WO2022262857A1 - Composés oxydes d'arylphosphine - Google Patents

Composés oxydes d'arylphosphine Download PDF

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Publication number
WO2022262857A1
WO2022262857A1 PCT/CN2022/099503 CN2022099503W WO2022262857A1 WO 2022262857 A1 WO2022262857 A1 WO 2022262857A1 CN 2022099503 W CN2022099503 W CN 2022099503W WO 2022262857 A1 WO2022262857 A1 WO 2022262857A1
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Prior art keywords
cycloalkyl
compound
alkyl
heteroaryl
haloalkyl
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PCT/CN2022/099503
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English (en)
Chinese (zh)
Inventor
谢雨礼
吴应鸣
樊后兴
钱立晖
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微境生物医药科技(上海)有限公司
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Priority to CN202280043087.3A priority Critical patent/CN117500813A/zh
Publication of WO2022262857A1 publication Critical patent/WO2022262857A1/fr

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    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system

Definitions

  • the present invention relates to the field of medicinal chemistry, and more specifically relates to a class of novel aryl phosphine oxide compounds, a preparation method thereof and the use of the compounds as EGFR inhibitors in the preparation of antitumor drugs.
  • Lung cancer is one of the most common malignant tumors. There are approximately 1.6 million new lung cancer cases worldwide each year, and approximately 1.4 million deaths due to lung cancer each year. Among them, non-small cell lung cancer (NSCLC) accounts for about 80%-85% of the total number of lung cancers (Nature, 2018, 553, 446–454).
  • NSCLC non-small cell lung cancer
  • the EGFR protein family is a class of protein kinases that are responsible for transmitting mitogenic signals and play an important role in growth and development. Analysis and research on a large number of in vitro tumor cells, animal models, and human tumor samples have shown that mutations in EGFR family proteins lead to the development of human tumors, and are one of the important causes of the occurrence and development of various cancers. Therefore, targeting and inhibiting the activity of EGFR mutant proteins is an important means of treating related tumors.
  • EGFR gene mutations can be found in approximately 12 to 47% of non-small cell lung cancers.
  • NSCLC the two most common types of EGFR gene mutations are exon 19 deletion (del19) and L858 missense mutation in exon 21. These two types of mutations lead to continuous ligand-independent activation of the EGFR protein.
  • NSCLC patients with EGFR protein Del19 or L858R mutations are more sensitive to targeted therapy with EGFR protein kinase inhibitors (EGFR TKIs) such as erlotinib, gefitinib, afatinib, or osimertinib, they can obtain a higher (60-85% However, this response usually does not last long, and most patients treated with first- or second-generation EGFR TKIs develop disease progression at about 11 months.
  • Drug resistance analysis shows that in about 50-70% of drug-resistant patients, the molecular mechanism of drug resistance is the second mutation of EGFR gene, called T790M mutation (T790M+) (Cancer Discov.2012, 2, 872-5). This secondary mutation makes the first-generation and second-generation EGFR TKIs lose their inhibitory activity against mutant tumor cells.
  • Osimertinib as a third-generation covalent EGFR TKI, was developed to treat tumors with EGFR del19 and L858R mutations with or without T790M mutations. Although osimertinib has a high response rate for drug resistance caused by the T790M mutation, about 70% of patients will eventually develop drug resistance, and the disease will re-progress after about 10 months (Lung Cancer.2017,108,228-231) .
  • Thress et al first reported the drug resistance analysis of osimertinib based on 15 patients, and found that about 40% of the drug resistance came from the C797S mutation (Nature Medicine, 2015, 21, 560-562).
  • ASCO Piotrowska and Zhou Caicun reported drug resistance analysis of 23 and 99 patients respectively, and the analysis results of both showed that about 22% of the drug resistance was caused by the C797S mutation.
  • the EGFR del19/L858R T790M C797S mutant is a newly emerged EGFR mutant after treatment with the third-generation EGFR TKI, and there are not many studies at present. Only a few fourth-generation EGFR TKIs have been reported to be able to inhibit the EGFR del19/L858R T790M C797S mutant. For example, Boehringer Ingelheim reported that a class of macrocyclic compounds BI-4020 has anti-EGFR del19/L858R T790M C797S mutant activity and in vivo anti-tumor activity (J Med Chem.2019, 62, 10272-10293).
  • the present invention provides a compound represented by general formula (1) or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
  • R 1 is -Cl or -Br
  • R 2 and R 3 are each independently -H, halogen, -CN, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C14) cycloalkyl;
  • R 4 and R 5 are each independently -H, halogen, -CN, -S(O) 2 R 8 , (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C14) cycloalkyl , (C6-C14) aryl, (3-11 yuan) heterocycloalkyl or (5-11 yuan) heteroaryl, wherein the (C1-C6) alkyl, (C1-C6) haloalkyl, ( C3-C14) cycloalkyl, (C6-C14) aryl, (3-11 yuan) heterocycloalkyl or (5-11 yuan) heteroaryl can be independently optionally replaced by one or more of the following groups Substitution: -H, halogen, -R 8 , -OH, -(CH 2 ) n OR 8 , -(CH 2 ) n NR 8 R 9 , -OR 8 , -NR 8
  • R 6 is -H, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C14) cycloalkyl, (C6-C14) aryl, (3-11) heterocycloalkyl or (5-11) heteroaryl, wherein the (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C14) cycloalkyl, (C6-C14) aryl, (3-11 member) heterocycloalkyl or (5-11 member) heteroaryl can be independently optionally substituted by one or more of the following groups: -H, halogen, -R 8 , -OH, -(CH 2 ) n OR 8 , -(CH 2 ) n NR 8 R 9 , -OR 8 , -NR 8 R 9 , -CN, -C(O)NR 8 R 9 , -NR 9 C(O)R 8 , -NR 9 S(O)
  • R 7 is (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C14) cycloalkyl, (C6-C14) aryl, (3-11) heterocycloalkyl or (5- 11-membered) heteroaryl, wherein the (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C14) cycloalkyl, (C6-C14) aryl, (3-11) hetero Cycloalkyl or (5-11 membered) heteroaryl can be independently and optionally substituted by one or more of the following groups: -H, halogen, -R 8 , -OH, -(CH 2 ) n OR 8 , -(CH 2 ) n NR 8 R 9 , -OR 8 , -NR 8 R 9 , -CN, -C(O)NR 8 R 9 , -NR 9 C(O)R 8 , -NR 9 S
  • R and R are each independently -H , (C1-C6) alkyl, (C1-C6) haloalkyl, or (C3-C14) cycloalkyl;
  • p is an integer of 0, 1 or 2
  • n is an integer of 0, 1, 2 or 3
  • m is an integer of 0, 1, 2 or 3.
  • R 2 and R 3 are each independently -H, -F, -Cl, -CN, (C1-C3)alkyl, (C1-C3 ) haloalkyl, (C3-C6) cycloalkyl.
  • R 2 and R 3 are each independently: -H, -F, -Cl, -CN, -CH 3 , -CF 3 or R 2 and R 3 are each independently preferably -H, -F or -CH 3 .
  • R 4 and R 5 are each independently -H, -F, -Cl, -CN, -S(O) 2 CH 3 , (C1- C3) alkyl, (C1-C3) haloalkyl, (C3-C6) cycloalkyl, phenyl, (3-6) heterocycloalkyl or (5-6) heteroaryl, wherein ( C1-C3) alkyl, (C1-C3) haloalkyl, (C3-C6) cycloalkyl, phenyl, (3-6) heterocycloalkyl or (5-6) heteroaryl can be independently Optionally substituted by one or more of the following groups: -H, -F, -Cl, -CH 3 , -OH, -OCH 3 , -CN; or the atoms connected to R 4 and R 5 can jointly form a 6-membered aryl group or (5-6 membered) heteroaryl group, wherein said 6-
  • R 6 is -H, (C1-C3) alkyl, (C1-C3) haloalkyl, (C3-C6) cycloalkyl, (C6 -C10) aryl, (3-6 member) heterocycloalkyl or (5-6 member) heteroaryl; wherein said (C1-C3) alkyl, (C1-C3) haloalkyl, (C3-C6 ) cycloalkyl, (C6-C10) aryl, (3-6 membered) heterocycloalkyl or (5-6 membered) heteroaryl may each independently be optionally substituted by one or more of the following groups:- H, -F, -Cl, -CH3 , -OH, -OCH3 , -CN.
  • R 6 is: -H, -CH 3 , -CH 2 CH 3 or R 6 is preferably -CH 2 CH 3 or R 6 is more preferably -CH 2 CH 3 .
  • R 7 is (C1-C3) alkyl, (C1-C3) haloalkyl, (C3-C5) cycloalkyl, aryl, (3 -6 yuan) heterocycloalkyl or (5-6 yuan) heteroaryl; wherein said (C1-C3) alkyl, (C1-C3) haloalkyl, (C3-C5) cycloalkyl, aryl, (3-6 membered) heterocycloalkyl or (5-6 membered) heteroaryl can be independently and optionally substituted by one or more of the following groups: -H, -F, -Cl, -CH 3 , - OH, -OCH 3 , -CN.
  • R 7 is: -CH 3 , -CH 2 CH 3 , -CF 3 or R 7 is preferably —CH 3 ; m is preferably 2 or 3.
  • representative compounds of the invention have one of the following structures:
  • Another object of the present invention is to provide a pharmaceutical composition, which contains a pharmaceutically acceptable carrier, diluent and/or excipient, and the compound of general formula (1) of the present invention, or its various isomers, Various crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used as active ingredients.
  • Another object of the present invention provides the compound represented by the general formula (1) of the present invention, or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the above-mentioned pharmaceutical composition It is used in the preparation of medicines for treating, regulating or preventing diseases related to EGFR mutation.
  • Another object of the present invention is also to provide a method for treating EGFR mutation-related diseases, including administering to the subject a therapeutically effective amount of the compound (1) described in the general formula of the present invention or its various isomers, various crystal forms, pharmaceutically acceptable Accepted salts, hydrates or solvates or pharmaceutical compositions described above.
  • the inventors found that among the compounds of general formula (1), the compound unexpectedly has a stronger EGFR (del19/T790M /C797S), EGFR (L858R/T790M/C797S), EGFR (del19/T790M) and EGFR (L858R/T790M) inhibitory activity, and in the in vivo pharmacokinetic experiment of mice, the compound of the present invention has more unexpectedly orally High Cmax.
  • the compounds of general formula (1) described above can be synthesized using standard synthetic techniques or known techniques combined with methods herein. In addition, solvents, temperatures and other reaction conditions mentioned herein may vary. Starting materials for the synthesis of compounds can be obtained synthetically or from commercial sources. The compounds described herein and other related compounds having various substituents can be synthesized using well known techniques and starting materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4 th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 th Ed., Vols. A and B (Plenum 2000, 2001), methods in Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3rd Ed., (Wiley 1999). The general methods of compound preparation can be varied by using appropriate reagents and conditions to introduce different groups into the formulas provided herein.
  • the compounds described herein are according to methods well known in the art.
  • the conditions of the method such as reactants, solvent, base, amount of the compound used, reaction temperature, time required for the reaction, etc., are not limited to those explained below.
  • the compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in the 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), wherein the compound of the general formula (1) can be prepared using the following general reaction scheme 1:
  • “Pharmaceutically acceptable” here refers to a substance, such as a carrier or diluent, that does not abolish the biological activity or properties of the compound, and that is relatively nontoxic, e.g., does not cause unwanted biological effects or Interact in a harmful manner with any of its components.
  • the term "pharmaceutically acceptable salt” refers to a form of a compound which does not cause significant irritation to the organism to which it is administered and which does not abolish the biological activity and properties of the compound.
  • the pharmaceutically acceptable salt is obtained by reacting the compound of general formula (1) with an acid, such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic 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 and other organic acids and acidic amino acids such as aspartic acid and glutamic acid.
  • an acid such as hydrochloric acid, hydrobromic acid, hydro
  • references to pharmaceutically acceptable salts are understood to 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, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol.
  • Solvates of compounds of general formula (1) are conveniently prepared or formed according to the methods described herein.
  • the hydrate of the compound of general formula (1) is conveniently prepared by recrystallization from a mixed solvent of water/organic solvent, and the organic solvent used includes but not limited to tetrahydrofuran, acetone, ethanol or methanol.
  • the compounds mentioned herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for purposes of the compounds and methods provided herein.
  • compounds of general formula (1) are prepared in different forms including, but not limited to, amorphous, pulverized and nano-particle sized forms.
  • the compound of the general formula (1) includes crystalline forms and may also be regarded as polymorphic forms.
  • Polymorphs include different lattice arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction spectra, infrared spectra, melting points, densities, hardness, crystal forms, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystal form to predominate.
  • the compounds of general formula (1) may have chiral centers and/or axial chirality and thus exist as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single non- Enantiomeric forms, and cis-trans isomeric forms occur.
  • Each chiral center or axial chirality will independently give rise to two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the invention.
  • the present invention is meant to include all such isomeric forms of these compounds.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds.
  • compounds can be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I), and C-14 ( 14 C).
  • radioactive isotopes 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. Stability, enhanced curative effect, extended drug half-life in vivo and other advantages. All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are encompassed within the scope of the invention.
  • alkyl means a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 6 carbon atoms. Lower alkyl groups having 1 to 4 carbon atoms are preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl. As used herein, “alkyl” includes unsubstituted and substituted alkyl groups, especially alkyl groups substituted with one or more halogens.
  • Preferred alkyl groups are selected from CH3 , CH3CH2 , CF3 , CHF2 , CF3CH2 , CF3 ( CH3 ) CH , iPr , nPr , iBu , nBu or tBu .
  • cycloalkyl means a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic), and if the carbocyclic ring contains at least one double bond, then a partially unsaturated cycloalkyl group may be referred to as "cycloalkyl". alkenyl", or if the carbocyclic ring contains at least one triple bond, a partially unsaturated cycloalkyl group may be referred to as a "cycloalkynyl”. Cycloalkyl groups can include monocyclic or polycyclic (eg, having 2, 3 or 4 fused rings) groups and spirocycles. In some embodiments, cycloalkyl groups are monocyclic.
  • cycloalkyls are monocyclic or bicyclic. Ring-forming carbon atoms of cycloalkyl groups can be optionally oxidized to form oxo or sulfide groups. Cycloalkyl also includes cycloalkylene. In some embodiments, cycloalkyl groups contain 0, 1, or 2 double bonds. In some embodiments, the cycloalkyl contains 1 or 2 double bonds (partially unsaturated cycloalkyl). In some embodiments, cycloalkyl groups can be fused with aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups.
  • cycloalkyl groups can be fused with aryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused with aryl and heterocycloalkyl groups. In some embodiments, a cycloalkyl group can be fused with an aryl group and a cycloalkyl group.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl , norpinenyl, norcarpanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexyl, etc.
  • aryl refers to a hydrocarbon aromatic group, aryl is monocyclic or polycyclic, eg a monocyclic aryl ring fused with one or more carbocyclic aromatic groups.
  • aryl groups include, but are not limited to, phenyl, naphthyl, and phenanthrenyl.
  • heteroaryl refers to an aromatic group containing one or more heteroatoms (O, S or N), and the heteroaryl is monocyclic or polycyclic.
  • a monocyclic heteroaryl ring is fused with one or more carbocyclic aromatic groups or other monocyclic heterocycloalkyl groups.
  • heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolyl, furyl, thienyl, Isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, benzene Pyridyl, pyrrolopyrimidinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl and 1H- Pyrrolo[2,3-b]pyridinyl.
  • heterocycloalkyl means a non-aromatic ring or ring system which may optionally contain as part of the ring structure one or more alkenylene groups having at least one group independently selected from boron, phosphorus, , nitrogen, sulfur, oxygen, and phosphorus heteroatom ring members.
  • a partially unsaturated heterocycloalkyl group may be referred to as a "heterocycloalkenyl” if the heterocycloalkyl group contains at least one double bond, or a partially unsaturated heterocycloalkyl group if the heterocycloalkyl group contains at least one triple bond. may be referred to as a "heterocycloalkynyl".
  • Heterocycloalkyl groups can include monocyclic, bicyclic, spiro, or polycyclic (eg, having two fused or bridged rings) ring systems.
  • heterocycloalkyl is a monocyclic group having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen.
  • the ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group can be optionally oxidized to form oxo or sulfide groups or other oxidized linkages (e.g., C(O), S(O), C(S), or S(O) 2, N-oxide, etc.), or the nitrogen atom can be quaternized.
  • a heterocycloalkyl group can be attached via a ring-forming carbon atom or a ring-forming heteroatom.
  • heterocycloalkyl groups contain 0 to 3 double bonds.
  • heterocycloalkyl groups contain 0 to 2 double bonds.
  • moieties having one or more aromatic rings fused to (i.e., sharing a bond with) the heterocycloalkyl ring such as piperidine, morpholine, azepine or Benzo derivatives such as thienyl.
  • a heterocycloalkyl group containing a fused aromatic ring may be attached via any ring-forming atom, including ring-forming atoms of a fused aromatic ring.
  • heterocycloalkyl include, but are not limited to, azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa -9-Azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrole Alkyl, quinyl, tetrahydrofuryl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolyl, tropane, 4,5,6,7-tetrahydrothiazolo[5,4 -c]pyridyl, 4,5
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • halo or halogen substitution
  • appearing before the group name means that the group is partially or fully halogenated, that is, substituted by F, Cl, Br or I in any combination, preferably Substituted by F or Cl.
  • the substituent "-O-CH 2 -O-" means that two oxygen atoms in the substituent are connected to two adjacent carbon atoms of heterocycloalkyl, aryl or heteroaryl, such as:
  • linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a single bond.
  • membered ring includes any ring structure.
  • member is meant to indicate the number of skeletal atoms that make up the ring.
  • cyclohexyl, pyridyl, pyranyl, and thienyl are six-membered rings
  • cyclopentyl, pyrrolyl, furyl, and thienyl are five-membered rings.
  • fragment refers to a specific portion or functional group of a molecule. Chemical fragments are generally considered to be chemical entities contained in or attached to molecules.
  • keys with wedge-shaped solid lines and dotted wedge keys Indicates the absolute configuration of a stereocenter, with a straight solid line bond and straight dashed keys Indicates the relative configuration of the stereocenter, with a wavy line Indicates wedge-shaped solid-line bond or dotted wedge key or with tilde Indicates a straight solid line key or straight dotted key
  • acceptable means that a formulation ingredient or active ingredient does not have an undue adverse effect on health for the general purpose of treatment.
  • treatment includes alleviating, suppressing or improving the symptoms or conditions of a disease; inhibiting the development of complications; improving or preventing the underlying metabolic syndrome; inhibiting the development of diseases or symptoms, Such as controlling the development of a disease or condition; alleviating a disease or a symptom; causing a disease or a symptom to regress; alleviating a complication caused by a disease or a symptom, or preventing or treating a symptom caused by a disease or a symptom.
  • a certain compound or pharmaceutical composition after administration, can improve a certain disease, symptom or situation, especially improve its severity, delay the onset, slow down the progression of the disease, or reduce the duration of the disease. Circumstances that may be attributable to or related to the administration, whether fixed or episodic, continuous or intermittent.
  • Active ingredient refers to the compound represented by the general formula (1), and the pharmaceutically acceptable inorganic or organic salts of the compound of the general formula (1).
  • the compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial chirality) and thus exist as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single non- Enantiomers occur in the form of enantiomers.
  • the asymmetric centers that can exist depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently give rise to two optical isomers and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the invention.
  • the present invention is meant to include all such isomeric forms of these compounds.
  • composition a compound or composition capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic action.
  • administered, administering, or administration means direct administration of the compound or composition, or administration of a prodrug, derivative, or analog of the active compound Wait.
  • the present invention provides a method of using the compound of general formula (1) or the pharmaceutical composition of the present invention to treat diseases, including but not limited to conditions involving EGFR mutations (such as cancer).
  • a method for treating cancer comprising administering an effective amount of any of the aforementioned pharmaceutical compositions comprising the compound of general structural formula (1) to an individual in need thereof.
  • the cancer is mediated by EGFR mutations.
  • the cancer is lung cancer, pancreatic cancer, colon cancer, bladder cancer, brain cancer, breast cancer, urothelial cancer, prostate cancer, ovarian cancer, head and neck cancer, gastric cancer, mesothelioma, or all cancer metastases.
  • the compounds of the present invention and their pharmaceutically acceptable salts can be made into various preparations, which contain the compounds of the present invention or their pharmaceutically acceptable salts and pharmaceutically acceptable excipients or carriers within the range of safe and effective amounts .
  • safe and effective amount means: the amount of the compound is sufficient to obviously improve the condition without causing severe side effects.
  • the safe and effective dose of the compound is determined according to the specific conditions such as the age, condition, and course of treatment of the subject to be treated.
  • “Pharmaceutically acceptable excipient or carrier” means: one or more compatible solid or liquid filler or gel substances, which are suitable for human use and must be of sufficient purity and low enough toxicity .
  • “Compatibility” herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound.
  • Examples of pharmaceutically acceptable excipients or carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
  • cellulose and derivatives thereof such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as stearic acid, magnesium stearate
  • calcium sulfate such as soybean oil, sesame oil,
  • the compounds of the present invention When the compounds of the present invention are administered, they can be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea, or
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • coatings and shell materials such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • Examples of usable embedding components are polymeric substances and waxy substances.
  • the active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms 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, etc.
  • 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
  • compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, 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 alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous 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 vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for topical administration of a compound of this invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required, if necessary.
  • the compounds of the present invention may 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 a pharmaceutically effective dosage when administered, for a person with a body weight of 60kg, the daily
  • the dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg.
  • factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.
  • 1 H-NMR was recorded by a Varian Mercury 400 nuclear magnetic resonance apparatus, and the chemical shifts were expressed in ⁇ (ppm); the silica gel used for separation was 200-300 mesh, and the ratio of the eluent was volume ratio.
  • CDCl 3 represents deuterated chloroform
  • DMSO-d 6 represents deuterated dimethyl sulfoxide
  • CD 3 OD represents deuterated methanol
  • t-BuOH represents tert-butanol
  • EtOAc represents ethyl acetate
  • Hexane stands for n-hexane
  • DCM stands for dichloromethane
  • MeOH stands for methanol
  • ACN stands for acetonitrile
  • 1,4-Dioxane stands for 1,4-dioxane
  • DMF stands for N,N-dimethylformamide
  • AcOH stands for acetic acid
  • THF stands for tetrahydrofuran
  • DMSO stands for dimethyl sulfoxide
  • hr stands for hour
  • min stands for minute
  • ICl stands for iodine chloride
  • KOAc stands for potassium acetate
  • K 3 PO 4 stands for potassium phosphate
  • Cs 2 CO 3 stands
  • Int_1-6 (562mg, 1.76mmol), MeOH (10mL), (methylsulfonyl)ethylene (188mg, 1.77mmol) were added to a 100mL single-necked bottle, and the reaction was stirred at room temperature under argon protection for 48 hours. The product was detected by LC-MS, and the mixture was concentrated to obtain a crude product, which was purified by column chromatography to obtain a brown oily product (40 mg, yield: 5.3%).
  • Int_1-8 (100mg, 0.69mmol) was dissolved in acetic acid (2ml), and a solution of iodine monochloride (144.4mg, 0.90mmol) in acetic acid (1mL) was added dropwise at 10°C. Naturally raised to room temperature and stirred for 2 hours. TLC detection showed that the reaction was complete.
  • the reaction solution was poured into 30 g of crushed ice and stirred for 10 minutes. Saturated aqueous sodium thiosulfate solution (1 ml) was added and stirred at room temperature for 5 minutes. Extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, the residue was column chromatographed to give a light yellow solid (80 mg, yield: 42.9%).
  • int_1-10 (6.3g, 28.5mmol) was dissolved in anhydrous tetrahydrofuran (200mL), and LiHMDS tetrahydrofuran solution (34.18ml, 34.18mmol, 1M) was added dropwise at 0°C under the protection of argon. After stirring at 0°C for 10 minutes, 5-bromo-2,4-dichloropyrimidine (7.14 g, 31.3 mmol) was added, and the mixture was naturally raised to room temperature and stirred for 2 hours.
  • reaction was quenched by adding saturated ammonium chloride aqueous solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was obtained by column chromatography as a yellow solid (5.06 g, yield: 43.1%).
  • int_1-7 (40mg, 0.094mmol) and int_1-12 (39mg, 0.094mmol) were added to tert-butanol (5 mL), then methanesulfonic acid (36mg, 0.38mmol) was added dropwise, and the reaction mixture was Reaction at 80°C overnight, LCMS monitoring complete reaction, concentrated under reduced pressure, then the crude product was separated and purified by Prep-HPLC (0.1% TFA) to obtain the target product as a yellow solid (13 mg, yield: 17.3%).
  • the target product was obtained as light yellow solid (1.07g, yield 64.3%).
  • the product was obtained as a white solid (400 mg, yield 46.7%).
  • reaction was quenched by adding saturated ammonium chloride aqueous solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by pulping to obtain the product as a yellow solid (340 mg, yield 44.4%).
  • Int_16-4 (100 mg, 250 ⁇ mol), int1_1-12 (106 mg, 250 ⁇ mol) and methanesulfonic acid (292 mg, 2000 ⁇ mol) were dissolved in 10 mL of tert-butanol.
  • the reaction was carried out overnight at 80 °C under the protection of argon.
  • LC-MS monitoring showed that the reaction was almost complete, and a small amount of raw materials remained.
  • Dilute hydrochloric acid was added to the reaction solution to adjust the pH to 2
  • the organic phase was washed twice with EA, the aqueous phase was adjusted to pH 10 with sodium hydroxide, and extracted with DCM.
  • the solvent was removed by concentration under reduced pressure, and the residue was purified by Prep-HPLC (0.1% FA).
  • Int_1-1 (3.55 g, 9.51 mmol), int_17-1 (2.07 g, 9.94 mmol), Pd(dppf) 2 Cl 2 (665 mg, 0.95 mmol) and potassium carbonate (2.57 g, 18.6 mmol) were added to 60 mL di In a mixed solution of oxane and 15mL of water. Heated to reflux overnight under the protection of argon. LC-MS monitored that the reaction was complete, and no raw materials remained.
  • the intermediate was obtained as a white solid (2.91 g, yield 82.0%).
  • the formate salt of the target product was obtained as a black solid after lyophilization (10 mg, yield 22.3%).
  • Int_1-12 (41 mg, 99 ⁇ mol), int_20-1 (30 mg, 76 ⁇ mol) and camphorsulfonic acid (113 mg, 486 ⁇ mol) were dissolved in 5 mL of tert-butanol.
  • the reaction was carried out overnight at 80 °C under the protection of argon.
  • LC-MS monitoring showed that the reaction was almost complete, and a small amount of raw materials remained.
  • Dilute hydrochloric acid was added to the reaction solution to adjust the pH to 2
  • the organic phase was washed twice with EA, the aqueous phase was adjusted to pH 10 with sodium hydroxide, and extracted with DCM.
  • the solvent was removed by concentration under reduced pressure, and the residue was purified by Prep-HPLC.
  • the formate salt of the product was obtained as a yellow solid after lyophilization (10 mg, yield 36.1%).
  • Embodiment 5-23 The synthesis of concrete compound 2-15,18,19,21-23
  • the target compounds 2-15, 18, 19, and 21-23 in Table 1 can be obtained by using the synthesis method of Example 1-4 and using different raw materials.
  • Comparative compound A was prepared according to the method described in Example 41 of WO2019/015655.
  • Example 24 Detection of the inhibitory activity of the compounds of the present invention on EGFR (del19/T790M/C797S), EGFR (L858R/T790M/C797S) or EGFR (WT) enzymes
  • WT or mutant EGFR protein was incubated with serially diluted compounds at 28°C for 10 minutes, then biotin-labeled universal tyrosine kinase substrate (TK) and ATP were added, and reacted at room temperature for 40 minutes. After terminating the reaction, Eu3+-Cryptate labeled antibody against TK and streptavidin-XL665 were added and incubated at room temperature for 60 minutes. The level of TK substrate phosphorylation was quantified by detecting the luminescence at 615 nm and 665 nm and calculating the ratio 665/615. The percent inhibition and IC50 of the compounds were calculated compared to the control group. The results are shown in Table 2 below.
  • +++ indicates that the inhibition rate is greater than 50%
  • N.D means activity not determined
  • the compounds of the present invention have better inhibitory activity on the enzymatic activity of EGFR (del19/T790M/C797S) and EGFR (L858R/T790M/C797S), and have better inhibitory activity on EGFR (WT). selective.
  • Example 25 Compounds of the present invention and comparative compound A have effects on EGFR (del19/T790M/C797S), EGFR (L858R/T790M/C797S), EGFR (del19/T790M), EGFR (L858R/T790M), EGFR (del19), EGFR ( Comparison of inhibitory activity of L858R) or EGFR (WT)
  • the HTRF method was used to determine the effect of the compound on EGFR(del19/T790M/C797S), EGFR(L858R/T790M/C797S), EGFR(del19/T790M), EGFR(L858R/T790M), EGFR(del19), EGFR(L858R) or EGFR( Inhibition of WT) enzyme activity. details as follows:
  • WT or mutant EGFR protein was incubated with serially diluted compounds at 28°C for 10 minutes, then biotin-labeled universal tyrosine kinase substrate (TK) and ATP were added, and reacted at room temperature for 40 minutes. After terminating the reaction, Eu3+-Cryptate labeled antibody against TK and streptavidin-XL665 were added and incubated at room temperature for 60 minutes. The level of TK substrate phosphorylation was quantified by detecting the luminescence at 615 nm and 665 nm and calculating the ratio 665/615. The percent inhibition and IC50 of the compounds were calculated compared to the control group. The results are shown in Table 3 below.
  • the compound 1 of the present invention has enzymes for EGFR (del19/T790M/C797S), EGFR (L858R/T790M/C797S), EGFR (del19/T790M) and EGFR (L858R/T790M)
  • the activity has better inhibitory activity, indicating that the introduction of sulfone group in the structure is beneficial to the inhibitory activity of EGFR (del19/T790M/C797S), EGFR (L858R/T790M/C797S), EGFR (del19/T790M) and EGFR (L858R/T790M)
  • 3000 Ba/F3 cells carrying EGFR (del19/T790M/C797S) were planted in a 384-well plate, and after one day of growth, compound was added in a gradient dilution (up to 500 nM for Ba/F3 cells). Three days after the compound was added, Cell Titer Glow was added to evaluate the cell growth, and the percentage of inhibition of cell growth and the IC50 value of the compound were calculated. The results are shown in Table 4 below.
  • Compound 1 of the present invention has strong anti-proliferation activity on Ba/F3 (EGFR del19/T790M/C797S ) triple mutant cells.
  • Embodiment 27 In vivo pharmacokinetic experiment of the compound of the present invention
  • CD-1 female mice aged 7 to 10 weeks were selected, and the doses of intravenous and oral administration were 2 mg/Kg and 10 mg/Kg, respectively. Mice were fasted for at least 12 hours before administration, fed again 4 hours after administration, and had free access to water throughout the experiment.
  • the animals in the intravenous group were administered with the corresponding compound through a single injection of the tail vein, and the administration volume was 10 ml/Kg. Animals in the oral group were given the corresponding compound by intragastric single injection, and the administration volume was 10 ml/Kg. The animals were weighed before administration, and the administration volume was calculated according to the body weight. Sample collection time: 0.083 (injection group), 0.25, 0.5, 1, 2, 4, 8, 24h.

Abstract

L'invention concerne une classe de composés oxydes d'arylphosphine. Plus précisément, la présente invention concerne une classe de composés tels que représentés dans la formule générale (1), un procédé de préparation associé, et l'utilisation des composés tels que représentés dans la formule générale (1) et des isomères, des formes cristallines et des sels pharmaceutiquement acceptables de ceux-ci en tant qu'inhibiteur d'EGFR dans la préparation de médicaments contre des maladies associées à l'EGFR telles que des tumeurs.
PCT/CN2022/099503 2021-06-17 2022-06-17 Composés oxydes d'arylphosphine WO2022262857A1 (fr)

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WO2019015655A1 (fr) * 2017-07-19 2019-01-24 正大天晴药业集团股份有限公司 Composé aryl-phosphore-oxygène utilisé en tant qu'inhibiteur de kinase egfr
CN109593102A (zh) * 2018-01-04 2019-04-09 深圳市塔吉瑞生物医药有限公司 一种氘代二苯氨基嘧啶类化合物的制备方法及其晶型
CN110467638A (zh) * 2018-05-09 2019-11-19 北京赛特明强医药科技有限公司 一种含有间氯苯胺类取代基的双氨基氯代嘧啶类化合物、制备方法及其应用
CN112538072A (zh) * 2019-09-21 2021-03-23 齐鲁制药有限公司 新型氨基嘧啶类egfr抑制剂
WO2021104441A1 (fr) * 2019-11-29 2021-06-03 江苏先声药业有限公司 Composé polyaromatique utilisé en tant qu'inhibiteur de kinase egfr

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102105150A (zh) * 2008-05-21 2011-06-22 阿里亚德医药股份有限公司 用作激酶抑制剂的磷衍生物
WO2017101803A1 (fr) * 2015-12-15 2017-06-22 合肥中科普瑞昇生物医药科技有限公司 Nouveau double inhibiteur de egfr et de alk
CN108689994A (zh) * 2017-07-01 2018-10-23 浙江同源康医药股份有限公司 用作alk激酶抑制剂的化合物及其应用
WO2019015655A1 (fr) * 2017-07-19 2019-01-24 正大天晴药业集团股份有限公司 Composé aryl-phosphore-oxygène utilisé en tant qu'inhibiteur de kinase egfr
CN109593102A (zh) * 2018-01-04 2019-04-09 深圳市塔吉瑞生物医药有限公司 一种氘代二苯氨基嘧啶类化合物的制备方法及其晶型
CN110467638A (zh) * 2018-05-09 2019-11-19 北京赛特明强医药科技有限公司 一种含有间氯苯胺类取代基的双氨基氯代嘧啶类化合物、制备方法及其应用
CN112538072A (zh) * 2019-09-21 2021-03-23 齐鲁制药有限公司 新型氨基嘧啶类egfr抑制剂
WO2021104441A1 (fr) * 2019-11-29 2021-06-03 江苏先声药业有限公司 Composé polyaromatique utilisé en tant qu'inhibiteur de kinase egfr

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