical combination as described in the third aspect
  • the cancer includes but is not limited to astrocytic carcinoma, breast cancer, cervical cancer, colorectal cancer , endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, pancreatic cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer, thyroid cancer, sarcoma, kidney cancer and bile duct cancer
  • the cancer includes, but is not limited to: pancreatic cancer, colorectal cancer, lung cancer, hepatocellular carcinoma, renal cancer, gastric cancer and bile duct cancer; and/or the KRAS
  • the dosage range of the pyrimidopyridone derivatives as described in the first aspect, their stereoisomers, tautomers, pharmaceutically acceptable salts or the pharmaceutical composition as described in the third aspect is selected from 10-100mg/kg, preferably 25-50mg/kg; the dose range of KRAS G12C inhibitor is selected from 3-100mg/kg, preferably 5-30mg/kg; the dose range of MEK inhibitor is selected from 0.1-0.2mg/kg, Preferably 0.125 mg/kg.
  • the KRAS G12C inhibitor is MRTX849, and the MEK inhibitor is Trametinib.
  • the cancer is a RAS family related cancer; preferably a KRAS, HRAS or NRAS G12C related cancer, KRAS, HRAS or NRAS G12D related cancer, KRAS, HRAS or NRAS G12V related cancer, KRAS, HRAS or NRAS G12S-related cancer, KRAS, HRAS or NRAS G12A-related cancer, KRAS, HRAS or NRAS G13D-related cancer, KRAS, HRAS or NRAS G13C-related cancer, KRAS, HRAS or NRAS Q61L-related cancer, KRAS, HRAS or NRAS A146T-related cancer, KRAS, HRAS or NRAS A146V-associated cancer or KRAS, HRAS or NRAS A146P-associated cancer.
  • a RAS family related cancer preferably a KRAS, HRAS or NRAS G12C related cancer, KRAS, HRAS or NRAS G12D related cancer, KRAS, HRAS or NRAS
  • a method of treating cancer comprising providing to a cancer patient a therapeutically effective amount of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof.
  • the cancer is a RAS family associated cancer.
  • the cancer is a SOS-L associated cancer.
  • the cancer is an NF-1/NF-2 related cancer.
  • compositions and methods provided by the present invention can be used to treat a variety of cancers, including prostate, breast, brain, skin, cervical cancer, testicular cancer, and the like. More specifically, cancers treatable by the compositions and methods of the present invention include, but are not limited to, tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, cephalic Neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid cancers and sarcomas.
  • tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, cephalic Neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid cancers and sarcomas.
  • Heart sarcomas (angiosarcomas, fibrosarcomas, rhabdomyosarcomas, liposarcoma), myxomas, rhabdomyomas, fibroids, lipomas and teratomas; lung: bronchial carcinoma (squamous squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma, mesothelioma; gastrointestinal tract: esophagus (squamous cell carcinoma) , adenocarcinoma, leiomyosarcoma, lymphoma), stomach (cancer, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glu
  • the cancer is a RAS family related cancer, such as a KRAS, NRAS or HRAS related cancer.
  • the RAS family-related cancer is non-small cell lung cancer or pancreatic cancer.
  • the cancer is a cancer associated with SOS 1.
  • the SOS 1-related cancer is lung adenocarcinoma, embryonal rhabdomyosarcoma, Sertoli cell testicular tumor, and granulosa cell tumor of the skin.
  • the cancer is an NF-1 related cancer.
  • the cancer is pancreatic cancer, colorectal cancer, lung cancer, hepatocellular carcinoma, kidney cancer, gastric cancer or bile duct cancer.
  • KRAS G12C refers to a mutated form of the mammalian KRAS protein containing the amino acid at amino acid position 12 replaced by cysteine for glycine.
  • KRAS G12D refers to a mutant form of the mammalian KRAS protein containing an amino acid with aspartic acid substituted for glycine at position 12.
  • the amino acid codons and residue positions of human KRAS were determined from the amino acid sequence determined by UniProtKB/Swi-prot P01116: Variant P.Gly 12 Asp.
  • KRAS G12V refers to a mutant form of mammalian KRAS protein containing the amino acid valine in place of glycine at position 12.
  • the amino acid codons and residue positions of human KRAS were determined according to the amino acid sequence determined by UniProtKB/Swi-prot P01116: Variant P.Gly 12 Val.
  • KRAS G12S refers to a mutant form of a mammalian KRAS protein containing the amino acid at amino acid position 12 with serine substituted for glycine.
  • the amino acid codons and residue positions of human KRAS were determined from the amino acid sequence identified by UniProtKB/SwissProt P 01116: variant p.Gly 12Ser.
  • KRAS G12A refers to a mutant form of the mammalian KRAS protein containing the amino acid at amino acid position 12 with alanine in place of glycine.
  • the amino acid codons and residue positions of human KRAS were determined from the amino acid sequence identified in UniProtKB/SwissProt P 01116: variant p.Gly 12Ala.
  • KRAS G13D refers to a mutant form of a mammalian KRAS protein containing the amino acid at amino acid position 13 aspartic acid in place of glycine.
  • the determination of amino acid codons and residue positions of human KRAS is based on the amino acid sequence determined by UniProtKB/SwissProt P01116: variant p.gly 13Asp.
  • KRAS G13C refers to a mutant form of the mammalian KRAS protein containing the amino acid at amino acid 13 replaced by cysteine for glycine.
  • the amino acid codons and residue positions of human KRAS were determined according to the amino acid sequence determined by UniProtKB/SwissProt-Prot P01116: Variant P.Gly 13Cys.
  • KRAS Q61L refers to a mutant form of the mammalian KRAS protein containing the amino acid leucine in place of glutamine at amino acid 61.
  • the determination of amino acid codons and residue positions of human KRAS is based on the amino acid sequence of UniProtKB/SwissProt P 01116: variant p.Gln61Leu.
  • KRAS A146T refers to a mutant form of the mammalian KRAS protein containing the amino acid at amino acid position 146 with threonine in place of alanine.
  • the amino acid codons and residue positions of human KRAS were determined from the amino acid sequence identified by UniProtKB/SwissProt P 01116: variant p.al46Thr.
  • KRAS A146V refers to a mutant form of the mammalian KRAS protein containing an amino acid at amino acid position 146 with a valine in place of alanine.
  • the amino acid codons and residue positions of human KRAS were determined from the amino acid sequence identified in UniProtKB/SwissProt P 01116: variant p.al46Val.
  • KRAS A146P refers to a mutated form of the mammalian KRAS protein containing the amino acid at amino acid position 146 in which a proline is substituted for alanine.
  • the amino acid codons and residue positions of human KRAS were determined from the amino acid sequence identified in UniProtKB/SwissProt P 01116: variant p.Al46Pro.
  • HRAS G12C refers to a mutated form of a mammalian HRAS protein containing the amino acid at amino acid position 12 replaced by cysteine for glycine. Based on the amino acid sequence identified in UniProtKB/SwissProt P 01112: variant p.Gly 12 Cys, the amino acid codons and residue positions of human HRAs were determined.
  • HRAS G12D refers to a mutant of a mammalian HRAS protein containing aspartic acid in place of glycine at amino acid position 12.
  • the amino acid codons and residue positions of human HRAs were determined based on UniProtKB/SwissProt P01112: Amino acid sequence of variant P.Gly 12Asp.
  • HRAS G12S refers to a mutant form of a mammalian HRAS protein containing 12 amino acids with serines substituted for glycines.
  • the amino acid codons and residue positions of human HRAS were determined according to the amino acid sequence determined by UniProtKB/SwissProt P01112: Variant P.Gly 12Ser.
  • HRAS G12A refers to a mutant form of a mammalian HRAS protein that replaces the amino acid at 12 with alanine for glycine.
  • the amino acid codons and residue positions of human KRAS were determined from the amino acid sequence identified in UniProtKB/SwissProt P01112: variant P.Gly 12Ala.
  • HRAS G13D refers to a mutant form of a mammalian HRAS protein containing an amino acid with aspartic acid substituted for glycine at position 13.
  • the amino acid codons and residue positions of human HRAS were determined according to the amino acid sequence determined by UniProtKB/Swi-prot P01112: variant p.gly 13Asp.
  • HRAS G13C is a mutant of mammalian HRAS protein, which contains cysteine in place of the amino acid of glycine at the 13th amino acid.
  • the determination of amino acid codons and residue positions of human HRAS was based on the amino acid sequence of UniProtKB/SwissProt-Prot P01112: variant P.Gly 13Cys.
  • HRAS Q61L refers to a mutated form of a mammalian HRAS protein containing the amino acid at amino acid position 61 in place of leucine in place of glutamine. Based on the amino acid sequence identified by UniProtKB/SwissProt P 01112 variant p.Gln61Leu, the amino acid codons and residue positions of human HRAs were determined.
  • HRAS A146T refers to a mutated form of a mammalian HRAS protein containing the amino acid at amino acid position 146 with a threonine substituted for alanine.
  • the amino acid codons and residue positions of human NRAS were determined from the amino acid sequence identified in UniProtKB/SwissProt P 01112: variant p.Al46Thr.
  • HRAS A146V refers to a mutant form of a mammalian HRAS protein containing the amino acid valine at amino acid position 146 in place of alanine. One amino acid replaces the alanine at amino acid position 146.
  • the amino acid codons and residue positions of human NRAS were determined from the amino acid sequence identified in UniProtKB/SwissProt P 01112: variant p.al46Val.
  • HRAS A146P refers to a mutated form of the mammalian HRAS protein containing the amino acid at amino acid position 146 where a proline is substituted for alanine. Amino acid codons and residue positions of human NRAS were determined from the amino acid sequence identified in UniProtKB/SwissProt P 01112: variant p.Al46Pro.
  • NRAS G12C refers to a mutant form of the mammalian NRAS protein containing the amino acid glycine at amino acid 12 replaced by cysteine.
  • the amino acid codons and residue positions of human NRAS were determined according to UniProtKB/SwissProt-Prot P01111: variant P.Gly 12Cys.
  • NRAS G12D refers to a mutant form of the mammalian NRAS protein that contains an amino acid with aspartic acid substituted for glycine at position 12.
  • the amino acid codons and residue positions of human NRAS were determined from the amino acid sequence determined by UniProtKB/Swi-prot P01111: Variant P.Gly 12 Asp.
  • NRAS G12S refers to a mutant form of the mammalian NRAS protein containing the amino acid serine substituted for glycine at amino acid 12.
  • the amino acid codons and residue positions of human NRAS were determined from the amino acid sequence identified by UniProtKB/SwissProt P01111: variant p.Gly 12Ser.
  • NRAS G12A refers to a mutant form of the mammalian NRAS protein containing the amino acid at amino acid 12 where alanine is substituted for glycine.
  • the determination of amino acid codons and residue positions of human KRAS was based on the amino acid sequence of UniProtKB/SwissProt P01111: variant p.Gly 12Ala.
  • NRAS G13D refers to a mutated form of the mammalian NRAS protein that contains an amino acid substitution of aspartic acid at amino acid 13 for glycine at the amino acid position.
  • the determination of amino acid codons and residue positions of human NRAS is based on the amino acid sequence determined by UniProtKB/SwissProt P 01111: variant p.Gly 13 Asp.
  • HNRas G13C refers to a mutant form of the mammalian NRAS protein containing the amino acid cysteine in place of glycine at amino acid 13.
  • the determination of amino acid codons and residue positions of human NRAS was based on the amino acid sequence of UniProtKB/SwissProt P01111: variant P.Gly 13Cys.
  • HRAS Q61L refers to a mutated form of a mammalian HRAS protein containing a leucine at amino acid position 61 in place of glutamine at amino acid position 61. Based on the amino acid sequence identified by UniProtKB/SwissProt P 01112 variant p.Gln61Leu, the amino acid codons and residue positions of human HRAs were determined.
  • NRAS A146T refers to a mutant form of the mammalian NRAS protein containing the amino acid threonine at amino acid 146 in place of alanine.
  • the amino acid codons and residue positions of human NRAS were determined from the amino acid sequence identified in UniProtKB/SwissProt P 01111: variant p.Al46Thr.
  • NRAS A146V refers to a mutant form of a mammalian NRAS protein containing the amino acid valine at amino acid 146 in place of alanine.
  • the amino acid codons and residue positions of human NRAS were determined from the amino acid sequence identified by UniProtKB/SwissProt P 01111: variant p.al46Val.
  • NRAS A146P refers to a mutated form of the mammalian NRAS protein containing an amino acid with a proline in place of alanine at amino acid 146.
  • the amino acid codons and residue positions of human NRAS were determined from the amino acid sequence identified by UniProtKB/SwissProt P 01111: variant p.Al46Pro.
  • RAS family member or “RAS family” refers to KRAS, HRAS, NRAS and activating mutants thereof, including positions G12, G13, Q61 and A146.
  • 'RAS family associated disease or disorder' refers to a disease or disorder associated with, mediated by, or having an activating RAS mutation, such as RAS at positions G12, G13, Q61 or A146.
  • RAS family related diseases or diseases are KRAS, HRAS or NRAS G12C related cancer, KRAS, HRAS or NRAS G12D related cancer, KRAS, HRAS or NRAS G12V related cancer, KRAS, HRAS or NRAS G12S related cancer, KRAS, HRAS or NRAS G12A-related cancer, KRAS, HRAS or NRAS G13D-related cancer, KRAS, HRAS or NRAS G13C-related cancer, KRAS, HRAS or NRAS Q61L-related cancer, KRAS, HRAS or NRAS A146T-related cancer, KRAS, HRAS or NRAS A146V-related cancer Cancer or KRAS, HRAS or NRAS 146P-related cancer.
  • SOS1-related disease or disorder refers to a disease or disorder associated with, mediated by, or having an activating SOS1 mutation.
  • activating SOS1 mutations include the SOS1N233S and SOS1N233Y mutations.
  • SOS1N233S refers to a mutant form of the mammalian SOS1 protein containing an amino acid substitution of serine for glutamine at amino acid position 233.
  • the determination of amino acid codons and residue positions for human SOS 1 was based on the amino acid sequence identified in UniProtKB/SwissProt Q 07889: variant p.Gln233Ser.
  • SOS1N233Y refers to a mutant form of the mammalian SOS1 protein in which amino acid 233 is replaced by an amino acid containing tyrosine in place of glutamine.
  • the determination of amino acid codons and residue positions of human SOS 1 was based on the amino acid sequence identified in UniProtKB/SwissProt Q 07889: variant p.Gln233Tyr.
  • SOS 1 inhibitor refers to a compound of the present invention, as described herein, represented by formula (I). These compounds negatively inhibit all or part of the interaction of SOS 1 with RAS family mutants or SOS 1 activating mutations, thereby reducing and/or modulating the nucleotide exchange activity of the RAS family member-SOS 1 complex.
  • KRAS inhibitor refers to inhibitors known in the art against various KRAS mutations. Inhibitors such as KRAS G12C, KRAS G12D, KRAS G12V can be targeted.
  • MEK signaling pathway inhibitors refer to inhibitors of RAF, MEK and ERK1/2 known in the art.
  • NF-1/NF-2-related disease or disorder refers to a disease or disorder caused by a loss-of-function mutation in the neurocellulase (NF-1) gene or the neurocellulase 2 (NF-2) gene.
  • loss-of-function mutation refers to any point mutation, splice site mutation, fusion, nonsense mutation (amino acid mutation to a stop codon), in-frame mutation or in-frame transfer mutation, including insertions and deletions, and the target cell Or homozygous deletion of a protein-encoding gene in a cancer cell, resulting in partial or complete loss of presence, activity, and/or function of the encoded protein.
  • Alkyl refers to a saturated aliphatic hydrocarbon group comprising 1-20 carbon atoms, or 1-10 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms , or a saturated linear or branched monovalent hydrocarbon group of 1-2 carbon atoms, wherein the alkyl group may be independently optionally substituted by one or more substituents described herein.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1 ,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2 - Dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-di Methylbutyl etc. Alkyl groups can be optionally substituted or unsubstituted.
  • Alkenyl refers to a linear or branched monovalent hydrocarbon group of 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one CC is sp 2 double bond, wherein the alkenyl group can be independently optionally substituted by one or more substituents described in the present invention, specific examples of which include, but are not limited to, vinyl, allyl and alkene Butyl and so on. Alkenyl groups can be optionally substituted or unsubstituted.
  • Cycloalkyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring comprising 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl , cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. Cycloalkyl groups can be optionally substituted or unsubstituted.
  • “Spirocycloalkyl” refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and the single rings share one carbon atom (called spiro atom) with each other, and the ring contains one or more aromatic systems with double bonds but none of the rings have fully conjugated pi electrons.
  • spiro atom carbon atom
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • spirocycloalkyl groups are divided into mono-spiro, double-spiro or poly-spirocycloalkyl groups, preferably mono-spiro and double-spirocycloalkyl groups, preferably 4-membered/5-membered, 4-membered Yuan/6 Yuan, 5 Yuan/5 Yuan or 5 Yuan/6 Yuan.
  • spirocycloalkyl include, but are not limited to:
  • “Fused cycloalkyl” refers to a 5- to 18-membered all-carbon polycyclic group containing two or more cyclic structures that share a pair of carbon atoms with each other, and one or more rings may contain one or more double bonds, But none of the rings have an aromatic system with fully conjugated pi electrons, preferably 6 to 12 membered, more preferably 7 to 10 membered. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl.
  • Non-limiting examples of "fused cycloalkyl” include, but are not limited to:
  • “Bridged cycloalkyl” refers to an all-carbon polycyclic group of 5 to 18 members, containing two or more cyclic structures, sharing two carbon atoms that are not directly connected to each other, and one or more rings may contain one or more Aromatic systems in which multiple double bonds, but none of the rings have fully conjugated pi electrons, are preferably 6 to 12 membered, more preferably 7 to 10 membered. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • Non-limiting examples of "bridged cycloalkyl” include, but are not limited to:
  • the cycloalkyl ring can be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring connected to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthalene base, benzocycloheptyl, etc.
  • Heterocyclyl “heterocycle” or “heterocyclic” are used interchangeably in this application, and are used interchangeably in this application, and all refer to a saturated or partially unsaturated monocyclic ring containing 3-12 ring atoms , bicyclic or tricyclic non-aromatic heterocyclic groups, wherein at least one ring atom atom is a heteroatom, such as oxygen, nitrogen, sulfur atom and the like. It preferably has a 5- to 7-membered monocyclic ring or a 7- to 10-membered bi- or tricyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulfur.
  • heterocyclyl examples include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidine base, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl and Piperazinyl.
  • the heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl.
  • Heterocyclyl groups can be optionally substituted or unsubstituted.
  • spiroheterocyclyls are classified into mono-spiroheterocyclyl, bis-spiroheterocyclyl or poly-spiroheterocyclyl, preferably mono-spiroheterocyclyl and bis-spiroheterocyclyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl group.
  • spiroheterocyclyl include, but are not limited to:
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups.
  • fused heterocyclyl include, but are not limited to:
  • bridged heterocyclyl include, but are not limited to:
  • Aryl refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused fashion.
  • aryl includes aromatic groups such as phenyl, naphthyl, tetrahydronaphthyl. Preferred aryl groups are C6 - C10 aryl groups, more preferred aryl groups are phenyl and naphthyl, and most preferred are phenyl groups.
  • Aryl groups can be substituted or unsubstituted.
  • the "aryl” can be fused with a heteroaryl, a heterocyclyl or a cycloalkyl, wherein the parent structure is linked together by an aryl ring, non-limiting examples include but are not limited to:
  • Heteroaryl refers to an aromatic 5- to 6-membered monocyclic or 9- to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen, and/or sulfur.
  • heteroaryl include, but are not limited to, furanyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl , oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzo-diazolyl Oxolyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindo
  • Heteroaryl groups can be optionally substituted or unsubstituted.
  • the heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples include but are not limited to:
  • Alkoxy refers to a group (alkyl-O-). Wherein, alkyl is as defined herein. Ci - C6 alkoxy groups are preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.
  • Haloalkyl refers to an alkyl group having one or more halogen substituents, wherein the alkyl group has the meaning as described herein.
  • haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, perfluoroethyl, 1,1-dichloroethyl, 1,2-dichloropropyl, and the like.
  • Halogen means fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.
  • Amino refers to -NH2 .
  • Cyano refers to -CN.
  • Niro refers to -NO2 .
  • Benzyl refers to -CH2 -phenyl.
  • Carboxyl refers to -C(O)OH.
  • Alcohol refers to -C(O) CH3 or Ac.
  • Carboxylate means -C(O)O(alkyl) or (cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, are substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
  • the terms "subject,” “individual,” or “patient” are used interchangeably to refer to any animal, including mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates animals and humans.
  • the patient is a human.
  • the subject has experienced and/or displayed at least one symptom of the disease or disease to be treated and/or prevented.
  • the subject has been identified or diagnosed with cancer with a KRAS G12 or G13 mutation (eg, as determined by an FDA-approved regulatory agency, such as an FDA-approved assay or kit).
  • the subject has a tumor that is positive for a KRAS G12C mutation, a KRAS G12D mutation, a KRAS G12S mutation, a KRAS G12V mutation, a KRAS G12A mutation, a KRAS G13D mutation, or a KRAS G13C mutation (eg, as approved by a regulatory agency-approved test or kit determination).
  • the subject can be a person with a KRAS G12C mutation, a KRAS G12D mutation, a KRAS G12V mutation, a KRAS G12S mutation, a KRAS G12A mutation, a KRAS G13D mutation, or a KRAS G13C mutation (e.g., an approved regulatory agency-such as an FDA-approved assay or reagent) Box) positive tumor patients.
  • a KRAS G12C mutation e.g., an approved regulatory agency-such as an FDA-approved assay or reagent
  • the subject can be a subject whose tumor has a KRAS G12C mutation, a KRAS G12D mutation, a KRAS G12V mutation, a KRAS G12S mutation, a KRAS G12A mutation, a KRAS G13D mutation, or a KRAS G13C mutation (eg, the tumor was approved by an FDA-approved regulatory agency, kit or assay).
  • the subject is suspected of having a KRAS G12 or G13 gene-related cancer.
  • the subject has a clinical record indicating that the subject has a tumor with a KRAS G12C mutation (and optionally the clinical record indicating that the subject should be treated with any of the compositions provided herein).
  • the term "pediatric patient” as used herein refers to a patient under the age of 16 at the time of diagnosis or treatment.
  • the term "child” can also be divided into the following subcategories: neonatal (from birth to first month of life); infant (1 month to two years); child (2 to 12 years); adolescent (12 years) Age to 21 (until but not including 22nd birthday).
  • Berhman RE Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th ed. Philadelphia: W.B. Saunders Company, 1996; Rudolph AM, et al. Rudolph's Pediatrics, 21st ed. New York: McGrow-Hill, 2002; and Avery MD, 1st LR. Pediatric Medicine, 2nd ed. Baltimore: Williams &Wilkins; 1994.
  • an "effective amount" of a compound refers to an amount sufficient to negatively modulate or inhibit SOS 1 enzymatic activity.
  • a "therapeutically effective dose” of a compound refers to an amount sufficient to ameliorate or somehow reduce symptoms, halt or reverse disease progression, or negatively modulate or inhibit SOS 1 activity. This dose can be given as a single dose or in a regimen to be effective.
  • treating means in any way ameliorating or otherwise altering the symptoms or pathology of a patient's condition, disorder, or disease.
  • improving the symptoms of a particular disease by use of a particular compound or pharmaceutical composition means any reduction, whether permanent or temporary, attributable to or associated with use of the composition Sexual, permanent or temporary.
  • the compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including, but not limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, constitute the part.
  • Diastereomers can be separated into individual diastereomers by methods such as chromatography, crystallization, distillation or sublimation on the basis of their physicochemical differences.
  • Enantiomers can be separated by converting chiral mixtures into diastereomeric mixtures by reaction with an appropriate optically active compound such as a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride , the diastereomers are separated, and the individual diastereomers are converted to the corresponding pure enantiomers.
  • the intermediates and compounds of the present invention may also exist in different tautomeric forms, and all such forms are included within the scope of the present invention.
  • optically active compounds that is, they have the ability to rotate the plane of plane-polarized light.
  • the prefixes D, L or R, S are used to denote the absolute configuration of the chiral center of the molecule.
  • the prefixes d, l or (+), (-) are used to designate the sign of the plane-polarized light rotation of the compound, (-) or l means the compound is levorotatory, and the prefix (+) or d means the compound is dextrorotatory.
  • the atoms or groups of atoms of these stereoisomers are connected to each other in the same order, but their steric structures are different.
  • a specific stereoisomer may be an enantiomer, and a mixture of isomers is often referred to as an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can result in no stereoselectivity or stereospecificity during chemical reactions.
  • the terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomers, devoid of optical activity.
  • Tautomer or "tautomeric form” means that isomers of structures of different energies can be interconverted through a low energy barrier.
  • proton tautomers ie, prototropic tautomers
  • Valence (valence) tautomers include interconversions that recombine bond electrons.
  • the structural formulas described herein include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers): such as R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers. Accordingly, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers, or geometric isomers thereof are within the scope of the present invention.
  • “Pharmaceutically acceptable salts” refer to salts of the compounds of the present invention which are safe and effective in humans or animals.
  • the salts of the compounds can be obtained by using a sufficient amount of base or acid in neat solution or in a suitable inert solution to obtain the corresponding addition salts.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts, etc.
  • Pharmaceutically acceptable acid addition salts include inorganic acid salts and organic acid salts, and the inorganic and organic acids include Hydrochloric acid, hydrobromic acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen sulfate, acetic acid, maleic acid, malonic acid, succinic acid, rice butenedioic acid, Phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, and methanesulfonic acid, among others (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977)).
  • the present invention provides an SOS1 inhibitor with a new structure.
  • the test results show that the pyrimidopyridone derivative exhibits excellent SOS1 inhibitory activity, and at the same time exhibits excellent safety and selectivity, and can be used to prepare and treat cancer.
  • drugs for diseases such as pancreatic cancer, colorectal cancer, lung cancer, hepatocellular cancer, kidney cancer, stomach cancer and bile duct cancer.
  • Fig. 1 is a graph showing the effect of the compounds involved in the present invention on the KRAS/ERK1/2 signal transduction pathway of K-562 cells.
  • Figure 2 is a graph showing the in vivo antitumor effect of the SOS1 inhibitor of the present invention and MRTX849 alone or in combination on the KRASG12C mutant MIAPaCa-2 pancreatic xenograft nude mouse model.
  • Figure 3 is a graph showing the effect of the SOS1 inhibitor of the present invention and MRTX849 alone or in combination on the body weight of the KRASG12C mutant MIAPaCa-2 pancreatic xenograft nude mouse model.
  • Figure 4 is a graph showing the in vivo antitumor effect of the SOS1 inhibitor of the present invention and Trametinib alone or in combination on a KRASG12D mutant HPAF-II pancreatic xenograft tumor nude mouse model.
  • Figure 5 is a graph showing the effect of the SOS1 inhibitor of the present invention and Trametinib alone or in combination on the body weight of KRASG12D mutant HPAF-II pancreatic xenograft nude mice model.
  • the mass spectrum was measured by LC/MS, and the ionization mode was ESI.
  • HPLC model Agilent 1260, Thermo Fisher U3000; Column model: Waters xbrige C18 (4.6*150mm, 3.5 ⁇ m); Mobile phase: A: ACN, B: Water (0.1% H 3 PO 4 ); Flow rate: 1.0mL/min; Gradient: 5%A for 1min, increase to 20%A within 4min, increase to 80%A within 8min, 80%A for 2min, back to 5%A within 0.1min; Wavelength: 220nm; Column Incubator: 35°C.
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.2mm-0.3mm, and the specification used for TLC separation and purification products is 0.4mm -0.5mm.
  • HATU 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1L.
  • reaction temperature is room temperature, which is 20°C-30°C.
  • the monitoring of the reaction progress in the embodiment adopts thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of the column chromatography used for purifying the compound or the developing solvent system of the thin layer chromatography method includes: A: Petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: n-hexane: ethyl acetate; the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or basic reagent can also be added Adjustments such as acetic acid or triethylamine, etc.
  • TLC thin layer chromatography
  • reaction solution was added with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound IN-1b (29.8 g, crude product, containing a small amount of triphenylene) as a white solid. oxyphosphorus).
  • reaction solution was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography to obtain the oily title compound IN-1d (5.5 g, yield 80%).
  • 2-Acetylthiophene IN-2a (10.0 g, 79.26 mmol) and aluminum trichloride (23.14 g, 173.54 mmol) were dispersed in chloroform (60 mL), and bromine (dissolved in carbon tetrachloride (90 mL) was slowly added dropwise. 13.48 g, 84.36 mmol). After the addition was completed, the reaction was carried out at room temperature for 4 hours, and the reaction of the raw material 2-acetylthiophene was monitored by TLC.
  • reaction solution was poured into ice water, extracted with ethyl acetate (30 ml ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography to obtain the title compound IN-2b (12.0 g, yield) as a yellow oil. 74%).
  • Tetraethyl titanate 60 mL was added to the round-bottomed flask, and compound IN-2b (6.0 g, 29.26 mmol) and (R)-(+)-tert-butylsulfinamide (9.58 g, 79.04 mmol) were sequentially added at room temperature ), the temperature was slowly raised to 100 °C for 1 hour, and the reaction of the raw materials was monitored by TLC for completeness.
  • reaction solution was cooled to room temperature, poured into ice water, extracted with ethyl acetate (50 ml ⁇ 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography to obtain the title compound IN-2c (8.6 g, yield 95%).
  • compound IN-2f (15.0 g, 48.98 mmol) and 2-formylbenzeneboronic acid (8.8 g, 58.78 mmol) were dissolved in 1,4-dioxane (100 mL) and water (10 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium (600 mg, 0.735 mmol) and sodium carbonate (10.4 g, 98.12 mmol) were added at room temperature, and the temperature was raised to 90° C. to react for 3 hours. The reaction of the raw materials was basically completed by TLC.
  • reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound IN-2g (7.9 g, yield 49%).
  • reaction solution was cooled to room temperature, hydrochloric acid (15 mL, 3N) was added, stirred for 30 minutes, filtered through a pad of celite, the filtrate was separated, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was filtered through silica gel Purification by column chromatography gave the title compound IN-3b (1.25 g, 72% yield) as a yellow oil.
  • reaction solution was quenched by dropwise addition of water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography to obtain the title compound IN-3d (150 mg, yield 58) as a white solid %).
  • reaction solution was poured into saturated aqueous sodium bicarbonate solution and quenched, extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound IN-4b as a yellow liquid ( 8.1 g, yield 73%).
  • reaction solution was cooled to room temperature, diluted hydrochloric acid (14.4 mL, 72.0 mmol, 5 M) was added, and the mixture was stirred at room temperature for 1 hour. TLC showed that the reaction of the starting materials was complete.
  • the reaction solution was diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound IN-4c (5.6 g, yield 83%) as a yellow liquid. .
  • reaction solution was cooled to room temperature, poured into vigorously stirred ice water, stirred continuously for 10 minutes, filtered, the filter cake was repeatedly washed with ethyl acetate, the filtrate was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Concentration gave the title compound IN-4e (9.0 g, crude) as a yellow oil, which was used directly in the next step.
  • reaction solution was poured into ice water and quenched, extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column to obtain the title compound IN-4f (2.8 g, two step yield 21%).
  • reaction solution was poured into ice water to quench, extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound IN-5b (2.9 g, two-step yield 33%).
  • reaction solution was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound IN-6b (5.9 g, yield 100%) as a pale yellow oil.
  • reaction solution was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound IN-7b (9.2 g, yield 78%) as pale yellow oil.
  • reaction solution was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound IN-7c (12.1 g, yield 86%) as pale yellow oil.
  • reaction solution was cooled to room temperature, poured into ice water (100 mL), stirred with ethyl acetate, filtered to remove insoluble matter, the aqueous phase was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound IN-8b (14.0 g, crude) was used directly in the next step.
  • the reaction solution was cooled to room temperature, adjusted to neutrality by adding saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, and the organic phases were combined, washed with saturated aqueous sodium bicarbonate solution, washed with saturated aqueous sodium sulfite solution, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain The title compound 1c (37.2 g, crude containing succinimide) as a white solid was used directly in the next step.
  • reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography to obtain the title compound 1d as a white solid (3.87 g, yield in three steps). 40%).
  • the fourth step 4-chloro-2-methyl-6-(methylamino)pyrimidine-5-carbaldehyde 1e
  • reaction solution was added with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography to obtain the title compound 1e (3.7 g, yield 94%) as a white solid.
  • the seventh step 4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2,8-dimethyl-6-(((S) -Tetrahydrofuran-3-yl)oxy)pyrido[2,3-d]pyrimidin-7(8H)-one 1
  • 4,6-Dichloro-2-methylpyrimidine 1a (15.2 g, 93.25 mmol) was added to aqueous ammonia solution (150 mL, 25%), the temperature was raised to 65° C. for 3 hours, and TLC showed that the reaction of the starting materials was completed. The reaction solution was concentrated to obtain the title compound 2a (11.9 g, crude product) as a white solid, which was directly used in the next step.
  • reaction solution was cooled to room temperature, adjusted to neutrality by adding saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, and the organic phases were combined, washed with saturated aqueous sodium bicarbonate solution, washed with aqueous sodium sulfite solution, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a white
  • the solid title compound 2b (11.82 g, crude) was used directly in the next step.
  • reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 2c (6.1 g, yield in three steps) as a white solid. 25%).
  • reaction solution was quenched by adding citric acid, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 2e as a pale yellow solid (1.0 g, yield twenty four%).
  • the seventh step 4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(((S)-tetrahydrofuran- 3-yl)oxy)pyrido[2,3-d]pyrimidin-7(8H)-one 2
  • the first step 4-chloro-6-((4-methoxybenzyl)amino)pyrimidine-5-carbaldehyde 3b
  • 4,6-Dichloro-5-pyrimidinecarboxaldehyde 3a (15.00g, 84.76mmol) was dissolved in dichloromethane (200mL), cooled to 0°C, and N,N-diisopropylethylamine (10.90g, 84.34 mmol), p-methoxybenzylamine (7.54 g, 54.96 mmol) was added dropwise after the dropwise addition, and the dropwise reaction was completed at 0° C. for 2 hours. TLC showed that the reaction of the raw materials was complete.
  • the reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to obtain a crude yellow solid, which was slurried with methyl tert-butyl ether, filtered, and washed with methyl tert-butyl ether on the filter cake to obtain the title compound 3b (12.1 g, yield 51) as a pale yellow solid. %).
  • reaction solution was quenched by adding citric acid, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 3c (900 mg, yield 32%) as a brown-yellow solid. ).
  • the fourth step 4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(((S)-tetrahydrofuran-3-yl) Oxy)pyrido[2,3-d]pyrimidin-7(8H)-one 3e
  • the fifth step 4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(((S)-tetrahydrofuran-3-yl)oxygen yl)pyrido[2,3-d]pyrimidin-7(8H)-one 3
  • the first step 4-(((R)-1-(3-(difluoromethyl)-2-fluoro-5-nitrophenyl)ethyl)amino)-8-(4-methoxybenzyl )-6-(((S)-tetrahydrofuran-3-yl)oxy)pyrido[2,3-d]pyrimidin-7(8H)-one 5a
  • the third step 4-(((R)-1-(3-(difluoromethyl)-2-fluoro-5-nitrophenyl)ethyl)amino)-8-methyl-6-(((( S)-Tetrahydrofuran-3-yl)oxy)pyrido[2,3-d]pyrimidin-7(8H)-one 5c
  • reaction solution was added with water, extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 6e (2.45 g, five-step yield 59%) as a white solid.
  • reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography to obtain the title compound 6f (1.08 g, yield 86%) as a pale yellow solid ).
  • reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 6h (251 mg, crude product) as a yellow solid, which was used directly with in the next step.
  • the ninth step 3-(4-(((R)-1-(3-acetamido-5-(trifluoromethyl)phenyl)ethyl)amino)-2,8-dimethyl-7-oxygen Substituted-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)piperidine-1-carboxylate tert-butyl ester 6j
  • reaction was quenched by dropwise addition of saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 7 g (858 mg, yield) as a white solid rate 99%).
  • the eleventh step (3-((R)-1-((2,8-dimethyl-7-oxo-6-(((S)-tetrahydrofuran-3-yl)oxy)-7,8 - Dihydropyrido[2,3-d]pyrimidin-4-yl)amino)ethyl)-4-fluoro-5-(trifluoromethyl)phenyl)carbamate 7l
  • reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 8b (185 mg, yield 51%) as a brown solid. .
  • reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 9b (105 mg, yield 29%) as a brown solid. .
  • reaction solution was cooled to room temperature, water was added, a solid was precipitated, filtered, and the filter cake was washed with water, then dissolved in dichloromethane, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 10d (3.04 g, crude product) as a white solid, which was directly used in the next step. step.
  • reaction solution was cooled to room temperature, water was added, a solid was precipitated, stirred at room temperature for 0.5 hours, filtered, and the filter cake was washed and dried to obtain a white solid mixture (product and undemethylated mixture), which was dissolved in hydrochloric acid/1,4-dioxane ( 25mL, 4N), heated to 70 °C and reacted for 2 hours, TLC showed that the reaction of the starting materials was completed.
  • the reaction solution was cooled to room temperature, diluted with methanol, stirred for 0.5 hours, filtered, the filter cake was washed with methanol, and dried to obtain the title compound 10e (2.07 g, crude product) as a pale yellow solid, which was directly used in the next step.
  • reaction solution was cooled to room temperature, water was added, stirred for 0.5 hours, filtered, the filter cake was washed with water, dissolved in ethyl acetate, washed with hydrochloric acid (1N), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 10 g (1.17 g of the title compound) as a yellow solid. , the yield is 97%).
  • reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 10i (120 mg, yield 77%) as a brown oil. ).
  • the reaction solution was filtered through celite, the filter cake was washed with methanol, the filtrate was concentrated, and the crude product was purified by Prep-TLC to obtain a crude yellow solid, which was dissolved with dilute hydrochloric acid (1N), extracted with ethyl acetate, discarded the organic phase, and the aqueous phase was saturated with sodium bicarbonate The aqueous solution was adjusted to basic, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-TLC to give the title compound 14 (31 mg, yield 27%) as a pale yellow solid.
  • reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 11b (200 mg, yield 84%) as a yellow solid. .
  • the seventh step 4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-8-methyl-6-(1-methylpyrrolidine- 3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one 11
  • Example 12 The compound of Example 12 was synthesized with reference to the synthesis method of Example 13.
  • the first step 4-chloro-6-(methylamino)pyrimidine-5-carbaldehyde 13a
  • reaction was quenched by dropwise addition of saturated aqueous citric acid solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 13b (144 mg, yield) as a yellow oil. 7%).
  • reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, the organic phase was washed with 1N hydrochloric acid, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to Prep-TLC to obtain the title compound 13c as a yellow solid (194 mg, yield 92 %).
  • reaction was quenched by dropwise addition of saturated aqueous citric acid solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 14a (176 mg, yield) as a yellow oil. 10%).
  • reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, the organic phase was washed with 1N hydrochloric acid, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 14b (252 mg, yield) as a brown solid. 97%).
  • the seventh step 4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-8-methyl-6-(((R)-1- Methylpyrrolidin-3-yl)oxy)pyrido[2,3-d]pyrimidin-7(8H)-one 14
  • reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 15a (260 mg, yield 89%) as a yellow solid. .
  • the seventh step 4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-8-methyl-6-(1-methylpiperidine- 3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one 15
  • reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 16b (200 mg, crude product) as a brown oil, which was directly used in the next step.
  • the fourth step 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methyl-6-(piperidin-3-yl) Pyrido[2,3-d]pyrimidin-7(8H)-one 16d
  • the fifth step 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methyl-6-(1-methylpiperidine- 3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one 16
  • N-Boc-3-piperidineacetic acid 17a (5.0 g, 20.55 mmol) was dissolved in N,N-dimethylformamide (50 mL), potassium carbonate (8.5 g, 61.65 mmol) and ethyl iodide (4.8 g) were added , 30.82 mmol), and reacted at room temperature for 5 hours.
  • the reaction solution was added with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 17b (5.2 g, yield 93%) as a yellow oil.
  • reaction solution was cooled to 0°C, quenched with saturated aqueous citric acid, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was subjected to silica gel column chromatography to obtain the crude product, which was slurried with petroleum ether. , filtered to give the title compound 17c (840 mg, 34% yield) as a yellow solid.
  • the fifth step 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methyl-6-((S)-1-methyl ylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one 17-1&4-(((R)-1-(3-(difluoromethyl)-2-fluoro Phenyl)ethyl)amino)-8-methyl-6-((R)-1-methylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one 17 -2
  • the configuration and properties of the compounds need to be further tested, and tentatively 18-1 and 18-2 are the above configurations.
  • Example 19 The compound of Example 19 was synthesized with reference to the synthesis method of Example 20.
  • Example 21 was synthesized.
  • the first step (2-(5-((R)-1-((2,8-dimethyl-7-oxo-6-(((S)-tetrahydrofuran-3-yl)oxy)-7 ,8-Dihydropyrido[2,3-d]pyrimidin-4-yl)amino)ethyl)thien-3-yl)benzyl)(methyl)carbamate 22a
  • the first step methyl(2-(5-((R)-1-((2-methyl-7-oxo-6-(((S)-tetrahydrofuran-3-yl)oxy)-7, 8-Dihydropyrido[2,3-d]pyrimidin-4-yl)amino)ethyl)thiophen-3-yl)phenyl)carbamate 23a
  • o-formylboronic acid IN-2j (5.0g, 33.35mmol) was dissolved in methylamine ethanol solution (30mL, 7M), palladium carbon (200mg, 10%) was added, and the reaction was carried out at room temperature for 5 hours under a hydrogen atmosphere. TLC detected that the reaction of the raw materials was complete. . The reaction solution was filtered through a pad of celite, the filter cake was washed, and the filtrate was concentrated to obtain the title compound 24a (5.3 g, crude product) as a pale yellow foamy solid, which was directly used in the next step.
  • reaction solution was added with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, slurried with crude petroleum ether and ethyl acetate (5/1), filtered, and the filter cake was washed and dried to obtain the title compound 24b (7.4 g, collected in two steps) as a white solid. rate 84%).
  • reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography to obtain the title compound 24c (800 mg, yield 48%) as a red oil. .
  • reaction was quenched by dropwise addition of saturated aqueous citric acid solution, adjusted to acidity, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 24d as a brown-yellow solid (7.2 g, 36% yield).
  • Compound treatment prepare a compound with a final concentration of 400 times. For example, if the final concentration of the detection is 5uM, prepare it to a concentration of 400 times, that is, 2mM. The compound was serially diluted to the set number of concentration points using an automatic micropipette.
  • Transfer the compound to the 384-well reaction plate Use the ultrasonic nanoliter liquid processing system to transfer 50nL of the above diluted compounds from the Echo 384-well plate to the 384-well reaction plate, and transfer 100% of the 50nL for both the negative and positive controls. DMSO.
  • Transfer 2x detection solution Prepare 2x Anti-Tag1-Tb3+ and Anti-Tag2-XL665 solutions with the Detection Buffer provided in the kit, transfer 10ul to a 384-well reaction plate, centrifuge at 1000rpm for 1 minute, and incubate at room temperature 60 minutes.
  • Reading Read the data fluorescence signal value (Ex665/Em615) with a microplate reader Envision.
  • Inhibition rate (%) (maximum value-sample value)/(maximum value-minimum value) ⁇ 100%.
  • the human chronic myelogenous leukemia cell K-562 (CCL-243) used in the present invention was purchased from American Type Culture Collection (ATCC). Cells were grown in RPMI 1640 medium with 10% fetal bovine serum (FBS) and 1% dual antibodies at 37°C, 5% CO 2 .
  • FBS fetal bovine serum
  • Inhibition rate (control well OD570nm-OD690nm - administration well OD570nm-OD690nm )/control well OD570nm-OD690nm ⁇ 100%
  • IC50 values were calculated from compound concentrations and corresponding inhibition ratios using Graphpad prism 5.0 software. The test results are shown in Table 2.
  • the compounds in the examples of the present invention can inhibit the proliferation of K-562 cells, and the activities of several compounds are comparable to BI-3402.
  • Protein sample preparation collect the cell suspension, centrifuge at 500g for 5 minutes, discard the supernatant, wash 3 times with PBS, and use 1 ⁇ SDS gel loading buffer (50mM Tris-HCl (pH 6.8), 100mM DTT, 2% SDS, 10% glycerol, 0.1% bromophenol blue) 100 ⁇ L of lysed cells. Cell lysates were denatured by heating at 100°C for 10 minutes.
  • 1 ⁇ SDS gel loading buffer 50mM Tris-HCl (pH 6.8), 100mM DTT, 2% SDS, 10% glycerol, 0.1% bromophenol blue
  • Compound 5 in the examples of the present invention has a significant inhibitory effect on the phosphorylation of ERK1/2 in K-562 cells, and the inhibitory activity is concentration-dependent, and the activity is roughly equivalent to that of BI-3402.
  • liver microsomes (20 mg protein/mL) from the -80°C refrigerator, pre-incubate on a 37°C water bath thermostatic shaker for 3 min, and thaw for use.
  • Control group (without ⁇ -NADPH): respectively take 25 ⁇ L of PB solution into 75 ⁇ L of the incubation system mixture described in (2), vortex for 30 s, mix well, the total reaction volume is 100 ⁇ L, and replicate. Put it into a 37°C water bath constant temperature shaker for incubation, and start timing. The sampling time points are 0min and 60min.
  • Sample group add 25 ⁇ L of ⁇ -NADPH solution (4 mM) to 75 ⁇ L of the reaction system described in (2), vortex for 30 s, mix well, and repeat the sample in a total reaction volume of 100 ⁇ L. Put it into a 37°C water bath constant temperature shaker for incubation, and start timing.
  • the sampling time points are 0min, 5min, 15min, 30min, and 60min.
  • CL int(liver) CL int(mic) ⁇ liver weight to body weight ratio ⁇ liver microsomal protein concentration per gram of liver
  • the stability of compounds 2, 3, 4, and 13 was significantly better than that of BI-3406, and the stability of compound 5 was comparable to that of BI-3406; in the stability test of rat liver microsomes, The stability of compounds 3, 5, 6, and 13 was significantly better than that of BI-3406, and the stability of compound 4 was comparable to that of BI-3406; in the stability test of mouse liver microsomes, compounds 2, 3, 4, 5, 6 ,13,18 The stability was significantly better than that of BI-3406. In conclusion, the stability of liver microsomes in different species of the compounds in the examples is significantly better than that of BI-3406.
  • Mix4in1 mixed solution take a certain amount of PB into a centrifuge tube, add a certain amount of MgCl2-PB (6mM) solution, then add human liver microsome (20mg/mL) solution, substrate working solution (Phe: 1A2 , 18 mM; Bup: 2B6, 12 mM; Amo: 2C8, 200 ⁇ M; Tes: 3A4, 4 mM), vortex and mix, and aliquot at 148 ⁇ L/tube.
  • Mix3in1 mixed solution take a certain amount of PB into a centrifuge tube, add a certain amount of MgCl2-PB (6mM) solution, then add human liver microsome (20mg/mL) solution, substrate working solution (Dic: 2C9 , 1.6mM; DM: 2D6, 800 ⁇ M, Mid: 3A, 400 ⁇ M), vortex to mix, and aliquot at 148 ⁇ L/tube.
  • Liver microsome substrate mixture 2C19 Take a certain amount of PB into a centrifuge tube, add a certain amount of MgCl2-PB (6mM) solution, and then add human liver microsome (20mg/mL) solution, the substrate works solution (Mep: 2C19, 4mM), mixed by vortex, and aliquoted at 148 ⁇ L/tube.
  • IC 50 >10 ⁇ mol/L can be considered as weak inhibition of CYP; 3 ⁇ mol/L ⁇ IC 50 ⁇ 10 ⁇ mol/L can be considered as moderate inhibition of CYP; IC 50 ⁇ 3 ⁇ mol/L can be considered as CYP Strong inhibition. It can be seen that BI-3406 exhibits moderate inhibitory activity in 2C9, 2C19, 2D6, 3A and other CYP450 subtypes.
  • the present invention is to illustrate a pyrimidopyridone derivative of the present invention as an SOS1 inhibitor and its preparation method and application through the above-mentioned examples, but the present invention is not limited to the above-mentioned examples, that is, it does not mean that Therefore, the present invention can only be implemented by relying on the above-mentioned embodiments.
  • Those skilled in the art should understand that any improvement of the present invention, the equivalent replacement of each raw material of the product of the present invention, the addition of auxiliary components, the selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

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Abstract

L'invention concerne un dérivé de pyrimido-pyridone en tant qu'inhibiteur de SOS1, son procédé de préparation et son utilisation. Le dérivé de pyrimido-pyridone a une structure telle que représentée dans la formule (I), et a des effets significatifs pour inhiber une voie de signalisation RAS et traiter et/ou prévenir des cancers. Les cancers comprennent le cancer du pancréas, le cancer colorectal, le cancer du poumon, le carcinome hépatocellulaire, le carcinome rénal, le cancer de l'estomac, le cholangiocarcinome et analogues.
PCT/CN2021/131012 2021-02-09 2021-11-16 Dérivé de pyrimido-pyridone en tant qu'inhibiteur de sos1, son procédé de préparation et son utilisation Ceased WO2022170802A1 (fr)

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115819251A (zh) * 2022-12-20 2023-03-21 沧州普瑞东方科技有限公司 一种(1r)-1-[3-(二氟甲基)-2-氟苯基]乙胺的制备方法
WO2024074827A1 (fr) 2022-10-05 2024-04-11 Sevenless Therapeutics Limited Nouveaux traitements de la douleur
WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations
WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras
WO2025059046A1 (fr) * 2023-09-11 2025-03-20 Kumquat Biosciences Inc. Inhibiteurs de sos1 destinés à être utilisés dans le traitement de cancers du sang à chromosome philadelphie positif
US12258366B2 (en) 2019-11-08 2025-03-25 Revolution Medicines, Inc. Bicyclic heteroaryl compounds and uses thereof
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025171296A1 (fr) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025255438A1 (fr) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Procédés de traitement d'une maladie ou d'un trouble lié à la protéine ras

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018172250A1 (fr) * 2017-03-21 2018-09-27 Bayer Pharma Aktiengesellschaft 2-méthyl-quinazolines
CN110167928A (zh) * 2016-12-22 2019-08-23 勃林格殷格翰国际有限公司 作为sos1抑制剂的新型经苄基氨基取代的喹唑啉和衍生物
WO2019201848A1 (fr) * 2018-04-18 2019-10-24 Bayer Pharma Aktiengesellschaft 2-méthyl-aza-quinazolines
CN111372932A (zh) * 2017-12-21 2020-07-03 勃林格殷格翰国际有限公司 作为sos1抑制剂的新颖苄氨基取代吡啶并嘧啶酮及衍生物
WO2020180770A1 (fr) * 2019-03-01 2020-09-10 Revolution Medicines, Inc. Composés hétérocyclyle bicycliques et leurs utilisations
WO2020180768A1 (fr) * 2019-03-01 2020-09-10 Revolution Medicines, Inc. Composés hétéroaryle bicycliques et leurs utilisations
WO2021092115A1 (fr) * 2019-11-08 2021-05-14 Revolution Medicines, Inc. Composés hétéroaryles bicycliques et leurs utilisations

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021249519A1 (fr) * 2020-06-11 2021-12-16 江苏恒瑞医药股份有限公司 Dérivé de pyridine-pyrimidine, son procédé de préparation et son utilisation pharmaceutique
CN114539245A (zh) * 2020-11-26 2022-05-27 上海翰森生物医药科技有限公司 含嘧啶并环类衍生物调节剂、其制备方法和应用
WO2022135590A1 (fr) * 2020-12-27 2022-06-30 上海凌达生物医药有限公司 Composés pyrimido-hétérocycliques, et leur procédé de préparation et leur utilisation
CN115043842A (zh) * 2021-03-09 2022-09-13 苏州泽璟生物制药股份有限公司 胺基取代双环类抑制剂及其制备方法和应用
WO2022240947A1 (fr) * 2021-05-12 2022-11-17 Revolution Medicines, Inc. Utilisation d'inhibiteurs de sos1 avec des inhibiteurs de mtor pour traiter des cancers
CN115724843A (zh) * 2021-08-31 2023-03-03 勤浩医药（苏州）有限公司 Sos1抑制剂、包含其的药物组合物及其用途

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110167928A (zh) * 2016-12-22 2019-08-23 勃林格殷格翰国际有限公司 作为sos1抑制剂的新型经苄基氨基取代的喹唑啉和衍生物
WO2018172250A1 (fr) * 2017-03-21 2018-09-27 Bayer Pharma Aktiengesellschaft 2-méthyl-quinazolines
CN111372932A (zh) * 2017-12-21 2020-07-03 勃林格殷格翰国际有限公司 作为sos1抑制剂的新颖苄氨基取代吡啶并嘧啶酮及衍生物
WO2019201848A1 (fr) * 2018-04-18 2019-10-24 Bayer Pharma Aktiengesellschaft 2-méthyl-aza-quinazolines
WO2020180770A1 (fr) * 2019-03-01 2020-09-10 Revolution Medicines, Inc. Composés hétérocyclyle bicycliques et leurs utilisations
WO2020180768A1 (fr) * 2019-03-01 2020-09-10 Revolution Medicines, Inc. Composés hétéroaryle bicycliques et leurs utilisations
WO2021092115A1 (fr) * 2019-11-08 2021-05-14 Revolution Medicines, Inc. Composés hétéroaryles bicycliques et leurs utilisations

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12258366B2 (en) 2019-11-08 2025-03-25 Revolution Medicines, Inc. Bicyclic heteroaryl compounds and uses thereof
WO2024074827A1 (fr) 2022-10-05 2024-04-11 Sevenless Therapeutics Limited Nouveaux traitements de la douleur
CN115819251A (zh) * 2022-12-20 2023-03-21 沧州普瑞东方科技有限公司 一种(1r)-1-[3-(二氟甲基)-2-氟苯基]乙胺的制备方法
CN115819251B (zh) * 2022-12-20 2024-04-09 沧州普瑞东方科技有限公司 一种(1r)-1-[3-(二氟甲基)-2-氟苯基]乙胺的制备方法
WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations
WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras
WO2025059046A1 (fr) * 2023-09-11 2025-03-20 Kumquat Biosciences Inc. Inhibiteurs de sos1 destinés à être utilisés dans le traitement de cancers du sang à chromosome philadelphie positif
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025171296A1 (fr) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025255438A1 (fr) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Procédés de traitement d'une maladie ou d'un trouble lié à la protéine ras

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