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WO2020156242A1 - Inhibiteur de shp2 et son utilisation - Google Patents

Inhibiteur de shp2 et son utilisation Download PDF

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Publication number
WO2020156242A1
WO2020156242A1 PCT/CN2020/072773 CN2020072773W WO2020156242A1 WO 2020156242 A1 WO2020156242 A1 WO 2020156242A1 CN 2020072773 W CN2020072773 W CN 2020072773W WO 2020156242 A1 WO2020156242 A1 WO 2020156242A1
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WO
WIPO (PCT)
Prior art keywords
amino
compound
piperidine
thio
methylpyrimidin
Prior art date
Application number
PCT/CN2020/072773
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English (en)
Chinese (zh)
Inventor
吴颢
吴文茂
陈忠研
李玲
朱林强
张展
吴云飞
林远望
冯东杰
赵新涛
余军
束庆玉
程见洪
韩晗
郭晶
兰宏
王家炳
丁列明
Original Assignee
贝达药业股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 贝达药业股份有限公司 filed Critical 贝达药业股份有限公司
Priority to CN202080008741.8A priority Critical patent/CN113316574B/zh
Publication of WO2020156242A1 publication Critical patent/WO2020156242A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the present invention relates to a series of compounds as inhibitors of Src homology region 2 (Src homology region 2-containing protein tyrosine phosphatase 2, SHP2), and preparation methods and pharmaceutical compositions thereof.
  • the present invention also relates to the use of the above-mentioned compound or its pharmaceutical composition in the treatment of SHP2-mediated diseases.
  • Src homology region 2 protein tyrosine phosphatase 2 is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene, and PTPN11 is the first The discovered proto-oncogene encoding tyrosine kinase (Chan R J et al.PTPN11 is the first identified proto-oncogene that encodes a tyrosine phosphatase.Blood, 2007,109:862-867), and the encoded SHP2 protein contains N-terminal SHP2 domain (N-SHP2), C-terminal SHP2 domain (C-SHP2), protein phosphatase catalytic domain (PTP), two C-terminal tyrosine residues (Y542 and Y580) and one rich Proline (Pro) motif.
  • SOS as a guanine nucleotide exchange factor (GEF)
  • GEF guanine nucleotide exchange factor
  • Ras-GTP further connects with downstream signaling systems to activate Ser/Thr kinase Raf1, etc., and then activate ERK under the action of the regulatory kinase MEK. After activation of ERK, it directly acts on target molecules in the cytoplasm or transfers to the nucleus to regulate genes Transcription to make cells proliferate or differentiate. This process may also be affected by SHP2 binding protein and substrate (SHP substrate-1, SHPS-1), Ras-GTPase activating protein (Ras-GAP) and other members of Src.
  • SHP2 binding protein and substrate SHP substrate-1, SHPS-1
  • Ras-GTPase activating protein Ras-GTPase activating protein
  • SHP2 protein not only regulates the Ras/ERK signaling pathway, it is also reported to regulate multiple signaling pathways such as JAK-STAT3, NF- ⁇ B, PI3K/Akt, RHO, and NFAT, thereby regulating cell proliferation, differentiation, migration, and apoptosis Features.
  • SHP2 has been proved to be related to many diseases, Tartaglia et al. (Tartaglia M et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet, 2001, 29:465-468) found that about 50% Patients with Noonan syndrome have missense mutations of PTPN11. In addition, studies have found that PTPN11 mutation is an important cause of JMML and a variety of leukemias (Tartaglia M et al. Nat Genet, 2003, 34: 148-150; Loh ML et al. Blood, 2004, 103: 2325-2331; Tartaglia M et al.
  • SHP2 inhibitors have received more and more attention as potential treatments.
  • Novartis's TNO155 entered phase I clinical trials for the treatment of solid tumors in 2017.
  • JAB-3068 designed and developed by Jacos entered a phase I clinical trial for the treatment of solid tumors in April 2018.
  • the RMC-4630 developed by Revolution conducted its first human clinical trial in August 2018. At present, there is no marketed product for this target at home and abroad. Therefore, the development of small molecule drugs that can target and inhibit the activity of SHP2 and provide patients with safer and more effective SHP2 inhibitors have important research significance.
  • the present invention relates to a compound used as an inhibitor of protein tyrosine phosphatase 2 (SHP2) containing Src homology region 2.
  • SHP2 protein tyrosine phosphatase 2
  • the compound of the present invention has a general structure as shown in Formula I or a pharmaceutically acceptable salt, tautomer, solvate, chelate, non-covalent complex or prodrug thereof,
  • R 1 is selected from hydrogen, hydroxy, C 1-8 alkyl, C 1-8 alkyl-containing substituent group, C 1-8 alkoxy, C 1-8 alkoxy group-containing substituent group, C 2-8 Alkenyl, substituted C 2-8 alkenyl, C 2-8 alkynyl or substituted C 2-8 alkynyl;
  • R 2 is selected from hydrogen, C 1-4 alkyl group or a substituted group containing C 1-4 alkyl;
  • R 3 is selected from hydrogen, amino, -C (O) NH 2, -C ⁇ N, hydroxy, C 1-8 alkyl, C 1-8 alkyl-containing substituent group, C 1-8 alkoxy or an C 1-8 alkoxy of the substituent;
  • R 4 is selected from hydrogen, halo, amino, amido, -C ⁇ N, carboxyl, hydroxyl, hydroxymethyl, C 1-8 alkyl, C 1-8 alkyl-containing substituent group, C 1-8 alkoxy group, a substituted group containing C 1-8 alkoxy, C 2-8 alkenyl group, a substituted group containing C 2-8 alkenyl, C 2-8 alkynyl group or a substituted group containing C 2-8 alkynyl;
  • a 1 is arbitrarily selected from CR 5 or N;
  • a 2 is arbitrarily selected from CR 6 or N;
  • a 3 is arbitrarily selected from CR 7 or N;
  • U is arbitrarily selected from C(R 8 ) 2 , O or NR 9 ;
  • R 5 , R 6 , R 7 , R 8 or R 9 are independently selected from hydrogen, halogen, amino, C 1-8 alkyl, substituted C 1-8 alkyl, C 1-8 alkoxy group, a substituted group containing C 1-8 alkoxy, C 2-8 alkenyl group, a substituted group containing C 2-8 alkenyl, C 2-8 alkynyl group or a substituted group containing C 2-8 alkynyl;
  • Ring A is optionally selected from a C 6-10 aryl group or a C 5-10 heteroaryl group, the C 5-10 heteroaryl group contains one or two N or S heteroatoms;
  • Rx is optionally selected from hydrogen, halogen, amino, substituted amino, sulfonyl, C 1-8 alkyl, substituted C 1-8 alkyl, C 1-8 alkoxy, substituted C 1-8 alkoxy, C 3-8 cycloalkyl or substituted C 3-8 cycloalkyl;
  • n 0, 1, 2, 3, or 4.
  • a 3 in formula I is N.
  • a 3 in formula I is N.
  • SHP2 inhibitory activity can be maintained, but hERG can be significantly improved.
  • R 1 in Formula I is selected from C 1-3 alkyl.
  • R 1 in Formula I is methyl
  • R 2 in Formula I is selected from hydrogen or C 1-3 alkyl.
  • R 2 in Formula I is hydrogen
  • R 3 in Formula I is selected from hydrogen, amino, or C 1-3 alkyl.
  • R 3 in Formula I is hydrogen or amino
  • R 4 of Formula I is selected from hydrogen, halo, amino, C 1-3 alkyl group or an unsubstituted C 1-3 alkyl.
  • R 4 in Formula I is hydrogen, fluorine or chlorine.
  • R 4 in Formula I is hydrogen or chlorine.
  • a 1 in formula I is selected from CR 5 or N, wherein R 5 is selected from halogen or halogen-substituted C 1-3 alkyl.
  • a 1 in formula I is selected from CR 5 or N, wherein R 5 is selected from F, Cl or trifluoromethyl.
  • a 1 in formula I is selected from CR 5 or N, wherein R 5 is selected from Cl or trifluoromethyl.
  • a 2 in formula I is selected from CR 6 or N, wherein R 6 is selected from amino or C 1-3 alkoxy.
  • a 2 in formula I is selected from CR 6 or N, wherein R 6 is selected from amino or methoxy.
  • a 3 in Formula I is selected from CH or N.
  • U in Formula I is selected from CH 2 or O.
  • ring A in formula I is selected from phenyl or C 5-6 heteroaryl, and the C 5-10 heteroaryl contains one or two N or S heteroatoms.
  • ring A in formula I is selected from phenyl
  • the formula I Arbitrarily selected from
  • the formula I Arbitrarily selected from
  • the present invention further provides some preferred technical solutions of the compound represented by formula I.
  • the compound of the present invention has the general structure shown in Formula II or a pharmaceutically acceptable salt, tautomer, solvate, chelate, non-covalent complex or prodrug thereof,
  • R 1 is selected from C 1-8 alkyl
  • R 2 is selected from hydrogen
  • R 3 is selected from H or amino
  • R 4 is selected from hydrogen and halogen
  • a 1 is selected from CR 5 ;
  • a 2 is selected from CR 6 ;
  • U is selected from C(R 8 ) 2 ;
  • R 5, R 6, R 8 are independently selected from hydrogen, halo, C 1-8 alkyl, substituted group containing C 1-8 alkyl;
  • Ring A is optionally selected from C 6-10 aryl groups.
  • the substituent-containing C 1-8 alkyl group may be a halogenated C 1-8 alkyl group, such as trifluoromethyl.
  • ring A in formula II is optionally substituted with hydrogen or C 1-8 alkoxy.
  • ring A in formula II is optionally substituted with hydrogen or methoxy.
  • R 1 in Formula II is methyl
  • R 4 in Formula II is hydrogen
  • U in Formula II is selected from CH 2 .
  • R 5 in Formula II is selected from Cl.
  • R 6 in Formula II is selected from NH 2 .
  • ring A in formula II is selected from phenyl.
  • the present invention further provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
  • the present invention further provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
  • the present invention also provides a pharmaceutical composition characterized by comprising a therapeutically effective amount of at least one compound represented by formula I or formula II and at least one pharmaceutically acceptable excipient.
  • the present invention further provides a pharmaceutical composition, characterized in that the mass percentage of the compound represented by structural formula I and pharmaceutically acceptable excipients is 0.0001:1-10.
  • the invention provides the application of the compound or pharmaceutical composition represented by structural formula I in the preparation of medicines.
  • the application is an application for preparing a medicine for treating, preventing, delaying or preventing cancer, cancer metastasis, cardiovascular disease, immune disease, fibrosis or eye disease.
  • the application is an application for preparing a medicine for treating diseases mediated by SHP2.
  • the disease is cancer.
  • the cancer is selected from Noonan syndrome, leopard spot syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myeloid leukemia, breast cancer, esophageal tumor , Lung cancer, colon cancer, head cancer, gastric cancer, lymphoma, glioblastoma, gastric cancer, pancreatic cancer or a combination thereof.
  • the application is an application for preparing an SHP2 inhibitor.
  • the present invention also provides a method for treating and/or preventing diseases mediated by SHP2, which comprises administering a therapeutically effective amount of at least any one compound or pharmaceutical composition represented by structural formula I to a subject.
  • the SHP2-mediated disease is cancer.
  • the present invention also provides a method for treating cancer, which comprises administering a therapeutically effective amount of at least any one compound or pharmaceutical composition represented by structural formula I to a subject.
  • the cancer is Noonan syndrome, leopard spot syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myeloid leukemia, breast Cancer, esophageal tumor, lung cancer, colon cancer, head cancer, stomach cancer, lymphoma, glioblastoma, gastric cancer, pancreatic cancer, or a combination thereof.
  • the treatment target is a human.
  • alkyl includes straight, branched or cyclic saturated alkyl groups.
  • alkyl includes but is not limited to methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, 3 -(2-Methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl and other similar groups group.
  • C 1-8 alkyl means comprising 7 or 8 carbon atoms, a straight chain, branched chain or cyclic Formally arranged groups.
  • alkenyl and alkynyl include linear, branched or cyclic alkenyl and alkynyl groups.
  • C 2-8 alkenyl and “C 2-8 alkynyl” refer to a linear, branched or cyclic arrangement containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms ⁇ alkenyl or alkynyl.
  • alkoxy refers to the oxyether form of the aforementioned linear, branched or cyclic alkyl group.
  • aryl refers to an unsubstituted or substituted monocyclic or polycyclic aromatic group including carbon atoms. It is preferably a 6 to 10 membered monocyclic or bicyclic aromatic group. Preferably it is phenyl and naphthyl. Most preferred is phenyl.
  • heteroaryl refers to a monovalent heteroatom group formed by removing a hydrogen atom from a carbon atom of a parent heteroaromatic ring system.
  • Heteroaryl groups include: 5- to 7-membered aromatic, monocyclic, including at least one heteroatom selected from N, O or S, for example, 1 to 4 heteroatoms, or preferably 1 to 3 heteroatoms, ring The other atoms on the above are carbon; the polyheteroaryl ring includes at least one heteroatom selected from N, O or S, for example, 1 to 4 heteroatoms, or preferably 1 to 3 heteroatoms, other atoms in the ring Is carbon, and at least one of the heteroatoms is on the aromatic ring.
  • heteroaryl groups are C 3-10 heteroaryl groups, including but not limited to, pyrrolyl, furyl, thienyl, pyridyl, pyranyl, pyrazolyl, pyrimidinyl, pyridazinyl, Pyrazinyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, triazole, indolyl, benzofuranyl, benzothiazolyl, benzimidazolyl, benzopyrazolyl, benzene And similar groups such as triazolyl, carbazolyl, quinolinyl, isoquinolinyl, purinyl and the like.
  • the heteroaryl group and the aryl group will not cross or contain each other. Therefore, according to the above definition, if at least one all-carbon aromatic ring is fused with a heterocyclic group, the result is a heteroaryl group instead of an aryl group.
  • Cycloalkyl refers to a cyclic group that is saturated or unsaturated but not aromatic. Depending on the specific level of saturation, the terms “cycloalkyl”, “cycloalkenyl” or “cycloalkynyl” are used respectively.
  • Representative cycloalkyl groups include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, or cyclohexene and similar groups.
  • the cycloalkyl group may be a C 3-10 cycloalkyl group, such as a C 3-6 cycloalkyl group.
  • Heterocyclic group refers to a saturated or unsaturated but not aromatic cyclic group, and one or more of the carbon atoms (and the connected hydrogen atoms) can be respectively the same or different hetero Atom and the corresponding attached hydrogen atom are replaced.
  • Representative heteroatoms that replace carbon atoms include, but are not limited to, N, P, O, S, and Si. When a specific degree of saturation needs to be described, the terms “heterocycloalkyl” or “heterocycloalkenyl” are used respectively.
  • heterocyclic groups include but are not limited to epoxy compounds, imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine, tetrahydrofuran or tetrahydropyran and similar groups .
  • the heterocycloalkyl group and the cycloalkyl group will not cross or contain each other. Therefore, according to the above definition, if at least one all-carbocyclic ring is fused with a heterocycloalkyl to form a di-, poly- or spiro-ring, it will still be defined as a heterocycloalkyl.
  • heteroaryl group is fused with a heterocyclic group to form a di-, poly- or spiro-ring, it will be defined as a heterocyclic group instead of a heteroaryl group.
  • Halogen refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). Preferred halogen refers to fluorine, chlorine and bromine.
  • Halo refers to a fluoro, chloro, bromo or iodo group.
  • the preferred halo groups refer to fluoro and chloro.
  • substitution means that one or more hydrogen atoms in a group are replaced by the same or different substituents.
  • substituents include, but are not limited to, halogen, amino, oxo, carbonyl, alkyl, alkoxy, aryl, cycloalkyl, heterocyclyl, and heteroaryl.
  • substituents include, but are not limited to halo, amino, methyl, -CH 3, trifluoromethyl, -CH 3.
  • alkyl or aryl or its prefixes appear in the name of a substituent (such as aralkyl, or dialkylamino), it shall be the same as the aforementioned "alkyl” and "aryl”"The definition defines the substituents.
  • the specified number of carbon atoms (such as C 1-6 ) will independently represent the number of carbon atoms in an alkyl moiety or in an alkyl moiety (where the alkyl group is the prefix stem) in a larger substituent.
  • the "compound” of the present invention includes the compound represented by formula I, and all pharmaceutically acceptable forms thereof. These pharmaceutically acceptable forms include salts, solvates, non-covalent complexes, chelates or their prodrugs, or any mixture of all the above forms.
  • the “pharmaceutically acceptable” refers to those that are well known for use in animals, especially those that can be used in humans.
  • composition in the present invention includes a product containing a specific quantity of a specific component, and also includes any product directly or indirectly obtained from a specific quantity of a specific component. Therefore, a pharmaceutical composition including the compound of the present invention as an active ingredient and a method for preparing the compound are the content of the present invention.
  • “Therapeutically effective amount” means that when a compound is administered to a subject to treat and prevent and/or inhibit at least one clinical symptom of a disease, condition, symptom, indication, and/or discomfort, it is sufficient for the disease, condition, A dose that produces a certain effect in the treatment of symptoms, indications or discomfort.
  • the specific "effective therapeutic dose” may vary according to the compound, the route of administration, the age of the patient, the weight of the patient, the type of disease or discomfort to be treated, the symptoms and severity, etc. Whenever possible, an appropriate dose may be obvious to those skilled in the art, or it may be determined by conventional experimental methods.
  • the compounds provided by the present invention may exist in the form of "pharmaceutically acceptable salts".
  • the salt of the compound provided by the present invention refers to a non-toxic pharmaceutically acceptable salt.
  • the form of the pharmaceutically acceptable salt includes a pharmaceutically acceptable acid/anion or base/cation salt.
  • Pharmaceutically acceptable acid/anionic salts generally exist in the form of protonation of basic nitrogen with inorganic or organic acids.
  • Typical organic or inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, lactic acid, succinic acid, maleic acid, fumaric acid, malic acid , Tartaric acid, citric acid, ⁇ -ketoglutaric acid, hippuric acid, benzoic acid, mandelic acid, methanesulfonic acid, isethionic acid, benzenesulfonic acid, oxalic acid, pamoic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid Acid, cyclohexylamine sulfonic acid, salicylic acid, saccharic acid or trifluoroacetic acid.
  • Pharmaceutically acceptable base/cation salts including, but not limited to, aluminum salt, calcium salt, chloroprocaine salt, choline, diethanolamine salt
  • the prodrug of the compound of the present invention is included in the protection scope of the present invention.
  • the prodrug is a functional derivative that is easily converted into a desired compound in vivo. Therefore, the term "administration" involved in the treatment method provided by the present invention includes the administration of the compound disclosed in the present invention, or although it is not clearly disclosed but can be transformed into the compound disclosed in the present invention in vivo after administration to the subject. disease.
  • the conventional methods for selecting and preparing suitable prodrug derivatives have been recorded in books such as "Design of Prodrugs” (Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985).
  • any substituent or variable at a specific position in one molecule is irrelevant to the definition of any substituent or variable at a specific position in other molecules. It is easy to understand that the compounds of the present invention can be selected according to the prior art of the subject to select suitable substituents or substitution forms to provide chemically stable and easy preparation and synthesis using the prior art of the subject or the method described in the present invention.
  • the present invention includes any possible solvate and polymorph.
  • the type of solvent that forms the solvate is not particularly limited, as long as the solvent is pharmacologically acceptable.
  • water, ethanol, propanol, acetone and similar solvents can be used.
  • pharmaceutically acceptable salt refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid.
  • pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), iron, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like. In particular, salts of ammonium, calcium, magnesium, potassium, and sodium are preferred.
  • Non-toxic organic bases that can be derivatized into pharmaceutically acceptable salts include primary, secondary and tertiary amines, as well as cyclic amines and amines containing substituents, such as naturally occurring and synthetic amines containing substituents.
  • non-toxic organic bases capable of forming salts, including ion exchange resins and arginine, betaine, caffeine, choline, N',N'-dibenzylethylene diamine, diethylamine, 2 -Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, haamine, isopropylamine , Lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.
  • the corresponding salt can be prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids.
  • acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, isethionic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, Hydrochloric acid, lactic acid, maleic acid, malic acid, mandelic acid, ⁇ -ketoglutaric acid, hippuric acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonate Acid etc.
  • malic acid citric acid, hydrobromic acid, hydrochloric acid, methanesulfonic acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid. More preferably, phosphoric acid, hydrochloric acid and malic acid. Since the compound represented by formula I will be used as a pharmaceutical, it is preferable to use a substantially pure form, for example, at least 60% purity, more suitably at least 75% purity, particularly suitably at least 98% purity (% is a weight ratio).
  • the pharmaceutical composition provided by the present invention includes the compound represented by formula I (or a pharmaceutically acceptable salt thereof) as an active component, a pharmaceutically acceptable excipient and other optional therapeutic components or adjuvants.
  • the pharmaceutical composition of the present invention includes oral, rectal, topical and Pharmaceutical composition for parenteral (including subcutaneous administration, intramuscular injection, intravenous administration) administration.
  • the pharmaceutical composition of the present invention can be conveniently prepared in a unit dosage form known in the art and prepared by any preparation method known in the pharmaceutical field.
  • the compound of formula I, or prodrug, or metabolite, or pharmaceutically acceptable salt of the present invention can be combined with drugs as the active component, and mixed with a drug carrier to form a drug combination Things.
  • the pharmaceutical carrier can take various forms, depending on the desired mode of administration, for example, oral or injection (including intravenous injection). Therefore, the pharmaceutical composition of the present invention may take the form of a separate unit suitable for oral administration, such as a capsule, cachet or tablet containing a predetermined dose of the active ingredient.
  • the pharmaceutical composition of the present invention may take the form of powder, granule, solution, aqueous suspension, non-aqueous liquid, oil-in-water emulsion, or water-in-oil emulsion.
  • the compound represented by Formula I or a pharmaceutically acceptable salt thereof can also be administered by a controlled release method and/or a delivery device.
  • the pharmaceutical composition of the present invention can be prepared by any pharmaceutical method. Generally, this method includes the step of associating the active ingredient with the carrier constituting one or more necessary ingredients.
  • the pharmaceutical composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely divided solid carrier or a mixture of both.
  • the product can be easily prepared into the desired appearance.
  • the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier and a compound represented by formula I, or a pharmaceutically acceptable salt thereof.
  • the compound represented by formula I, or a pharmaceutically acceptable salt thereof, and one or more other compounds having therapeutic activity in combination are also included in the pharmaceutical composition of the present invention.
  • the drug carrier used in the present invention can be, for example, a solid carrier, a liquid carrier or a gas carrier.
  • solid carriers include lactose, gypsum powder, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, mannitol, sorbitol, microcrystalline cellulose, inorganic salts , Starch, pregelatinized starch, powdered sugar, dextrin, etc.
  • liquid carriers include syrup, peanut oil, olive oil and water.
  • gas carriers include carbon dioxide and nitrogen.
  • water, ethylene glycol, oils, alcohols, flavor enhancers, preservatives, coloring agents, etc. can be used for oral liquid preparations such as suspensions, elixirs and solutions; and carriers, such as starches, sugars, Microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants, etc. can be used in oral solid preparations such as powders, capsules and tablets. In view of ease of administration, tablets and capsules are preferred for oral preparations. Alternatively, standard aqueous or non-aqueous formulation techniques can be used for tablet coating.
  • Tablets containing the compound or pharmaceutical composition of the present invention can be prepared by, optionally, mixing, compression or molding with one or more auxiliary components or adjuvants.
  • the active ingredient is in a free-flowing form such as powder or granules, mixed with lubricants, inert diluents, surface active or dispersing agents, and compressed in a suitable machine to obtain compressed tablets.
  • the powdered compound or pharmaceutical composition is wetted with an inert liquid diluent, and then molded in a suitable machine to form a molded tablet.
  • each tablet contains about 0.01 mg to 5 g of active ingredient, and each cachet or capsule contains about 0.1 mg to 0.5 g of active ingredient.
  • a dosage form intended for oral administration to humans contains about 0.1 mg to about 0.5 g of the active ingredient, compounded with a suitable and convenient metering auxiliary material, which accounts for about 5% to 99.99% of the total pharmaceutical composition .
  • the unit dosage form generally contains about 0.1mg to about 0.5g of effective ingredients, typically 0.1mg, 0.2mg, 0.5mg, 1mg, 2mg, 2.5mg, 5mg, 10mg, 25mg, 50mg, 100mg, 200mg, 300mg, 400mg Or 500mg.
  • the pharmaceutical composition suitable for parenteral administration provided by the present invention can be prepared as an aqueous solution or suspension by adding active components into water.
  • Suitable surfactants such as sodium lauryl sulfate, polysorbate-80 (Tween-80), polyoxyethylene hydrogenated castor oil, and poloxamer may be included.
  • glycerol liquid polyethylene glycol, and their mixtures in oil, dispersion systems can also be prepared.
  • a preservative may also be included in the pharmaceutical composition of the present invention to prevent the growth of harmful microorganisms.
  • the present invention provides pharmaceutical compositions suitable for injection use, including sterile aqueous solutions or dispersion systems.
  • the above-mentioned pharmaceutical composition can be prepared in the form of a sterile powder that can be used for immediate preparation of sterile injection.
  • the final injection form must be sterile, and for easy injection, it must be easy to flow.
  • the pharmaceutical composition must be stable during preparation and storage. Therefore, preservation against contamination by microorganisms such as bacteria and fungi is preferred.
  • the carrier can be a solvent or dispersion medium, for example, water, ethanol, polyol (such as glycerol, propylene glycol, liquid polyethylene glycol), vegetable oil, and suitable mixtures thereof.
  • the pharmaceutical composition provided by the present invention may be in a form suitable for topical administration, for example, aerosol, emulsion, ointment, lotion, dusting, or other similar dosage forms. Further, the pharmaceutical composition provided by the present invention can be in a form suitable for use in a transdermal drug delivery device.
  • These preparations can be prepared using the compound represented by formula I of the present invention, or a pharmaceutically acceptable salt thereof, through conventional processing methods.
  • an emulsion or ointment is prepared by adding a hydrophilic material and water (the total amount of the two is about 5 wt% to 50 wt% of the compound) to prepare a cream or ointment with the desired consistency.
  • the pharmaceutical composition provided by the present invention can be made into a form suitable for rectal administration with a solid as a carrier.
  • Suppositories in which the mixture forms a unit dose are the most preferred dosage form.
  • Suitable excipients include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently prepared. First, the pharmaceutical composition is mixed with softened or melted excipients, then cooled and molded.
  • the above-mentioned pharmaceutical preparations may also include, as appropriate, one or more additional adjuvant components, such as diluents, buffers, flavoring agents, binders, surfactants, and additives. Thickeners, lubricants, preservatives (including antioxidants), etc. Further, other adjuvants may also include penetration enhancers that regulate the isotonic pressure of the drug and blood.
  • additional adjuvant components such as diluents, buffers, flavoring agents, binders, surfactants, and additives. Thickeners, lubricants, preservatives (including antioxidants), etc.
  • other adjuvants may also include penetration enhancers that regulate the isotonic pressure of the drug and blood.
  • the pharmaceutical composition containing the compound represented by Formula I, or a pharmaceutically acceptable salt thereof can also be prepared in the form of a powder or a concentrated solution.
  • ACE-Cl 1-chloroethyl chloroformate
  • BOP Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate
  • DBU 1,8-diazabicycloundec-7-ene
  • DIPEA or DIEA N,N-diisopropylethylamine
  • DMSO dimethyl sulfoxide
  • EGTA ethylene glycol diaminoethyl ether tetraacetic acid
  • HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
  • LDA lithium diisopropylamide
  • MsCl methanesulfonyl chloride
  • NBS N-bromosuccinimide
  • NMP N-methyl-2-pyrrolidone
  • Pd 2 (dba) 3 Tris(dibenzylideneacetone)dipalladium
  • PE petroleum ether
  • PPA polyphosphoric acid
  • TFA trifluoroacetic acid
  • THF Tetrahydrofuran
  • Ti(OEt) 4 Tetraethyl titanate
  • TMEDA Tetramethylethylenediamine
  • xantphos 4,5-bisdiphenylphosphine-9,9-dimethylxanthene.
  • the starting material for the synthesis of M11 is 6-methoxy-1-indanone
  • the intermediate compound M10 in Table 1 is prepared by a method similar to the foregoing intermediate 5-9 -M14.
  • Example 1 Compound (S)-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-((2-amino-3 -Chloropyridin-4-yl)sulfanyl)-3-methylpyrimidin-4(3H)-one
  • Example 2 Compound (S)-5-((2-amino-3-chloropyridin-4-yl)thio)-2-(1-amino-6-methoxy-1,3-dihydrospiro [Indene-2,4'-piperidine]-1'-yl)-3-methylpyrimidin-4(3H)-one
  • Example 3 Compound (S)-5-((2-amino-3-chloropyridin-4-yl)thio)-2-(1-amino-6-chloro-1,3-dihydrospiro[indene -2,4'-Piperidine]-1'-yl)-3-Methylpyrimidin-4(3H)-one
  • Example 15 Compound (S)-6-amino-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-((2 ,3-Dichlorophenyl)thio)-3-methylpyrimidin-4(3H)-one
  • Example 16 Compound (S)-6-amino-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-((2 Preparation of -amino-3-chloropyridin-4-yl)thio)-3-methylpyrimidine-4(3H)-one:
  • the synthesis of compound 18-2 refers to the preparation method of compound 16-3.
  • SHP2 is allosterically activated by the binding of a bis-tyrosyl-phosphorylated peptide to its Src homology 2 (SH2) domain.
  • SH2 Src homology 2
  • the subsequent activation step results in the release of the SHP2 auto-inhibitory interface, which in turn activates the SHP2 protein tyrosine phosphatase (PTP) and can be used for substrate recognition and reaction catalysis.
  • PTP protein tyrosine phosphatase
  • the surrogate DiFMUP was used to monitor the catalytic activity of SHP2 in the rapid fluorescence assay format.
  • the compound of the present invention (10mM stock solution) was diluted to an appropriate multiple with 100% DMSO.
  • the final test concentration of the compound of the present invention was 10 ⁇ M, 3.3333 ⁇ M, 1.1111 ⁇ M, 0.3704 ⁇ M, 0.1235 ⁇ M, 0.0412 ⁇ M, 0.0137 ⁇ M, 0.0046 ⁇ M, 0.0015 ⁇ M , 0.00 ⁇ M;
  • Inhibition rate% [1-(Conversion_ sample -Conversion_ min )/(Conversion_ max -Conversion_ min )] ⁇ 100%
  • Conversion_sample is the conversion rate reading of the sample
  • Conversion_min is the average value of the blank control well, representing the conversion rate reading of the wells without enzyme activity
  • Conversion_max is the average value of the positive control well ratio, representing the conversion rate reading of the wells without compound inhibition.
  • the analysis software GraphPad Prism log (inhibitor) vs. response-Variable slope was used to fit the dose-response curve, and the IC 50 value of the compound to the enzyme activity was calculated.
  • the IC 50 data of some examples are shown in Table 3.
  • the compound of the present invention has an allosteric inhibitory effect on SHP2 phosphatase.
  • An in vitro cell assay was used to evaluate the effects of the compounds of the present invention on the proliferation of lung squamous cell carcinoma KYSE-520 cells and leukemia cells MV-4-11 cells.
  • the detection method used in the experiment is the CELL TITER-GLO (CTG) luminescence method, which can detect the number of living cells by quantitatively measuring ATP. Because ATP participates in a variety of enzymatic reactions in organisms, it is an indicator of living cell metabolism. Its content directly reflects the number and cell state of cells.
  • CCG CELL TITER-GLO
  • Inhibition rate% (1-(administration group value-zero adjustment group value)/(blank group value-zero adjustment group value)*100
  • the compound of the present invention has a good inhibitory effect on the proliferation of KYSE-520 cells and the proliferation of MV-4-11 cells.
  • Example C Inhibition test of hERG potassium ion channel
  • the whole cell patch clamp technique was used to detect the blocking effect of the test compound on the hERG channel.
  • the HEK293 cell line stably expressing the hERG potassium channel was cultured in DMEM medium containing 10% fetal bovine serum and 0.8 mg/mL G418 at a culture temperature of 37°C and a carbon dioxide concentration of 5%.
  • the cell density In order to maintain the electrophysiological activity of cells, the cell density must not exceed 80%.
  • the cells were separated with TrypLE TM Express before the experiment, and 3*103 cells were spread on a cover glass and cultured in a 24-well plate (final volume: 500 ⁇ L). After 18 hours, the experiment was performed.
  • Cisapride positive control
  • the weighed 1.2mg cisap must be prepared into a 10mM stock solution using 243 ⁇ L DMSO.
  • the cisapride stock solution was diluted successively with DMSO at a 10-fold dilution from high to low to a 10 ⁇ M dilution.
  • the whole cell patch clamp voltage stimulation scheme for recording the whole cell hERG potassium current is as follows: when the whole cell seal is formed, the cell membrane voltage is clamped to -80mV. The clamping voltage is depolarized from -80mV to -50mV for 0.5 seconds, then stepped to 30mV for 2.5 seconds, and then quickly restored to -50mV for 4 seconds to stimulate the tail current of the hERG channel. Collect data repeatedly every 10 seconds to observe the effect of the drug on the hERG tail current. A stimulus of -50mV for 0.5 seconds was used as leakage current detection. The experimental data is collected by EPC-10 amplifier (HEKA) and stored in PatchMaster (HEKA) software.
  • HEKA EPC-10 amplifier
  • HEKA PatchMaster
  • the capillary glass tube is drawn into a recording electrode with a microelectrode drawing instrument. Operate the microelectrode manipulator under the inverted microscope to contact the recording electrode on the cell, and apply negative pressure suction to form a G ⁇ seal. After forming the G ⁇ seal, perform fast capacitance compensation, and then continue to give negative pressure to suck and break the cell membrane to form a whole-cell recording mode. Then perform slow capacitance compensation and record the film capacitance and series resistance. No leakage compensation is given.
  • the drug When the hERG current recorded by the whole cell stabilizes, the drug is administered, and each drug concentration acts for 5 minutes (or the current stabilizes). Place the cover glass covered with cells in the recording bath in the inverted microscope.
  • the test compound and the compound-free external fluid flow through the recording bath sequentially by gravity perfusion to act on the cells, and the vacuum pump is used to carry out the liquid during recording. exchange.
  • the current detected by each cell in the compound-free external fluid serves as its own control group. Test multiple cells independently and repeatedly. All electrophysiological experiments were performed at room temperature.

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Abstract

L'invention concerne un composé destiné à être utilisé en tant qu'inhibiteur de la protéine tyrosine phosphatase 2 (SHP2) contenant une région d'homologie Src 2 (tel que représenté dans la formule I), et une composition pharmaceutique de celui-ci ainsi que son procédé de préparation, et son utilisation dans le traitement de maladies induites par SHP2. Le composé selon l'invention agit par la participation à un certain nombre de processus, tels que la régulation de la prolifération cellulaire, l'apoptose, la migration et l'angiogenèse.
PCT/CN2020/072773 2019-01-31 2020-01-17 Inhibiteur de shp2 et son utilisation WO2020156242A1 (fr)

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US11179397B2 (en) 2018-10-03 2021-11-23 Gilead Sciences, Inc. Imidazopyrimidine derivatives
WO2021257736A1 (fr) 2020-06-18 2021-12-23 Revolution Medicines, Inc. Méthodes de retardement, de prévention et de traitement de la résistance acquise aux inhibiteurs de ras
WO2022060836A1 (fr) 2020-09-15 2022-03-24 Revolution Medicines, Inc. Dérivés d'indole servant d'inhibiteurs dans le traitement du cancer
WO2022060583A1 (fr) 2020-09-03 2022-03-24 Revolution Medicines, Inc. Utilisation d'inhibiteurs de sos1 pour traiter des malignités à mutations de shp2
WO2022235866A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras covalents et leurs utilisations
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
WO2022259157A1 (fr) 2021-06-09 2022-12-15 Novartis Ag Combinaison pharmaceutique triple comprenant du dabrafenib, du trametinib et un inhibiteur de shp2
WO2022269525A1 (fr) 2021-06-23 2022-12-29 Novartis Ag Associations pharmaceutiques comprenant un inhibiteur de kras g12c et leurs utilisations pour le traitement de cancers
WO2023031781A1 (fr) 2021-09-01 2023-03-09 Novartis Ag Combinaisons pharmaceutiques comprenant un inhibiteur de tead et leurs utilisations pour le traitement de cancers
WO2023060253A1 (fr) 2021-10-08 2023-04-13 Revolution Medicines, Inc. Inhibiteurs de ras
CN116348466A (zh) * 2020-09-23 2023-06-27 南京明德新药研发有限公司 吡嗪硫联苯基类化合物及其应用
WO2023172940A1 (fr) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Méthodes de traitement du cancer du poumon réfractaire immunitaire
WO2023230205A1 (fr) 2022-05-25 2023-11-30 Ikena Oncology, Inc. Inhibiteurs de mek et leurs utilisations
WO2023240263A1 (fr) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Inhibiteurs de ras macrocycliques
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
WO2024216048A1 (fr) 2023-04-14 2024-10-17 Revolution Medicines, Inc. Formes cristallines d'inhibiteurs de ras, compositions les contenant et leurs procédés d'utilisation
WO2024216016A1 (fr) 2023-04-14 2024-10-17 Revolution Medicines, Inc. Formes cristallines d'un inhibiteur de ras
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

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US11179397B2 (en) 2018-10-03 2021-11-23 Gilead Sciences, Inc. Imidazopyrimidine derivatives
EP4056563A4 (fr) * 2019-11-08 2024-02-21 Nanjing Sanhome Pharmaceutical Co., Ltd. Composé utilisé comme inhibiteur de shp2 et son utilisation
CN112778276A (zh) * 2019-11-08 2021-05-11 南京圣和药业股份有限公司 作为shp2抑制剂的化合物及其应用
WO2021257736A1 (fr) 2020-06-18 2021-12-23 Revolution Medicines, Inc. Méthodes de retardement, de prévention et de traitement de la résistance acquise aux inhibiteurs de ras
WO2022060583A1 (fr) 2020-09-03 2022-03-24 Revolution Medicines, Inc. Utilisation d'inhibiteurs de sos1 pour traiter des malignités à mutations de shp2
WO2022060836A1 (fr) 2020-09-15 2022-03-24 Revolution Medicines, Inc. Dérivés d'indole servant d'inhibiteurs dans le traitement du cancer
CN116348466A (zh) * 2020-09-23 2023-06-27 南京明德新药研发有限公司 吡嗪硫联苯基类化合物及其应用
WO2022235864A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras
WO2022235866A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras covalents et leurs utilisations
WO2022235870A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras pour le traitement du cancer
WO2022259157A1 (fr) 2021-06-09 2022-12-15 Novartis Ag Combinaison pharmaceutique triple comprenant du dabrafenib, du trametinib et un inhibiteur de shp2
WO2022269525A1 (fr) 2021-06-23 2022-12-29 Novartis Ag Associations pharmaceutiques comprenant un inhibiteur de kras g12c et leurs utilisations pour le traitement de cancers
WO2023031781A1 (fr) 2021-09-01 2023-03-09 Novartis Ag Combinaisons pharmaceutiques comprenant un inhibiteur de tead et leurs utilisations pour le traitement de cancers
WO2023060253A1 (fr) 2021-10-08 2023-04-13 Revolution Medicines, Inc. Inhibiteurs de ras
WO2023172940A1 (fr) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Méthodes de traitement du cancer du poumon réfractaire immunitaire
WO2023230205A1 (fr) 2022-05-25 2023-11-30 Ikena Oncology, Inc. Inhibiteurs de mek et leurs utilisations
WO2023240263A1 (fr) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Inhibiteurs de ras macrocycliques
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
WO2024216048A1 (fr) 2023-04-14 2024-10-17 Revolution Medicines, Inc. Formes cristallines d'inhibiteurs de ras, compositions les contenant et leurs procédés d'utilisation
WO2024216016A1 (fr) 2023-04-14 2024-10-17 Revolution Medicines, Inc. Formes cristallines d'un inhibiteur de ras
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

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