WO2021139678A1 - Inhibiteur pyridopyrimidine de protéine mutante kras g12c - Google Patents

Inhibiteur pyridopyrimidine de protéine mutante kras g12c Download PDF

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WO2021139678A1
WO2021139678A1 PCT/CN2021/070462 CN2021070462W WO2021139678A1 WO 2021139678 A1 WO2021139678 A1 WO 2021139678A1 CN 2021070462 W CN2021070462 W CN 2021070462W WO 2021139678 A1 WO2021139678 A1 WO 2021139678A1
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cancer
compound
alkyl
group
kras
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PCT/CN2021/070462
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Chinese (zh)
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徐伟
吴曙光
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广州百霆医药科技有限公司
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Publication of WO2021139678A1 publication Critical patent/WO2021139678A1/fr

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    • 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
    • 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
    • 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
    • A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the present invention belongs to the field of medical technology; the present invention relates to new substituted pyridopyrimidine derivatives, specifically to the compound represented by the general formula (I), its isomers or deuterated compounds, and pharmaceutically acceptable salts thereof,
  • the pharmaceutical preparation and the pharmaceutical composition are used in the preparation and treatment of cancer proliferative diseases.
  • RAS protein plays an important role in regulating normal cell growth and proliferation. According to the degree of conservation of RAS amino acid sequence, it can be divided into three types: KRAS, HRAS, and NRAS. RAS is in different "activated” or “inactivated” states by combining with low molecular weight guanine trinucleotide phosphate (GTP) or guanine dinucleotide phosphate (GDP).
  • GTP low molecular weight guanine trinucleotide phosphate
  • GDP guanine dinucleotide phosphate
  • the RAS protein binds to GDP on the plasma membrane of resting cells to form GDP-RAS, which makes RAS in an inactive state; when the cell is stimulated by mitogens and other activating factors, the GDP combined with GDP-RAS and GDP-RAS Free GTP is exchanged, GDP is released, and at the same time, a state where RAS and GTP are combined is formed, that is, activated GTP-RAS. Only activated GTP-RAS can activate the downstream signal pathway of RAS and transmit normal RAS signals. Since the normal RAS protein has GTP hydrolase activity that hydrolyzes GTP into GDP, it can regulate the exchange between activated GTP-RAS and inactivated GDP-RAS, and maintain the balance between RAS activation and inactivation signals.
  • the exchange function between the regulated activated GTP-RAS and the inactivated GDP-RAS is out of control, which keeps the RAS signal in an active state, continuously activates downstream growth signals, stimulates abnormal cell proliferation and induces tumor The occurrence and maintenance of tumor growth (Nature Review cancer 3:11-22, 2003).
  • KRAS Kerat Rev Drug Discov 2014, 13: 828-851
  • HRAS HRAS
  • NRAS NRAS
  • K-RAS Zika virus oncogene
  • G12 glycine at position 12
  • G13 glycine at position 13
  • Q61 glutamine at position 61
  • the G12 mutation has the highest incidence (Nat Rev Drug Discov 2014, 13: 828-851).
  • K-RASRAS G12C mutation refers to the mutation of glycine at position 12 of K-RAS protein to cysteine, which is the most common subtype of K-RAS mutation.
  • the frequency of K-RAS G12C mutation tumors is pancreatic cancer (57%), colorectal cancer (35%), biliary tract cancer (28%), small intestine cancer (17%), lung cancer (16%), endometrial cancer ( 15%) and ovarian cancer (14%) (Seminars in Cancer Biology. 2019 Jun 27.pii: S1044-579X(18)30060-9).
  • Malignant tumors with K-RAS G12C mutations generally do not respond to conventional treatment methods, so patients have a poor clinical prognosis and short survival time.
  • K-RAS G12C mutant protein inhibitor is a new drug target discovered in recent years for anti-RAS targeted therapy (Nature 503:548-551, 2013).
  • K-RAS G12C covalent inhibitor uses the nucleophilic reactivity of the mutated 12th cysteine to design small molecule compounds.
  • K-RAS G12C allosteric pocket It is modified with disulfide bonds to enter the K-RAS G12C allosteric pocket and block K -RAS G12C mutant protein is activated to inhibit tumor growth, but there is still no new K-RAS G12C inhibitor with sufficient high potency and high safety that has been approved by regulatory agencies for marketing. Therefore, in this technical field, there is still an urgent need to discover new selective K-RAS G12C inhibitors for targeted therapy of K-RAS G2C mutant tumors.
  • the present invention provides a compound represented by the general formula (I), its isomer, its pharmaceutically acceptable salt or its deuterated product:
  • X is selected from a 4-8 membered saturated or partially saturated monocyclic ring containing 1 or 2 N atoms, or a 6-12 membered saturated or partially saturated bicyclic ring containing 1 or 2 N atoms, bridged ring, fused ring, spiro
  • the cyclic heterocycloalkyl group may be optionally substituted with 1, 2 or 3 R 6 which are the same or different;
  • R 1 and R 2 are selected from H, halogen, NH 2 , OH, C 1-3 alkyl and C 1-3 heteroalkyl, and the substituents may be optionally substituted by one or more;
  • R 3 is selected from 4-6 membered monocyclic or 6-12 membered bicyclic aryl, heteroaryl, cycloalkyl, heterocycloalkyl, the aryl, heteroaryl, cycloalkyl, heterocycloalkane
  • the group may be substituted by 1, 2 or 3 R 7 which are the same or different;
  • R 4 is selected from H, alkyl, aminoalkyl, alkylaminoalkyl, haloalkyl, hydroxyalkyl, dihydroxyalkyl, -A-NR 8 R 9 , 4-6 membered heterocyclic group, 4-6 Membered heterocyclylalkyl, 5-6 membered aryl, 5-6 membered heteroaryl or heteroarylalkyl, where A, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl or hetero The arylalkyl group may be optionally substituted by one or more R 10 which are the same or different;
  • A is selected from C 1-4 alkylene
  • L is a bond or -NH-
  • R 5 is selected from:
  • R 6 is selected from the group consisting of nitrile group, C 1-3 alkyl group, amino group, halogen, and hydroxyl group;
  • R 7 is selected from halogen, amino, hydroxy, C 1-3 alkyl or halogen substituted C 1-3 alkyl;
  • R 8 is selected from H, or C 1- 3 alkyl
  • R 9 is selected from H, C 1-3 alkyl, heteroalkyl, hydroxyalkyl, acyl;
  • R 10 is selected from H, hydroxyl, halogen,
  • Z is selected from bond, O, S, NR 11 ;
  • R 11 is selected from H or C 1-3 alkylene
  • R 12 is selected from halogen, CF3, and hydroxyalkyl
  • R 13 is selected from H, C 1-3 alkyl, alkylaminoalkyl, alkylaminoalkyl, heterocyclylaminoalkyl, halogen, amido, nitrile, hydroxyalkyl, CF 3 , CF 2 , Methoxy, trifluoromethylamino, alkene;
  • R 14 is selected from H, alkyl, and hydroxyalkyl
  • R 15 is selected from absent, H or C 1-3 alkyl
  • hetero refers to heteroatoms or heteroatoms (atomic groups containing heteroatoms), and heteroatoms refer to atoms other than carbon (C) and hydrogen (H) and atomic groups containing these heteroatoms, such as oxygen ( O), nitrogen (N), sulfur (S), etc.; heteroatom groups refer to C 1-3 heteroalkyl, C 1-6 heteroalkyl, C 1-8 heteroalkyl, 3-8 membered heterocycloalkyl, 5-6 membered heterocyclic aryl, 5-6 membered heterocycloalkenyl, etc;
  • R 5 is selected from:
  • R 3 is selected from:
  • R 4 is selected from:
  • the compound of the present invention isomers, its pharmaceutically acceptable salt or its deuterated compounds are selected from:
  • Certain compounds shown herein may be stereoisomers, including optical isomers and conformational isomers, represented by the general symbol R or S.
  • the present invention also provides the above-mentioned compounds, their pharmaceutically acceptable salts, their isomers, and their deuterated compounds are used in the preparation of cancer drugs.
  • the cancer includes lung cancer, pancreatic cancer, rectal/colon cancer, cholangiocarcinoma, small bowel cancer, endometrial cancer, stomach cancer, ovarian cancer, prostate cancer, cervical cancer, liver cancer, peritoneal cancer, soft tissue cancer, Leukemia, lymphoma, breast cancer, urothelial cancer, testicular cancer, skin cancer, esophageal cancer, thyroid cancer, esophageal cancer, bone cancer and eye cancer.
  • the present invention adopts the electrophoresis gel migration analysis method (gel mobility shift assay) to determine the unique electrophoretic migration change of the covalent binding complex formed by the compound and the cell KRAS G12C mutant protein; the principle is based on the combination of the compound and the K-RAS G12C mutant protein The molecular weight of the formed covalent complex increases. Compared with the free KRAS G12C mutant protein, a corresponding electrophoresis band lag occurs during electrophoresis.
  • Electrophoresis gel migration analysis showed that the compound of the present invention can selectively bind to the KRAS G12C mutant protein in human non-small cell lung cancer NCI-H358 cells containing the KRAS G12C mutation to form a compound-mutant complex, resulting in electrophoretic coagulation.
  • pharmaceutically acceptable salt refers to a salt prepared with a relatively non-toxic acid or base with a compound having a specific substituent discovered in the present invention.
  • an acid addition salt can be obtained by contacting the compound of the present invention in a neutral form with a sufficient amount of acid in a suitable pure solution or an inert solvent.
  • Inorganic acids include hydrochloric acid, sulfuric acid, hydrogen sulfate, carbonic acid, hydrogen carbonate, phosphoric acid, phosphorous acid, monohydrogen phosphate, and dihydrogen phosphate , Hydrobromic acid, hydroiodic acid and nitric acid; organic acids include such as lactic acid, benzenesulfonic acid, acetic acid, propionic acid, malonic acid, isobutyric acid, suberic acid, benzoic acid, phthalic acid, p-toluenesulfonic acid , Citric acid, tartaric acid, maleic acid, amino acids, glucuronic acid.
  • the general formula of the specific compound in the present invention contains acidic or basic groups, and therefore can be converted into acid or base addition salts.
  • stereo or geometric isomers refers to cis and trans isomers, (R)- and (S)-enantiomers, (-)- and (+)-enantiomers, (D)- Isomers, (L)-isomers, diastereomers, and racemic mixtures are all included in the scope of the present invention.
  • cis-trans isomer or "geometric isomer” is due to the fact that double bonds or single bonds of ring-forming carbon atoms cannot rotate freely.
  • enantiomer or “optical isomer” refers to stereoisomers that are mirror images of each other.
  • diastereomer refers to an isomer in which a molecule has more than two chiral centers and has a non-mirror image relationship between the molecules.
  • Dashed key with wedge And a wedge-shaped solid line key ( or ) Refers to the absolute configuration of a steric center in a molecule.
  • tautomers means that the isomers of different functional groups in the molecules of the compound of the present invention are in dynamic equilibrium and can be rapidly transformed into each other.
  • alkyl refers to a linear or branched saturated hydrocarbon group.
  • the alkyl group is a C 1-3 alkyl group; in other embodiments, the alkyl group is a C 1-6 alkyl group.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl (including isopropyl and n-propyl), butyl (including n-butyl, isobutyl), pentyl (including n-pentyl, Isopentyl and neopentyl), hexyl.
  • the alkyl group can be monovalent (such as methyl), divalent (such as methylene), multivalent (such as methine), and can be mono-substituted (such as -CH 2 F) or multi-substituted (-CF 3 ).
  • alkenyl refers to a straight or branched hydrocarbon group containing one or more carbon-carbon double bonds.
  • the alkenyl group is C 2-4 alkenyl; in other embodiments, the alkenyl group is C 2-6 alkenyl; in other embodiments, the alkenyl group is C 2-8 alkenyl.
  • ring refers to substituted or unsubstituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, aryl.
  • the ring includes single ring, double ring and multiple ring. The number of atoms in the ring is defined as the number of ring members.
  • hetero refers to heteroatoms or heteroatom groups (atomic groups containing heteroatoms), that is, atoms other than carbon (C) and hydrogen (H) and atomic groups containing these heteroatoms, such as oxygen (O), nitrogen (N), Sulfur (S) and so on.
  • cycloalkyl refers to a cyclic alkyl group including a monocyclic, bicyclic or tricyclic ring system, wherein the bicyclic or tricyclic ring system includes a spiro ring, a bridged ring, and a fused ring; the alkyl group may be monovalent or divalent , Multivalent, can also be single substitution or multiple substitution.
  • cycloalkenyl refers to a cyclic alkenyl group containing one or more unsaturated carbon-carbon double bonds, wherein the bicyclic or tricyclic ring system includes a spiro ring, a bridged ring, and a fused ring; the alkyl group may be one Valence, divalent, multivalent, and can also be mono- or multi-substitution.
  • cycloalkynyl refers to a cyclic alkyl group containing one or more carbon-carbon triple bonds, including monocyclic, bicyclic, and polycyclic ring systems, wherein the bicyclic or tricyclic ring systems include spiro, fused, and bridged rings.
  • the alkyl group can be monovalent, divalent, multivalent, and can also be mono- or multi-substituted.
  • heterocycloalkyl refers to a cyclized heteroalkyl, including monocyclic, bicyclic, and polycyclic ring systems, where bicyclic or tricyclic ring systems include spiro, fused, and bridged rings.
  • heterocyclenyl refers to a cyclized heteroalkenyl group, including monocyclic, bicyclic, and polycyclic ring systems, wherein the bicyclic or tricyclic ring systems include spiro, fused, and bridged rings.
  • heterocyclic alkynyl refers to a cyclized heterocyclic alkynyl group, including monocyclic, bicyclic, and polycyclic ring systems, wherein the bicyclic or tricyclic ring systems include spiro, fused, and bridged rings.
  • aromatic ring refers to a polyunsaturated carbocyclic ring system, including monocyclic, bicyclic, and polycyclic ring systems, in which at least one ring is aromatic and can be monovalent, divalent, multivalent, or Is single substitution or multiple substitution.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art.
  • the specific embodiments and preferred embodiments listed below include but are not limited to the examples of the present invention.
  • the embodiment of the compound of general formula (I) is prepared according to the general reaction scheme (A), wherein R 1 , R 2 , R 3 , R 4 , R 5 , X, L and Z are as defined above.
  • the reactant A1 and concentrated ammonia are heated and reacted in a pressure tube to obtain compound A2
  • the acid chloride obtained by the reaction of A2 and oxalyl chloride directly reacts with liquid ammonia to obtain compound A3, and A3 and oxalyl chloride are heated to form a ring reaction.
  • the embodiment of the compound of general formula (I) is prepared according to the general reaction scheme (B), wherein R 1 , R 2 , R 3 , R 4 , R 5 , X, L and Z are as defined above.
  • the reactant B1 reacts with oxalyl chloride to obtain compound B2
  • B2 reacts with thiourea to obtain compound B3
  • B3 is heated to reflux to form a ring reaction to obtain B4
  • B4 reacts with phosphorus oxychloride to obtain compound B5, B5 and Structural units X and R5 in the compound are reacted in sequence to obtain compound B6,
  • B6 is reacted with different R3 groups to obtain compound B7, and B7 is reacted with structural units substituted with different R4 groups to obtain compound B8.
  • the crude compound B (100.0 mg, 0.5 mmol, 1.00 eq) was dissolved in 0.6 mL of toluene, and N,N-diisopropylethylamine (196.3 mg, 1.5 mmol, 3.00 eq) was added under the protection of nitrogen. The mixture was stirred at 70°C for 30 minutes, phosphorus oxychloride (232.8 mg, 1.5 mmol, 3.00 eq) was added, and the mixture was stirred at reflux at 100°C for 2.5 hours. After the reaction was completed, the solvent was spin-dried under reduced pressure, water (1mL) was added, and the mixture was extracted with ethyl acetate (1mL ⁇ 3).
  • Dissolve compound B (90.6mg, 0.39mmol, 1.00eq) in 3.86mL of dichloromethane under ice bath, add N,N-diisopropylethylamine (49.94mg, 0.39mmol, 1.00eq), add (S) -4N tert-butoxycarbonyl-2 methylpiperazine (77.39 mg, 0.39 mmol, 1.00 eq), stirred at room temperature for 1 hour. After the completion of the reaction, the solvent was spin-dried under reduced pressure, water (10.0 mL) was added, and the mixture was extracted with ethyl acetate (10.0 mL ⁇ 3).
  • the purpose of this experiment is to verify the compound of the present invention and human non-small cell lung cancer NCI-H358 cells (KRAS G12C mutation), human non-small cell lung cancer A549 cells (KRAS G12S mutation) and non-small cell lung cancer HCC827 cells (KRAS wild type) KRAS Covalent binding activity of G12C mutant protein.
  • Tumor cell lines Three human non-small cell lung cancer cell lines: NCI-H358 cells (KRAS G12C mutation), A549 cells (KRAS G12S mutation) and HCC827 cells (KRAS wild type).
  • RPMI1640 medium RPMI1640 medium
  • DMEM cell culture medium fetal bovine serum
  • trypsin-0.53mM EDTA digestion solution DMSO
  • penicillin-streptomycin KRAS antibody (Sigma)
  • the secondary antibody is Anti-rabbit IgG -HRP
  • Cell Titer-Gio detection kit Promega microplate detector, cell culture flask, cell culture microplate (96 or 384 well), CO 2 constant temperature incubator, FluorChemR detector (ProteinSimple).
  • the present invention adopts the gel mobility shift assay to measure the unique electrophoretic migration changes of the covalent binding complex formed by the compound and the cell KRAS G12C mutant protein; the principle is based on the combination of the compound and the K-RAS G12C mutant protein. Compared with the free KRAS G12C mutant protein, the molecular weight of the covalent complex increases, and the corresponding electrophoretic band lag occurs during electrophoresis.
  • the tumor cells Resuscitate the tumor cells cryopreserved in liquid nitrogen, culture the cells with a cell culture medium containing 10% fetal bovine serum and 10% penicillin-streptomycin.
  • a cell culture medium containing 10% fetal bovine serum and 10% penicillin-streptomycin.
  • digest and centrifuge to collect the cells and resuspend them in the culture medium ; Inoculate the cells according to the number of 5000-10000 cells per well, and place them in a carbon dioxide incubator at a constant temperature of 37°C, 5% CO 2, and saturated humidity.
  • the cells were washed with phosphate buffered saline (PBS), and then in RIPA buffer (50mm Tris, pH7.5, 150mm NaCl, 1% NP-40, 0.5% deoxycholic acid).
  • PBS phosphate buffered saline
  • RIPA buffer 50mm Tris, pH7.5, 150mm NaCl, 1% NP-40, 0.5% deoxycholic acid.
  • the purpose of this experiment is to verify the compounds of the present invention against human non-small cell lung cancer NCI-H358 cells (KRAS G12C mutation), human non-small cell lung cancer A549 cells (KRAS G12S mutation) and non-small cell lung cancer HCC827 cells (KRAS wild type). Proliferation.
  • Tumor cell lines Three human non-small cell lung cancer cell lines: NCI-H358 cells (KRAS G12C mutation), A549 cells (KRAS G12S mutation) and HCC827 cells (KRAS wild type).
  • Main reagents and instruments RPMI1640 medium, DMEM cell culture medium, fetal bovine serum, 0.25% trypsin-0.53mM EDTA digestion solution, DMSO, penicillin-streptomycin, Cell Titer-Gio detection kit.
  • the tumor cells Resuscitate the tumor cells cryopreserved in liquid nitrogen, culture the cells with a cell culture medium containing 10% fetal bovine serum and 10% penicillin-streptomycin.
  • a cell culture medium containing 10% fetal bovine serum and 10% penicillin-streptomycin.
  • digest and centrifuge to collect the cells and resuspend them in the culture medium ; Inoculate cells according to the number of 5000-10000 cells per well, and place them in a constant temperature 37°C, 5% CO 2 , saturated humidity carbon dioxide incubator for overnight culture.
  • Each test compound of the present invention is diluted into 10 concentration gradients, respectively added to the corresponding wells of the cell plate, and then the cell plate is returned to the carbon dioxide incubator to continue culturing for 72 hours. After incubation, add Promega CellTiter-Glo reagent to each well of the cell plate, incubate at room temperature for 10 minutes, use Promega microplate detector to detect the luminescence signal, and calculate the IC50 value.
  • the compound of the present invention shows a higher anti-proliferative activity inhibitory activity against KRAS G12C mutant human non-small cell lung cancer NCL-H358 cells, but has a higher antiproliferative activity against KRAS G12S mutant human non-small cell lung cancer A549 cells and KRAS wild type HCC827 cells.
  • Weak antiproliferative activity (Table 2). The results of the anti-proliferation experiment are consistent with the results obtained by the aforementioned gel mobility analysis method, indicating the high selectivity of the compound of the present invention on KRAS G12C mutant tumor cells.

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Abstract

La présente invention appartient au domaine technique de la médecine, et le contenu spécifique de l'invention concerne un inhibiteur pyridopyrimidine de protéine mutante KRAS G12C représenté par la formule générale (I), un sel pharmaceutiquement acceptable de celui-ci, un stéréoisomère de celui-ci et un composé deutéré de celui-ci. La présente invention concerne en outre un procédé de préparation dudit composé et un procédé de préparation d'un sel pharmaceutiquement acceptable du composé, une préparation pharmaceutique de celui-ci et une composition pharmaceutique. La présente invention concerne en outre une application dudit composé et d'un sel pharmaceutiquement acceptable du composé, d'une préparation pharmaceutique de celui-ci et d'une composition pharmaceutique dans le traitement de maladies prolifératives cancéreuses provoquées par une protéine mutante KRAS G12C.
PCT/CN2021/070462 2020-01-07 2021-01-06 Inhibiteur pyridopyrimidine de protéine mutante kras g12c WO2021139678A1 (fr)

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WO2022060836A1 (fr) 2020-09-15 2022-03-24 Revolution Medicines, Inc. Dérivés d'indole servant d'inhibiteurs dans le traitement du cancer
WO2022171191A1 (fr) * 2021-02-11 2022-08-18 Jingrui Biopharma Co., Ltd. Composés en tant qu'agents anticancéreux
WO2022193982A1 (fr) * 2021-03-15 2022-09-22 药雅科技(上海)有限公司 Préparation et utilisation d'un inhibiteur de la mutéine krasg12c
US11453683B1 (en) 2019-08-29 2022-09-27 Mirati Therapeutics, Inc. KRas G12D inhibitors
WO2022235864A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras
WO2022235870A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras pour le traitement du cancer
WO2022266206A1 (fr) 2021-06-16 2022-12-22 Erasca, Inc. Conjugués d'inhibiteurs de kras
US11548888B2 (en) 2019-01-10 2023-01-10 Mirati Therapeutics, Inc. KRas G12C inhibitors
WO2023060253A1 (fr) 2021-10-08 2023-04-13 Revolution Medicines, Inc. Inhibiteurs de ras
CN116120315A (zh) * 2023-04-19 2023-05-16 山东绿叶制药有限公司 一种kras g12c抑制剂及其应用
WO2023114954A1 (fr) 2021-12-17 2023-06-22 Genzyme Corporation Composés pyrazolopyrazine utilisés comme inhibiteurs de la shp2
US11702418B2 (en) 2019-12-20 2023-07-18 Mirati Therapeutics, Inc. SOS1 inhibitors
EP4227307A1 (fr) 2022-02-11 2023-08-16 Genzyme Corporation Composés pyrazolopyrazine en tant qu'inhibiteurs de shp2
WO2023172940A1 (fr) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Méthodes de traitement du cancer du poumon réfractaire immunitaire
WO2023240263A1 (fr) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Inhibiteurs de ras macrocycliques
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EP4269405A4 (fr) * 2020-12-22 2024-07-24 Shanghai Kechow Pharma Inc Préparation et procédé d'application d'un composé hétérocyclique utilisé en tant qu'inhibiteur de kras
WO2022171191A1 (fr) * 2021-02-11 2022-08-18 Jingrui Biopharma Co., Ltd. Composés en tant qu'agents anticancéreux
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WO2023114954A1 (fr) 2021-12-17 2023-06-22 Genzyme Corporation Composés pyrazolopyrazine utilisés comme inhibiteurs de la shp2
EP4227307A1 (fr) 2022-02-11 2023-08-16 Genzyme Corporation Composés pyrazolopyrazine en tant qu'inhibiteurs de shp2
WO2023172940A1 (fr) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Méthodes de traitement du cancer du poumon réfractaire immunitaire
WO2023240263A1 (fr) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Inhibiteurs de ras macrocycliques
WO2024081674A1 (fr) 2022-10-11 2024-04-18 Aadi Bioscience, Inc. Polythérapies pour le traitement du cancer
WO2024102421A2 (fr) 2022-11-09 2024-05-16 Revolution Medicines, Inc. Composés, complexes, et leurs procédés de préparation et d'utilisation
WO2024131777A1 (fr) * 2022-12-19 2024-06-27 杭州中美华东制药有限公司 Composé chimérique de kras-protac, son procédé de préparation et son utilisation
WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations
WO2024211663A1 (fr) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Composés macrocycliques condensés en tant qu'inhibiteurs de ras
WO2024211712A1 (fr) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Composés macrocycliques condensés en tant qu'inhibiteurs de ras
CN116120315A (zh) * 2023-04-19 2023-05-16 山东绿叶制药有限公司 一种kras g12c抑制剂及其应用
CN116120315B (zh) * 2023-04-19 2023-06-09 山东绿叶制药有限公司 一种kras g12c抑制剂及其应用

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