[go: up one dir, main page]

WO2021190467A1 - 含螺环的喹唑啉化合物 - Google Patents

含螺环的喹唑啉化合物 Download PDF

Info

Publication number
WO2021190467A1
WO2021190467A1 PCT/CN2021/082251 CN2021082251W WO2021190467A1 WO 2021190467 A1 WO2021190467 A1 WO 2021190467A1 CN 2021082251 W CN2021082251 W CN 2021082251W WO 2021190467 A1 WO2021190467 A1 WO 2021190467A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
compound
cycloalkyl
general formula
alkoxy
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/CN2021/082251
Other languages
English (en)
French (fr)
Inventor
谢雨礼
樊后兴
曹刚
钱立晖
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wigen Biomedicine Technology Shanghai Co Ltd
Original Assignee
Wigen Biomedicine Technology Shanghai Co Ltd
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 Wigen Biomedicine Technology Shanghai Co Ltd filed Critical Wigen Biomedicine Technology Shanghai Co Ltd
Priority to US17/799,060 priority Critical patent/US12391692B2/en
Priority to CA3170068A priority patent/CA3170068A1/en
Priority to CN202180023241.6A priority patent/CN115335379B/zh
Priority to EP21776359.8A priority patent/EP4130000A4/en
Priority to JP2022552910A priority patent/JP7773987B2/ja
Publication of WO2021190467A1 publication Critical patent/WO2021190467A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention belongs to the field of medicinal chemistry, and more specifically, to a class of spirocyclic quinazoline compounds, a preparation method thereof, and the use of this class of compounds as K-Ras G12C inhibitors in the preparation of anti-tumor drugs.
  • 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 they 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%), while it is relatively rare in breast, ovarian, and brain cancers ( ⁇ 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 with specific gene mutations and Ras pathways. Over-activated non-cancerous patients 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.
  • K-Ras G12C mutant protein is a cutting-edge drug target.
  • Cell reported targeting K- ARS-1620, a covalent inhibitor of Ras G12C mutations [Cell,2018,172:578-589].
  • Patent WO2018/143315 reported that a class of spirocyclic compounds have K-Ras G12C activity and anti-tumor activity in mice.
  • Its general formula A and representative compound B (Example 35 in the patent) are structured as follows (the definition of each symbol in the formula Please refer to the patent):
  • the present invention aims to provide a compound represented by the general formula (1), or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof:
  • n is an integer of 1 or 2;
  • n is an integer of 1 or 2;
  • R 1 is H, halogen, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl or C3-C6 cycloalkyl;
  • R 2 is C1-C3 alkyl or halogenated C1-C3 alkyl
  • R 3 is Wherein R a is H or F, R b is H, F, Cl or Me, R c is H, F, Cl or Me, R d is F, Cl, NH 2 , Me or cyclopropyl, R e , R f, R g, R h, R i, R j and R k are independently H, F, Cl, OH, OMe, NH 2, CF 3, C1-C3 alkyl or C3-C6 cycloalkyl group;
  • R 4 is Wherein n 1 and n 2 are independently an integer of 1 or 2, m 1 , m 2 , m 3 and m 4 are independently an integer of 0, 1, 2, 3 or 4, and m 5 is an integer of 1, 2 or 3;
  • A is -CH 2 -, -O-, -S-, -SO-, -SO 2 -or -N(C1-C3 alkyl)-, V is -CH 2 -, -SO 2 -or -CO- , L is -O-, -S-, -SO 2 -, -SO- or -CO-;
  • X represents 5-7 membered heteroaryl or partially saturated 5-7 membered heterocycloalkyl;
  • Y is C3- C6 cycloalkyl, heterocycloalkyl, (C3-C6) cycloalkyl-(C1-C3)alkyl- or heterocycloalkyl-(C1-C3)alkyl-;
  • R 1 is H, F, Cl, Me, Et, isopropyl, vinyl, ethynyl or cyclopropyl.
  • R 2 is CH 3 , CH 3 CH 2 , CF 3 CH 2 , CHF 2 CH 2 or CF 3 (CH 3 )CH.
  • R 3 is
  • R 4 is:
  • 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 as an active ingredient the compound represented by the general formula (1) of the present invention, or each of its isomers Forms, crystal forms, pharmaceutically acceptable salts, hydrates or solvates.
  • the present invention also provides a compound represented by the general formula (1), or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate or a pharmaceutical composition as described above. Preparation of applications for treating, regulating and/or preventing diseases related to K-Ras G12C mutant protein.
  • 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 represented by the general formula (1) of the present invention, or each isomer thereof , Each crystal form, pharmaceutically acceptable salt, hydrate or solvate, or the above-mentioned pharmaceutical composition of the present invention.
  • the diseases mediated by the K-Ras G12C mutation may be blood cancers and solid tumors.
  • 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.
  • the solvent, temperature and other reaction conditions mentioned here can be changed.
  • the starting materials used for the synthesis of the compounds can be synthesized or obtained from commercial sources.
  • 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:
  • the embodiment of the compound of general formula (1) can be prepared according to general reaction scheme 1, wherein m, n, R 1 , R 2 , R 3 and R 4 are as defined above, PG represents a protecting group, and X represents boronic acid, boronic acid ester Or trifluoroborate.
  • compound A1 (refer to WO2018/143315 synthesis) and compound A2 react under basic conditions to form compound A3, compound A3 and R 4 H react under basic conditions to form compound A4, compound A4 and R 2 OH reacts under strong alkaline conditions to produce compound A5, compound A5 and R 1 -X undergo coupling reaction to obtain compound A6, compound A6 and R 3 -X undergo coupling reaction again to obtain compound A7, and compound A7 is deprotected Compound A8 is obtained, and compound A8 is reacted with acryloyl chloride or acrylic anhydride to obtain target compound A9.
  • “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 general 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, etc.
  • 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 the 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 spectrum, infrared spectrum, melting point, density, hardness, crystal form, 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 an axial chirality and/or chiral center, and therefore is a racemate, a racemic mixture, a single enantiomer, a diastereomeric compound, and a single diastereomer
  • the forms of enantiomers, and cis-trans isomers appear.
  • Each such axial chirality 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.
  • the compound of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), and C-14 ( 14 C).
  • radioisotopes such as tritium ( 3 H), iodine-125 ( 125 I), and C-14 ( 14 C).
  • heavy hydrogen can be used to replace hydrogen atoms to form deuterated compounds.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • deuterated drugs Compared with non-deuterated drugs, deuterated drugs generally have reduced toxic side effects and increased drugs. Stability, enhanced efficacy, and prolonged half-life of drugs in vivo. All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
  • 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 2 , CF 3 (CH 3 )CH, i Pr, n Pr, i Bu, n Bu, or t Bu.
  • alkenyl refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon double bond, including straight and branched chain groups of 1 to 6 carbon atoms.
  • a lower alkenyl group containing 1 to 4 carbon atoms such as vinyl, 1-propenyl, 1-butenyl or 2-methylpropenyl.
  • alkynyl refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon triple bond, including straight and branched chain groups of 1 to 6 carbon atoms. Preference is given to lower alkenyl groups containing 1 to 4 carbon atoms, such as ethynyl, 1-propynyl or 1-butynyl.
  • 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 like.
  • 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.
  • heteroaryl refers to an aromatic group containing one or more heteroatoms (O, S, or N), and a heteroaryl group is monocyclic or polycyclic, such as a monocyclic heteroaryl ring and one Or multiple carbocyclic 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, benzopyridyl and pyrrolopyrimidinyl.
  • heterocycloalkyl refers to a saturated or partially unsaturated ring system group containing one or more heteroatoms (O, S, or N), wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom Optionally quaternized as ring atoms.
  • 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.
  • halo or 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.
  • 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 (axial chirality), and are therefore classified as racemates, racemic mixtures, single enantiomers, diastereomeric compounds, and single diastereomers. The form appears.
  • 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 in the scope of the present invention.
  • the present invention is meant to include all such isomeric forms of these compounds.
  • composition composition
  • agent composition or medicament
  • 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 any of the aforementioned pharmaceutical compositions protecting the compound of structural formula (1).
  • 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 1000 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.
  • MeCN stands for acetonitrile
  • DCM dichloromethane
  • DIPEA diisopropylethylamine
  • Dioxane stands for 1,4-dioxane
  • DMF dimethylformamide
  • h stands for Hours
  • K 3 PO 4 stands for potassium phosphate
  • min stands for minutes
  • MS mass spectrometry
  • NaH stands for sodium hydride
  • NMR nuclear magnetic resonance
  • Pd 2 (dba) 3 stands for tris(dibenzylideneacetone) dipalladium
  • Pd(dppf) Cl 2 stands for 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride
  • TFA CF 3 COOH
  • TLC thin layer chromatography
  • THF stands for tetrahydrofuran
  • Xantphos stands for 4, 5-bis(diphenylphosphine)-9,9-di
  • Trifluoroethanol (0.75 g, 7.5 mmol) was dissolved in anhydrous DMF (10 mL), NaH (60%, 0.60 g, 15.0 mmol) was added under ice bath, and stirred at room temperature for 5 min to obtain sodium trifluoroethoxide.
  • Compound 1-4 (3.45g, 5.0mmol) was dissolved in anhydrous THF (40mL), the prepared above was added with sodium trifluoroethoxide DMF solution, stirred overnight at room temperature, the reaction was complete, water was added, extracted with EA, the organic phase was dried and concentrated Column chromatography gave compound 1-5 (3.54g, yield 92.1%), MS (ESI): 769.2[M+1] + .
  • the target compound 2-132 was obtained.
  • the compound of the present application may have axial chirality.
  • Compounds with axial chirality can be resolved to obtain two chiral isomers.
  • Chromatographic column is CHIRALPAK AD-H (20 ⁇ 250mm, 5 ⁇ m); mobile phase: isopropanol-n-hexane (40:60); flow rate: 12mL/min; detection wavelength: 254nm.
  • the segmented liquid was concentrated and dried by rotary evaporation to obtain products 73-a and 73-b:
  • the first axial chiral isomer 73-a; column retention time: 8.532min;
  • the second axial chiral isomer 73-b; column retention time: 10.126min.
  • the first axial chiral isomer 67-a; column retention time: 5.413 min;
  • the second axial chiral isomer 67-b; column retention time: 7.938min.
  • Example 134 Compound detection of pERK and ERK protein content in H358 cells
  • H358 cells were planted in a 24-well plate. After one day of growth, add the test compound (at a 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 it with the DMSO group to calculate the percentage of compounds that inhibit the activity of pERK. The results are shown in Table 2 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 ++ 40 ++ 41 ++ 42 ++ 43 ++ 44 +++ 45 +++ 46 +++ 47 +++ 48 ++ 49 +++ 50 ++ 51 +++ 52 +++ 53 +++ 54 +++++
  • +++ 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 + 43 + 44 +++ 45 +++ 46 +++ 47 +++ 48 ++ 49 +++ 50 ++ 51 +++ 52 +++ 53 +++ 54 +++ 55 +++ 56 +++ 57 ++ 58 +++ 59 +++ 60 +++ 61 +++ 62 +++ 63 +++ 64 +++ 65 ++ 66 67 +++ 68 +++ 69 +++
  • +++ means that the IC 50 of the compound is less than 0.3 ⁇ M.
  • the anti-proliferative activity of the compounds of the present invention on H358 cells is less than 0.3 ⁇ M.
  • R 4 is a non-aromatic heterocyclic ring or a spiro ring
  • the compounds have strong inhibitors of the RAS pathway ERK phosphorylation activity, and the compound has a strong inhibitory activity on the proliferation of tumor cells H358 with K-RAS G12C mutation.
  • the solvent control group was intragastrically administered with 0.5% CMC-Na once a day; the compound administration group was intragastrically administered with 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 4 below.
  • the compound of the present invention has strong anti-tumor activity in vivo. It can shrink tumor after continuous administration of 10 mg/kg/day for 21 days.
  • the in vivo activity of compounds 6, 14, 28, 60 and 103 are all stronger than the control drugs.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

本发明涉及一种通式(1)所示的化合物及其制备方法，及式(1)化合物及其各异构体、各晶型、药学上可接受的盐作为G12C突变体K-Ras蛋白不可逆抑制剂在抗肿瘤等Ras相关疾病的药物制备中的用途。

Description

含螺环的喹唑啉化合物
本申请要求申请日为2020年3月25日的中国专利申请CN202010222766X的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明属涉及药物化学领域，更具体而言，涉及一类含螺环的喹唑啉化合物，及其制备方法和该类化合物作为K-Ras G12C抑制剂在制备抗肿瘤药物中的用途。
背景技术
Ras蛋白家族是细胞内重要的信号转导传递分子，在生长发育中发挥了重要的作用。大量的体外肿瘤细胞，动物模型以及人类肿瘤样本的分析和研究表明Ras家族蛋白的过度激活是人类肿瘤发展的早期事件，是多种癌症发生和发展的重要诱因之一。因此靶向和抑制Ras蛋白的活性是治疗相关肿瘤的重要手段。
Ras蛋白存在两种形式，其与GDP结合，处于未激活静息状态；而当细胞接收诸如生长因子刺激等信号时，Ras蛋白与GTP结合，被激活。活化的Ras蛋白招募多种信号转接蛋白，促进下游信号分子诸如ERK，S6的磷酸化，从而激活Ras信号转导通路，调节细胞生长、存活、迁移和分化。Ras蛋白自身的GTPase酶活性可将GTP水解回GDP。并且细胞内存在GTP酶激活蛋白(GAPs)与Ras相互作用大大促进Ras GTPase的活性，从而防止Ras蛋白的过度激活。
Ras蛋白家族中K-Ras,H-Ras以及N-Ras蛋白上的突变是多种肿瘤的常见的基因突变之一，是导致肿瘤中Ras蛋白过度激活的主要因素。与野生型的Ras蛋白相比，这些突变导致Ras蛋白活性不为调控，稳定结合GTP，持续激活，从而促进肿瘤细胞的生长，迁移以及分化。这其中K-Ras蛋白的突变最为常见，占所有Ras突变的85％，而N-Ras(12％)和H-Ras(3％)则相对少见。K-Ras突变在多种癌症中极为普遍：包括胰腺癌(95％)、结肠直肠癌(45％)和肺癌(25％)等，而在乳腺癌、卵巢癌和脑癌中相对罕见(<2％)。K-Ras突变位点主要集中于G12位，其中G12C的突变最为常见。例如在非小细胞肺癌(NSCLC)中，K-Ras G12C占所有K-Ras突变的50％，其次是G12V和G12D。基因组学研究表明，非小细胞肺癌中的K-Ras突变不与EGFR、ALK、ROS1、RET和BRAF突变共存，而与STK11、KEAP1和TP53等突变共存，提示K-Ras突变可能与STK11、KEAP1和TP53突变等协同作用参与细胞的恶性转变，增 生和侵袭。除了肿瘤以外，Ras蛋白的异常激活也参与了包括糖尿病，神经退行性疾病等非肿瘤性疾病，由此可见，靶向Ras蛋白的小分子化合物可使大批携带特定基因变异的癌症病人和Ras通路过度激活的非癌症性病人受益。
自从肿瘤中Ras突变被发现四十年来，虽然我们对Ras通路致病机制有了更为深入的了解，但是对于大量携带Ras蛋白突变以及Ras通路过度激活的病人，临床上尚未有有效的靶向Ras蛋白的治疗手段上市。因此开发高活性的针对Ras蛋白特别是突变频率较高的K-Ras G12C蛋白的小分子抑制剂，具有重要的临床意义。
K-Ras G12C突变蛋白作为一个前沿的药物靶点，目前的研究还不是很多，只有少数化合物进入临床研究阶段，比如Amgen公司的AMG510和Mirati公司的MRTX849。2018年Cell上报道了靶向K-Ras G12C突变的共价抑制剂ARS-1620[Cell,2018,172:578-589]。专利WO2018/143315中报道了一类螺环化合物具有K-Ras G12C活性及小鼠体内抗肿瘤活性，其通式A及代表化合物B(专利中实施例35)结构如下(式中各符号的定义请参照该专利)：
Figure PCTCN2021082251-appb-000001
目前，研究和发现具有K-Ras G12C活性好，并且药代动力学性质优良的化合物存在迫切的需求。
发明内容
本发明旨在提供一种通式(1)所示的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：
Figure PCTCN2021082251-appb-000002
通式(1)中：
m为1或2的整数；
n为1或2的整数；
R 1为H、卤素、C1-C3烷基、C2-C4烯基、C2-C4炔基或C3-C6环烷基；
R 2为C1-C3烷基或卤代C1-C3烷基；
R 3为
Figure PCTCN2021082251-appb-000003
Figure PCTCN2021082251-appb-000004
其中R a为H或F，R b为H、F、Cl或Me，R c为H、F、Cl或Me，R d为F、Cl、NH 2、Me或环丙基，R e、R f、R g、R h、R i、R j和R k独立为H、F、Cl、OH、OMe、NH 2、CF 3、C1-C3烷基或C3-C6环烷基；
R 4为
Figure PCTCN2021082251-appb-000005
Figure PCTCN2021082251-appb-000006
Figure PCTCN2021082251-appb-000007
Figure PCTCN2021082251-appb-000008
其中n 1和n 2独立为1或2的整数，m 1、m 2、m 3和m 4独立为0、1、2、3或4的整数，m 5为1、2或3的整数；A为-CH 2-、-O-、-S-、-SO-、-SO 2-或-N(C1-C3烷基)-，V为-CH 2-、-SO 2-或-CO-，L为-O-、-S-、-SO 2-、-SO-或-CO-；X表示5-7元杂芳基或部分饱和的5-7元杂环烷基；Y为C3-C6环烷基、杂环烷基、(C3-C6)环烷基-(C1-C3)烷基-或杂环烷基-(C1-C3)烷基-；R l和R m独立为C1-C3烷基、卤代C1-C3烷基、羟基取代C1-C3烷基、氰基取代C1-C3烷基、C3-C6环烷基、(C1-C3)烷氧基-(C2-C3)烷基-、(卤代C1-C3)烷氧基-(C2-C3)烷基-、(C3-C6)环烷基-(C1-C3)烷基-；或R l和R m共N原子形成3-8元杂环烷基，所述3-8元杂环烷基可被1-3个选自OH、卤素、氰基、C1-C3烷基、C3-C6环烷基、杂环烷基、(C1-C3)烷氧基或(卤代C1-C3)烷氧基取代；R n为C1-C3烷基、C2-C4烯基、C2-C4炔基、C3-C6环烷基、杂环烷基、卤代C1-C3烷基、羟基取代C1-C3烷基、氰基取代C1-C3烷基、(C1-C3)烷氧基-(C2-C3)烷基-、(卤代C1-C3)烷氧基-(C2-C3)烷基-、(C3-C6)环烷基-(C1-C3)烷基-或杂环烷基-(C1-C3)烷基-；和R o为、OH、卤素、氰基、C1-C3烷基、C1-C3烷氧基或C3-C6环烷基。
在另一优选例中，其中所述通式(1)中，R 1为H、F、Cl、Me、Et、异丙基、乙烯基、乙炔基或环丙基。
在另一优选例中，其中所述通式(1)中，R 2为CH 3、CH 3CH 2、CF 3CH 2、CHF 2CH 2或CF 3(CH 3)CH。
在另一优选例中，其中所述通式(1)中，R 3为
Figure PCTCN2021082251-appb-000009
Figure PCTCN2021082251-appb-000010
Figure PCTCN2021082251-appb-000011
在另一优选例中，其中所述通式(1)中，R 4为：
Figure PCTCN2021082251-appb-000012
Figure PCTCN2021082251-appb-000013
Figure PCTCN2021082251-appb-000014
Figure PCTCN2021082251-appb-000015
Figure PCTCN2021082251-appb-000016
在各种不同实施方式中，本发明代表性化合物具有以下结构之一：
Figure PCTCN2021082251-appb-000017
Figure PCTCN2021082251-appb-000018
Figure PCTCN2021082251-appb-000019
Figure PCTCN2021082251-appb-000020
Figure PCTCN2021082251-appb-000021
Figure PCTCN2021082251-appb-000022
Figure PCTCN2021082251-appb-000023
Figure PCTCN2021082251-appb-000024
Figure PCTCN2021082251-appb-000025
本发明的另一个目的是提供了一种药物组合物，其含有药理上可接受的赋形剂或载体，以及作为活性成分的本发明通式(1)所示的化合物、或其各异构体、各晶型、药学上可接受盐、水合物或溶剂合物。
本发明还提供了一种通式(1)所示的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物或如上所述的药物组合物在制备治疗、调节和/或预防与K-Ras G12C突变体蛋白相关的疾病的应用。
本发明的再一个目的提供了一种治疗由K-Ras G12C突变介导的疾病的方法，其包括给与受试者本发明通式(1)所示的上述化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，或本发明的上述药物组合物。所述K-Ras G12C突变介导的疾病可为血液癌和实体瘤。
通过合成和仔细研究了多类涉及具有K-RAS G12C抑制作用的新化合物，发明人发现在通式(1)所示的化合物中，当R 4为非芳香杂环或者螺环时，化合物具有很强的K-RAS G12C抑制活性。此外，化合物在小鼠体内抗肿瘤活性评价中，也展现了很强的体内抗肿瘤活性。
应理解，本发明的前述一般性描述和以下详细描述都是示例性和说明性的，旨在提供对所要求保护的本发明的进一步说明。
化合物的合成
下面具体地描述本发明通式(1)化合物的制备方法，但这些具体方法不对本发明构成任何限制。
以上说明的通式(1)化合物可使用标准的合成技术或公知的技术与文中结合的方法来合成。此外，在此提到的溶剂，温度和其他反应条件可以改变。用于化合物的合成的起始物料可以由合成或从商业来源上获得。本文所述的化合物和其他具有不同取代基的有关化合物可使用公知的技术和原料来合成，包括发现于March，ADVANCED ORGANIC CHEMISTRY 4 th Ed.，(Wiley 1992)；Carey和Sundberg，ADVANCED ORGANIC CHEMISTRY 4 th Ed.，Vols.A和B(Plenum 2000，2001)，Green和Wuts，PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 rd Ed.，(Wiley 1999)中的方法。化合物制备的一般方法可通过使用适当的试剂和在此提供的分子式中引入不同基团的条件来改变。
一方面，本文所述的化合物根据工艺中公知的方法。然而方法的条件，例如反应物、溶剂、碱、所用化合物的量、反应温度、反应所需时间等不限于下面的解释。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制 得，这样的组合可由本发明所属领域的技术人员容易的进行。一方面，本发明还提供了一种所述的通式(1)所示化合物的制备方法，其采用下列一般反应流程1制备：
一般反应流程1
Figure PCTCN2021082251-appb-000026
通式(1)化合物的实施方式可根据一般反应流程1制备,其中m、n、R 1、R 2、R 3和R 4如上文中所定义，PG表示保护基，X表示硼酸、硼酸酯或三氟硼酸盐。如一般反应流程1所示,化合物A1(参照WO2018/143315合成)和化合物A2在碱性条件下反应生成化合物A3，化合物A3和R 4H在碱性条件下反应生成化合物A4，化合物A4和R 2OH在强碱性条件下反应生成化合物A5，化合物A5和R 1-X进行偶联反应得到化合物A6，化合物A6和R 3-X再次进行偶联反应得到化合物A7，化合物A7脱除保护基得到化合物A8，化合物A8和丙烯酰氯或者丙烯酸酐反应得到目标化合物A9。
化合物的进一步形式
“药学上可接受”这里指一种物质，如载体或稀释液，不会使化合物的生物活性或性质消失，且相对无毒，如，给予个体某物质，不会引起不想要的生物影响或以有害的方式与任何其含有的组分相互作用。
术语“药学上可接受的盐”指一种化合物的存在形式，该形式不会引起对给药有机体的重要的刺激，且不会使化合物的生物活性和性质消失。在某些具体方面，药学上可接受的盐是通过通式(1)化合物与酸反应获得，如盐酸、氢溴酸、氢氟酸、硫酸、磷酸、硝酸、磷酸等无机酸，甲酸、乙酸、丙酸、草酸、三氟乙酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯磺酸、对甲苯磺酸等有机酸以及天冬氨酸、谷氨酸等酸性氨基酸。
应理解药学上可接受的盐的参考包括溶剂添加形式或结晶形式，尤其是溶剂化物或多晶型。溶剂化物含有化学计量或非化学计量的溶剂，且是在与药学上可接受溶剂如水，乙醇等，结晶化过程中选择性形成的。当溶剂是水时形成水合物，或当溶剂是乙醇时形成醇化物。通式(1)化合物的溶剂化物按照本文所述的方法，很方便的制得或形成。举例说明，通式(1)化合物的水合物从水/有机溶剂的混合溶剂中重结晶而方便的制得，使用的有机溶剂包括但不限于，四氢呋喃、丙酮、乙醇或甲醇。此外，在此提到的化合物能够以非溶剂化和溶剂化形式存在。总之，对于在此提供的化合物和方法为目的，溶剂化形式被认为相当于非溶剂化形式。
在其他具体实施例中，通式(1)化合物被制备成不同的形式，包括但不限于，无定形，粉碎形和毫微-粒度形式。此外，通式(1)化合物包括结晶型，也可以作为多晶型。多晶型包括化合物的相同元素组成的不同晶格排列。多晶型通常有不同的X-射线衍射谱、红外光谱、熔点、密度、硬度、晶型、光和电的性质、稳定性和溶解性。不同的因素如重结晶溶剂，结晶速率和贮存温度可能引起单一晶型为主导。
在另一个方面，通式(1)化合物存在轴手性和/或手性中心，并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式、和顺反异构体的形式出现。每个这种轴手性将独立地产生两个旋光异构体，并且所有可能的旋光异构体和非对映体混合物以及纯或部分纯的化合物包括在本发明的范围之内。本发明意味着包括这些化合物的所有这种异构形式。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)、碘-125( 125I)和C-14( 14C)。又例如，可用重氢取代氢原子形成氘代化合物，氘与碳构成的键比普通氢和碳构成的键更 坚固，相比于未氘代药物，通常氘代药物具有降低毒副作用、增加药物稳定性、增强疗效、延长药物体内半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包含在本发明的范围之内。
术语
如果无另外说明，用于本发明申请，包括说明书和权利要求书中的术语，定义如下。必须注意，在说明书和所附的权利要求书中，如果文中无另外清楚指示，单数形式“一个”包括复数意义。如果无另外说明，使用质谱、核磁、HPLC、蛋白化学、生物化学、重组DNA技术和药理的常规方法。在本申请中，如果无另外说明，使用“或”或“和”指“和/或”。
除非另有规定，“烷基”指饱和的脂肪烃基团，包括1至6个碳原子的直链和支链基团。优选含有1至4个碳原子的低级烷基，例如甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔丁基。如本文所用，“烷基”包括未取代和取代的烷基，尤其是被一个或多个卤素所取代的烷基。优选的烷基选自CH 3、CH 3CH 2、CF 3、CHF 2、CF 3CH 2、CF 3(CH 3)CH、 iPr、 nPr、 iBu、 nBu或 tBu。
除非另有规定，“烯基”指含有碳-碳双键的不饱和脂肪烃基团，包括1至6个碳原子的直链和支链基团。优选含有1至4个碳原子的低级烯基，例如乙烯基、1-丙烯基、1-丁烯基或2-甲基丙烯基。
除非另有规定，“炔基”指含有碳-碳叁键的不饱和脂肪烃基团，包括1至6个碳原子的直链和支链基团。优选含有1至4个碳原子的低级烯基，例如乙炔基、1-丙炔基或1-丁炔基。
除非另有规定，“环烷基”指3至6元全碳单环脂肪烃基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。例如，环丙基、环丁基、环戊基、环己烷、环己二烯等。
除非另有规定，“烷氧基”指通过醚氧原子键合到分子其余部分的烷基。代表性的烷氧基为具有1-6个碳原子的烷氧基，如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基和叔丁氧基。如本文所用，“烷氧基”包括未取代和取代的烷氧基，尤其是被一个或多个卤素所取代的烷氧基。优选的烷氧基选自OCH 3、OCF 3、CHF 2O、CF 3CH 2O、 i-PrO、 n-PrO、 i-BuO、 n-BuO或 t-BuO。
除非另有规定，“杂芳基”指含有一个或多个杂原子(O、S或N)的芳香基团，杂芳基是单环或多环的，例如单环杂芳基环与一个或多个碳环芳香基团或其它单环杂环基基团稠和。杂芳基的例子包括但不限于，吡啶基、哒嗪基、咪唑基、嘧啶基、吡唑基、三唑基、 吡嗪基、喹啉基、异喹啉基、四唑基、呋喃基、噻吩基、异噁唑基、噻唑基、噁唑基、异噻唑基、吡咯基、吲哚基、苯并咪唑基、苯并呋喃基、苯并噻唑基、苯并噻吩基、苯并噁唑基、苯并吡啶基和吡咯并嘧啶基。
除非另有规定，“杂环烷基”指含有一个或多个杂原子(O、S或N)的饱和或部分不饱和环体系基团，其中氮和硫原子任选地被氧化，氮原子任选地被季铵化，作为环原子。除非另有说明，“杂环烷基”的环体系可以是单环、双环、螺环或多环的环体系。“杂环烷基”可以通过一个以上环碳或杂原子连接于分子的其余部分。“杂环烷基”的例子包括但不限于吡咯烷、哌啶、N-甲基哌啶、四氢咪唑、吡唑烷、丁内酰胺、戊内酰胺、咪唑啉酮、乙内酰脲、二氧戊环、邻苯二甲酰亚胺、哌啶、嘧啶-2,4(1H,3H)-二酮、1,4-二氧六环、吗啉、硫代吗啉、硫代吗啉-S-氧化物、硫代吗啉-S,S-氧化物、哌嗪、吡喃、吡啶酮、3-吡咯啉、噻喃、吡喃酮、四氢呋喃、四氢噻吩、奎宁环、2-氮杂螺[3.3]庚烷等。
除非另有规定，“卤素”(或卤代基)是指氟、氯、溴或碘。在基团名前面出现的术语“卤代”(或“卤素取代”)表示该基团是部分或全部卤代，也就是说，以任意组合的方式被F，Cl，Br或I取代，优选被F或Cl取代。
特定药学及医学术语
术语“可接受的”，如本文所用，指一个处方组分或活性成分对一般治疗目标的健康没有过分的有害影响。
术语“治疗”、“治疗过程”或“疗法”如本文所用，包括缓和、抑制或改善疾病的症状或状况；抑制并发症的产生；改善或预防潜在代谢综合症；抑制疾病或症状的产生，如控制疾病或情况的发展；减轻疾病或症状；使疾病或症状减退；减轻由疾病或症状引起的并发症，或预防或治疗由疾病或症状引起的征兆。如本文所用，某一化合物或药物组合物，给药后，可以使某一疾病、症状或情况得到改善，尤指其严重度得到改善，延迟发病，减缓病情进展，或减少病情持续时间。无论固定给药或临时给药、持续给药或间歇给药，可以归因于或与给药有关的情况。
“活性成分”指通式(1)所示化合物，以及通式(1)化合物的药学上可接受的无机或有机盐。本发明的化合物可以含有一个或多个不对称中心(轴手性)，并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式出现。可以存在的不对称中心，取决于分子上各种取代基的性质。每个这种不对称中心将独立地产生两个旋光异构体，并且所有可能的旋光异构体和非对映体混合物以及纯或部分纯的化合物包括在本发明的范围之内。本发明意味着包括这些化合物的所有这种异构形式。
“化合物(compound)”、“组合物(composition)”、“药剂(agent)”或“医药品(medicine or  medicament)”等词在此可交替使用，且都是指当施用于个体(人类或动物)时，能够透过局部和/或全身性作用而诱发所亟求的药学和/或生理反应的一种化合物或组合物。
“施用(administered、administering或、administration)”一词在此是指直接施用所述的化合物或组合物，或施用活性化合物的前驱药(prodrug)、衍生物(derivative)、或类似物(analog)等。
虽然用以界定本发明较广范围的数值范围与参数皆是约略的数值，此处已尽可能精确地呈现具体实施例中的相关数值。然而，任何数值本质上不可避免地含有因个别测试方法所致的标准偏差。在此处，“约”通常是指实际数值在一特定数值或范围的正负10％、5％、1％或0.5％之内。或者是，“约”一词代表实际数值落在平均值的可接受标准误差之内，视本领域技术人员的考虑而定。除了实验例之外，或除非另有明确的说明，当可理解此处所用的所有范围、数量、数值与百分比(例如用以描述材料用量、时间长短、温度、操作条件、数量比例及其它相似者)均经过“约”的修饰。因此，除非另有相反的说明，本说明书与附随权利要求书所揭示的数值参数皆为约略的数值，且可视需求而更动。至少应将这些数值参数理解为所指出的有效位数与采用一般进位法所得到的数值。
除非本说明书另有定义，此处所用的科学与技术词汇的含义与本领域技术人员所理解的惯用的意义相同。此外，在不和上下文冲突的情形下，本说明书所用的单数名词涵盖该名词的复数型；而所用的复数名词时亦涵盖该名词的单数型。
治疗用途
本发明提供了使用本发明化合物或药物组合物治疗疾病的方法，包括但不限于涉及G12C K-Ras、G12C H-Ras和/或G12C N-Ras突变的病况(例如癌症)。
在一些事实方案中，提供了用于癌症治疗的方法，该方法包括给予有需要的个体有效量的任何前述的保护结构式(1)化合物的药物组合物。在一些实施方案中，癌症由K-Ras、H-Ras和/或G12C N-Ras突变介导。在其它实施方案中，该癌症是肺癌、胰腺癌、结肠癌、MYH相关息肉病或结肠直肠癌。
给药途径
本发明的化合物及其药学上可接受的盐可制成各种制剂，其中包含安全、有效量范围内的本发明化合物或其药学上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全、有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。化合物的安全、有效量根据治疗对象的年龄、病情、疗程等具体情况来确定。
“药学上可以接受的赋形剂或载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的 是组合物中各组份能与本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药理上可以接受的赋形剂或载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2021082251-appb-000027
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
施用本发明化合物时，可以口服、直肠、肠胃外(静脉内、肌肉内或皮下)、局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬 浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选50～1000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明提到的上述特征，或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以任何可提供相同、均等或相似目的替代性特征取代。因此除有特别说明，所揭示的特征仅为均等或相似特征的一般性例子。
具体实施方式
在下面的说明中将会详细阐述上述化合物、方法、药物组合物的各个具体方面、特性和优势，使本发明的内容变得十分明了。在此应理解，下述的详细说明及实例描述了具体的实施例，仅用于参考。在阅读了本发明的说明内容后，本领域的技术人员可对本发明作各种改动或修改，这些等价形势同样落于本申请所限定的范围。
所有实施例中， 1H-NMR用Vian Mercury 400核磁共振仪记录，化学位移以δ(ppm)表示；分离用硅胶未说明均为200-300目，洗脱液的配比均为体积比。
本发明采用下述缩略词:MeCN代表乙腈；DCM代表二氯甲烷；DIPEA代表二异丙基乙基胺；Dioxane代表1,4-二氧六环；DMF代表二甲基甲酰胺；h代表小时；K 3PO 4代表磷酸钾；min代表分钟；MS代表质谱；NaH代表氢化钠；NMR代表核磁共振；Pd 2(dba) 3代表三(二亚苄基丙酮)二钯；Pd(dppf)Cl 2代表1,1'-双(二苯基膦基)二茂铁]二氯化钯；TFA(CF 3COOH)代表三氟乙酸；TLC代表薄层色谱；THF代表四氢呋喃；Xantphos代表4,5-双(二苯基膦)-9,9-二甲基氧杂蒽。
实施例1 1-(7-(6-环丙基-2-(3-((二甲胺基)甲基)氮杂环丁-1-基)-7-(5-甲基-1H-吲唑-4-基)-8-(2,2,2-三氟乙氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬-2-基)丙-2-烯-1-酮(化合物1)的合成
Figure PCTCN2021082251-appb-000028
步骤1：化合物1-3的合成
将化合物1-1(5.53g,13.1mmol)悬浮于dioxane(80mL)中，冰浴下加入DIPEA(10.1g,78.6mmol)，再加入1-2(2.96g,13.1mmol)搅拌30min，恢复室温搅拌1h，TLC检测，反应完全，加水，EA萃取，有机相干燥浓缩，EA打浆得黄色固体1-3(4.52g,收率56.3％)。
1H NMR(400MHz,DMSO-d 6)δ:8.26(d,J＝1.5Hz,1H),3.79(s,4H),3.65(s,4H),1.86(t,J＝5.3Hz,4H),1.39(s,9H)；MS(ESI):MS(ESI):611.2[M+1] +.
步骤2：化合物1-4的合成
将化合物1-3(4.28g,7.0mmol)溶于DMF(40mL)和THF(40mL)的混合溶液中，加入1-(氮杂环丁-3-基)-N,N-二甲基甲胺(1.60g,14.0mmol)，DABCO(155mg,1.4mmol)，室温搅拌过夜，反应完全，加水，EA萃取，有机相干燥浓缩，柱层析得化合物1-4(3.62g,收率75.1％)，MS(ESI):689.2[M+1] +。
步骤3：化合物1-5的合成
三氟乙醇(0.75g,7.5mmol)溶于无水DMF(10mL)中，冰浴下加入NaH(60％,0.60g,15.0mmol)，室温搅拌5min，得到三氟乙醇钠。将化合物1-4(3.45g,5.0mmol)溶于无水THF(40mL)中，上述制好的加入三氟乙醇钠DMF溶液，室温搅拌过夜，反应完全，加 水，EA萃取，有机相干燥浓缩，柱层析得化合物1-5(3.54g,收率92.1％)，MS(ESI):769.2[M+1] +。
步骤4：化合物1-6的合成
向单口瓶中，加入化合物1-5(3.08g,4.0mmol)，环丙基硼酸(0.43g,5.0mmol)，Pd(dppf)Cl 2(0.59g,0.8mmol)，K 3PO 4(0.85g,4.0mmol)，依次加入MeCN(40mL)，dioxane(40mL)和H 2O(16.5mL)，氮气保护下，100℃搅拌5h，反应完全，柱层析得化合物1-6(1.78g,收率65.2％)，MS(ESI):683.3[M+1] +。
步骤5：化合物1-7的合成
向单口瓶中，加入化合物1-6(1.37g,2.0mmol)，5-甲基-1H-吲唑-4-硼酸(0.53g,3.0mmol)，Pd 2(dba) 3(0.27g,0.3mmol)，Xatphos(0.35g,0.6mmol)，K 3PO 4(0.85g,4.0mmol)，加入dioxane(30mL)和H 2O(3mL)，氮气保护下，120℃搅拌过夜，反应完全，柱层析得化合物1-7(557mg,收率26.4％)，MS(ESI):735.4[M+1] +。
步骤6：化合物1-8的合成
将化合物1-7(515mg,0.7mmol)溶于DCM(10mL)中，加入TFA(3mL)，室温搅拌2h，反应完全，浓缩，饱和碳酸钠碱化，EA萃取，干燥浓缩得化合物1-8(445mg,收率100％)，MS(ESI):635.4[M+1] +。
步骤7：化合物1的合成
将化合物1-8(318mg,0.4mmol)溶于干燥DCM(15mL)中，冰盐浴冷却下加入DIPEA(65mg,0.5mmol)，缓慢加入丙烯酰氯(43mg,0.48mmol)，冰浴下继续反应2h，反应液用饱和食盐水洗，有机相干燥浓缩，柱层析得化合物1(181mg,收率65.8％)。
1H NMR(400MHz,DMSO-d 6)δ12.93(s,1H),7.43-7.45(m,2H),7.31(d,J＝8.4Hz,1H),7.10(s,1H),6.34(dd,J＝16.9,10.3Hz,1H),6.09-6.14(m,1H),5.67-5.70(m,1H),4.80-4.90(m,1H),4.49-4.59(m,1H),4.02-4.10(m,4H),3.83-3.87(m,2H),3.74(s,2H),3.57(s,4H),2.10-2.15(m,12H),1.92-2.02(m,4H),1.26-1.29(m,1H),0.48-0.61(m,4H),MS(ESI):689.4[M+1] +。
采用手性柱分离纯化的方法，可以得到化合物1的两个轴手性异构体：
Figure PCTCN2021082251-appb-000029
实施例2-132化合物2-132的合成
采用不同原料，根据实施例1中类似的合成方法得到目标化合物2-132。
表1
Figure PCTCN2021082251-appb-000030
Figure PCTCN2021082251-appb-000031
Figure PCTCN2021082251-appb-000032
Figure PCTCN2021082251-appb-000033
Figure PCTCN2021082251-appb-000034
Figure PCTCN2021082251-appb-000035
Figure PCTCN2021082251-appb-000036
Figure PCTCN2021082251-appb-000037
Figure PCTCN2021082251-appb-000038
Figure PCTCN2021082251-appb-000039
Figure PCTCN2021082251-appb-000040
Figure PCTCN2021082251-appb-000041
实施例133化合物73的手性拆分
本申请的化合物可以有轴手性。有轴手性的化合物可以拆分得到二个手性异构体。
将样品溶于乙醇中，浓度为25mg/mL，进样量为500μL。制备型色谱条件：色谱柱为CHIRALPAK AD-H(20×250mm，5μm)；流动相：异丙醇-正己烷(40∶60)；流速：12mL/min；检测波长：254nm。将分段液进行旋蒸浓缩、干燥得到产物73-a和73-b：
第一个轴手性异构体：73-a；色谱柱保留时间：8.532min；
第二个轴手性异构体：73-b；色谱柱保留时间：10.126min.
采用相似的拆分方法，对化合物67进行手性拆分，各自分别得到其两个手性异构体67-a和67-b，其色谱柱保留时间如下：
第一个轴手性异构体：67-a；色谱柱保留时间：5.413min；
第二个轴手性异构体：67-b；色谱柱保留时间：7.938min.
本申请中的其它化合物也可以用相似的方法进行手性拆分。
实施例134化合物对H358细胞内pERK和ERK蛋白含量的检测
H358细胞种植于24孔板中，生长一天后，加入待测化合物(浓度为1μM)，化合物作用24小时后，裂解细胞后，将细胞裂解液，转移至96孔ELISA板子中，运用ELISA试剂盒(abcam 176660)测定裂解液中pERK和ERK水平,计算pERK和ERK的比值，并与DMSO组对比，计算化合物抑制pERK活性的百分比，结果见下列表2。
表2.本发明化合物对H358细胞内pERK水平的抑制活性
化合物 抑制率(％) 化合物 抑制率(％) 化合物 抑制率(％)
1 +++ 2 +++ 3 ++
4 +++ 5 +++ 6 +++
7 +++ 8 ++ 9 +++
10 +++ 11 +++ 12 +++
13 +++ 14 +++ 15 +++
16 +++ 17 +++ 18 +++
19 +++ 20 ++ 21 +++
22 +++ 23 +++ 24 +++
25 +++ 26 ++ 27 ++
28 +++ 29 +++ 30 +++
31 +++ 32 +++ 33 ++
34 +++ 35 +++ 36 ++
37 +++ 38 +++ 39 ++
40 ++ 41 ++ 42 ++
43 ++ 44 +++ 45 +++
46 +++ 47 +++ 48 ++
49 +++ 50 ++ 51 +++
52 +++ 53 +++ 54 +++
55 +++ 56 +++ 57 ++
58 +++ 59 +++ 60 +++
61 +++ 62 +++ 63 +++
64 +++ 65 ++ 66 ++
67 +++ 68 +++ 69 +++
70 +++ 71 +++ 72 +++
73 +++ 74 +++ 75 ++
76 +++ 77 +++ 78 +++
79 +++ 80 ++ 81 +++
82 +++ 83 ++ 84 ++
85 +++ 86 ++ 87 +++
88 ++ 89 +++ 90 ++
91 +++ 92 ++ 93 +++
94 ++ 95 +++ 96 +++
97 +++ 98 +++ 99 +++
100 +++ 101 +++ 102 +++
103 +++ 104 +++ 105 +++
106 +++ 107 +++ 108 +++
109 +++ 110 +++ 111 +++
112 +++ 113 ++ 114 +++
115 +++ 116 +++ 117 +++
118 +++ 119 +++ 120 +++
121 +++ 122 +++ 123 +++
124 +++ 125 +++ 126 +++
127 +++ 128 +++ 129 +++
130 +++ 131 +++ 132 +++
1-a +++ 1-b +++ 67-a +++
67-b +++ 73-a +++ 73-b +++
B +++        
+表示抑制率小于或等于50％
++表示抑制率为50％至90％
+++表示抑制率大于90％。
实施例135化合物对H358细胞的抗增殖活性
2500个H358细胞种植于超低吸附的96孔板(corning,7007)中，生长一天后，加入梯度稀释化合物(最高5μM,5倍稀释，一共五个剂量)，加入化合物三天后，加入Cell Titer Glow(Promega,G9681)评价小球的生长情况，计算IC 50值，结果见下列表3。
表3.本发明化合物对H358细胞的抗增殖活性
化合物 IC 50 化合物 IC 50 化合物 IC 50
1 +++ 2 +++ 3 ++
4 +++ 5 +++ 6 +++
7 +++ 8 ++ 9 +++
10 +++ 11 +++ 12 +++
13 +++ 14 +++ 15 +++
16 +++ 17 +++ 18 +++
19 +++ 20 ++ 21 +++
22 +++ 23 +++ 24 +++
25 ++ 26 ++ 27 ++
28 +++ 29 +++ 30 +++
31 +++ 32 +++ 33 ++
34 +++ 35 +++ 36 ++
37 +++ 38 ++ 39 ++
40 + 41 ++ 42 +
43 + 44 +++ 45 +++
46 +++ 47 +++ 48 ++
49 +++ 50 ++ 51 +++
52 +++ 53 +++ 54 +++
55 +++ 56 +++ 57 ++
58 +++ 59 +++ 60 +++
61 +++ 62 +++ 63 +++
64 +++ 65 ++ 66 ++
67 +++ 68 +++ 69 +++
70 +++ 71 +++ 72 +++
73 +++ 74 +++ 75 ++
76 +++ 77 +++ 78 +++
79 +++ 80 ++ 81 +++
82 +++ 83 ++ 84 ++
85 +++ 86 ++ 87 +++
88 ++ 89 +++ 90 ++
91 +++ 92 + 93 +++
94 ++ 95 +++ 96 ++
97 +++ 98 +++ 99 +++
100 +++ 101 +++ 102 +++
103 +++ 104 +++ 105 +++
106 +++ 107 +++ 108 +++
109 +++ 110 +++ 111 ++
112 +++ 113 ++ 114 +++
115 +++ 116 +++ 117 +++
118 +++ 119 +++ 120 +++
121 +++ 122 +++ 123 +++
124 +++ 125 +++ 126 +++
127 +++ 128 +++ 129 +++
130 +++ 131 +++ 132 +++
1-a +++ 1-b +++ 67-a +++
67-b +++ 73-a +++ 73-b +++
B +++        
+表示化合物的·IC 50大于1μM
++表示化合物的IC 50为0.3至1μM
+++表示化合物的IC 50小于0.3μM。
从表2和表3数据可知，本发明化合物对H358细胞的抗增殖活性绝大多数化合物都小于0.3μM，R 4为非芳香杂环或者螺环时，化合物都具有很强的抑制剂RAS通路的ERK磷酸化活性，并且化合物具有很强的抑制携带K-RAS G12C突变肿瘤细胞H358的增殖活性。
实施例136小鼠体内抗肿瘤活性评价
人胰腺癌Mia PaCa-2细胞用含10％胎牛血清的1640于37℃、5％CO 2培养箱中常规培养，传代后，待细胞达到所需量时，收集细胞。将1×10 7个Mia PaCa-2细胞注射入每只裸小鼠左侧背部，待肿瘤生长至150mm 3后，将动物随机分组开始给药。分别为1)溶剂对照组，8只；2)化合物6组、化合物14组、化合物28组、化合物44组、化合物60组、化合物103组和对照药物B(WO2018/143315中实施例35)组，每组8只。溶剂对照组每天一次灌胃0.5％CMC-Na；化合物给药组每天一次灌胃化合物0.5％CMC-Na悬浮液。每周二、四测定肿瘤体积，测量小鼠体重，于给药第21天处死裸小鼠，试验结果见下表4。
表4.化合物对人胰腺癌Mia PaCa-2裸小鼠移植瘤的实验治疗作用
Figure PCTCN2021082251-appb-000042
由上表数据可知，本发明化合物具有很强的体内抗肿瘤活性，10mg/kg/day连续给药21天后可以使肿瘤退缩，化合物6、14、28、60和103体内活性均强于对照药物B。

Claims (10)

  1. 一种如通式(1)所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：
    Figure PCTCN2021082251-appb-100001
    通式(1)中：
    m为1或2的整数；
    n为1或2的整数；
    R 1为H、卤素、C1-C3烷基、C2-C4烯基、C2-C4炔基或C3-C6环烷基；
    R 2为C1-C3烷基或卤代C1-C3烷基；
    R 3为
    Figure PCTCN2021082251-appb-100002
    Figure PCTCN2021082251-appb-100003
    其中R a为H或F，R b为H、F、Cl或Me，R c为H、F、Cl或Me，R d为F、Cl、NH 2、Me或环丙基，R e、R f、R g、R h、R i、R j和R k独立为H、F、Cl、OH、OMe、NH 2、CF 3、C1-C3烷基或C3-C6环烷基；
    R 4为
    Figure PCTCN2021082251-appb-100004
    Figure PCTCN2021082251-appb-100005
    Figure PCTCN2021082251-appb-100006
    其中n 1和n 2独立为1或2的整数，m 1、m 2、m 3和m 4独立为0、1、2、3或4的整数，m 5为1、2或3的整数；A为-CH 2-、-O-、-S-、-SO-、-SO 2-或-N(C1-C3烷基)-，V为-CH 2-、-SO 2-或-CO-，L为-O-、-S-、-SO 2-、-SO-或-CO-；X表示5-7元杂芳基或部分饱和的5-7元杂环烷基；Y为C3-C6环烷基、杂环烷基、(C3-C6)环烷基-(C1-C3)烷基-或杂环烷基-(C1-C3)烷基-；R l和R m独立为C1-C3烷基、卤代C1-C3烷基、羟基取代C1-C3烷基、氰基取代C1-C3烷基、C3-C6环烷基、(C1-C3)烷氧基-(C2-C3)烷基-、(卤代C1-C3)烷氧基-(C2-C3)烷基-、(C3-C6)环烷基-(C1-C3)烷基-；或R l和R m共N原子形成3-8元杂环烷基，所述3-8元杂环烷基可被1-3个选自OH、卤素、氰基、C1-C3烷基、C3-C6环烷基、杂环烷基、(C1-C3)烷氧基或(卤代C1-C3)烷氧基取代；R n为C1-C3烷基、C2-C4烯基、C2-C4炔基、C3-C6环烷基、杂环烷基、卤代C1-C3烷基、羟基取代C1-C3烷基、氰基取代C1-C3烷基、(C1-C3)烷氧基-(C2-C3)烷基-、(卤代C1-C3)烷氧基-(C2-C3)烷基-、(C3-C6)环烷基-(C1-C3)烷基-或杂环烷基-(C1-C3)烷基-；和R o为、OH、卤素、氰基、C1-C3烷基、C1-C3烷氧基或C3-C6环烷基。
  2. 如权利要求1所述的化合物，其中所述通式(1)中，R 1为H、F、Cl、Me、Et、异丙基、乙烯基、乙炔基或环丙基。
  3. 如权利要求1-2中任一项所述的化合物，其中所述通式(1)中，R 2为CH 3、CH 3CH 2、CF 3CH 2、CHF 2CH 2或CF 3(CH 3)CH。
  4. 如权利要求1-3中任一项所述的化合物，其中所述通式(1)中，R 3为
    Figure PCTCN2021082251-appb-100007
    Figure PCTCN2021082251-appb-100008
  5. 如权利要求1-4中任一项所述的化合物，其中所述通式(1)中，R 4为：
    Figure PCTCN2021082251-appb-100009
    Figure PCTCN2021082251-appb-100010
    Figure PCTCN2021082251-appb-100011
    Figure PCTCN2021082251-appb-100012
    Figure PCTCN2021082251-appb-100013
  6. 如权利要求1-5中任一项所述的化合物，或其一种药学上可接受的盐，其中所述化合物具有以下结构之一：
    Figure PCTCN2021082251-appb-100014
    Figure PCTCN2021082251-appb-100015
    Figure PCTCN2021082251-appb-100016
    Figure PCTCN2021082251-appb-100017
    Figure PCTCN2021082251-appb-100018
    Figure PCTCN2021082251-appb-100019
    Figure PCTCN2021082251-appb-100020
    Figure PCTCN2021082251-appb-100021
    Figure PCTCN2021082251-appb-100022
  7. 一种药物组合物，其特征在于，其含有药学上可接受的赋形剂或载体，以及作为活性成分的如权利要求1-6任一项所述的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物。
  8. 一种如权利要求1-6任一项所述的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物或如权利要求7所述的药物组合物在制备治疗、调节和/或预防与K-Ras G12C突变体蛋白相关的疾病的应用。
  9. 一种治疗由K-Ras G12C突变介导的疾病的方法，其包括给与受试者如权利要求 1-6中任一项所述的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物或如权利要求7所述的药物组合物。
  10. 如权利要求9所述的方法，其中所述的疾病是癌症，所述癌症是血液癌和实体瘤。
PCT/CN2021/082251 2020-03-25 2021-03-23 含螺环的喹唑啉化合物 Ceased WO2021190467A1 (zh)

Priority Applications (5)

Application Number Priority Date Filing Date Title
US17/799,060 US12391692B2 (en) 2020-03-25 2021-03-23 Spiro ring-containing quinazoline compound
CA3170068A CA3170068A1 (en) 2020-03-25 2021-03-23 Spiro ring-containing quinazoline compound
CN202180023241.6A CN115335379B (zh) 2020-03-25 2021-03-23 含螺环的喹唑啉化合物
EP21776359.8A EP4130000A4 (en) 2020-03-25 2021-03-23 SPIRO-RING-CONTAINING QUINAZOLINE COMPOUND
JP2022552910A JP7773987B2 (ja) 2020-03-25 2021-03-23 スピロ環含有キナゾリン化合物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010222766.X 2020-03-25
CN202010222766 2020-03-25

Publications (1)

Publication Number Publication Date
WO2021190467A1 true WO2021190467A1 (zh) 2021-09-30

Family

ID=77889931

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/082251 Ceased WO2021190467A1 (zh) 2020-03-25 2021-03-23 含螺环的喹唑啉化合物

Country Status (6)

Country Link
US (1) US12391692B2 (zh)
EP (1) EP4130000A4 (zh)
JP (1) JP7773987B2 (zh)
CN (1) CN115335379B (zh)
CA (1) CA3170068A1 (zh)
WO (1) WO2021190467A1 (zh)

Cited By (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022135470A1 (zh) * 2020-12-22 2022-06-30 上海科州药物研发有限公司 作为kras抑制剂的杂环化合物的制备及其应用方法
WO2022152313A1 (zh) * 2021-01-18 2022-07-21 成都百裕制药股份有限公司 嘧啶衍生物及其在医药上的应用
US11453683B1 (en) 2019-08-29 2022-09-27 Mirati Therapeutics, Inc. KRas G12D inhibitors
WO2022235864A1 (en) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Ras inhibitors
WO2022235870A1 (en) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Ras inhibitors for the treatment of cancer
WO2022247760A1 (zh) * 2021-05-22 2022-12-01 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
WO2022266206A1 (en) 2021-06-16 2022-12-22 Erasca, Inc. Kras inhibitor conjugates
US11548888B2 (en) 2019-01-10 2023-01-10 Mirati Therapeutics, Inc. KRas G12C inhibitors
WO2023060253A1 (en) 2021-10-08 2023-04-13 Revolution Medicines, Inc. Ras inhibitors
WO2023114954A1 (en) 2021-12-17 2023-06-22 Genzyme Corporation Pyrazolopyrazine compounds as shp2 inhibitors
US11702418B2 (en) 2019-12-20 2023-07-18 Mirati Therapeutics, Inc. SOS1 inhibitors
EP4227307A1 (en) 2022-02-11 2023-08-16 Genzyme Corporation Pyrazolopyrazine compounds as shp2 inhibitors
WO2023172940A1 (en) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Methods for treating immune refractory lung cancer
WO2023240263A1 (en) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Macrocyclic ras inhibitors
US11845761B2 (en) 2020-12-18 2023-12-19 Erasca, Inc. Tricyclic pyridones and pyrimidones
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 (en) 2022-10-11 2024-04-18 Aadi Bioscience, Inc. Combination therapies for the treatment of cancer
WO2024102421A2 (en) 2022-11-09 2024-05-16 Revolution Medicines, Inc. Compounds, complexes, and methods for their preparation and of their use
EP4083042A4 (en) * 2019-12-27 2024-07-31 Wigen Biomedicine Technology (Shanghai) Co., Ltd. SPIRO-RING-CONTAINING QUINAZOLINE COMPOUND
WO2024206858A1 (en) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions for inducing ras gtp hydrolysis and uses thereof
WO2024211712A1 (en) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Condensed macrocyclic compounds as ras inhibitors
WO2024211663A1 (en) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Condensed macrocyclic compounds as ras inhibitors
WO2024216016A1 (en) 2023-04-14 2024-10-17 Revolution Medicines, Inc. Crystalline forms of a ras inhibitor
WO2024216048A1 (en) 2023-04-14 2024-10-17 Revolution Medicines, Inc. Crystalline forms of ras inhibitors, compositions containing the same, and methods of use thereof
WO2024229406A1 (en) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Combination therapy for a ras related disease or disorder
US12162893B2 (en) 2020-09-23 2024-12-10 Erasca, Inc. Tricyclic pyridones and pyrimidones
US12208099B2 (en) 2018-09-10 2025-01-28 Mirati Therapeutics, Inc. Combination therapies
WO2025034702A1 (en) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 for use in the treatment of ras protein-related disease or disorder
WO2025067459A2 (en) 2023-09-29 2025-04-03 D3 Bio (Wuxi) Co., Ltd. Therapies for the treatment of cancer
WO2025080946A2 (en) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Ras inhibitors
US12281113B2 (en) 2020-09-11 2025-04-22 Mirati Therapeutics, Inc. Crystalline forms of a KRas G12C inhibitor
US12336995B2 (en) 2018-09-10 2025-06-24 Mirati Therapeutics, Inc. Combination therapies
US12377101B2 (en) 2018-12-05 2025-08-05 Mirati Therapeutics, Inc. Combination therapies
WO2025171296A1 (en) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Ras inhibitors
US12398154B2 (en) 2020-12-15 2025-08-26 Mirati Therapeutics, Inc. Azaquinazoline pan-KRas inhibitors
US12421253B2 (en) 2020-12-16 2025-09-23 Mirati Therapeutics, Inc. Tetrahydropyridopyrimidine pan-KRas inhibitors
WO2025240847A1 (en) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Ras inhibitors
US12485122B2 (en) 2018-09-10 2025-12-02 Mirati Therapeutics, Inc. Combination of palbociclib and adagrasib for lung cancer
WO2025255438A1 (en) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Methods of treating a ras protein-related disease or disorder

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018143315A1 (ja) 2017-02-02 2018-08-09 アステラス製薬株式会社 キナゾリン化合物
CN108779097A (zh) * 2015-11-16 2018-11-09 亚瑞克西斯制药公司 包含取代的杂环基的2-取代的喹唑啉化合物及其使用方法
WO2020028706A1 (en) * 2018-08-01 2020-02-06 Araxes Pharma Llc Heterocyclic spiro compounds and methods of use thereof for the treatment of cancer
WO2020113071A1 (en) * 2018-11-29 2020-06-04 Araxes Pharma Llc Compounds and methods of use thereof for treatment of cancer
WO2020177629A1 (zh) * 2019-03-01 2020-09-10 劲方医药科技(上海)有限公司 螺环取代的嘧啶并环类化合物，其制法与医药上的用途
CN112110918A (zh) * 2019-06-21 2020-12-22 劲方医药科技(上海)有限公司 螺环取代的嘧啶并环类化合物，其制法与医药上的用途

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3280708B1 (en) 2015-04-10 2021-09-01 Araxes Pharma LLC Substituted quinazoline compounds and methods of use thereof
CN113045570A (zh) * 2019-12-27 2021-06-29 微境生物医药科技(上海)有限公司 含螺环的喹唑啉化合物
CN113754659A (zh) * 2020-06-01 2021-12-07 微境生物医药科技(上海)有限公司 含螺环的喹唑啉化合物
JP2023508482A (ja) 2019-12-27 2023-03-02 ウィゲン・バイオメディシン・テクノロジー・（シャンハイ）・カンパニー・リミテッド スピロ環含有キナゾリン化合物

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108779097A (zh) * 2015-11-16 2018-11-09 亚瑞克西斯制药公司 包含取代的杂环基的2-取代的喹唑啉化合物及其使用方法
WO2018143315A1 (ja) 2017-02-02 2018-08-09 アステラス製薬株式会社 キナゾリン化合物
CN110267957A (zh) * 2017-02-02 2019-09-20 安斯泰来制药株式会社 喹唑啉化合物
WO2020028706A1 (en) * 2018-08-01 2020-02-06 Araxes Pharma Llc Heterocyclic spiro compounds and methods of use thereof for the treatment of cancer
WO2020113071A1 (en) * 2018-11-29 2020-06-04 Araxes Pharma Llc Compounds and methods of use thereof for treatment of cancer
WO2020177629A1 (zh) * 2019-03-01 2020-09-10 劲方医药科技(上海)有限公司 螺环取代的嘧啶并环类化合物，其制法与医药上的用途
CN112110918A (zh) * 2019-06-21 2020-12-22 劲方医药科技(上海)有限公司 螺环取代的嘧啶并环类化合物，其制法与医药上的用途

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CAREYSUNDBERG: "ADVANCED ORGANIC CHEMISTRY", vol. A, B, 2000, WILEY
CELL, vol. 172, 2018, pages 578 - 589
GREENWUTS: "PROTECTIVE GROUPS IN ORGANIC SYNTHESIS", 1999, WILEY

Cited By (43)

* 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
US12485122B2 (en) 2018-09-10 2025-12-02 Mirati Therapeutics, Inc. Combination of palbociclib and adagrasib for lung cancer
US12336995B2 (en) 2018-09-10 2025-06-24 Mirati Therapeutics, Inc. Combination therapies
US12208099B2 (en) 2018-09-10 2025-01-28 Mirati Therapeutics, Inc. Combination therapies
US12377101B2 (en) 2018-12-05 2025-08-05 Mirati Therapeutics, Inc. Combination therapies
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
US12304915B2 (en) 2019-12-20 2025-05-20 Mirati Therapeutics, Inc. SOS1 inhibitors
US11702418B2 (en) 2019-12-20 2023-07-18 Mirati Therapeutics, Inc. SOS1 inhibitors
EP4083042A4 (en) * 2019-12-27 2024-07-31 Wigen Biomedicine Technology (Shanghai) Co., Ltd. SPIRO-RING-CONTAINING QUINAZOLINE COMPOUND
US12286431B2 (en) 2020-09-11 2025-04-29 Mirati Therapeutics, Inc. Crystalline forms of a KRas G12C inhibitor
US12281113B2 (en) 2020-09-11 2025-04-22 Mirati Therapeutics, Inc. Crystalline forms of a KRas G12C inhibitor
US12162893B2 (en) 2020-09-23 2024-12-10 Erasca, Inc. Tricyclic pyridones and pyrimidones
US12398154B2 (en) 2020-12-15 2025-08-26 Mirati Therapeutics, Inc. Azaquinazoline pan-KRas inhibitors
US12421253B2 (en) 2020-12-16 2025-09-23 Mirati Therapeutics, Inc. Tetrahydropyridopyrimidine pan-KRas inhibitors
US11845761B2 (en) 2020-12-18 2023-12-19 Erasca, Inc. Tricyclic pyridones and pyrimidones
WO2022135470A1 (zh) * 2020-12-22 2022-06-30 上海科州药物研发有限公司 作为kras抑制剂的杂环化合物的制备及其应用方法
WO2022152313A1 (zh) * 2021-01-18 2022-07-21 成都百裕制药股份有限公司 嘧啶衍生物及其在医药上的应用
WO2022235864A1 (en) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Ras inhibitors
WO2022235870A1 (en) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Ras inhibitors for the treatment of cancer
WO2022247760A1 (zh) * 2021-05-22 2022-12-01 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
WO2022266206A1 (en) 2021-06-16 2022-12-22 Erasca, Inc. Kras inhibitor conjugates
WO2023060253A1 (en) 2021-10-08 2023-04-13 Revolution Medicines, Inc. Ras inhibitors
WO2023114954A1 (en) 2021-12-17 2023-06-22 Genzyme Corporation Pyrazolopyrazine compounds as shp2 inhibitors
EP4227307A1 (en) 2022-02-11 2023-08-16 Genzyme Corporation Pyrazolopyrazine compounds as shp2 inhibitors
WO2023172940A1 (en) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Methods for treating immune refractory lung cancer
WO2023240263A1 (en) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Macrocyclic ras inhibitors
WO2024081674A1 (en) 2022-10-11 2024-04-18 Aadi Bioscience, Inc. Combination therapies for the treatment of cancer
WO2024102421A2 (en) 2022-11-09 2024-05-16 Revolution Medicines, Inc. Compounds, complexes, and methods for their preparation and of their use
WO2024206858A1 (en) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions for inducing ras gtp hydrolysis and uses thereof
WO2024211663A1 (en) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Condensed macrocyclic compounds as ras inhibitors
WO2024211712A1 (en) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Condensed macrocyclic compounds as ras inhibitors
WO2024216048A1 (en) 2023-04-14 2024-10-17 Revolution Medicines, Inc. Crystalline forms of ras inhibitors, compositions containing the same, and methods of use thereof
WO2024216016A1 (en) 2023-04-14 2024-10-17 Revolution Medicines, Inc. Crystalline forms of a ras inhibitor
WO2024229406A1 (en) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Combination therapy for a ras related disease or disorder
WO2025034702A1 (en) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 for use in the treatment of ras protein-related disease or disorder
WO2025067459A2 (en) 2023-09-29 2025-04-03 D3 Bio (Wuxi) Co., Ltd. Therapies for the treatment of cancer
WO2025080946A2 (en) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Ras inhibitors
WO2025171296A1 (en) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Ras inhibitors
WO2025240847A1 (en) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Ras inhibitors
WO2025255438A1 (en) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Methods of treating a ras protein-related disease or disorder

Also Published As

Publication number Publication date
CN115335379A (zh) 2022-11-11
CN115335379B (zh) 2024-03-29
JP7773987B2 (ja) 2025-11-20
EP4130000A4 (en) 2024-07-10
US20230128824A1 (en) 2023-04-27
CA3170068A1 (en) 2021-09-30
US12391692B2 (en) 2025-08-19
EP4130000A1 (en) 2023-02-08
JP2023519815A (ja) 2023-05-15

Similar Documents

Publication Publication Date Title
CN115335379B (zh) 含螺环的喹唑啉化合物
CN114929704B (zh) 含螺环的喹唑啉化合物
CN113767103B (zh) 新型螺环类K-Ras G12C抑制剂
CN114901661B (zh) 新型K-Ras G12C抑制剂
WO2020259432A1 (zh) Kras-g12c抑制剂
EP4144732A1 (en) Benzothiazolyl biaryl compound, and preparation method and use
WO2021213317A1 (zh) Hpk1抑制剂及其制备方法和用途
CN115785068A (zh) Kif18a抑制剂
CN116390728B (zh) 喹唑啉衍生物及其制备方法和用途
CN111763215A (zh) 一种具有含氮杂环结构的化合物及其制备方法和用途
CN113045570A (zh) 含螺环的喹唑啉化合物
WO2022012593A1 (zh) 5，6-二氢吡嗪并[2，3-c]异喹啉化合物
WO2022095909A1 (zh) 用作ntrk激酶抑制剂的化合物及其应用
WO2022002100A1 (zh) 新型苯并咪唑化合物
CN113754659A (zh) 含螺环的喹唑啉化合物
WO2022171088A1 (zh) 吡唑并[3,4-d]嘧啶-3-酮衍生物
RU2851633C1 (ru) Соединения хиназолина, содержащие спиро-кольцо
EP4596553A1 (en) Salt of dioxane quinoline compound, crystal form thereof, preparation methods therefor and uses thereof
WO2021244505A1 (zh) 新型吡嗪化合物
EP4653445A1 (en) Cdk inhibitor and crystal form of pharmaceutically acceptable salt thereof, and use thereof
WO2022171135A1 (zh) 含螺环的喹唑啉衍生物
CN118027024A (zh) 吡啶并[1,2-a]嘧啶-4-酮衍生物及其制备方法和用途
WO2022228511A1 (zh) 作为Wee-1抑制剂的稠环化合物及其制备方法和用途
CN117222649A (zh) 吡咯并嘧啶衍生物及其制备方法和用途
CN118772107A (zh) Hdac抑制剂及其用途

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: 21776359

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 3170068

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2022552910

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2021776359

Country of ref document: EP

Effective date: 20221025

WWG Wipo information: grant in national office

Ref document number: 17799060

Country of ref document: US