WO2022199589A1 - Dérivés de pyrimidine - Google Patents

Dérivés de pyrimidine Download PDF

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Publication number
WO2022199589A1
WO2022199589A1 PCT/CN2022/082343 CN2022082343W WO2022199589A1 WO 2022199589 A1 WO2022199589 A1 WO 2022199589A1 CN 2022082343 W CN2022082343 W CN 2022082343W WO 2022199589 A1 WO2022199589 A1 WO 2022199589A1
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Prior art keywords
phenyl
pharmaceutically acceptable
methoxy
chloro
compound
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PCT/CN2022/082343
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English (en)
Chinese (zh)
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吴凌云
王才林
赵乐乐
黎健
陈曙辉
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南京明德新药研发有限公司
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Publication of WO2022199589A1 publication Critical patent/WO2022199589A1/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
    • A61K31/33—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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • 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 Table
    • 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 a series of pyrimidine derivatives and their applications in preparing medicines for treating related diseases, and specifically discloses a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and their applications in preparing medicines for treating relative diseases.
  • LRRK2 kinase Mutation and overexpression of LRRK2 kinase have increasingly been shown to be fundamental factors in the induction of neurodegenerative diseases, characterized by selective degeneration and cell death of dopaminergic neurons in the substantia nigra. Affects 1% of the population over the age of 65, with hereditary patients accounting for 5-10% of the affected population. In the early stages of the disease, the most obvious symptoms are shaking, slow movement and difficulty walking. Cognitive and behavioral problems also develop later in life, and dementia is often seen later in life.
  • LRRK2 leucine-rich repeat kinase 2
  • NM_198578.2 The NCBI engagement sequence for human LRRK2 mRNA is NM_198578.2.
  • Evidence shows that LRRK2 phosphorylates ⁇ -synuclein at serine-129 and that this phosphorylated form constitutes an important part of Lewy bodies.
  • single nucleotide polypeptides in the functional domain of LRRK2 have been shown to cause common and sporadic neurodegenerative diseases.
  • LRRK2 mutations have identified more than 20 LRRK2 mutations in families with late-onset neurodegenerative disease.
  • the G2019S mutation co-segregates with autosomal dominant and it causes approximately 6% of familial cases and 3% of sporadic cases in Europe.
  • the G2019S mutation occurs in the highly conserved kinase domain, so the G2019S mutation may have an effect on kinase activity.
  • amino acid substitutions at another residue, R1441 have also been implicated in neurodegenerative diseases and have been shown to increase LRRK2 kinase activity.
  • the present invention aims to invent a compound that can highly inhibit LRRK2 kinase, thereby further inventing a drug that can well treat neurodegenerative diseases.
  • the present invention provides compounds of formula (I), pharmaceutically acceptable salts thereof and tautomers thereof,
  • W is selected from
  • L is selected from a single bond and -CH 2 -;
  • R 1 and R 2 are each independently selected from H, F, Cl, Br, I, OH, CN, NH 2 and COOH, or each independently selected from: C 1 optionally substituted with 1, 2 or 3 Rs -6 alkyl, C 1-6 heteroalkyl, 4-6 membered heterocycloalkyl and R a -L 1 -, and R 1 and R 2 are not selected from:
  • R a is selected from H, phenyl, 5-6 membered heteroaryl, C 4-6 cycloalkyl and 4-6 membered heterocycloalkyl;
  • R 1 and R 2 are linked together, building blocks is selected from optionally substituted with 1, 2 or 3 R
  • R 1 with connected together, structural units Selected from optionally substituted with 1, 2 or 3 Rs:
  • R 3 is selected from F, Cl, Br, I, OH, CN, CF 3 and NH 2 ;
  • R 4 are each independently selected from H, F, Cl, Br and I;
  • R 5 and R 6 are independently selected from H, halogen, OH, CN, NH 2 , NO 2 , COOH and R b -L 2 -L 3 -L 4 -, or are independently selected from optionally 2 or 3 R-substituted: C 1-6 alkyl, C 1-6 heteroalkyl, C 4-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl , and R 5 and R 6 are not selected from optionally substituted by 1, 2 or 3 halogens
  • R b is selected from H, halogen, OH, CN, NH 2 , NO 2 , COOH, or optionally substituted with 1 , 2 or 3 Rs: C 1-6 alkyl, C 1-6 heteroalkyl , C 4-6 cycloalkyl, 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl;
  • R 5 and R 6 are linked together, building blocks is selected to form an optionally substituted with 1, 2 or 3 Rs:
  • R 7 is selected from H, halogen, OH, CN, NH 2 , NO 2 , COOH, or from: NH 2 and C 1-3 alkyl optionally substituted with 1, 2 or 3 Rs;
  • R 8 is selected from F, Cl, Br, I, OH, CN and NH 2 ;
  • R is selected from halogen, OH, CN, NH2 , COOH, or selected from: C1-3 alkyl and C1-3 heteroalkyl optionally substituted with 1, 2 or 3 R';
  • R' is selected from F, Cl, Br, I, OH, CN, NH2 , COOH, Me, Et, CF3 , CHF2 , CH2F , NHCH3 and N( CH3 ) 2 ;
  • the number of heteroatoms or heteroatomic groups is independently selected from 1, 2 or 3, respectively.
  • R is selected from F, Cl, Br, I, OH, CN, NH and COOH, or from : Me, Et, Other variables are as defined in the present invention.
  • the above R is selected from F, Cl, Br, I, OH, CN, NH2 , -N( CH3 ) 2 , COOH, Me, Et, CF3 , CHF2 , CH2F , Other variables are as defined in the present invention.
  • the above Ra is selected from H, phenyl and 6-membered heterocycloalkyl, and other variables are as defined herein.
  • the above Ra is selected from H, phenyl and morpholinyl, and other variables are as defined in the present invention
  • Ra is selected from H
  • Other variables are as defined in the present invention.
  • Ra-L 1 - is selected from optionally substituted with 1, 2 or 3 Rs:
  • Other variables are as defined in the present invention.
  • R 1 and R 2 are independently selected from H, F, Cl, Br, I, OH, CN, NH 2 and COOH, or are independently selected from optionally 1, 2 Or 3 R-substituted: C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 alkylamino, N,N'-di(C 1-2 alkyl ) amino- and 5-6 membered heterocycloalkyl, other variables are as defined in the present invention.
  • R 1 and R 2 are independently selected from H, F, Cl, Br, I, OH, CN, NH 2 , COOH, or independently selected from optionally 1, 2 Or 3 R substituted: Me, Other variables are as defined in the present invention;
  • R 1 and R 2 are independently selected from H, F, Cl, Br, I, OH, CN, NH 2 , COOH, CF 3 , Other variables are as defined in the present invention.
  • R 1 and R 2 are linked together, the structural unit selected from Other variables are as defined in the present invention.
  • Rb is selected from H halogen, OH, CN, NH2 , NO2 and COOH, or selected from optionally substituted with 1, 2 or 3 Rs: C1-3 alkylamino, C 1-3 alkoxy, C 1-3 alkylthio, N,N'-bis(C 1-2 alkyl)amino, pyrrolidinyl, morpholinyl, piperazinyl, pyridyl and pyrimidinyl, Other variables are as defined in the present invention.
  • Rb is selected from H halogen, OH, CN, NH2 , NO2 and COOH, or selected from optionally substituted with 1, 2 or 3 Rs:
  • Other variables are as defined in the present invention.
  • R b is selected from the group consisting of: H, halogen, OH, CN, NH 2 , NO 2 , COOH, Other variables are as defined in the present invention.
  • R b -L 2 -L 3 -L 4 - is selected from:
  • Other variables are as defined in the present invention.
  • R 5 and R 6 are independently selected from H, halogen, OH, CN, NH 2 , NO 2 and COOH, or independently selected from optionally 1, 2 or 3 R substituted: C1-3 heteroalkyl, thiazolyl, pyrimidinyl, pyridyl, thienyl, piperidinyl, morpholinyl and piperazinyl, other variables are as defined in the present invention.
  • R 5 and R 6 are each independently selected from H, F, Cl, Br, I, OH, CN, NH 2 , NO 2 and COOH, or independently selected from optionally 1, 2 or 3 R substitutions: Other variables are as defined in the present invention.
  • R 5 and R 6 are independently selected from H, F, Cl, Br, I, OH, CN, NH 2 , NO 2 , COOH, Other variables are as defined in the present invention.
  • R7 is selected from H, or optionally substituted with 1, 2 or 3 Rs: NH2 and CH3 , other variables are as defined herein.
  • R 7 is selected from H, -N(CH 3 ) 2 and CH 3 , and other variables are as defined in the present invention.
  • R 5 and R 6 are linked together, the structural unit Selected from: Other variables are as defined in the present invention.
  • the above-mentioned compounds are selected from
  • R 1 , R 2 , R 3 and R 4 are as defined in the present invention.
  • the present invention also provides compounds, pharmaceutically acceptable salts or tautomers thereof, selected from the group consisting of:
  • the above-mentioned compound, a pharmaceutically acceptable salt thereof, or a tautomer thereof is selected from the group consisting of:
  • the present invention also provides the use of the above compounds, their pharmaceutically acceptable salts and their tautomers in preparing medicines related to LRRK2 kinase inhibitors.
  • salts refers to salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting the neutral forms of such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, and methanesulfonic acids; also include salts of amino acids such as arginine, etc.
  • inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate,
  • Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts.
  • the neutral form of the compound is regenerated by contacting the salt with a base or acid in a conventional manner and isolating the parent compound.
  • the parent form of a compound differs from its various salt forms by certain physical properties, such as solubility in polar solvents.
  • pharmaceutically acceptable salts pertain to derivatives of compounds of the present invention wherein the parent compound is modified by salt formation with an acid or salt formation with a base.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include conventional nontoxic salts or quaternary ammonium salts of the parent compound, such as those formed from nontoxic inorganic or organic acids.
  • non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxy, hydroxynaphthalene, isethionic acid, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, Pamoic acid, pantothenic acid, phenylacetic acid, phosphoric
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.
  • the compounds provided herein also exist in prodrug forms.
  • Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the present invention.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.
  • Certain compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the present invention.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to within the scope of the present invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • Optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art
  • the diastereoisomers were resolved and the pure enantiomers recovered.
  • separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
  • active ingredient refers to a chemical entity that is effective in treating the target disorder, disease or condition.
  • substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable of.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically achievable basis.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with up to two Rs, with independent options for R in each case.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • substituent When a substituent is vacant, it means that the substituent does not exist. For example, when X in AX is vacant, it means that the structure is actually A. When a substituent's bond can be cross-linked to two atoms on a ring, the substituent can bond to any atom on the ring. When a listed substituent does not indicate through which atom it is attached to a compound included in the general formula but not specifically mentioned, such substituent may be bonded through any of its atoms. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds. For example, structural unit Indicates that it can be substituted at any position on cyclohexyl or cyclohexadiene.
  • ring means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl, or heteroaryl. So-called rings include monocyclic, bicyclic, spirocyclic, paracyclic or bridged rings.
  • the number of atoms in a ring is generally defined as the number of ring members, eg, "5-7 membered ring” means 5-7 atoms arranged around it. Unless otherwise specified, the ring optionally contains 1 to 3 heteroatoms.
  • 5-7 membered ring includes, for example, phenyl, pyridine, and piperidinyl; on the other hand, the term “5-7 membered heterocycloalkyl ring” includes pyridyl and piperidinyl, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, wherein each "ring" independently meets the above definition.
  • heterocycle or “heterocyclyl” means a stable heteroatom or heteroatom-containing monocyclic, bicyclic, or tricyclic ring, which may be saturated, partially unsaturated, or unsaturated ( aromatic), which contain carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a benzene ring to form a bicyclic ring.
  • Nitrogen and sulfur heteroatoms can optionally be oxidized (ie, NO and S(O)p, where p is 1 or 2).
  • Nitrogen atoms can be substituted or unsubstituted (ie, N or NR, where R is H or other substituents already defined herein).
  • the heterocycle can be attached to any heteroatom or pendant carbon atom to form a stable structure.
  • the heterocycles described herein may undergo substitution at the carbon or nitrogen positions if the resulting compound is stable.
  • the nitrogen atoms in the heterocycle are optionally quaternized.
  • a preferred solution is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred solution is that the total number of S and O atoms in the heterocycle does not exceed 1.
  • aromatic heterocyclic group or “heteroaryl” means an aromatic ring of a stable 5, 6, 7 membered monocyclic or bicyclic or 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S.
  • Nitrogen atoms can be substituted or unsubstituted (ie, N or NR, where R is H or other substituents already defined herein).
  • Nitrogen and sulfur heteroatoms can optionally be oxidized (ie, NO and S(O)p, where p is 1 or 2). Notably, the total number of S and O atoms on the aromatic heterocycle does not exceed 1.
  • Bridged rings are also included in the definition of heterocycle.
  • a bridged ring is formed when one or more atoms (ie, C, O, N, or S) link two non-adjacent carbon or nitrogen atoms.
  • Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a triple ring. In bridged rings, substituents on the ring may also appear on the bridge.
  • heterocyclic compounds include, but are not limited to: acridinyl, azacinyl, benzimidazolyl, benzofuranyl, benzomercaptofuranyl, benzomercaptophenyl, benzoxazolyl, benzoxanyl oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, Carboline, chromanyl, chromene, cinnolinyldecahydroquinolyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b] tetrahydrofuranyl, furanyl, furanyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl
  • hydrocarbyl or its subordinate concepts (such as alkyl, alkenyl, alkynyl, aryl, etc.) by itself or as part of another substituent means straight chain, branched chain or cyclic Hydrocarbon radicals or combinations thereof, can be fully saturated (such as alkyl), mono- or polyunsaturated (such as alkenyl, alkynyl, aryl), can be mono- or polysubstituted, and can be monovalent (such as methyl), divalent (such as methylene), or polyvalent (such as methine), and may include divalent or polyvalent radicals with the specified number of carbon atoms (such as C1 -C12 for 1 to 12 carbons) , C 1-12 is selected from C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 ; C 3-12 is selected from C 3 , C4
  • Hydrocarbyl includes but is not limited to aliphatic hydrocarbon groups and aromatic hydrocarbon groups
  • the aliphatic hydrocarbon groups include chain and cyclic groups, specifically including but not limited to alkyl, alkenyl, and alkynyl groups
  • the aromatic hydrocarbon groups include but are not limited to 6-12 membered aromatic hydrocarbon groups, such as benzene, naphthalene, etc.
  • the term “hydrocarbyl” refers to straight or branched chain radicals or combinations thereof, which may be fully saturated, mono- or polyunsaturated, and may include divalent and polyvalent radicals.
  • saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl) Methyl, cyclopropylmethyl, and homologues or isomers of n-pentyl, n-hexyl, n-heptyl, n-octyl and other atomic groups.
  • Unsaturated hydrocarbon groups have one or more double or triple bonds, examples of which include but are not limited to vinyl, 2-propenyl, butenyl, crotyl, 2-prenyl, 2-(butadienyl) , 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers body.
  • heterohydrocarbyl or its subordinate concepts (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.) by itself or in combination with another term means a stable straight, branched chain A cyclic or cyclic hydrocarbon radical or a combination thereof, consisting of a certain number of carbon atoms and at least one heteroatom.
  • heteroalkyl by itself or in combination with another term refers to a stable straight chain, branched chain hydrocarbon radical or combination thereof, consisting of a certain number of carbon atoms and at least one heteroatom.
  • the heteroatoms are selected from B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized.
  • a heteroatom or heteroatom group can be located at any internal position within a heterohydrocarbyl group, including where the hydrocarbyl group is attached to the rest of the molecule, but the terms "alkoxy,”"alkylamino,” and “alkylthio" (or thioalkoxy) ) is a conventional expression referring to those alkyl groups attached to the rest of the molecule through an oxygen, amino or sulfur atom, respectively.
  • Up to two heteroatoms may be consecutive, eg -CH2 -NH- OCH3 .
  • cycloalkyl refers to any one of the groups listed above.
  • heterocycloalkyl or subordinate concepts thereof (such as aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl , heterocycloalkynyl, etc.) by themselves or in combination with other terms represent cyclized “hydrocarbyl”, “heterohydrocarbyl”, respectively.
  • a heteroatom may occupy the position at which the heterocycle is attached to the remainder of the molecule.
  • cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocyclyl groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuranindol-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
  • alkyl is used to denote a straight or branched chain saturated hydrocarbon group, which may be monosubstituted (eg -CH2F ) or polysubstituted (eg -CF3 ), may be monovalent (eg methyl), divalent (eg methylene), or polyvalent (eg methine).
  • alkyl groups examples include methyl (Me), ethyl (Et), propyl (eg, n-propyl and isopropyl), butyl (eg, n-butyl, isobutyl, s-butyl) , t-butyl), pentyl (eg, n-pentyl, isopentyl, neopentyl) and the like.
  • alkenyl refers to an alkyl group having one or more carbon-carbon double bonds at any position in the chain, which may be mono- or poly-substituted, and may be mono-, di-, or polyvalent.
  • alkenyl groups include vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexamadienyl, and the like.
  • alkynyl refers to an alkyl group having one or more carbon-carbon triple bonds at any point in the chain, which may be mono- or polysubstituted, and may be mono-, di-, or polyvalent.
  • alkynyl groups include ethynyl, propynyl, butynyl, pentynyl and the like.
  • cycloalkyl includes any stable cyclic or polycyclic hydrocarbon group, any carbon atom is saturated, may be mono- or polysubstituted, and may be monovalent, divalent or polyvalent.
  • examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclodecane, and the like.
  • cycloalkenyl includes any stable cyclic or polycyclic hydrocarbon group containing one or more unsaturated carbon-carbon double bonds at any position on the ring, which may be mono- or polysubstituted, It can be one price, two price or multiple price.
  • examples of such cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and the like.
  • a cycloalkynyl group includes any stable cyclic or polycyclic hydrocarbon group containing one or more carbon-carbon triple bonds at any position on the ring, which may be mono- or polysubstituted, and which may be a price, double price or multiple price.
  • halogen or “halogen” by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
  • haloalkyl is intended to include monohaloalkyl and polyhaloalkyl.
  • halo( C1 - C4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like Wait.
  • examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • Alkoxy represents the above-mentioned alkyl groups having the specified number of carbon atoms attached through an oxygen bridge, and unless otherwise specified, C 1-6 alkoxy includes C 1 , C 2 , C 3 , C 4 , C 5 and C 6 of the alkoxy. Examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, and S- pentoxy.
  • aryl refers to a polyunsaturated aromatic hydrocarbon substituent, which may be mono- or polysubstituted, monovalent, divalent or polyvalent, which may be monocyclic or polycyclic (such as 1 to 3 rings; at least one of which is aromatic), fused together or covalently linked.
  • heteroaryl refers to an aryl group (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatoms are selected from B, N, O, and S, wherein nitrogen and sulfur atoms are optionally oxidized, and nitrogen atoms are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • Non-limiting examples of aryl or heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrrolyl oxazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl azolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thiophene base, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-
  • aryl when used in conjunction with other terms (eg, aryloxy, arylthio, aralkyl) includes aryl and heteroaryl rings as defined above.
  • aralkyl is intended to include those radicals in which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, etc.), including wherein a carbon atom (eg, methylene) has been replaced by, for example, oxygen Atoms are substituted for those alkyl groups such as phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like.
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, affinity substitution reaction).
  • representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters, etc.; acyloxy, such as acetoxy, trifluoroacetoxy, and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to: formyl; acyl groups, such as alkanoyl groups (eg, acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl groups, such as tert-butoxycarbonyl (Boc) ; Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); Arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
  • hydroxy protecting group refers to a protecting group suitable for preventing hydroxyl side reactions.
  • Representative hydroxy protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (eg acetyl); arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and tert-butyl
  • acyl groups such as alkanoyl (eg acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenyl
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
  • aq stands for water
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • EDC represents N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride
  • m-CPBA 3-chloroperoxybenzoic acid
  • eq represents equivalent, equivalent
  • CDI represents Carbonyldiimidazole
  • DCM for dichloromethane
  • PE for petroleum ether
  • DIAD diisopropyl azodicarboxylate
  • DMF N,N-dimethylformamide
  • DMSO dimethyl sulfoxide
  • EtOAc for ethyl acetate Ester
  • EtOH for ethanol
  • MeOH for methanol
  • CBz benzyloxycarbonyl
  • the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction method (SXRD), the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuK ⁇ radiation, and the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
  • SXRD single crystal X-ray diffraction method
  • the cultured single crystal is collected by Bruker D8 venture diffractometer
  • the light source is CuK ⁇ radiation
  • the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
  • the compound diethyl phosphonate (20.00 g, 144.82 mmol, 18.69 mL) was slowly added dropwise to a solution of methylmagnesium bromide (3.0 M tetrahydrofuran solution, 160.00 mL, 480 mmol) in tetrahydrofuran (300 mL), and the mixture was controlled
  • the inner temperature is lower than 10°C. The temperature was slowly raised to room temperature and stirred for 5 hours.
  • the mixture was filtered and concentrated, the resulting residue was diluted with aqueous hydrochloric acid (1 N, 80 mL), the pH was adjusted to about 2, and the resulting mixture was filtered.
  • the filtrate was extracted with dichloromethane (100 mL ⁇ 2), the aqueous layer was separated, and the pH was adjusted to about 9 with aqueous sodium bicarbonate solution, then extracted with dichloromethane (200 mL ⁇ 2).
  • the organic layer was dried over anhydrous sodium sulfate and concentrated to dryness.
  • reaction solution was concentrated under reduced pressure, and the residue was separated and purified by high performance liquid chromatography to obtain (2-((5-chloro-2-((4-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl ) dimethylphosphine oxide (27.0 mg), yield: 42%.
  • Lithium aluminum tetrahydride (198.14 mg, 5.22 mmol) was dissolved in tetrahydrofuran (10 mL), and then 5-amino-2-methyl-isoindoline-1,3-dione was added to the reaction solution at 10 degrees Celsius (400 mg, 2.27 mmol) in tetrahydrofuran (10 mL). The reaction solution was stirred at 80°C for 3 hours.
  • 2-Dimethylphosphoryl benzonitrile (70.0 mg, 0.391 mmol) was dissolved in methanol (10 mL), and wet palladium on carbon (10%, 20 mg) was added to the reaction solution.
  • the reaction solution was reacted under a hydrogen (50 psi) atmosphere at 20°C for 16 hours.
  • the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow solid, which was rinsed with a small amount of ethyl acetate to obtain the crude product 2-dimethylphosphorylbenzylamine (70.0 mg, yellow solid).
  • reaction solution was concentrated, separated and purified by thin layer chromatography (15/1 dichloromethane/methanol) to obtain 2,5-dichloro-N-[(2-dimethylphosphorylphenyl)methyl]pyrimidine-4- Amine (0.1 g, yellow solid, yield: 66%).
  • reaction solution was concentrated under reduced pressure, and the residue was separated and purified by high performance liquid chromatography to obtain 1-[6-[[5-chloro-4-[(2-dimethylphosphorylphenyl)methylamino]pyrimidin-2-yl ]Amino]-5-methoxy-indoline-1-yl]-2-(dimethylamino)acetyl (40.00 mg), yield: 23%.
  • Reaction solution 10mM hydroxyethylpiperazineethanesulfonic acid (PH7.5); 2mM magnesium chloride; 0.5mM ethylene glycol diethyl ether diaminetetraacetic acid; 0.002% polyoxyethylene fatty alcohol ether; 1mM dithiothreitol and 1% DMSO;
  • LRRK2 Recombinant Human Protein express recombinant full-length human LRRK2 Protein in insect Sf9 cells with baculovirus using GST tag;.
  • Substrate 0.4uM Fluorescein-ERM (LRRKtide)peptide; 57uM ATP.
  • HTRF Homogeneous time-resolved fluorescence
  • Test sample (compound prepared in each example) LRRK2 kinase inhibitory activity Compound 1 +++ Compound 2 +++ Compound 3 +++ Compound 4 +++ Compound 5 +++ Compound 6 +++ Compound 7 +++ Compound 8 +++ Compound 9 +++ Compound 10 +++ Compound 11 +++ Compound 12 +++ Compound 13 +++ Compound 14 +++ Compound 15 +++ Compound 16 +++ Compound 17 +++ Compound 18 +++ Compound 19 +++ Compound 20 +++ Compound 21 +++ Compound 22 +++ Compound 23 +++ Compound 24 +++ Compound 25 +++ Compound 26 +++ Compound 27 +++ Compound 28 +++ Compound 29 +++ Compound 30 +++ Compound 31 + Compound 32 + Compound 33 ++ Compound 34 +++ Compound 35 +++ Compound 36 +++ Compound 37 ++
  • the compounds of the present invention have significant and even unexpected LRRK2 kinase inhibitory activity.

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Abstract

L'invention concerne une série de dérivés de pyrimidine et leur utilisation dans la préparation d'un médicament pour le traitement de maladies associées. L'invention concerne spécifiquement un composé tel que représenté par la formule (I) ou un sel pharmaceutiquement acceptable de celui-ci, et son utilisation dans la préparation d'un médicament pour le traitement de maladies associées.
PCT/CN2022/082343 2021-03-23 2022-03-22 Dérivés de pyrimidine WO2022199589A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116870016A (zh) * 2022-12-01 2023-10-13 希格生科（深圳）有限公司 杂芳环化合物及其医药用途

Citations (16)

* 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
WO2012151561A1 (fr) * 2011-05-04 2012-11-08 Ariad Pharmaceuticals, Inc. Composés permettant d'inhiber la prolifération cellulaire dans les cancers induits par l'egfr
CN103153064A (zh) * 2010-10-14 2013-06-12 阿里亚德医药股份有限公司 抑制egfr导致的癌症中细胞增殖的方法
US20140066406A1 (en) * 2008-05-21 2014-03-06 Ariad Pharmaceuticals, Inc. Phosphorus Derivatives as Kinase Inhibitors
CN106699810A (zh) * 2015-11-17 2017-05-24 清华大学 一种含氮杂环化合物及其制备方法与在抑制激酶活性中的应用
WO2017086829A1 (fr) * 2015-11-19 2017-05-26 Закрытое акционерное общество "Р-Фарм" (ЗАО "Р-Фарм") Dichloroacétates de n4-[2-(diméthyl-phosphinoyl)phényl]-n4-(2-méthoxy-4-pipéridin-1-ylphényl)-5-chlor-pirimidin-2,4-diamines substituées en tant que modulateurs d'alk et d'egfr destinés au traitement du cancer
WO2018102366A1 (fr) * 2016-11-30 2018-06-07 Ariad Pharmaceuticals, Inc. Anilinopyrimidines en tant qu'inhibiteurs de kinase 1 progénitrices hématopoïétiques (hpk1)
CN109071512A (zh) * 2016-02-03 2018-12-21 重庆复创医药研究有限公司 作为激酶抑制剂的含磷化合物
WO2019120121A1 (fr) * 2017-12-21 2019-06-27 深圳市塔吉瑞生物医药有限公司 Composé de diphénylaminopyrimidine inhibant l'activité de kinase
CN110467637A (zh) * 2018-05-09 2019-11-19 北京赛特明强医药科技有限公司 一种含有氧化膦类取代苯胺的双氨基氯代嘧啶类化合物、制备方法及其应用
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
CN111718325A (zh) * 2019-03-22 2020-09-29 烟台药物研究所 一种2,4,5-取代嘧啶类化合物及其制备方法和应用
WO2020200191A1 (fr) * 2019-04-04 2020-10-08 Betta Pharmaceuticals Co., Ltd Inhibiteurs d'egfr, compositions et procédés associés
WO2020249048A1 (fr) * 2019-06-12 2020-12-17 上海科技大学 Régulateur de protéine alk et son application antitumorale
WO2021125803A1 (fr) * 2019-12-16 2021-06-24 한국화학연구원 Nouveau dérivé de pyrimidine et utilisation correspondante
WO2021190417A1 (fr) * 2020-03-23 2021-09-30 齐鲁制药有限公司 Nouvel inhibiteur aminopyrimidine d'egfr

Patent Citations (16)

* 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
US20140066406A1 (en) * 2008-05-21 2014-03-06 Ariad Pharmaceuticals, Inc. Phosphorus Derivatives as Kinase Inhibitors
CN103153064A (zh) * 2010-10-14 2013-06-12 阿里亚德医药股份有限公司 抑制egfr导致的癌症中细胞增殖的方法
WO2012151561A1 (fr) * 2011-05-04 2012-11-08 Ariad Pharmaceuticals, Inc. Composés permettant d'inhiber la prolifération cellulaire dans les cancers induits par l'egfr
CN106699810A (zh) * 2015-11-17 2017-05-24 清华大学 一种含氮杂环化合物及其制备方法与在抑制激酶活性中的应用
WO2017086829A1 (fr) * 2015-11-19 2017-05-26 Закрытое акционерное общество "Р-Фарм" (ЗАО "Р-Фарм") Dichloroacétates de n4-[2-(diméthyl-phosphinoyl)phényl]-n4-(2-méthoxy-4-pipéridin-1-ylphényl)-5-chlor-pirimidin-2,4-diamines substituées en tant que modulateurs d'alk et d'egfr destinés au traitement du cancer
CN109071512A (zh) * 2016-02-03 2018-12-21 重庆复创医药研究有限公司 作为激酶抑制剂的含磷化合物
WO2018102366A1 (fr) * 2016-11-30 2018-06-07 Ariad Pharmaceuticals, Inc. Anilinopyrimidines en tant qu'inhibiteurs de kinase 1 progénitrices hématopoïétiques (hpk1)
WO2019120121A1 (fr) * 2017-12-21 2019-06-27 深圳市塔吉瑞生物医药有限公司 Composé de diphénylaminopyrimidine inhibant l'activité de kinase
CN110467637A (zh) * 2018-05-09 2019-11-19 北京赛特明强医药科技有限公司 一种含有氧化膦类取代苯胺的双氨基氯代嘧啶类化合物、制备方法及其应用
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
CN111718325A (zh) * 2019-03-22 2020-09-29 烟台药物研究所 一种2,4,5-取代嘧啶类化合物及其制备方法和应用
WO2020200191A1 (fr) * 2019-04-04 2020-10-08 Betta Pharmaceuticals Co., Ltd Inhibiteurs d'egfr, compositions et procédés associés
WO2020249048A1 (fr) * 2019-06-12 2020-12-17 上海科技大学 Régulateur de protéine alk et son application antitumorale
WO2021125803A1 (fr) * 2019-12-16 2021-06-24 한국화학연구원 Nouveau dérivé de pyrimidine et utilisation correspondante
WO2021190417A1 (fr) * 2020-03-23 2021-09-30 齐鲁制药有限公司 Nouvel inhibiteur aminopyrimidine d'egfr

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEN, YONGFEI ET AL.: "Discovery of N-(5-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methyl-1, 4-diazepan-1-yl)phenyl)acrylamide (CHMFL-ALK/EGFR-050) as a potent ALK/EGFR dual kinase inhibitor capable of overcoming a variety of ALK/EGFR associated drug resistant mutants in NSCLC", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 139, 31 December 2017 (2017-12-31), pages 674 - 697, XP055600563, DOI: 10.1016/j.ejmech.2017.08.035 *
HUANG, WEISHENG ET AL.: "Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase", JOURNAL OF MEDICINAL CHEMISTRY, vol. 59, no. 10, 31 December 2016 (2016-12-31), pages 4948 - 4964, XP055480025, DOI: 10.1021/acs.jmedchem.6b00306 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116870016A (zh) * 2022-12-01 2023-10-13 希格生科（深圳）有限公司 杂芳环化合物及其医药用途
CN116870016B (zh) * 2022-12-01 2024-05-28 希格生科（深圳）有限公司 杂芳环化合物及其医药用途

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