WO2021027911A1 - Nouvel inhibiteur de k-ras g12c spirocyclique - Google Patents

Nouvel inhibiteur de k-ras g12c spirocyclique Download PDF

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WO2021027911A1
WO2021027911A1 PCT/CN2020/109099 CN2020109099W WO2021027911A1 WO 2021027911 A1 WO2021027911 A1 WO 2021027911A1 CN 2020109099 W CN2020109099 W CN 2020109099W WO 2021027911 A1 WO2021027911 A1 WO 2021027911A1
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substituted
alkyl
group
general formula
halogen
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PCT/CN2020/109099
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English (en)
Chinese (zh)
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谢雨礼
樊后兴
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微境生物医药科技(上海)有限公司
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Priority to CN202080029934.1A priority Critical patent/CN113767103B/zh
Publication of WO2021027911A1 publication Critical patent/WO2021027911A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—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
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—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

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.
  • the Ras protein family is an important signal transduction and transmission molecule in the cell, 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 an important cause of the occurrence and development of a variety of cancers. Therefore, targeting and inhibiting the activity of Ras protein are important means to treat related tumors.
  • Ras protein binds to GDP and is in an inactive resting state.
  • 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 a variety of 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%), etc., and 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 effect with TP53 mutation and other factors participates 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.
  • the present invention aims to provide a class of compounds with general structural formula as shown in formula (1), or each of its optical isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
  • L is a chemical bond or NH
  • A is a bivalent 4-12 membered saturated or partially saturated monocyclic, bicyclic, bridged or spiro ring containing 1-2 N atoms.
  • the monocyclic, bicyclic, bridged or spiro ring may be optionally substituted by one R 2 is substituted with one or more, when a plurality of R & lt substituted 2, R 2 may be the same or different, R 2 is H, CN, C1-C3 alkyl, halogen substituted C1-C3 alkyl or cyano-substituted C1- C3 alkyl;
  • 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.
  • the substituents may be the same or different;
  • R a , R b , R c and R d are all H, and R e and R f and their connected carbon atoms form a C3-C6 cycloalkyl or C4-C6 heterocyclic ring; or, R c , R d , R e and R f are both H, R a and R b and the carbon atom to which they are attached form a C3-C6 cycloalkyl or C4-C6 heterocyclic ring; or, R a, R b, R e and R f are both H, R c and R d and the carbon atom to which they are connected form a C3-C6 cycloalkyl or C4-C6 heterocyclic ring; and
  • E is an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of the K-Ras mutant protein
  • Y is a chemical bond or C1-C6 alkylene group
  • R 3 is an amino-substituted alkyl group, cycloalkyl group, alkyl-substituted amido group, heterocyclic group, aryl group or heteroaryl group.
  • the heterocyclic group, aryl group or heteroaryl group can be substituted by 1-3 The group is substituted: halogen, O, CN, OH, hydroxy substituted alkyl, dialkyl substituted amino, C1-C6 alkyl, C3-C6 cycloalkyl, halogen substituted C1-C3 alkyl or halogen substituted C1 -C3 alkoxy, when substituted by multiple substituents, the substituents may be the same or different.
  • L is a chemical bond or NH
  • A is a bivalent 4-12 membered saturated or partially saturated monocyclic, bicyclic, bridged or spiro ring containing 1-2 N atoms.
  • the monocyclic, bicyclic, bridged or spiro ring may be optionally substituted by one R 2 is substituted with one or more, when a plurality of R & lt substituted 2, R 2 may be the same or different, R 2 is H, CN, C1-C3 alkyl, halogen substituted C1-C3 alkyl or cyano-substituted C1- C3 alkyl;
  • 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.
  • the substituents may be the same or different;
  • Y is a chemical bond or C1-C6 alkylene group
  • R 3 is an amino-substituted alkyl group, cycloalkyl group, alkyl-substituted amido group, heterocyclic group, aryl group or heteroaryl group.
  • the heterocyclic group, aryl group or heteroaryl group can be substituted by 1-3 The group is substituted: halogen, O, CN, OH, hydroxy substituted alkyl, dialkyl substituted amino, C1-C6 alkyl, C3-C6 cycloalkyl, halogen substituted C1-C3 alkyl or halogen substituted C1 -C3 alkoxy, when it is substituted by multiple substituents, the substituents may be the same or different;
  • R a , R b , R c and R d are all H, and R e and R f and their connected carbon atoms form a C3-C6 cycloalkyl or C4-C6 heterocyclic ring; or, R c , R d , R e and R f are both H, R a and R b and the carbon atom to which they are attached form a C3-C6 cycloalkyl or C4-C6 heterocyclic ring; or, R a, R b, R e and R f are both H, R c and R d and the carbon atom to which they are connected form a C3-C6 cycloalkyl or C4-C6 heterocyclic ring; and
  • E is an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of the K-Ras mutant protein.
  • E is a group containing an electrophilic carbon-carbon double bond or a carbon-carbon triple bond.
  • E is: Among them, R 4 is H, F, CF 3 , OMe or -CH 2 OMe, and R 5 is H, Me, Et, CN, -CONH 2 , -CH 2 F, -CHF 2 , CF 3 , -CH 2 OH , CH 2 OMe,
  • -ALE is: Wherein, n is 1 or 2, L is a chemical bond or NH, and R 2 is H, CN, C1-C3 alkyl, halogen substituted C1-C3 alkyl, or cyano substituted C1-C3 alkyl.
  • Y is a chemical bond, -CH 2 -, -CH(Me)- or -CH 2 CH 2 -.
  • R 1 is: Wherein R 6 and R 7 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 3 is: Where n is 1, 2 or 3, R 8 and R 9 are independently H, 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, R 10 is C1-C3 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl alkyl, C1-C3 alkoxy alkane Group, halogen substituted C1-C3 alkyl, halogen substituted C3-C6 cycloalkyl or
  • the compound has one of the structures listed in Table 1 below:
  • 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, or each of its optical isomers, pharmaceutically acceptable The inorganic or organic salt as the active ingredient.
  • Another object of the present invention is to provide the use of the above-mentioned compound of the present invention, or each of its optical isomers, or pharmaceutically acceptable inorganic or organic salts, for preparing and treating RAS-related diseases.
  • 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 or 2:
  • Embodiment of the compounds of formula (1) was prepared according to the general reaction Scheme 1, wherein R a, R b, R c , R d, R e, R f, R 1, R 2, R 3, A , E and Y are as defined above.
  • the raw material S (synthesized with reference to the method described in the preparation examples 1-9 of this patent) and the fragment A produce A1 under alkaline conditions, and the protective group of A1 (such as Boc) is removed to obtain A2, A2 and R1-X yielded A3, A3 a compound in the presence of an oxidant A4, A4 and reaction fragment R 3 -Y-OH to generate under appropriate conditions A5, A5 removing the protecting group (e.g., Cbz) to give A6, A6, and acid chlorides Or the acid anhydride compound reacts to form A7.
  • the protective group of A1 such as Boc
  • intermediate A1 generates B1 in the presence of an oxidizing agent
  • B1 is hydrolyzed to B2 under alkaline conditions
  • B2 reacts with R 3 -YX fragments under appropriate conditions to generate B3, and B3 removes the protective group ( For example, Boc) obtains B4
  • B4 is coupled with R1-X to obtain B5
  • B5 is deprotected (for example, Cbz) to obtain B6, and B6 is reacted with acid chloride or acid anhydride compound to generate B7.
  • “Pharmaceutically acceptable” here refers to a substance, such as a carrier or 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 does 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 addition 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.
  • Solvates of the compound of formula (1) are conveniently prepared or formed according to the methods described herein.
  • the hydrate of the compound of 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, dioxane, tetrahydrofuran, 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 formula (1) is prepared in different forms, including, but not limited to, amorphous, pulverized, and nano-particle size forms.
  • the compound of 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 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 formula (1) has one or more stereocenters and is therefore in the form of racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers appear.
  • 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. 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 , i Pr, n Pr, i Bu, c Pr, n Bu or t Bu.
  • 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, c PrO, 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, benzopyridyl and pyrrolopyrimidinyl.
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • 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 unduly harmful effects on the health of the general treatment target.
  • treatment include 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 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 the 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 Etc., and can form an equivalent amount of the active compound in the subject of administration.
  • 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 protective structure (1) compound pharmaceutical compositions.
  • 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 excipient or carrier” refers 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) humectant, 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 gly
  • 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, spray 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 compound 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, wherein the dosage is the pharmaceutically effective dosage considered to be administered.
  • the daily administration dose is usually 1 to 1000 mg, preferably 10 to 500 mg.
  • the specific dosage should also consider factors such as the route of administration, the patient's health status, etc., which are within the skill range of a skilled physician.
  • Ar stands for argon; aq stands for aqueous solution; (Boc) 2 O stands for di-tert-butyl dicarbonate; CDCl 3 stands for deuterated chloroform; CD 3 OD stands for deuterated methanol; CH 3 CN stands for Acetonitrile; CH 3 NO 2 stands for nitromethane; (COCl) 2 stands for oxalyl chloride; Cs 2 CO 3 stands for cesium carbonate; CuI stands for cuprous iodide; DBU stands for 1,8-diaza heterocycle [5,4,0 ]Undecene-7; DCM stands for dichloromethane; DIPEA stands for diisopropylethylamine; Dioxane stands for 1,4-dioxane; DMF stands for dimethylformamide; DMSO stands for dimethyl sulfoxide; EA stands for ethyl acetate; EtOH stands for ethanol; EtONa stands for sodium
  • the target intermediate S-2 was obtained by the synthesis method of intermediate S-1, ESI-MS m/z: 470.1 [M+H] + .
  • the target intermediate S-3 was obtained by the synthesis method of intermediate S-1, ESI-MS m/z:472.1[ M+H] + .
  • the target intermediate S-5 was obtained by the synthetic method of intermediate S-4, ESI-MS m/z: 470.1 [M+H] + .
  • the target intermediate S-6 was obtained by the synthesis method of fragment S-4, ESI-MS m/z: 472.1 [M+H] + .
  • the target intermediate S-8 was obtained by the synthesis method of fragment S-7, ESI-MS m/z: 470.1 [M+H] + .
  • the target intermediate S-9 was obtained by the synthesis method of fragment S-7, ESI-MS m/z: 456.1 [M+H] + .
  • Compound 1 was prepared according to Method A as described below:
  • Example 94 2-((S)-1-(2-fluoroacryloyl)-4-(7'-(8-methylnaphthalene-1-yl)-1'-(((S)-1- (Methylpyrrolidin-2-yl)methyl)-2'-oxy-1',5',7',8'-tetrahydro-2'H-spiro[cyclopropane-1,6'-pyrido[ Synthesis of 3,4-d]pyrimidine)-4'-yl)piperazin-2-yl)acetonitrile (compound 94)
  • Example 166 Detection of pERK and ERK protein content in H358 cells by compounds
  • 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 pERK activity. The results are shown in Table 2 below.
  • Compound Inhibition rate(%) 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 ++
  • +++ means 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 +++
  • IC 50 of the compound is 1 to 30 ⁇ M
  • +++ means that the IC 50 of the compound is less than 1 ⁇ M.

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Abstract

La présente invention concerne un composé spirocyclique et son procédé de préparation et son utilisation, en particulier un composé représenté par la formule (1) et son procédé de préparation, et l'utilisation du composé de formule (1) et des isomères optiques, des formes cristallines et des sels pharmaceutiquement acceptables De ceux-ci en tant qu'inhibiteurs irréversibles d'une protéine K-Ras mutante G12C dans la préparation de médicaments pour des maladies associées à Ras de type antitumoraux.
PCT/CN2020/109099 2019-08-15 2020-08-14 Nouvel inhibiteur de k-ras g12c spirocyclique WO2021027911A1 (fr)

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WO2021107160A1 (fr) * 2019-11-29 2021-06-03 Taiho Pharmaceutical Co., Ltd. Composé ayant une activité inhibitrice contre la mutation kras g12d
WO2021257736A1 (fr) 2020-06-18 2021-12-23 Revolution Medicines, Inc. Méthodes de retardement, de prévention et de traitement de la résistance acquise aux inhibiteurs de ras
WO2022060583A1 (fr) 2020-09-03 2022-03-24 Revolution Medicines, Inc. Utilisation d'inhibiteurs de sos1 pour traiter des malignités à mutations de shp2
US11453683B1 (en) 2019-08-29 2022-09-27 Mirati Therapeutics, Inc. KRas G12D inhibitors
WO2022247760A1 (fr) * 2021-05-22 2022-12-01 上海科州药物研发有限公司 Composés hétérocycliques utiles en tant qu'inhibiteurs de kras, leur préparation et leur utilisation thérapeutique
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
WO2023031781A1 (fr) 2021-09-01 2023-03-09 Novartis Ag Combinaisons pharmaceutiques comprenant un inhibiteur de tead et leurs utilisations pour le traitement de cancers
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
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 (fr) 2022-10-11 2024-04-18 Aadi Bioscience, Inc. Polythérapies pour le traitement du cancer
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

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Cited By (17)

* 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
US11964989B2 (en) 2019-08-29 2024-04-23 Mirati Therapeutics, Inc. KRas G12D inhibitors
US11453683B1 (en) 2019-08-29 2022-09-27 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
WO2021107160A1 (fr) * 2019-11-29 2021-06-03 Taiho Pharmaceutical Co., Ltd. Composé ayant une activité inhibitrice contre la mutation kras g12d
US11702418B2 (en) 2019-12-20 2023-07-18 Mirati Therapeutics, Inc. SOS1 inhibitors
WO2021257736A1 (fr) 2020-06-18 2021-12-23 Revolution Medicines, Inc. Méthodes de retardement, de prévention et de traitement de la résistance acquise aux inhibiteurs de ras
WO2022060583A1 (fr) 2020-09-03 2022-03-24 Revolution Medicines, Inc. Utilisation d'inhibiteurs de sos1 pour traiter des malignités à mutations de shp2
US11845761B2 (en) 2020-12-18 2023-12-19 Erasca, Inc. Tricyclic pyridones and pyrimidones
WO2022247760A1 (fr) * 2021-05-22 2022-12-01 上海科州药物研发有限公司 Composés hétérocycliques utiles en tant qu'inhibiteurs de kras, leur préparation et leur utilisation thérapeutique
WO2022266206A1 (fr) 2021-06-16 2022-12-22 Erasca, Inc. Conjugués d'inhibiteurs de kras
WO2023031781A1 (fr) 2021-09-01 2023-03-09 Novartis Ag Combinaisons pharmaceutiques comprenant un inhibiteur de tead et leurs utilisations pour le traitement de cancers
WO2024081674A1 (fr) 2022-10-11 2024-04-18 Aadi Bioscience, Inc. Polythérapies pour le traitement du cancer
WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations

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