WO2021129824A1 - Nouvel inhibiteur du k-ras g12c - Google Patents

Nouvel inhibiteur du k-ras g12c Download PDF

Info

Publication number
WO2021129824A1
WO2021129824A1 PCT/CN2020/139544 CN2020139544W WO2021129824A1 WO 2021129824 A1 WO2021129824 A1 WO 2021129824A1 CN 2020139544 W CN2020139544 W CN 2020139544W WO 2021129824 A1 WO2021129824 A1 WO 2021129824A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
substituted
compound
halogen
cycloalkyl
Prior art date
Application number
PCT/CN2020/139544
Other languages
English (en)
Chinese (zh)
Inventor
谢雨礼
樊后兴
曹刚
钱立晖
Original Assignee
微境生物医药科技(上海)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 微境生物医药科技(上海)有限公司 filed Critical 微境生物医药科技(上海)有限公司
Priority to CN202080090785.XA priority Critical patent/CN114901661B/zh
Publication of WO2021129824A1 publication Critical patent/WO2021129824A1/fr

Links

Classifications

    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention belongs to the field of medicinal chemistry, and more specifically, to a new type of K-Ras G12C inhibitor, its preparation method and the use method of the compound.
  • Ras protein family is an important signal transduction and transmission molecule in cells, which plays an important role in growth and development.
  • the analysis and research of a large number of in vitro tumor cells, animal models and human tumor samples show that the excessive activation of Ras family proteins is an early event in the development of human tumors, and is one of the important causes of the occurrence and development of many cancers. Therefore, targeting and inhibiting the activity of Ras protein are important means for the treatment of related tumors.
  • Ras protein There are two forms of Ras protein. It binds to GDP and is in an inactive resting state; when cells receive signals such as growth factor stimulation, Ras protein binds to GTP and is activated.
  • the activated Ras protein recruits a variety of signal transfer proteins, promotes the phosphorylation of downstream signal molecules such as ERK and S6, thereby activating the Ras signal transduction pathway, regulating cell growth, survival, migration and differentiation.
  • the GTPase activity of Ras protein itself can hydrolyze GTP back to GDP.
  • GAPs GTPase activating proteins
  • K-Ras, H-Ras and N-Ras proteins in the Ras protein family are one of the common gene mutations in many tumors, and are the main factors leading to the excessive activation of Ras protein in tumors. Compared with the wild-type Ras protein, these mutations cause the Ras protein activity to be unregulated, stably bind to GTP, and continue to activate, thereby promoting the growth, migration and differentiation of tumor cells.
  • K-Ras protein mutations are the most common, accounting for 85% of all Ras mutations, while N-Ras (12%) and H-Ras (3%) are relatively rare.
  • K-Ras mutations are extremely common in a variety of cancers: including pancreatic cancer (95%), colorectal cancer (45%) and lung cancer (25%), and relatively rare in breast cancer, ovarian cancer and brain cancer ( ⁇ 2%). K-Ras mutation sites are mainly concentrated in G12, and G12C mutations are the most common. For example, in non-small cell lung cancer (NSCLC), K-Ras G12C accounts for 50% of all K-Ras mutations, followed by G12V and G12D.
  • NSCLC non-small cell lung cancer
  • Genomics studies have shown that the K-Ras mutation in non-small cell lung cancer does not coexist with EGFR, ALK, ROS1, RET, and BRAF mutations, but coexists with mutations such as STK11, KEAP1, and TP53, suggesting that K-Ras mutations may be associated with STK11, KEAP1 Synergistic effects with TP53 mutations are involved in the malignant transformation, proliferation and invasion of cells.
  • the abnormal activation of Ras protein is also involved in non-neoplastic diseases such as diabetes and neurodegenerative diseases. It can be seen that small molecule compounds targeting Ras protein can enable a large number of cancer patients and Ras with specific gene mutations. Non-cancerous patients with excessive activation of the pathway benefit.
  • Ras protein treatment is launched. Therefore, the development of highly active small molecule inhibitors against Ras protein, especially K-Ras G12C protein with high mutation frequency, has important clinical significance.
  • Mirati Company reported in patents WO2017/201161, WO2019/099524 and US2019/270743 K-Ras G12C inhibitors with tetrahydropyridopyrimidine as the core. These compounds have disadvantages such as poor activity or instability. For example, in US2019/270743 The stability of compound A (Example 7) is poor. In addition, some compounds have low activity. For example, the anti-proliferative activity of compound B (Example 494) in WO2019/099524 on NCI-H358 cells is greater than 1 ⁇ M.
  • the present invention aims to provide a compound represented by formula (1), each of its optical isomers, each of its crystal forms, its pharmaceutically acceptable salt, its hydrate or its solvate:
  • Y is a chemical bond or C1-C6 alkylene group
  • R 1 is an aryl group or a heteroaryl group, and the aryl group or heteroaryl group can be substituted by 1-3 of the following groups: halogen, hydroxyl, amino, C1-C3 alkyl, C2-C4 alkenyl, C3 -C6 cycloalkyl, C1-C3 alkoxy, halogen-substituted C1-C3 alkyl or halogen-substituted C1-C3 alkoxy, when substituted by multiple substituents, the substituents may be the same or different;
  • R 2 is an aminoalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, and the heterocycloalkyl, aryl or heteroaryl group can be substituted by 1 to 3 of the following groups : H, halogen, CN, OH, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, -(C1-C3 alkyl)-cyano, -(C1-C3 alkyl)- (C1-C3 alkoxy),
  • R 3 and R 4 are independently H, D, halogen or C1-C3 alkyl
  • the saturated heterocycloalkyl, partially saturated heterocycloalkyl or heteroaryl group can be 1-3 of the following groups are substituted: H, D, halogen, CN, NMe 2 , NEt 2 , SMe, C1-C3 alkyl, C3-C6 cycloalkyl, -C(O)O-(C1-C3 alkyl), -C(O)NH-(C1-C3 alkane Group), -C(O)NMe 2 , -C(O)NEt 2 , -(C1-C3 alkyl)-NMe 2 , -(C1-C3 alkyl)-NEt 2 , halogen substituted C1-C3 alkyl Or cyano substituted C1-C3 alkyl, when it is substituted by multiple substituents,
  • R 5 is C3-C6 cycloalkyl, -(C1-C3 alkyl)-cyano, -(C1-C3 alkyl)-hydroxy, -(C1-C3 alkyl)-(C3-C6 cycloalkyl) , -(C1-C3 alkyl)-(C1-C3 alkoxy), -(C1-C3 alkyl)-(halogen substituted C1-C3 alkoxy), heterocycloalkyl, partially saturated heterocycloalkane Group, heteroaryl, -(C1-C3 alkyl)-heterocycloalkyl, -(C1-C3 alkyl)-heteroaryl or -(C1-C3 alkyl)-NR 6 R 7 , the hetero Cycloalkyl, partially saturated heterocycloalkyl, heteroaryl, -(C1-C3 alkyl)-heterocycloalkyl or -(C1-
  • substituents When substituted by multiple substituents, the substituents may be the same or Different, wherein R 6 and R 7 are independently H, C1-C3 alkyl, C3-C6 cycloalkyl, or halogen substituted C1-C3 alkyl.
  • Y is a chemical bond, -CH 2 -, -CH(Me)- or -CH 2 CH 2 -.
  • R 1 is: Wherein R a and R b are independently H, halogen, hydroxy, amino, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C1-C3 alkoxy, halogen substituted C1-C3 alkyl Or halogen substituted C1-C3 alkoxy.
  • R 2 is: Where n is 1, 2 or 3, R c and R d are independently H, halogen, CN, OH, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, halogen substituted C1-C3 Alkyl or halogen substituted C1-C3 alkoxy, R e is C1-C3 alkyl, C3-C6 cycloalkyl, deuterated C1-C3 alkyl, -(C1-C3 alkyl)-cyano, -( C1-C3 alkyl)-(C1-C3 alkoxy), -(C1-C3 alkyl)-(C3-C6 cycloalkyl), deuterated C1-C3 alkyl, halogen substituted C1-C3 alkyl or The halogen-substituted C1-C3 alkoxy group, when substituted
  • Q is wherein, R 3 and R 4 are independently H or D; for
  • the representative compound of the present invention has one of the following structures:
  • Another object of the present invention is to provide a pharmaceutical composition, which contains a pharmacologically acceptable excipient or carrier, and the compound of the general formula (1) of the present invention, its optical isomers, its crystal forms, Its pharmaceutically acceptable salt, its hydrate or its solvate is used as the active ingredient.
  • Another object of the present invention is to provide the above-mentioned compound of the present invention, each of its optical isomers, each of its crystal forms, its pharmaceutically acceptable salt, its hydrate or its solvate in the preparation of drugs for the treatment of RAS-related diseases In the application.
  • Another object of the present invention is to provide a method for treating diseases mediated by K-Ras G12C mutation, which comprises administering to a subject the above-mentioned compound of the present invention, each of its optical isomers, each of its crystal forms, and its A pharmaceutically acceptable salt, its hydrate or its solvate.
  • the disease mediated by the K-Ras G12C mutation is preferably cancer, such as blood cancer and solid tumor.
  • the heteroaryl group is connected with acrylamide by a carbon-carbon single bond
  • the activity of the compound is very poor, as listed above, the anti-proliferative activity of compound B on NCI-H358 cells is greater than 1 ⁇ M; in addition, When it is a heterocycloalkyl group or lacks an electron withdrawing group such as CO beside the N atom, the compound has poor stability.
  • the inventors found that when the 2 (R 5 group) position of acrylamide is substituted with a bulky heteroaryl or substituted heteroaryl, the compound also has good K-RAS G12C inhibitory activity and compound stability
  • the 2-position of acrylamide in patent US2019/270743 is replaced with a smaller group, the stability of the compound is poor, such as compound A listed above.
  • the compound of general formula (1) described above can be synthesized using standard synthesis techniques or well-known techniques and methods combined in the text. In addition, the solvent, temperature and other reaction conditions mentioned here can be changed.
  • the starting materials for the synthesis of the compound can be synthesized or obtained from commercial sources such as, but not limited to, Aldrich Chemical Co. (Milwaukee, Wis.) or Sigma Chemical Co. (St. Louis, Mo.).
  • the compounds described herein and other related compounds with different substituents can be synthesized using well-known techniques and raw materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4 th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 th Ed., Vols.
  • the compounds described herein are according to methods well known in the art.
  • the conditions of the method such as reactants, solvents, bases, amounts of compounds used, reaction temperature, time required for the reaction, etc. are not limited to the following explanations.
  • the compounds of the present invention can also be conveniently prepared by combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention belongs.
  • the present invention also provides a method for preparing the compound represented by the general formula (1), which is prepared by the following general reaction scheme 1, scheme 2 or scheme 3:
  • the embodiment of the compound of general formula (1) can be prepared according to general reaction scheme 1 (method A), wherein R 1 , R 2 , Y and Q are as defined above, PG and PG 1 represent different protecting groups for amine groups, and X represents Br, I, triflate, boric acid, borate or potassium fluoroborate.
  • the raw material A1 (synthesized with reference to patent WO2017/201161) is oxidized to obtain compound A2, compound A2 and R 2 -Y-OH are reacted under alkaline conditions to obtain compound A3, and compound A3 is deprotected.
  • PG e.g.
  • Boc yields compound A4, compound A4 and R 1 -X are coupled to yield compound A5, compound A5 removes the protective group PG 1 (such as Cbz) to yield compound A6, compound A6 and Q-COOH undergo condensation reaction to form the target compound A7.
  • PG 1 such as Cbz
  • the embodiment of the compound of general formula (1) can be prepared according to general reaction scheme 2 (method B), wherein R 1 , R 2 , Y and R 5 are as defined above, W represents Br or I, and K represents boric acid, boric acid ester Or potassium fluoroborate, in which R 5 is directly connected to K is a carbon atom.
  • the general reaction scheme, the intermediate compound A6 and B1 is a condensation reaction to give compound B2 2, R 5 -K compound B2 and a Suzuki coupling reaction to give the final product B3.
  • the embodiment of the compound of general formula (1) can be prepared according to general reaction scheme 3 (method C), wherein R 1 , R 2 , Y and R 5 are as defined above, W represents Br or I, and R 5 is directly connected to H Is the nitrogen atom. As shown in general reaction scheme 2, intermediate B2 and compound R 5 -H undergo Ullman coupling reaction to obtain the final product C1.
  • “Pharmaceutically acceptable” here refers to a substance, such as a carrier or a diluent, that does not make the biological activity or properties of the compound disappear, and is relatively non-toxic. For example, when a substance is administered to an individual, it will not cause unwanted biological effects or Interacts with any components it contains in a harmful way.
  • pharmaceutically acceptable salt refers to a form of a compound that does not cause important irritation to the administered organism and does not cause the biological activity and properties of the compound to disappear.
  • pharmaceutically acceptable salts are obtained by reacting compounds of formula (1) with acids, such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, phosphoric acid and other inorganic acids, formic acid, acetic acid, Propionic acid, oxalic acid, trifluoroacetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.
  • Organic acids and acidic amino acids such as aspartic acid and glutamic acid.
  • references to pharmaceutically acceptable salts include solvent-added forms or crystalline forms, especially solvates or polymorphs.
  • Solvates contain stoichiometric or non-stoichiometric solvents, and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc.
  • a hydrate is formed when the solvent is water, or an alcoholate is formed when the solvent is ethanol.
  • the solvate of the compound of general formula (1) is conveniently prepared or formed according to the method described herein.
  • the hydrate of the compound of general formula (1) is conveniently prepared by recrystallization from a mixed solvent of water/organic solvent.
  • the organic solvent used includes, but is not limited to, tetrahydrofuran, acetone, ethanol or methanol.
  • the compounds mentioned here can exist in unsolvated and solvated forms. In summary, for the purposes of the compounds and methods provided herein, the solvated form is considered equivalent to the unsolvated form.
  • the compound of general formula (1) is prepared in different forms, including, but not limited to, amorphous, pulverized, and nano-particle size forms.
  • the compound of general formula (1) includes a crystalline form and may also be a polymorphic form.
  • Polymorphs include different lattice arrangements of the same elemental composition of the compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal forms, optical and electrical properties, stability, and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystal form to dominate.
  • the compound of general formula (1) has one or more stereocenters, and is therefore classified as racemates, racemic mixtures, single enantiomers, diastereomeric compounds, and single diastereomers.
  • the asymmetric centers that can exist depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible mixtures of optical isomers and diastereomers and pure or partially pure compounds are included within the scope of the present invention.
  • the present invention is meant to include all such isomeric forms of these compounds.
  • Alkyl refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 6 carbon atoms. It is preferably a lower alkyl group containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl.
  • alkyl includes unsubstituted and substituted alkyl groups, especially alkyl groups substituted with one or more halogens.
  • Preferred alkyl groups are selected from CH 3 , CH 3 CH 2 , CF 3 , CHF 2 , CF 3 CH, i Pr, n Pr, i Bu, n Bu or t Bu.
  • Alkylene refers to a divalent alkyl group as defined above; for example, methylene, ethylene and the like.
  • Cycloalkyl refers to a 3- to 6-membered all-carbon monocyclic aliphatic hydrocarbon group in which one or more rings may contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system.
  • cyclopropyl, cyclobutyl, cyclopentyl, cyclohexane, cyclohexadiene and the like are examples of the rings.
  • Alkoxy refers to an alkyl group bonded to the rest of the molecule through an ether oxygen atom.
  • Representative alkoxy groups are those with 1-6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy And tert-butoxy.
  • alkoxy includes unsubstituted and substituted alkoxy, especially alkoxy substituted with one or more halogens.
  • Preferred alkoxy groups are selected from OCH 3 , OCF 3 , CHF 2 O, CF 3 CH 2 O, i- PrO, n- PrO, i- BuO, n- BuO or t- BuO.
  • Aryl refers to a group having at least one aromatic ring structure, that is, a carbocyclic aryl group having a conjugated ⁇ -electron system, such as a benzene ring and a naphthalene ring.
  • Heteroaryl refers to an aromatic group containing one or more heteroatoms (O, S, or N).
  • the heteroaryl group is monocyclic or polycyclic, such as a monocyclic heteroaryl ring and one or more carbocyclic rings. Aromatic groups or other monocyclic heterocyclic groups are condensed.
  • heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, furanyl , Thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxanyl Azolyl, benzopyridinyl and pyrrolopyrimidinyl.
  • Heterocycloalkyl refers to a saturated or partially unsaturated ring system group containing one or more heteroatoms (O, S, or N), wherein nitrogen and sulfur atoms are optionally oxidized, and nitrogen atoms are optionally quaternized. Ammonization as a ring atom. Unless otherwise specified, the "heterocycloalkyl” ring system may be a monocyclic, bicyclic, spirocyclic or polycyclic ring system. "Heterocycloalkyl” can be attached to the rest of the molecule through more than one ring carbon or heteroatom.
  • heterocycloalkyl examples include, but are not limited to, pyrrolidine, piperidine, N-methylpiperidine, tetrahydroimidazole, pyrazolidine, butyrolactam, valerolactam, imidazolinone, hydantoin, Dioxolane, phthalimide, piperidine, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorph Phinoline-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, 2-Azaspiro[3.3]heptane and so on.
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • halogen substitution appearing in front of a group name means that the group is partially or fully halogenated, that is, substituted by F, Cl, Br or I in any combination, preferably Replaced by F or Cl.
  • bond refers to a chemical bond between two atoms or between two fragments (when the atoms connected by a bond are considered part of a larger structure).
  • bond refers to a chemical bond between two atoms or between two fragments (when the atoms connected by a bond are considered part of a larger structure).
  • bond when the group described herein is a bond, the lack of a reference group allows a bond to be formed between the remaining defined groups.
  • membered ring includes any cyclic structure.
  • element means to indicate the number of skeletal atoms constituting the ring.
  • cyclohexyl, pyridyl, pyranyl, and thiopyranyl are six-membered rings
  • cyclopentyl, pyrrolyl, furyl, and thienyl are five-membered rings.
  • fragment refers to a specific part or functional group of a molecule. Chemical fragments are generally considered to be chemical entities contained or attached to molecules.
  • acceptable refers to a prescription component or active ingredient that does not have undue harmful effects on the health of the general treatment target.
  • treatment includes alleviating, inhibiting or improving the symptoms or conditions of diseases; inhibiting the occurrence of complications; improving or preventing underlying metabolic syndrome; inhibiting the occurrence of diseases or symptoms, Such as controlling the development of diseases or conditions; reducing diseases or symptoms; reducing diseases or symptoms; reducing complications caused by diseases or symptoms, or preventing or treating signs caused by diseases or symptoms.
  • a certain compound or pharmaceutical composition after administration, can improve a certain disease, symptom or condition, especially its severity, delay the onset, slow the progression of the disease, or reduce the duration of the disease. Regardless of fixed administration or temporary administration, continuous administration or intermittent administration, it can be attributed to or related to the situation of administration.
  • Active ingredient refers to the compound represented by the general formula (1) and the pharmaceutically acceptable inorganic or organic salt of the compound of the general formula (1).
  • the compounds of the present invention may contain one or more asymmetric centers, and therefore appear as racemates, racemic mixtures, single enantiomers, diastereomeric compounds, and single diastereomers.
  • the asymmetric centers that can exist depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible mixtures of optical isomers and diastereomers and pure or partially pure compounds are included within the scope of the present invention.
  • the present invention is meant to include all such isomeric forms of these compounds.
  • composition refers to when administered to an individual (human or medicament).
  • agent a compound or composition that can induce a desired pharmaceutical and/or physiological response through local and/or systemic effects.
  • administered refers to the direct administration of the compound or composition, or the administration of a prodrug, derivative, or analog of the active compound Wait.
  • the present invention provides methods of using the compounds or pharmaceutical compositions of the present invention to treat diseases, including but not limited to conditions involving G12C K-Ras, G12C H-Ras, and/or G12C N-Ras mutations (such as cancer).
  • a method for cancer treatment comprises administering to an individual in need an effective amount of a pharmaceutical composition of any of the aforementioned protective structure (1) compounds.
  • the cancer is mediated by K-Ras, H-Ras, and/or G12C N-Ras mutations.
  • the cancer is lung cancer, pancreatic cancer, colon cancer, MYH-related polyposis, or colorectal cancer.
  • the compound of the present invention and its pharmaceutically acceptable salt can be prepared into various preparations, which contain a safe and effective amount of the compound of the present invention or its pharmaceutically acceptable salt and a pharmacologically acceptable excipient or carrier. .
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the safe and effective amount of the compound is determined according to the age, condition, and course of treatment of the subject to be treated.
  • “Pharmaceutically acceptable excipients or carriers” refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and sufficiently low toxicity . "Compatibility” here means that each component of the composition can be blended with the compound of the present invention and between them without significantly reducing the efficacy of the compound.
  • Examples of pharmacologically acceptable excipients or carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose,
  • the compound of the present invention when administered, it can be administered orally, rectally, parenterally (intravenous, intramuscular, or subcutaneous), or locally.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glycty
  • Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the active compound or the release of the compound in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microcapsules with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the dosage form of the compound of the present invention for topical administration includes ointment, powder, patch, propellant and inhalant.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment.
  • the administered dose is usually 1 to 2000 mg, preferably 50 to 100 mg.
  • the specific dosage should also consider factors such as the route of administration and the patient's health status, which are all within the skill range of a skilled physician.
  • Compound 1 was prepared according to Method A as described below:
  • Compound 128 was prepared according to Method C as described below:
  • Example 149 Compound detection of pERK and ERK protein content in H358 cells
  • H358 cells are planted in a 24-well plate. After one day of growth, add the test compound (concentration of 1 ⁇ M). After the compound acts for 24 hours, after lysing the cells, transfer the cell lysate to a 96-well ELISA plate and use an ELISA kit (abcam 176660) Determine the levels of pERK and ERK in the lysate, calculate the ratio of pERK and ERK, and compare with the DMSO group, calculate the percentage of compounds that inhibit the activity of pERK. The results are shown in Table 6 below.
  • Compound Inhibition rate(%) Compound Inhibition rate(%) Compound Inhibition rate(%) 1 +++ 2 +++ 3 ++ 4 +++ 5 +++ 6 +++ 7 + 8 +++ 9 +++ 10 +++ 11 +++ 12 +++ 13 +++ 14 ++ 15 +++ 16 +++ 17 +++ 18 +++ 19 +++ 20 +++ twenty one +++ twenty two +++ twenty three +++ twenty four +++ 25 +++ 26 +++ 27 +++ 28 +++ 29 +++ 30 +++ 31 +++ 32 +++ 33 +++ 34 +++ 35 +++ 36 +++ 37 +++ 38 +++ 39 ++
  • +++ means that the inhibition rate is greater than 90%.
  • Compound IC 50 Compound IC 50 Compound IC 50 1 +++ 2 +++ 3 ++ 4 +++ 5 +++ 6 +++ 7 + 8 +++ 9 +++ 10 +++ 11 +++ 12 +++ 13 +++ 14 +++ 15 +++ 16 +++ 17 +++ 18 +++ 19 +++ 20 +++ twenty one +++ twenty two +++ twenty three +++ twenty four +++ 25 +++ 26 +++ 27 +++ 28 +++ 29 +++ 30 +++ 31 +++ 32 +++ 33 +++ 34 +++ 35 +++ 36 +++ 37 +++ 38 +++ 39 ++ 40 ++ 41 + 42 +
  • +++ means that the IC 50 of the compound is less than 0.3 ⁇ M.
  • the carbon-nitrogen single bond has a stronger dipole moment than the carbon-carbon single bond, and the nitrogen atom loses part of the electrons, which is beneficial to the stability of the intermediate state after the addition of acrylamide by the cysteine of the K-RAS protein.
  • the compound of the invention has strong activity.
  • the compound of the present invention has a bulky heteroaryl group or substituted heteroaryl group at the 2-position of acrylamide, such as imidazolyl or pyrimidinyl
  • the compound also has good K-RAS G12C inhibitory activity, which is presumed to be The N atom on the heteroaryl group facilitates the binding to the K-RAS protein.
  • Mia PaCa-2 cells were routinely cultured in a 1640 containing 10% fetal bovine serum in a 37°C, 5% CO 2 incubator. After passage, when the cells reached the required amount, the cells were collected. 1 ⁇ 10 7 Mia PaCa-2 cells were injected into the left back of each nude mouse. After the tumor grew to 150 mm 3 , the animals were randomly divided into groups to start the administration. Respectively 1) solvent control group, 8 animals; 2) compound 1, compound 5, compound 70, compound 92, and compound 121 groups, each with 8 animals.
  • the solvent control group was given 0.5% CMC-Na by intragastric administration once a day; compound 1, compound 5, compound 70, compound 92, and compound 121 groups were given 0.5% CMC-Na suspension once a day.
  • the tumor volume was measured every Tuesday and Thursday, and the body weight of the mice was measured. Nude mice were sacrificed on the 21st day of administration. The test results are shown in Table 9 below.
  • the compound of the present invention Compared with the control drug A, the compound of the present invention has stronger in vitro activity and compound stability. At the same time, the in vivo anti-tumor test also shows that the compound of the present invention has better in vivo activity, indicating that the compound of the present invention has better clinical application. Efficacy and medicinal properties.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé tel que représenté dans la formule (I) et son procédé de préparation, et l'utilisation du composé de formule (1), des isomères optiques, des formes cristallines, des sels pharmaceutiquement acceptables, des hydrates ou des solvates de celui-ci en tant qu'inhibiteurs irréversibles d'une protéine K-Ras à mutation G12C dans la préparation de médicaments contre des maladies associées à Ras, tels que des médicaments antitumoraux.
PCT/CN2020/139544 2019-12-27 2020-12-25 Nouvel inhibiteur du k-ras g12c WO2021129824A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202080090785.XA CN114901661B (zh) 2019-12-27 2020-12-25 新型K-Ras G12C抑制剂

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201911386644.8 2019-12-27
CN201911386644.8A CN113045565A (zh) 2019-12-27 2019-12-27 新型K-Ras G12C抑制剂

Publications (1)

Publication Number Publication Date
WO2021129824A1 true WO2021129824A1 (fr) 2021-07-01

Family

ID=76507334

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/139544 WO2021129824A1 (fr) 2019-12-27 2020-12-25 Nouvel inhibiteur du k-ras g12c

Country Status (2)

Country Link
CN (2) CN113045565A (fr)
WO (1) WO2021129824A1 (fr)

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
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
WO2023008462A1 (fr) 2021-07-27 2023-02-02 東レ株式会社 Médicament pour le traitement et/ou la prévention du cancer
WO2023060253A1 (fr) 2021-10-08 2023-04-13 Revolution Medicines, Inc. Inhibiteurs de ras
WO2023081840A1 (fr) * 2021-11-05 2023-05-11 Frontier Medicines Corporation Inhibiteurs de kras g12c
WO2023114954A1 (fr) 2021-12-17 2023-06-22 Genzyme Corporation Composés pyrazolopyrazine utilisés comme inhibiteurs de la shp2
US11697657B2 (en) 2019-10-28 2023-07-11 Merck Sharp & Dohme Llc Small molecule inhibitors of KRAS G12C mutant
US11702418B2 (en) 2019-12-20 2023-07-18 Mirati Therapeutics, Inc. SOS1 inhibitors
WO2023150394A1 (fr) * 2022-02-07 2023-08-10 Frontier Medicines Corporation Méthodes pour traiter le cancer
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
WO2023240189A1 (fr) * 2022-06-10 2023-12-14 Bristol-Myers Squibb Company Dérivés de tétrahydropyrido 3,4-d pyrimidine utilisés en tant qu'inhibiteurs de kras
US11890285B2 (en) 2019-09-24 2024-02-06 Mirati Therapeutics, Inc. Combination therapies
US11932633B2 (en) 2018-05-07 2024-03-19 Mirati Therapeutics, Inc. KRas G12C inhibitors
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
US12065430B2 (en) 2018-10-26 2024-08-20 Taiho Pharmaceutical Co., Ltd. Indazole compound or salt thereof
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

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117813306A (zh) * 2021-05-22 2024-04-02 上海科州药物研发有限公司 作为kras抑制剂的杂环化合物，及其制备和治疗用途

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019099524A1 (fr) * 2017-11-15 2019-05-23 Mirati Therapeutics, Inc. Inhibiteurs de kras g12c
CN109843856A (zh) * 2016-05-18 2019-06-04 米拉蒂治疗股份有限公司 Kras g12c抑制剂
US20190270743A1 (en) * 2017-11-15 2019-09-05 Mirati Therapeutics, Inc. Kras g12c inhibitors
CN110256421A (zh) * 2019-06-26 2019-09-20 微境生物医药科技(上海)有限公司 Kras-g12c抑制剂
WO2019195609A2 (fr) * 2018-04-04 2019-10-10 Arvinas Operations, Inc. Modulateurs de protéolyse et procédés d'utilisation associés

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3401314B1 (fr) * 2013-03-15 2023-11-08 Araxes Pharma LLC Inhibiteurs covalents de kras g12c
WO2018064510A1 (fr) * 2016-09-29 2018-04-05 Araxes Pharma Llc Inhibiteurs de protéines mutantes kras g12c
SG11202005881YA (en) * 2017-12-21 2020-07-29 Boehringer Ingelheim Int Novel benzylamino substituted pyridopyrimidinones and derivatives as sos1 inhibitors

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109843856A (zh) * 2016-05-18 2019-06-04 米拉蒂治疗股份有限公司 Kras g12c抑制剂
WO2019099524A1 (fr) * 2017-11-15 2019-05-23 Mirati Therapeutics, Inc. Inhibiteurs de kras g12c
US20190270743A1 (en) * 2017-11-15 2019-09-05 Mirati Therapeutics, Inc. Kras g12c inhibitors
WO2019195609A2 (fr) * 2018-04-04 2019-10-10 Arvinas Operations, Inc. Modulateurs de protéolyse et procédés d'utilisation associés
CN110256421A (zh) * 2019-06-26 2019-09-20 微境生物医药科技(上海)有限公司 Kras-g12c抑制剂

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11932633B2 (en) 2018-05-07 2024-03-19 Mirati Therapeutics, Inc. KRas G12C inhibitors
US12065430B2 (en) 2018-10-26 2024-08-20 Taiho Pharmaceutical Co., Ltd. Indazole compound or salt thereof
US11548888B2 (en) 2019-01-10 2023-01-10 Mirati Therapeutics, Inc. KRas G12C inhibitors
US11453683B1 (en) 2019-08-29 2022-09-27 Mirati Therapeutics, Inc. KRas G12D inhibitors
US11964989B2 (en) 2019-08-29 2024-04-23 Mirati Therapeutics, Inc. KRas G12D inhibitors
US11890285B2 (en) 2019-09-24 2024-02-06 Mirati Therapeutics, Inc. Combination therapies
US11697657B2 (en) 2019-10-28 2023-07-11 Merck Sharp & Dohme Llc Small molecule inhibitors of KRAS G12C mutant
US11702418B2 (en) 2019-12-20 2023-07-18 Mirati Therapeutics, Inc. SOS1 inhibitors
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
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
WO2023008462A1 (fr) 2021-07-27 2023-02-02 東レ株式会社 Médicament pour le traitement et/ou la prévention du cancer
WO2023060253A1 (fr) 2021-10-08 2023-04-13 Revolution Medicines, Inc. Inhibiteurs de ras
WO2023081840A1 (fr) * 2021-11-05 2023-05-11 Frontier Medicines Corporation Inhibiteurs de kras g12c
WO2023114954A1 (fr) 2021-12-17 2023-06-22 Genzyme Corporation Composés pyrazolopyrazine utilisés comme inhibiteurs de la shp2
WO2023150394A1 (fr) * 2022-02-07 2023-08-10 Frontier Medicines Corporation Méthodes pour traiter le cancer
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
WO2023240189A1 (fr) * 2022-06-10 2023-12-14 Bristol-Myers Squibb Company Dérivés de tétrahydropyrido 3,4-d pyrimidine utilisés en tant qu'inhibiteurs de kras
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
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

Also Published As

Publication number Publication date
CN114901661B (zh) 2024-07-23
CN113045565A (zh) 2021-06-29
CN114901661A (zh) 2022-08-12

Similar Documents

Publication Publication Date Title
WO2021129824A1 (fr) Nouvel inhibiteur du k-ras g12c
CN113767103B (zh) 新型螺环类K-Ras G12C抑制剂
WO2021129820A1 (fr) Composé de quinazoline contenant un cycle spiro
CN115335379B (zh) 含螺环的喹唑啉化合物
CN113544128B (zh) Kras-g12c抑制剂
RU2719428C2 (ru) Индазольные соединения в качестве ингибиторов киназы fgfr, их получение и применение
WO2021213317A1 (fr) Inhibiteur de hpk1, son procédé de préparation et son utilisation
CN116390728B (zh) 喹唑啉衍生物及其制备方法和用途
WO2021254384A1 (fr) Nouveau dérivé de pyrido[2,3-d]pyrimidine-7(8h)-one
WO2023280182A1 (fr) Composé servant d'inhibiteur de kat6
CN113045570A (zh) 含螺环的喹唑啉化合物
WO2022095909A1 (fr) Composé utilisé comme inhibiteur de ntrk et son application
WO2022002100A1 (fr) Nouveau composé de benzimidazole
CN113166148B (zh) 作为cdk-hdac双通路抑制剂的杂环化合物
WO2020173417A1 (fr) Régulateur de transport nucléaire contenant de l'acryloyle et ses utilisations
WO2022171088A1 (fr) Dérivé de pyrazolo[3,4-d]pyrimidin-3-one
CN113754659A (zh) 含螺环的喹唑啉化合物
WO2022012593A1 (fr) Composé 5,6-dihydropyrazino[2,3-c]isoquinoléine
WO2021244505A1 (fr) Nouveau composé de pyrazine
TWI831325B (zh) 作為atr抑制劑的萘啶衍生物及其製備方法
WO2022228511A1 (fr) Composé à cycle fusionné utilisé comme inhibiteur de wee-1, son procédé de préparation et son utilisation
WO2022171126A1 (fr) Composé cyclique fusionné utilisé comme inhibiteur de wee-1
WO2023134608A1 (fr) Composés cycliques fusionnés servant d'inhibiteurs de hpk1
CN116783194A (zh) 含螺环的喹唑啉衍生物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20907299

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20907299

Country of ref document: EP

Kind code of ref document: A1