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WO2022199589A1 - Pyrimidine derivatives - Google Patents

Pyrimidine derivatives 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
Prior art date
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Ceased
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PCT/CN2022/082343
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French (fr)
Chinese (zh)
Inventor
吴凌云
王才林
赵乐乐
黎健
陈曙辉
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Medshine Discovery Inc
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Medshine Discovery Inc
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Publication of WO2022199589A1 publication Critical patent/WO2022199589A1/en
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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

A series of pyrimidine derivatives and the use thereof in the preparation of a drug for treating related diseases. Specifically disclosed are a compound as represented by formula (I) or a pharmaceutically acceptable salt thereof, and the use thereof in the preparation of a drug for treating related diseases

Description

嘧啶衍生物Pyrimidine derivatives

本申请主张如下优先权：This application claims the following priority:

PCT/CN2021/082459，申请日2021年03月23日。PCT/CN2021/082459, filed on March 23, 2021.

技术领域technical field

本发明涉及一系列嘧啶衍生物及其在制备治疗相关疾病药物中的应用，具体公开了式(I)所示化合物或其药学上可接受的盐及其在制备治疗相关疾病药物中的应用。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.

背景技术Background technique

LRRK2激酶的突变及过表达越来越多地被证明是诱发神经退行性疾病的根本因素，以黑质区中多巴胺能神经元的选择性变性和细胞死亡为主要特征。影响着1％的65岁以上的人群，其中遗传性患者占发病人群的5-10％。该疾病的早期，最明显的症状表现为摇动,活动缓慢和行走困难。后期还会出现认知和行为问题，晚期通常会出现痴呆。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.

越来越多的证据显示富含亮氨酸重复序列的激酶2(LRRK2)突变与神经退行性疾病有不可分割的联系，LRRK2是一种在催化磷酸化和GTP-GDP水解中涉及的2527氨基酸蛋白。人类LRRK2mRNA的NCBI参与序列是NM_198578.2。证据显示，LRRK2在丝氨酸-129处磷酸化a-突触核蛋白，并且这一磷酸化形式构成路易体的重要部分。另外，已经显示LRRK2的功能结构域中的单核苷酸多肽性引起常见性且散发性神经退行性疾病。目前为止，研究人员已经在患有迟发型神经退行性疾病的家族中识别了超过20个LRRK2突变。例如G2019S突变与常染色体显性共分离，并且其在欧洲导致约6％的家庭性病例和3％散发性病例。G2019S突变发生在高度保守的激酶结构域，因此G2019S突变可能对激酶活性有影响。此外，在另一残基R1441上的氨基酸取代也与神经退行性疾病有关，并且显示提高了LRRK2激酶的活性。在转基因小鼠模型中的突变体LRRK2蛋白R1441G的过度表达与多巴胺释放减少有关，显示LRRK2抑制剂也能积极地调节多巴胺的释放并且在治疗以及多巴胺释放减少有关，显示LRRK2抑制剂也能积极地调节多巴胺的释放并且在治疗以降低的多巴胺水平为特征的疾病中具有潜在效用。相关的数据进一步显示了LRRK2激酶活性抑制剂也可用于治疗相关的神经变性疾病。Growing evidence shows that mutations in leucine-rich repeat kinase 2 (LRRK2), a 2527 amino acid involved in catalytic phosphorylation and GTP-GDP hydrolysis, are inextricably linked to neurodegenerative diseases protein. The NCBI engagement sequence for human LRRK2 mRNA is NM_198578.2. Evidence shows that LRRK2 phosphorylates α-synuclein at serine-129 and that this phosphorylated form constitutes an important part of Lewy bodies. In addition, single nucleotide polypeptides in the functional domain of LRRK2 have been shown to cause common and sporadic neurodegenerative diseases. To date, researchers have identified more than 20 LRRK2 mutations in families with late-onset neurodegenerative disease. For example 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. In addition, amino acid substitutions at another residue, R1441, have also been implicated in neurodegenerative diseases and have been shown to increase LRRK2 kinase activity. Overexpression of the mutant LRRK2 protein R1441G in a transgenic mouse model was associated with reduced dopamine release, showing that LRRK2 inhibitors also positively regulate dopamine release and were associated with treatment as well as reduced dopamine release, showing that LRRK2 inhibitors also positively Modulates dopamine release and has potential utility in the treatment of diseases characterized by reduced dopamine levels. Relevant data further show that inhibitors of LRRK2 kinase activity are also useful in the treatment of related neurodegenerative diseases.

因此，开发有效的LRRK2激酶以及突变的LRRK2激酶的抑制剂成为目前治疗神经退行性疾病的一条重要的途径。本发明旨在发明一种可以高度对LRRK2激酶抑制的化合物，从而进一步发明可以很好的治疗神经退行性疾病的药物。Therefore, the development of effective LRRK2 kinase and mutant LRRK2 kinase inhibitors has become an important way to treat neurodegenerative diseases. 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.

ACS Med.Chem.Lett.2015,6,584-589公开了化合物JH-II-127，属于LRRK2激酶抑制剂，其结构式如式(III)所示：ACS Med.Chem.Lett.2015,6,584-589 discloses compound JH-II-127, which belongs to LRRK2 kinase inhibitor, and its structural formula is shown in formula (III):

Figure PCTCN2022082343-appb-000001
Figure PCTCN2022082343-appb-000001

发明内容SUMMARY OF THE INVENTION

本发明提供式(I)化合物、其药学上可接受的盐及其互变异构体，The present invention provides compounds of formula (I), pharmaceutically acceptable salts thereof and tautomers thereof,

Figure PCTCN2022082343-appb-000002
Figure PCTCN2022082343-appb-000002

其中，in,

W选自

Figure PCTCN2022082343-appb-000003
W is selected from
Figure PCTCN2022082343-appb-000003

L选自单键和-CH 2-； L is selected from a single bond and -CH 2 -;

R 1和R 2分别独立地选自H、F、Cl、Br、I、OH、CN、NH 2和COOH，或分别独立地选自任选被1、2或3个R取代的：C 1-6烷基、C 1-6杂烷基、4～6元杂环烷基和R a-L 1-，且R 1、R 2不选自：

Figure PCTCN2022082343-appb-000004
Figure PCTCN2022082343-appb-000005
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:
Figure PCTCN2022082343-appb-000004
Figure PCTCN2022082343-appb-000005

R a选自H、苯基、5～6元杂芳基、C 4-6环烷基和4～6元杂环烷基； R a is selected from H, phenyl, 5-6 membered heteroaryl, C 4-6 cycloalkyl and 4-6 membered heterocycloalkyl;

L 1选自-C(＝O)-、-C(＝O)NH-、-S(＝O)-、-S(＝O) 2-、-CH 2-和-CH 2CH 2-； L 1 is selected from -C(=O)-, -C(=O)NH-, -S(=O)-, -S(=O) 2 -, -CH 2 - and -CH 2 CH 2 -;

或者，R 1与R 2连接在一起，结构单元

Figure PCTCN2022082343-appb-000006
选自任选被1、2或3个R取代的
Figure PCTCN2022082343-appb-000007
Alternatively, R 1 and R 2 are linked together, building blocks
Figure PCTCN2022082343-appb-000006
is selected from optionally substituted with 1, 2 or 3 R
Figure PCTCN2022082343-appb-000007

或者，R 1与

Figure PCTCN2022082343-appb-000008
连接在一起，结构单元
Figure PCTCN2022082343-appb-000009
选自任选被1、2或3个R取代的： Alternatively, R 1 with
Figure PCTCN2022082343-appb-000008
connected together, structural units
Figure PCTCN2022082343-appb-000009
Selected from optionally substituted with 1, 2 or 3 Rs:

Figure PCTCN2022082343-appb-000010
Figure PCTCN2022082343-appb-000010

R 3选自F、Cl、Br、I、OH、CN、CF 3和NH 2； R 3 is selected from F, Cl, Br, I, OH, CN, CF 3 and NH 2 ;

R 4分别独立地选自H、F、Cl、Br和I； R 4 are each independently selected from H, F, Cl, Br and I;

R 5和R 6分别独立地选自H、卤素、OH、CN、NH 2、NO 2、COOH和R b-L 2-L 3-L 4-，或分别独立地选自任选被1、2或3个R取代的：C 1-6烷基、C 1-6杂烷基、C 4-6环烷基、4～6元杂环烷基、苯基和5～6元杂芳基，且R 5和R 6不选自任选被1、2或3个卤素取代的

Figure PCTCN2022082343-appb-000011
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
Figure PCTCN2022082343-appb-000011

R b选自H、卤素、OH、CN、NH 2、NO 2、COOH，或选自任选被1、2或3个R取代的：C 1-6烷基、C 1- 6杂烷基、C 4-6环烷基、4～6元杂环烷基和5～6元杂芳基； 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;

L 2、L 3和L 4分别独立地选自单键、O、S、NH、-C(＝O)-、-C(＝O)NH-、-S(＝O)-、-S(＝O) 2-、-(CH 2) 1-3-、苯基、5～6元杂芳基和4～6元杂环烷基，且L 2、L 3和L 4不同时选自单键； L 2 , L 3 and L 4 are each independently selected from single bond, O, S, NH, -C(=O)-, -C(=O)NH-, -S(=O)-, -S( =O) 2 -, -(CH 2 ) 1-3 -, phenyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl, and L 2 , L 3 and L 4 are not simultaneously selected from mono- key;

或者，R 5和R 6连接在一起，结构单元

Figure PCTCN2022082343-appb-000012
选自形成一个任选被1、2或3个R取代的： Alternatively, R 5 and R 6 are linked together, building blocks
Figure PCTCN2022082343-appb-000012
is selected to form an optionally substituted with 1, 2 or 3 Rs:

Figure PCTCN2022082343-appb-000013
Figure PCTCN2022082343-appb-000013

R 7选自H、卤素、OH、CN、NH 2、NO 2、COOH，或选自任选被1、2或3个R取代的：NH 2和C 1-3烷基； 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选自F、Cl、Br、I、OH、CN和NH 2； R 8 is selected from F, Cl, Br, I, OH, CN and NH 2 ;

R选自卤素、OH、CN、NH 2、COOH，或选自任选被1、2或3个R’取代的：C 1-3烷基和C 1-3杂烷基； 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’选自F、Cl、Br、I、OH、CN、NH 2、COOH、Me、Et、CF 3、CHF 2、CH 2F、NHCH 3和N(CH 3) 2； R' is selected from F, Cl, Br, I, OH, CN, NH2 , COOH, Me, Et, CF3 , CHF2 , CH2F , NHCH3 and N( CH3 ) 2 ;

所述C 1-6杂烷基、C 1-3杂烷基、4～6元杂环烷基和5～6元杂芳基之杂原子或杂原子团，选自-C(＝O)NH-、-NH-、-C(＝NH)-、-S(＝O) 2NH-、-S(＝O)NH-、-N＝、-O-、-S-、-O-N＝、-C(＝O)O-、-C(＝O)-、-S(＝O)-、 -S(＝O) 2-和-NHC(＝O)NH-； The heteroatom or heteroatom group of the C 1-6 heteroalkyl, C 1-3 heteroalkyl, 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl group is selected from -C(=O)NH -, -NH-, -C(=NH)-, -S(=O) 2 NH-, -S(=O)NH-, -N=, -O-, -S-, -ON=, - C(=O)O-, -C(=O)-, -S(=O)-, -S(=O) 2- and -NHC(=O)NH-;

以上任何一种情况下，杂原子或杂原子团的数目分别独立地选自1、2或3。In any of the above cases, the number of heteroatoms or heteroatomic groups is independently selected from 1, 2 or 3, respectively.

在本发明的一些方案中，上述R选自F、Cl、Br、I、OH、CN、NH 2和COOH，或选自任选被1、2或3个R’取代的：C 1-3烷基、C 1-3烷氧基和C 1-3烷基-C(＝O)-，其他变量如本发明所定义； In some aspects of the present invention, the above R is selected from F, Cl, Br, I, OH, CN, NH2 and COOH, or from optionally substituted with 1, 2 or 3 R': C1-3 Alkyl, C 1-3 alkoxy and C 1-3 alkyl-C(=O)-, other variables are as defined in the present invention;

在本发明的一些方案中，上述R选自F、Cl、Br、I、OH、CN、NH 2和COOH，或选自任选被1、2或3个R’取代的：Me、Et、

Figure PCTCN2022082343-appb-000014
其他变量如本发明所定义； In some aspects of the present invention, the above R is selected from F, Cl, Br, I, OH, CN, NH and COOH, or from : Me, Et,
Figure PCTCN2022082343-appb-000014
Other variables are as defined in the present invention;

在本发明的一些方案中，上述R选自F、Cl、Br、I、OH、CN、NH 2、-N(CH 3) 2、COOH、Me、Et、CF 3、CHF 2、CH 2F、

Figure PCTCN2022082343-appb-000015
其他变量如本发明所定义。 In some aspects of the invention, the above R is selected from F, Cl, Br, I, OH, CN, NH2 , -N( CH3 ) 2 , COOH, Me, Et, CF3 , CHF2 , CH2F ,
Figure PCTCN2022082343-appb-000015
Other variables are as defined in the present invention.

在本发明的一些方案中，上述Ra选自H、苯基和6元杂环烷基，其他变量如本发明所定义。In some embodiments of the present invention, the above Ra is selected from H, phenyl and 6-membered heterocycloalkyl, and other variables are as defined herein.

在本发明的一些方案中，上述Ra选自H、苯基和吗啉基，其他变量如本发明所定义；In some aspects of the present invention, the above Ra is selected from H, phenyl and morpholinyl, and other variables are as defined in the present invention;

在本发明的一些方案中，上述Ra选自H、

Figure PCTCN2022082343-appb-000016
其他变量如本发明所定义。 In some aspects of the present invention, above-mentioned Ra is selected from H,
Figure PCTCN2022082343-appb-000016
Other variables are as defined in the present invention.

在本发明的一些方案中，上述Ra-L 1-选自任选被1、2或3个R取代的：

Figure PCTCN2022082343-appb-000017
Figure PCTCN2022082343-appb-000018
其他变量如本发明所定义。 In some aspects of the invention, the above Ra-L 1 - is selected from optionally substituted with 1, 2 or 3 Rs:
Figure PCTCN2022082343-appb-000017
Figure PCTCN2022082343-appb-000018
Other variables are as defined in the present invention.

在本发明的一些方案中，上述R 1和R 2分别独立地选自H、F、Cl、Br、I、OH、CN、NH 2和COOH，或分别独立地选自任选被1、2或3个R取代的：C 1-3烷基、C 1-3烷氧基、C 1-3烷硫基、C 1-3烷氨基、N,N’-二(C 1-2烷基)氨基-和5～6元杂环烷基，其他变量如本发明所定义。 In some aspects of the present invention, the above 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.

在本发明的一些方案中，上述R 1和R 2分别独立地选自H、F、Cl、Br、I、OH、CN、NH 2、COOH，或分别独立地选自任选被1、2或3个R取代的：Me、

Figure PCTCN2022082343-appb-000019
Figure PCTCN2022082343-appb-000020
其他变量如本发明所定义； In some embodiments of the present invention, the above 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,
Figure PCTCN2022082343-appb-000019
Figure PCTCN2022082343-appb-000020
Other variables are as defined in the present invention;

在本发明的一些方案中，上述R 1和R 2分别独立地选自H、F、Cl、Br、I、OH、CN、NH 2、COOH、CF 3、

Figure PCTCN2022082343-appb-000021
其他变量如本发明所定义。 In some aspects of the present invention, the above R 1 and R 2 are independently selected from H, F, Cl, Br, I, OH, CN, NH 2 , COOH, CF 3 ,
Figure PCTCN2022082343-appb-000021
Other variables are as defined in the present invention.

在本发明的一些方案中，上述结构单元

Figure PCTCN2022082343-appb-000022
选自
Figure PCTCN2022082343-appb-000023
其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned structural units
Figure PCTCN2022082343-appb-000022
selected from
Figure PCTCN2022082343-appb-000023
Other variables are as defined in the present invention.

在本发明的一些方案中，上述R 1与R 2连接在一起，结构单元

Figure PCTCN2022082343-appb-000024
选自
Figure PCTCN2022082343-appb-000025
其他变量如本发明所定义。 In some aspects of the present invention, the above R 1 and R 2 are linked together, the structural unit
Figure PCTCN2022082343-appb-000024
selected from
Figure PCTCN2022082343-appb-000025
Other variables are as defined in the present invention.

在本发明的一些方案中，上述R 1与

Figure PCTCN2022082343-appb-000026
连接在一起，结构单元
Figure PCTCN2022082343-appb-000027
选自
Figure PCTCN2022082343-appb-000028
其他变量如本发明所定义。 In some aspects of the present invention, the above R 1 and
Figure PCTCN2022082343-appb-000026
connected together, structural units
Figure PCTCN2022082343-appb-000027
selected from
Figure PCTCN2022082343-appb-000028
Other variables are as defined in the present invention.

在本发明的一些方案中，上述Rb选自H卤素、OH、CN、NH 2、NO 2和COOH，或选自任选被1、2或3个R取代的：C 1-3烷氨基、C 1-3烷氧基、C 1-3烷硫基、N,N’-二(C 1-2烷基)氨基、吡咯烷基、吗啉基、哌嗪基、吡啶基和嘧啶基，其他变量如本发明所定义。 In some aspects of the present invention, the above 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.

在本发明的一些方案中，上述Rb选自H卤素、OH、CN、NH 2、NO 2和COOH，或选自任选被1、2或3个R取代的：

Figure PCTCN2022082343-appb-000029
其他变量如本发明所定义； In some aspects of the present invention, the above Rb is selected from H halogen, OH, CN, NH2 , NO2 and COOH, or selected from optionally substituted with 1, 2 or 3 Rs:
Figure PCTCN2022082343-appb-000029
Other variables are as defined in the present invention;

在本发明的一些方案中，上述R b选自：H、卤素、OH、CN、NH 2、NO 2、COOH、

Figure PCTCN2022082343-appb-000030
Figure PCTCN2022082343-appb-000031
其他变量如本发明所定义。 In some aspects of the present invention, the above R b is selected from the group consisting of: H, halogen, OH, CN, NH 2 , NO 2 , COOH,
Figure PCTCN2022082343-appb-000030
Figure PCTCN2022082343-appb-000031
Other variables are as defined in the present invention.

在本发明的一些方案中，上述L 2、L 3和L 4分别独立地选自：单键、O、S、NH、-C(＝O)-、-C(＝O)NH-、 -S(＝O)-、-S(＝O) 2-、-CH 2-、-CH 2CH 2-、苯基、吡啶基、吡唑基、咪唑基、吡啶基、嘧啶基、噻吩基、恶唑基、噻唑基、异恶唑基和异噻唑基，其他变量如本发明所定义。 In some aspects of the present invention, the above L 2 , L 3 and L 4 are each independently selected from: single bond, O, S, NH, -C(=O)-, -C(=O)NH-, - S(=O)-, -S(=O) 2 -, -CH 2 -, -CH 2 CH 2 -, phenyl, pyridyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, thienyl, Oxazolyl, thiazolyl, isoxazolyl and isothiazolyl, other variables are as defined herein.

在本发明的一些方案中，上述L 2、L 3和L 4分别独立地选自：单键、O、S、NH、-C(＝O)-、-C(＝O)NH-、-S(＝O)-、-S(＝O) 2-、-CH 2-、-CH 2CH 2-、

Figure PCTCN2022082343-appb-000032
其他变量如本发明所定义。 In some aspects of the present invention, the above L 2 , L 3 and L 4 are each independently selected from: single bond, O, S, NH, -C(=O)-, -C(=O)NH-, - S(=O)-, -S(=O) 2 -, -CH 2 -, -CH 2 CH 2 -,
Figure PCTCN2022082343-appb-000032
Other variables are as defined in the present invention.

在本发明的一些方案中，上述R b-L 2-L 3-L 4-选自：

Figure PCTCN2022082343-appb-000033
Figure PCTCN2022082343-appb-000034
Figure PCTCN2022082343-appb-000035
其他变量如本发明所定义。 In some aspects of the present invention, the above R b -L 2 -L 3 -L 4 - is selected from:
Figure PCTCN2022082343-appb-000033
Figure PCTCN2022082343-appb-000034
Figure PCTCN2022082343-appb-000035
Other variables are as defined in the present invention.

在本发明的一些方案中，上述R 5和R 6分别独立地选自H、卤素、OH、CN、NH 2、NO 2和COOH，或分别独立地选自任选被1、2或3个R取代的：C 1-3杂烷基、噻唑基、嘧啶基、吡啶基、噻吩基、哌啶基、吗啉基和哌嗪基，其他变量如本发明所定义。 In some aspects of the present invention, the above 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.

在本发明的一些方案中，上述R 5和R 6分别独立地选自H、F、Cl、Br、I、OH、CN、NH 2、NO 2和COOH，或分别独立地选自任选被1、2或3个R取代的：

Figure PCTCN2022082343-appb-000036
Figure PCTCN2022082343-appb-000037
其他变量如本发明所定义。 In some aspects of the present invention, the above 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:
Figure PCTCN2022082343-appb-000036
Figure PCTCN2022082343-appb-000037
Other variables are as defined in the present invention.

在本发明的一些方案中，上述R 5和R 6分别独立地选自H、F、Cl、Br、I、OH、CN、NH 2、NO 2、 COOH、

Figure PCTCN2022082343-appb-000038
其他变量如本发明所定义。 In some aspects of the present invention, the above R 5 and R 6 are independently selected from H, F, Cl, Br, I, OH, CN, NH 2 , NO 2 , COOH,
Figure PCTCN2022082343-appb-000038
Other variables are as defined in the present invention.

在本发明的一些方案中，上述R 7选自H，或选自任选被1、2或3个R取代的：NH 2和CH 3，其他变量如本发明所定义。 In some embodiments of the invention, the above R7 is selected from H, or optionally substituted with 1, 2 or 3 Rs: NH2 and CH3 , other variables are as defined herein.

在本发明的一些方案中，上述R 7选自H、-N(CH 3) 2和CH 3，其他变量如本发明所定义。 In some aspects of the present invention, the above R 7 is selected from H, -N(CH 3 ) 2 and CH 3 , and other variables are as defined in the present invention.

在本发明的一些方案中，上述R 5和R 6连接在一起，结构单元

Figure PCTCN2022082343-appb-000039
选自：
Figure PCTCN2022082343-appb-000040
Figure PCTCN2022082343-appb-000041
Figure PCTCN2022082343-appb-000042
其他变量如本发明所定义。 In some aspects of the present invention, the above R 5 and R 6 are linked together, the structural unit
Figure PCTCN2022082343-appb-000039
Selected from:
Figure PCTCN2022082343-appb-000040
Figure PCTCN2022082343-appb-000041
Figure PCTCN2022082343-appb-000042
Other variables are as defined in the present invention.

在本发明的一些方案中，上述化合物选自In some aspects of the invention, the above-mentioned compounds are selected from

Figure PCTCN2022082343-appb-000043
Figure PCTCN2022082343-appb-000043

R 1、R 2、R 3和R 4如本发明所定义。 R 1 , R 2 , R 3 and R 4 are as defined in the present invention.

本发明还提供化合物、其药学上可接受的盐或其互变异构体，其选自：The present invention also provides compounds, pharmaceutically acceptable salts or tautomers thereof, selected from the group consisting of:

Figure PCTCN2022082343-appb-000044
Figure PCTCN2022082343-appb-000044

Figure PCTCN2022082343-appb-000045
Figure PCTCN2022082343-appb-000045

Figure PCTCN2022082343-appb-000046
Figure PCTCN2022082343-appb-000046

Figure PCTCN2022082343-appb-000047
Figure PCTCN2022082343-appb-000047

在本发明的一些方案中，上述化合物、其药学上可接受的盐或其互变异构体，其选自：In some aspects of the present invention, the above-mentioned compound, a pharmaceutically acceptable salt thereof, or a tautomer thereof, is selected from the group consisting of:

Figure PCTCN2022082343-appb-000048
Figure PCTCN2022082343-appb-000048

本发明还提供了上述化合物、其药学上可接受的盐及其互变异构体在制备LRRK2激酶抑制剂相关药物中的应用。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.

相关定义Related Definitions

除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered indeterminate or unclear without specific definitions, but should be understood in its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding commercial product or its active ingredient. As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue , without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.

术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐(参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977))。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。The term "pharmaceutically acceptable 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. When the compounds of the present invention contain relatively acidic functional groups, 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. When the compounds of the present invention contain relatively basic functional groups, 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. , and salts of organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977)). 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.

优选地，以常规方式使盐与碱或酸接触，再分离母体化合物，由此再生化合物的中性形式。化合物的母体形式与其各种盐的形式的不同之处在于某些物理性质，例如在极性溶剂中的溶解度不同。Preferably, 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.

本文所用的“药学上可接受的盐”属于本发明化合物的衍生物，其中，通过与酸成盐或与碱成盐的方式修饰所述母体化合物。药学上可接受的盐的实例包括但不限于：碱基比如胺的无机酸或有机酸盐、酸根比如羧酸的碱金属或有机盐等等。药学上可接受的盐包括常规的无毒性的盐或母体化合物的季铵盐，例如无毒的无机酸或有机酸所形成的盐。常规的无毒性的盐包括但不限于那些衍生自无机酸和有机酸的盐，所述的无机酸或有机酸选自2-乙酰氧基苯甲酸、2-羟基乙磺酸、乙酸、抗坏血酸、苯磺酸、苯甲酸、碳酸氢根、碳酸、柠檬酸、依地酸、乙烷二磺酸、乙烷磺酸、富马酸、葡庚糖、葡糖酸、谷氨酸、 乙醇酸、氢溴酸、盐酸、氢碘酸盐、羟基、羟萘、羟乙磺酸、乳酸、乳糖、十二烷基磺酸、马来酸、苹果酸、扁桃酸、甲烷磺酸、硝酸、草酸、双羟萘酸、泛酸、苯乙酸、磷酸、多聚半乳糖醛、丙酸、水杨酸、硬脂酸、亚乙酸、琥珀酸、氨基磺酸、对氨基苯磺酸、硫酸、单宁、酒石酸和对甲苯磺酸。As used herein, "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. Examples of 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. Conventional 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 acid, polygalactaraldehyde, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, sulfamic acid, p-aminobenzenesulfonic acid, sulfuric acid, tannin, Tartaric acid and p-toluenesulfonic acid.

本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。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.

除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。In addition to salt forms, 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. Furthermore, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.

本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。Certain compounds of the present invention may exist in unsolvated as well as solvated forms, including hydrated forms. In general, solvated and unsolvated forms are equivalent and are intended to be included within the scope of the present invention.

本发明的某些化合物可以具有不对称碳原子(光学中心)或双键。外消旋体、非对映异构体、几何异构体和单个的异构体都包括在本发明的范围之内。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.

除非另有说明，用楔形键和虚线键

Figure PCTCN2022082343-appb-000049
表示一个立体中心的绝对构型，用
Figure PCTCN2022082343-appb-000050
表示一个立体中心的相对构型。当本文所述化合物含有烯属双键或其它几何不对称中心，除非另有规定，它们包括E、Z几何异构体。同样地，所有的互变异构形式均包括在本发明的范围之内。 Use wedge and dotted keys unless otherwise specified
Figure PCTCN2022082343-appb-000049
To represent the absolute configuration of a stereocenter, use
Figure PCTCN2022082343-appb-000050
Represents the relative configuration of a stereocenter. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include E, Z geometric isomers unless otherwise specified. Likewise, all tautomeric forms are included within the scope of the present invention.

本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。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.

可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。Optically active (R)- and (S)-isomers, as well as D and L 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. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), 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. In addition, 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).

本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。 The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, 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.

术语“活性成分”、“治疗剂”，“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。The terms "active ingredient", "therapeutic agent", "active substance" or "active agent" refer to a chemical entity that is effective in treating the target disorder, disease or condition.

术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。The terms "optional" or "optionally" mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. .

术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为酮基(即＝O)时，意味着两个氢原子被取代。酮取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。The term "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. When the substituent is a keto group (ie =0), it means that two hydrogen atoms are substituted. Ketone substitution does not occur on aromatic groups. The term "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.

当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When any variable (eg, R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may optionally be substituted with up to two Rs, with independent options for R in each case. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。 When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.

当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。When one of the variables is selected from a single bond, it means that the two groups connected to it are directly connected, for example, when L in A-L-Z represents a single bond, it means that the structure is actually A-Z.

当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当一个取代基的键可以交叉连接到一个环上的两个原子时，这种取代基可以与这个环上的任意原子相键合。当所列举的取代基中没有指明其通过哪一个原子连接到化学结构通式中包括但未具体提及的化合物时，这种取代基可以通过其任何原子相键合。取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。例如，结构单元

Figure PCTCN2022082343-appb-000051
表示其可在环己基或者环己二烯上的任意一个位置发生取代。 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
Figure PCTCN2022082343-appb-000051
Indicates that it can be substituted at any position on cyclohexyl or cyclohexadiene.

除非另有规定，术语“杂”表示杂原子或杂原子团(即含有杂原子的原子团)，包括碳(C)和氢(H)以外的原子以及含有这些杂原子的原子团，例如包括氧(O)、氮(N)、硫(S)、硅(Si)、锗(Ge)、铝(Al)、硼(B)、-O-、-S-、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O) 2-，以及任选被取代的-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O) 2N(H)-或-S(＝O)N(H)-。 Unless otherwise specified, the term "hetero" means a heteroatom or heteroatom group (ie, a group containing a heteroatom), including atoms other than carbon (C) and hydrogen (H) and groups containing such heteroatoms, including, for example, oxygen (O ), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al), boron (B), -O-, -S-, =O, =S, -C(= O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O) 2- , and optionally substituted -C(=O)N (H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H) - or -S(=O)N(H)-.

除非另有规定，“环”表示被取代或未被取代的环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。所谓的环包括单环、联环、螺环、并环或桥环。环上原子的数目通常被定义为环的元数，例如，“5～7元环”是指环绕排列5～7个原子。除非另有规定，该环任选地包含1～3个杂原子。因此，“5～7元环”包括例如苯基、吡啶和哌啶基；另一方面，术语“5～7元杂环烷基环”包括吡啶基和哌啶基，但不包括苯基。术语“环”还包括含有至少一个环的环系，其中的每一个“环”均独立地符合上述定义。Unless otherwise specified, "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. Thus, "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. The term "ring" also includes ring systems containing at least one ring, wherein each "ring" independently meets the above definition.

除非另有规定，术语“杂环”或“杂环基”意指稳定的含杂原子或杂原子团的单环、双环或三环，它们可以是饱和的、部分不饱和的或不饱和的(芳族的)，它们包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子，其中上述任意杂环可以稠合到一个苯环上形成双环。氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。该杂环可以附着到任何杂原子或碳原子的侧基上从而形成稳定的结构。如果产生的化合物是稳定的，本文所述的杂环可以发生碳位或氮位上的取代。杂环中的氮原子任选地被季铵化。一个优选方案是，当杂环中S及O原子的总数超过1时，这些杂原子彼此不相邻。另一个优选方案是，杂环中S及O原子的总数不超过1。如本文所用，术语“芳族杂环基团”或“杂芳基”意指稳定 的5、6、7元单环或双环或7、8、9或10元双环杂环基的芳香环，它包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。值得注意的是，芳香杂环上S和O原子的总数不超过1。桥环也包含在杂环的定义中。当一个或多个原子(即C、O、N或S)连接两个不相邻的碳原子或氮原子时形成桥环。优选的桥环包括但不限于：一个碳原子、两个碳原子、一个氮原子、两个氮原子和一个碳-氮基。值得注意的是，一个桥总是将单环转换成三环。桥环中，环上的取代基也可以出现在桥上。Unless otherwise specified, the term "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. As used herein, the term "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.

杂环化合物的实例包括但不限于：吖啶基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并巯基呋喃基、苯并巯基苯基、苯并恶唑基、苯并恶唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异恶唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、苯并二氢吡喃基、色烯、噌啉基十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、吲哚烯基、二氢吲哚基、中氮茚基、吲哚基、3H-吲哚基、异苯并呋喃基、异吲哚基、异二氢吲哚基、异喹啉基、异噻唑基、异恶唑基、亚甲二氧基苯基、吗啉基、萘啶基，八氢异喹啉基、恶二唑基、1,2,3-恶二唑基、1,2,4-恶二唑基、1,2,5-恶二唑基、1,3,4-恶二唑基、恶唑烷基、恶唑基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪、吩噻嗪、苯并黄嘌呤基、酚恶嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并恶唑、吡啶并咪唑、吡啶并噻唑、吡啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、四唑基，6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、异噻唑基噻吩基、噻吩并恶唑基、噻吩并噻唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基和呫吨基。还包括稠环和螺环化合物。Examples of 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, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indole dolyl, isobenzofuranyl, isoindolyl, isoindoline, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl , Octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3, 4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindole, pyrimidinyl, phenanthridine, phenanthroline, phenazine, phenothiazine, benzoxanthine, phenoxazinyl , phthalazinyl, piperazinyl, piperidinyl, piperidinone, 4-piperidinone, piperonyl, pteridyl, purinyl, pyranyl, pyrazinyl, pyrazolidine, pyrazole Linoyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinoline group, 4H-quinazinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl , 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthyl, thiazole base, isothiazolylthienyl, thienooxazolyl, thienothiazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl , 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl. Also included are fused and spiro compounds.

除非另有规定，术语“烃基”或者其下位概念(比如烷基、烯基、炔基、芳基等等)本身或者作为另一取代基的一部分表示直链的、支链的或环状的烃原子团或其组合，可以是完全饱和的(如烷基)、单元或多元不饱和的(如烯基、炔基、芳基)，可以是单取代或多取代的，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)，可以包括二价或多价原子团，具有指定数量的碳原子(如C 1-C 12表示1至12个碳，C 1-12选自C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11和C 12；C 3-12选自C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11和C 12。)。“烃基”包括但不限于脂肪烃基和芳香烃基，所述脂肪烃基包括链状和环状，具体包括但不限于烷基、烯基、炔基，所述芳香烃基包括但不限于6-12元的芳香烃基，例如苯、萘等。在一些实施例中，术语“烃基”表示直链的或支链的原子团或它们的组合，可以是完全饱和的、单元或多元不饱和的，可以包括二价和多价原子团。饱和烃原子团的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、异丁基、环己基、(环己基)甲基、环丙基甲基，以及正戊基、正己基、正庚基、正辛基等原子团的同系物或异构体。不饱和烃基具有一个或多个双键或三键，其实例包括但不限于乙烯基、2-丙烯基、丁烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2，4-戊二烯基、3-(1，4-戊二烯基)、乙炔基、1-和3-丙炔基，3-丁炔基，以及更高级的同系物和异构体。 Unless otherwise specified, the term "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 , C5 , C6 , C7 , C8 , C9 , C10 , C11 and C12 .). "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, and the aromatic hydrocarbon groups include but are not limited to 6-12 membered aromatic hydrocarbon groups, such as benzene, naphthalene, etc. In some embodiments, 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. Examples of 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.

除非另有规定，术语“杂烃基”或者其下位概念(比如杂烷基、杂烯基、杂炔基、杂芳基等等)本身或者与另一术语联合表示稳定的直链的、支链的或环状的烃原子团或其组合，有一定数目的碳原子和至少一个杂原子组成。在一些实施例中，术语“杂烷基”本身或者与另一术语联合表示稳定的直链的、支链的烃原子团或其组合物，有一定数目的碳原子和至少一个杂原子组成。在一个典型实施例中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。杂原子或杂原子团可以位于杂烃基的任何内部位置，包括该烃基附着于分子其余部分的位置，但术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烷基基团。实例包括但不限于-CH 2-CH 2-O-CH 3、-CH 2-CH 2-NH-CH 3、-CH 2-CH 2-N(CH 3)-CH 3、-CH 2-S-CH 2-CH 3、-CH 2-CH 2、-S(O)-CH 3、-CH 2-CH 2-S(O) 2-CH 3、-CH＝CH-O-CH 3、-CH 2-CH＝N-OCH 3和–CH＝CH-N(CH 3)-CH 3。至多两个杂原子可以是连续的，例如-CH 2-NH-OCH 3。 Unless otherwise specified, the term "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. In some embodiments, the term "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. In a typical embodiment, 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. Examples include, but are not limited to -CH2 - CH2 -O- CH3 , -CH2 - CH2 -NH- CH3 , -CH2 - CH2 -N( CH3 ) -CH3 , -CH2 -S -CH 2 -CH 3 , -CH 2 -CH 2 , -S(O)-CH 3 , -CH 2 -CH 2 -S(O) 2 -CH 3 , -CH=CH-O-CH 3 , - CH 2 -CH=N-OCH 3 and -CH=CH-N(CH 3 )-CH 3 . Up to two heteroatoms may be consecutive, eg -CH2 -NH- OCH3 .

除非另有规定，术语“环烃基”、“杂环烃基”或者其下位概念(比如芳基、杂芳基、环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基等等)本身或与其他术语联合分别表示环化的“烃基”、“杂烃基”。此外，就杂烃基或杂环烃基(比如杂烷基、杂环烷基)而言，杂原子可以占据该杂环附着于分子其余部分的位置。环烃基的实例包括但不限于环戊基、环己基、1-环己烯基、3-环己烯基、环庚基等。杂环基的非限制性实例包括1-(1,2,5,6-四氢吡啶基)、1-哌啶基、2-哌啶基，3-哌啶基、4-吗啉基、3-吗啉基、四氢呋喃-2-基、四氢呋喃吲哚-3-基、四氢噻吩-2-基、四氢噻吩-3-基，1-哌嗪基和2-哌嗪基。Unless otherwise specified, the terms "cycloalkyl", "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. Additionally, in the case of a heterohydrocarbyl or heterocyclic hydrocarbyl group (eg, heteroalkyl, heterocycloalkyl), a heteroatom may occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Non-limiting examples of 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.

除非另有规定，术语“烷基”用于表示直链或支链的饱和烃基,可以是单取代(如-CH 2F)或多取代的(如-CF 3)，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。烷基的例子包括甲基(Me)，乙基(Et)，丙基(如，n-丙基和异丙基)，丁基(如，n-丁基，异丁基，s-丁基，t-丁基)，戊基(如，n-戊基，异戊基，新戊基)等。 Unless otherwise specified, the term "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). Examples of alkyl groups 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.

除非另有规定，“烯基”指在链的任何位点上具有一个或多个碳碳双键的烷基,可以是单取代或多取代的，可以是一价、二价或者多价。烯基的例子包括乙烯基，丙烯基，丁烯基，戊烯基，己烯基，丁间二烯基，戊间二烯基，己间二烯基等。Unless otherwise specified, "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. Examples of alkenyl groups include vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexamadienyl, and the like.

除非另有规定，“炔基”指在链的任何位点上具有一个或多个碳碳三键的烷基，可以是单取代或多取代的，可以是一价、二价或者多价。炔基的例子包括乙炔基，丙炔基，丁炔基，戊炔基等。Unless otherwise specified, "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. Examples of alkynyl groups include ethynyl, propynyl, butynyl, pentynyl and the like.

除非另有规定，环烷基包括任何稳定的环状或多环烃基，任何碳原子都是饱和的，可以是单取代或多取代的，可以是一价、二价或者多价。这些环烷基的实例包括，但不限于，环丙基、降冰片烷基、[2.2.2]二环辛烷、[4.4.0]二环癸烷等。Unless otherwise specified, 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.

除非另有规定，环烯基包括任何稳定的环状或多环烃基，该烃基在环的任何位点含有一个或多个不饱和的碳-碳双键，可以是单取代或多取代的，可以是一价、二价或者多价。这些环烯基的实例包括，但不限于，环戊烯基、环己烯基等。Unless otherwise specified, 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.

除非另有规定，环炔基包括任何稳定的环状或多环烃基，该烃基在环的任何位点含有一个或多个碳-碳三键，可以是单取代或多取代的，可以是一价、二价或者多价。Unless otherwise specified, 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.

除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。此外，术语“卤代烷基”意在包括单卤代烷基和多卤代烷基。例如，术语“卤代(C 1-C 4)烷基”意在包括但 不仅限于三氟甲基、2，2，2-三氟乙基、4-氯丁基和3-溴丙基等等。除非另有规定，卤代烷基的实例包括但不仅限于：三氟甲基、三氯甲基、五氟乙基，和五氯乙基。 Unless otherwise specified, the term "halogen" or "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom. Furthermore, the term "haloalkyl" is intended to include monohaloalkyl and polyhaloalkyl. For example, the term "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. Unless otherwise specified, examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.

“烷氧基”代表通过氧桥连接的具有特定数目碳原子的上述烷基，除非另有规定，C 1-6烷氧基包括C 1、C 2、C 3、C 4、C 5和C 6的烷氧基。烷氧基的例子包括但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基和S-戊氧基。除非另有规定，术语“芳基”表示多不饱和的芳族烃取代基，可以是单取代或多取代的，可以是一价、二价或者多价，它可以是单环或多环(比如1至3个环；其中至少一个环是芳族的)，它们稠合在一起或共价连接。术语“杂芳基”是指含有一至四个杂原子的芳基(或环)。在一个示范性实例中，杂原子选自B、N、O和S，其中氮和硫原子任选地被氧化，氮原子任选地被季铵化。杂芳基可通过杂原子连接到分子的其余部分。芳基或杂芳基的非限制性实施例包括苯基、1-萘基、2-萘基、4-联苯基、1-吡咯基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-恶唑基、4-恶唑基、2-苯基-4-恶唑基、5-恶唑基、3-异恶唑基、4-异恶唑基、5-异恶唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-苯并噻唑基、嘌呤基、2-苯并咪唑基、5-吲哚基、1-异喹啉基、5-异喹啉基、2-喹喔啉基、5-喹喔啉基、3-喹啉基和6-喹啉基。上述任意一个芳基和杂芳基环系的取代基选自下文所述的可接受的取代基。 "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. Unless otherwise specified, the term "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. The term "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-indolyl, 1-Isoquinolinyl, 5-isoquinolinyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolinyl and 6-quinolinyl. Substituents to any of the foregoing aryl and heteroaryl ring systems are selected from the acceptable substituents described below.

除非另有规定，芳基在与其他术语联合使用时(例如芳氧基、芳硫基、芳烷基)包括如上定义的芳基和杂芳基环。因此，术语“芳烷基”意在包括芳基附着于烷基的那些原子团(例如苄基、苯乙基、吡啶基甲基等)，包括其中碳原子(如亚甲基)已经被例如氧原子代替的那些烷基，例如苯氧基甲基、2-吡啶氧甲基3-(1-萘氧基)丙基等。Unless otherwise specified, aryl when used in conjunction with other terms (eg, aryloxy, arylthio, aralkyl) includes aryl and heteroaryl rings as defined above. Thus, the term "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.

术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。The term "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). For example, 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.

术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "thiol protecting group". The term "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-butyldimethylsilyl (TBS) and the like. The term "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.

本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。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.

本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：aq代表水；HATU代表O-(7-氮杂苯 并三唑-1-基)-N，N，N'，N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁基羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH 3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc 2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl 2代表氯化亚砜；CS 2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；NCS代表1-氯吡咯烷-2,5-二酮；n-Bu 4NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点；LDA代表二异丙基胺基锂。 The solvent used in the present invention is commercially available. The following abbreviations are used in the present invention: aq stands for water; HATU stands for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate ; EDC represents N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA represents 3-chloroperoxybenzoic acid; eq represents equivalent, equivalent; CDI represents Carbonyldiimidazole; DCM for dichloromethane; PE for petroleum ether; DIAD for diisopropyl azodicarboxylate; DMF for N,N-dimethylformamide; DMSO for dimethyl sulfoxide; EtOAc for ethyl acetate Ester; EtOH for ethanol; MeOH for methanol; CBz for benzyloxycarbonyl, an amine protecting group; BOC for tert-butylcarbonyl, an amine protecting group; HOAc for acetic acid; NaCNBH 3 for sodium cyanoborohydride ; rt for room temperature; O/N for overnight; THF for tetrahydrofuran; Boc 2 O for di-tert-butyl dicarbonate; TFA for trifluoroacetic acid; DIPEA for diisopropylethylamine ; Sulfone; CS 2 for carbon disulfide; TsOH for p-toluenesulfonic acid; NFSI for N-fluoro-N-(benzenesulfonyl)benzenesulfonamide; NCS for 1-chloropyrrolidine-2,5-dione; n-Bu 4 NF stands for tetrabutylammonium fluoride; iPrOH stands for 2-propanol; mp stands for melting point; LDA stands for lithium diisopropylamide.

本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：

Figure PCTCN2022082343-appb-000052
扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。 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 CuKα radiation, and the scanning mode is:
Figure PCTCN2022082343-appb-000052
After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.

化合物依据本领域常规命名原则或者

Figure PCTCN2022082343-appb-000053
软件命名，市售化合物采用供应商目录名称。 Compounds are named according to conventional nomenclature in the art or
Figure PCTCN2022082343-appb-000053
Software naming, commercially available compounds use supplier catalog names.

具体实施方式Detailed ways

下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。The present invention will be described in detail by the following examples, but it does not mean any unfavorable limitation of the present invention.

实施例1Example 1

(2-((5-氯-2-((4-甲氧基苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧化膦(2-((5-Chloro-2-((4-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

Figure PCTCN2022082343-appb-000054
Figure PCTCN2022082343-appb-000054

第一步first step

二甲基氧膦dimethyl phosphine oxide

0℃条件下，向甲基溴化镁(3.0M四氢呋喃溶液,160.00mL,480mmol)的四氢呋喃溶液(300mL)中缓慢滴加化合物膦酸二乙酯(20.00g,144.82mmol,18.69mL)，控制内温低于10℃。缓慢升温至室温搅拌5小时。反应结束，将反应液置于冰浴中依次加入饱和碳酸氢钠溶液40mL和乙醇160mL，有大量白色固体析出，过滤除去白色固体，滤液浓缩至40mL并加入150mL甲苯，浓缩后，加入二氯甲烷130mL，乙醇13mL，搅拌1小时，过滤，滤液浓缩得到粗品直接用于下一步化合物二甲基氧膦(45.00g,无色油 状)。Under the condition of 0°C, 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 reaction was completed, the reaction solution was placed in an ice bath and 40 mL of saturated sodium bicarbonate solution and 160 mL of ethanol were added successively, a large amount of white solid was precipitated, the white solid was removed by filtration, the filtrate was concentrated to 40 mL and 150 mL of toluene was added. After concentration, dichloromethane was added. 130 mL, 13 mL of ethanol, stirred for 1 hour, filtered, and the filtrate was concentrated to obtain the crude product which was directly used in the next step compound dimethyl phosphine oxide (45.00 g, colorless oil).

1H NMR:(400MHz,CDCl 3)δ1.59(dd,J＝3.6,14.4Hz,6H). 1 H NMR: (400 MHz, CDCl 3 ) δ 1.59 (dd, J=3.6, 14.4 Hz, 6H).

第二步second step

(2-氨基苯基)二甲基氧化膦(2-Aminophenyl)dimethylphosphine oxide

Figure PCTCN2022082343-appb-000055
Figure PCTCN2022082343-appb-000055

将2-碘苯胺溶液(12.50g,57.07mmol)和二甲基氧化膦(5.35g,68.49mmol)，K 3PO 4(14.54g,68.49mmol)，4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(660.44mg,1.14mmol)和醋酸钯(256.26mg,1.14mmol)置于DMF(80mL)中，反应混合物在氮气保护下，加热至150℃并搅拌16小时。将混合物过滤并浓缩，将所得残余物用盐酸水溶液(1N，80mL)稀释，调节pH值至大约2，将所得混合物过滤。滤液用二氯甲烷(100mL×2)萃取，将水层分离出来，并且用碳酸氢钠水溶液将pH值调节至约9，然后用二氯甲烷(200mL×2)萃取。有机层用无水硫酸钠干燥并浓缩至干。将粗产物通过重结晶(石油醚：乙酸乙酯＝5:1)纯化，得(2-氨基苯基)二甲基氧化膦(6.00g,白色固体)，产率：62.15％。 1H NMR:(400MHz,CDCl 3):δ7.20(m,1H),7.04(m,1H),6.69-6.58(m,2H),5.35(br s,2H),1.75(s,3H),1.71(s,3H). A solution of 2-iodoaniline (12.50 g, 57.07 mmol) and dimethylphosphine oxide (5.35 g, 68.49 mmol), K 3 PO 4 (14.54 g, 68.49 mmol), 4,5-bis(diphenylphosphine) -9,9-Dimethylxanthene (660.44 mg, 1.14 mmol) and palladium acetate (256.26 mg, 1.14 mmol) were placed in DMF (80 mL), and the reaction mixture was heated to 150 °C under nitrogen and stirred for 16 Hour. 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. The crude product was purified by recrystallization (petroleum ether:ethyl acetate=5:1) to give (2-aminophenyl)dimethylphosphine oxide (6.00 g, white solid), yield: 62.15%. 1 H NMR: (400MHz, CDCl 3 ): δ 7.20 (m, 1H), 7.04 (m, 1H), 6.69-6.58 (m, 2H), 5.35 (br s, 2H), 1.75 (s, 3H) ,1.71(s,3H).

MS-ESI计算值[M+H] +170，实测值170.1。 MS-ESI calculated [M+H] + 170, found 170.1.

第三步third step

(2-((2,5-二氯嘧啶-4-基)氨基)苯基)二甲基氧化膦(2-((2,5-Dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

Figure PCTCN2022082343-appb-000056
Figure PCTCN2022082343-appb-000056

在16℃下，向(2-氨基苯基)二甲基氧化膦(2.50g,14.8mmol)和2,4,5-三氯嘧啶(2.85g,15.5mmol)的DMF(20mL)混合物中，加入DI石油醚A(3.82g,29.6mmol)。然后将反应混合物加热至70℃并搅拌16小时。将反应混合物用水(50mL)稀释，并用乙酸乙酯(40mL×3)萃取。将合并的有机相用饱和盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤并真空浓缩。粗产物在乙醇中重结晶，得(2-((2,5-二氯嘧啶-4-基)氨基)苯基)二甲基氧化膦(3.20g,白色固体)，产率：68.4％。 1H NMR:(400MHz,CD 3OD)δ8.50(m,1H),8.35-8.28(m,1H),7.69-7.59(m,2H),7.36-7.28(m,1H),1.91(s,3H),1.88(s,3H). To a mixture of (2-aminophenyl)dimethylphosphine oxide (2.50 g, 14.8 mmol) and 2,4,5-trichloropyrimidine (2.85 g, 15.5 mmol) in DMF (20 mL) at 16 °C, DI petroleum ether A (3.82 g, 29.6 mmol) was added. The reaction mixture was then heated to 70°C and stirred for 16 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was recrystallized from ethanol to give (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (3.20 g, white solid), yield: 68.4%. 1 H NMR: (400MHz, CD 3 OD) δ 8.50 (m, 1H), 8.35-8.28 (m, 1H), 7.69-7.59 (m, 2H), 7.36-7.28 (m, 1H), 1.91 (s) ,3H),1.88(s,3H).

MS-ESI计算值[M+H] +316；317；318，实测值316；317；318。 MS-ESI calculated [M+H] + 316; 317; 318, found 316; 317; 318.

第四步the fourth step

(2-((5-氯-2-((4-甲氧基苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧化膦(2-((5-Chloro-2-((4-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

将(2-((2,5-二氯嘧啶-4-基)氨基)苯基)二甲基氧化膦(50.0mg,0.158mmol)溶于叔丁醇(5mL)中，然后向反应液加入4-甲氧基苯胺(23.4mg,0.190mmol)和甲烷磺酸(45.6mg,0.475mmol)。反应液在90℃，搅拌12小时。反应液减压浓缩，剩余物经高效液相色谱法分离纯化得到(2-((5-氯-2-((4-甲氧基苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧化膦(27.0mg)，产率：42％。 1H NMR:(400MHz,CDCl 3)δ12.41(s,1H),10.42(s,1H),8.45-8.42(m,1H),7.80(s,1H),7.43-7.40(m,2H),7.37-7.34(m,2H),7.29-7.27(m,1H),6.92-6.89(m,2H),3.85(s,3H),1.88-1.85(m,6H)。 (2-((2,5-Dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (50.0 mg, 0.158 mmol) was dissolved in tert-butanol (5 mL), and then added to the reaction solution 4-Methoxyaniline (23.4 mg, 0.190 mmol) and methanesulfonic acid (45.6 mg, 0.475 mmol). The reaction solution was stirred at 90°C for 12 hours. The 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%. 1 H NMR: (400MHz, CDCl 3 )δ 12.41(s,1H), 10.42(s,1H), 8.45-8.42(m,1H), 7.80(s,1H), 7.43-7.40(m,2H) , 7.37-7.34(m, 2H), 7.29-7.27(m, 1H), 6.92-6.89(m, 2H), 3.85(s, 3H), 1.88-1.85(m, 6H).

MS-ESI计算值[M+H] +403和405，实测值403和405。 MS-ESI calculated [M+H] + 403 and 405, found 403 and 405.

实施例2Example 2

5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-甲氧基-3-(三氟甲基)苯基]嘧啶-2,4-二胺5-Chloro-N4-(2-dimethylphosphorylphenyl)-N2-[4-methoxy-3-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine

Figure PCTCN2022082343-appb-000057
Figure PCTCN2022082343-appb-000057

根据实施例1中第四步方法，将对甲氧基苯胺替换为4-甲氧基-3-(三氟甲基)苯胺，得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-甲氧基-3-(三氟甲基)苯基]嘧啶-2,4-二胺(36.00mg)，产率：42％。 1H NMR:(400MHz,CD3OD)δ8.18-8.15(m,2H),7.70-7.65(m,2H),7.61-7.58(m,1H),7.46(br.s.,1H),7.40-7.37(m,1H),7.24-7.22(m,1H),3.95(s,3H),1.89(s,3H),1.86(s,3H). According to the fourth step method in Example 1, p-methoxyaniline was replaced with 4-methoxy-3-(trifluoromethyl)aniline to obtain 5-chloro-N4-(2-dimethylphosphorylbenzene) yl)-N2-[4-methoxy-3-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine (36.00 mg), yield: 42%. 1 H NMR:(400MHz,CD3OD)δ8.18-8.15(m,2H),7.70-7.65(m,2H),7.61-7.58(m,1H),7.46(br.s.,1H),7.40- 7.37(m,1H),7.24-7.22(m,1H),3.95(s,3H),1.89(s,3H),1.86(s,3H).

MS-ESI计算值[M+H] +471和473，实测值471和473。 MS-ESI calculated [M+H] + 471 and 473, found 471 and 473.

实施例3Example 3

5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-(2-甲基噻唑-4-基)苯基]嘧啶-2,4-二胺5-Chloro-N4-(2-dimethylphosphorylphenyl)-N2-[3-(2-methylthiazol-4-yl)phenyl]pyrimidine-2,4-diamine

Figure PCTCN2022082343-appb-000058
Figure PCTCN2022082343-appb-000058

根据实施例1中第四步方法，将对甲氧基苯胺替换为3-(2-甲基噻唑-4-基)苯胺，得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-(2-甲基噻唑-4-基)苯基]嘧啶-2,4-二胺(30.00mg)，产率：37％。 1H NMR:(400MHz,CD 3OD)δ8.26(s,1H),8.17-8.16(m,1H),8.04-8.01(m,2H),7.76-7.74(m,1H),7.69-7.65(m,1H),7.57-7.55(m,2H),7.30-7.29(m,2H),2.99(s,3H),1.90(s,3H),1.87(s,3H). According to the fourth step method in Example 1, p-methoxyaniline was replaced with 3-(2-methylthiazol-4-yl)aniline to obtain 5-chloro-N4-(2-dimethylphosphorylphenyl) )-N2-[3-(2-methylthiazol-4-yl)phenyl]pyrimidine-2,4-diamine (30.00 mg), yield: 37%. 1 H NMR: (400MHz, CD 3 OD) δ 8.26 (s, 1H), 8.17-8.16 (m, 1H), 8.04-8.01 (m, 2H), 7.76-7.74 (m, 1H), 7.69-7.65 (m,1H),7.57-7.55(m,2H),7.30-7.29(m,2H),2.99(s,3H),1.90(s,3H),1.87(s,3H).

MS-ESI计算值[M+H] +470和472，实测值470和472。 MS-ESI calculated [M+H] + 470 and 472, found 470 and 472.

实施例4Example 4

3-[[5-氯-4-(2-二甲基磷酰基苯胺)嘧啶-2-基]氨基]-4-甲氧基-本甲酰胺3-[[5-Chloro-4-(2-dimethylphosphorylanilide)pyrimidin-2-yl]amino]-4-methoxy-benzamide

Figure PCTCN2022082343-appb-000059
Figure PCTCN2022082343-appb-000059

根据实施例1中第四步方法，将对甲氧基苯胺替换为3-氨基-4-甲氧基-本甲酰胺，得到3-[[5-氯-4-(2-二甲基磷酰基苯胺)嘧啶-2-基]氨基]-4-甲氧基-本甲酰胺(23.00mg)，产率：27％。 1H NMR:(400MHz,CD 3OD)δ8.24-8.19(m,2H),8.01(s,1H),7.92-7.90(m,1H),7.67-7.62(m,1H),7.50-7.45(m,1H),7.37-7.34(m,1H),7.24-7.22(m,1H),3.94(s,3H),1.90(s,3H),1.86(s,3H). According to the fourth step method in Example 1, p-methoxyaniline was replaced with 3-amino-4-methoxy-benzamide to obtain 3-[[5-chloro-4-(2-dimethylphosphorus Acylaniline)pyrimidin-2-yl]amino]-4-methoxy-benzamide (23.00 mg), yield: 27%. 1 H NMR: (400MHz, CD 3 OD) δ 8.24-8.19 (m, 2H), 8.01 (s, 1H), 7.92-7.90 (m, 1H), 7.67-7.62 (m, 1H), 7.50-7.45 (m,1H),7.37-7.34(m,1H),7.24-7.22(m,1H),3.94(s,3H),1.90(s,3H),1.86(s,3H).

MS-ESI计算值[M+H] +446和448，实测值446和448。 MS-ESI calculated [M+H] + 446 and 448, found 446 and 448.

实施例5Example 5

3-[[5-氯-4-(2-二甲基磷酰基苯胺)嘧啶-2-基]氨基]-N-甲基-本甲酰胺3-[[5-Chloro-4-(2-dimethylphosphorylanilide)pyrimidin-2-yl]amino]-N-methyl-benzamide

Figure PCTCN2022082343-appb-000060
Figure PCTCN2022082343-appb-000060

根据实施例1中第四步方法，将对甲氧基苯胺替换为3-氨基-N-甲基-苯甲酰胺，得到3-[[5-氯-4-(2-二甲基磷酰基苯胺)嘧啶-2-基]氨基]-N-甲基-本甲酰胺(31.00mg)，产率：35％。 1H NMR:(400MHz,CD 3OD)δ8.23(s,1H),8.15(br.s.,1H),7.88(s,1H),7.72-7.65(m,2H),7.57-7.55(m,1H),7.50-7.46(m,2H),7.40-7.37(m,1H),2.91(s,3H),1.90-1.86(m,6H). According to the fourth step method in Example 1, p-methoxyaniline is replaced with 3-amino-N-methyl-benzamide to obtain 3-[[5-chloro-4-(2-dimethylphosphoryl Aniline)pyrimidin-2-yl]amino]-N-methyl-benzamide (31.00 mg), yield: 35%. 1 H NMR: (400MHz, CD 3 OD) δ 8.23(s, 1H), 8.15(br.s., 1H), 7.88(s, 1H), 7.72-7.65(m, 2H), 7.57-7.55( m,1H),7.50-7.46(m,2H),7.40-7.37(m,1H),2.91(s,3H),1.90-1.86(m,6H).

MS-ESI计算值[M+H] +430和432，实测值430和432。 MS-ESI calculated [M+H] + 430 and 432, found 430 and 432.

实施例6Example 6

5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-(1-哌啶甲基)苯基]嘧啶-2,4-二胺5-Chloro-N4-(2-dimethylphosphorylphenyl)-N2-[3-(1-piperidinylmethyl)phenyl]pyrimidine-2,4-diamine

Figure PCTCN2022082343-appb-000061
Figure PCTCN2022082343-appb-000061

根据实施例1中第四步方法，将对甲氧基苯胺替换为3-(1-哌啶甲基)苯胺，得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-(1-哌啶甲基)苯基]嘧啶-2,4-二胺(31.00mg)，产率：32％。 1H NMR:(400MHz,CD 3OD)δ8.24(s,1H),8.20(br.s.,1H),7.76-7.70(m,1H),7.63(s,1H),7.59-7.54(m,2H),7.51-7.50(m,2H),7.47-7.43(m,1H),4.29(s,2H),3.43-3.41(d,J＝12.0Hz,2H),2.98(t,J＝12.0Hz,2H),1.90-1.87(m,6H),1.86-1.82(m,5H),1.55-1.45(m,1H). According to the fourth step method in Example 1, p-methoxyaniline is replaced with 3-(1-piperidinemethyl)aniline to obtain 5-chloro-N4-(2-dimethylphosphorylphenyl)-N2 -[3-(1-Piperidinylmethyl)phenyl]pyrimidine-2,4-diamine (31.00 mg), yield: 32%. 1 H NMR: (400MHz, CD 3 OD) δ 8.24(s, 1H), 8.20(br.s., 1H), 7.76-7.70(m, 1H), 7.63(s, 1H), 7.59-7.54( m, 2H), 7.51-7.50(m, 2H), 7.47-7.43(m, 1H), 4.29(s, 2H), 3.43-3.41(d, J=12.0Hz, 2H), 2.98(t, J= 12.0Hz, 2H), 1.90-1.87(m, 6H), 1.86-1.82(m, 5H), 1.55-1.45(m, 1H).

MS-ESI计算值[M+H] +470和472，实测值470和472。 MS-ESI calculated [M+H] + 470 and 472, found 470 and 472.

实施例7Example 7

5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-(2-甲基嘧啶-4-基)苯基]嘧啶-2,4-二胺5-Chloro-N4-(2-dimethylphosphorylphenyl)-N2-[3-(2-methylpyrimidin-4-yl)phenyl]pyrimidine-2,4-diamine

Figure PCTCN2022082343-appb-000062
Figure PCTCN2022082343-appb-000062

根据实施例1中第四步方法，将对甲氧基苯胺替换为3-(2-甲基嘧啶-4-基)苯胺，得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-(2-甲基嘧啶-4-基)苯基]嘧啶-2,4-二胺(42.00mg,)，产率：53％。 1H NMR:(400MHz,CD 3OD)δ9.02(br.s.,1H),8.46(br.s.,1H),8.37(br.s.,1H),8.32-8.27(m,2H),8.17(br.s.,1H),7.79-7.78(m,1H),7.68-7.66(m,2H),7.32(br.s.,2H),2.92(br.s.,3H),1.89(s,3H),1.86(s,3H). According to the fourth step method in Example 1, p-methoxyaniline was replaced with 3-(2-methylpyrimidin-4-yl)aniline to obtain 5-chloro-N4-(2-dimethylphosphorylphenyl) )-N2-[3-(2-methylpyrimidin-4-yl)phenyl]pyrimidine-2,4-diamine (42.00 mg, ), yield: 53%. 1 H NMR: (400MHz, CD 3 OD) δ 9.02 (br.s., 1H), 8.46 (br.s., 1H), 8.37 (br.s., 1H), 8.32-8.27 (m, 2H) ),8.17(br.s.,1H),7.79-7.78(m,1H),7.68-7.66(m,2H),7.32(br.s.,2H),2.92(br.s.,3H), 1.89(s, 3H), 1.86(s, 3H).

MS-ESI计算值[M+H] +465和467，实测值465和467。 MS-ESI calculated [M+H] + 465 and 467, found 465 and 467.

实施例8Example 8

[3-[[5-氯-4-(2-二甲基磷酰基苯胺基)嘧啶-2-基]胺]苯基]甲磺酰胺[3-[[5-Chloro-4-(2-dimethylphosphorylanilino)pyrimidin-2-yl]amine]phenyl]methanesulfonamide

Figure PCTCN2022082343-appb-000063
Figure PCTCN2022082343-appb-000063

根据实施例1中第四步方法，将对甲氧基苯胺替换为3-氨基苄磺酰胺，得到[3-[[5-氯-4-(2-二甲基磷酰基苯胺基)嘧啶-2-基]胺]苯基]甲磺酰胺(20.0mg)，产率：3.2％。 1H NMR:(400MHz,CD 3OD)δ8.17-8.12(m,2H),7.76-7.71(m,1H),7.62-7.58(m,1H),7.48-7.40(m,4H),7.36(br.s.,1H),4.26(s,2H),1.90-1.87(m,6H). According to the fourth step method in Example 1, p-methoxyaniline was replaced with 3-aminobenzylsulfonamide to obtain [3-[[5-chloro-4-(2-dimethylphosphorylanilino)pyrimidine- 2-yl]amine]phenyl]methanesulfonamide (20.0 mg), yield: 3.2%. 1 H NMR: (400MHz, CD 3 OD) δ 8.17-8.12 (m, 2H), 7.76-7.71 (m, 1H), 7.62-7.58 (m, 1H), 7.48-7.40 (m, 4H), 7.36 (br.s.,1H),4.26(s,2H),1.90-1.87(m,6H).

MS-ESI计算值[M+H] +466和468，实测值466和468。 MS-ESI calculated [M+H] + 466 and 468, found 466 and 468.

实施例9Example 9

1-[3-[[5-氯-4-(2-二甲基磷酰基苯胺基)嘧啶-2-基]胺]-4-氟-苯基]乙酮1-[3-[[5-Chloro-4-(2-dimethylphosphorylanilino)pyrimidin-2-yl]amine]-4-fluoro-phenyl]ethanone

Figure PCTCN2022082343-appb-000064
Figure PCTCN2022082343-appb-000064

根据实施例1中第四步方法，将对甲氧基苯胺替换为1-(3-氨基-4-氟-苯基)乙酮，得到1-[3-[[5-氯-4-(2-二甲基磷酰基苯胺基)嘧啶-2-基]胺]-4-氟-苯基]乙酮(39.0mg)，产率：43％。 1H NMR:(400MHz,CD3OD)δ8.26(s,1H),8.17-8.14(m,1H),8.07-8.03(m,2H),7.67-7.61(m,1H),7.45-7.40(m,1H),7.33(br.s.,2H),2.54(s,3H),1.89(s,3H),1.86(s,3H). According to the fourth step method in Example 1, p-methoxyaniline was replaced with 1-(3-amino-4-fluoro-phenyl)ethanone to obtain 1-[3-[[5-chloro-4-( 2-Dimethylphosphorylanilino)pyrimidin-2-yl]amine]-4-fluoro-phenyl]ethanone (39.0 mg), yield: 43%. 1 H NMR: (400MHz, CD3OD) δ 8.26(s, 1H), 8.17-8.14(m, 1H), 8.07-8.03(m, 2H), 7.67-7.61(m, 1H), 7.45-7.40(m ,1H),7.33(br.s.,2H),2.54(s,3H),1.89(s,3H),1.86(s,3H).

MS-ESI计算值[M+H] +433和435，实测值433和435。 MS-ESI calculated [M+H] + 433 and 435, found 433 and 435.

实施例10Example 10

3-[[5-氯-4-(2-二甲基磷酰基苯胺)嘧啶-2-基]氨基]-4-甲氧基-N-苯基-苯甲酰胺3-[[5-Chloro-4-(2-dimethylphosphorylanilide)pyrimidin-2-yl]amino]-4-methoxy-N-phenyl-benzamide

Figure PCTCN2022082343-appb-000065
Figure PCTCN2022082343-appb-000065

根据实施例1中第四步方法，将对甲氧基苯胺替换为3-氨基-4-甲氧基-N-苯基-苯甲酰胺，得到3-[[5-氯-4-(2-二甲基磷酰基苯胺)嘧啶-2-基]氨基]-4-甲氧基-N-苯基-苯甲酰胺(32.0mg)，产率：38％。 1H NMR:(400MHz,CD 3OD)δ8.21-8.16(m,3H),7.93-7.91(m,1H),7.66(d,J＝8.0Hz,2H),7.57-7.52(m,1H),7.41-7.35(m,3H),7.26(d,J＝8.5Hz,1H),7.18-7.15(m,2H),3.98(s,3H),1.87(s,3H),1.84(s,3H). According to the fourth step method in Example 1, p-methoxyaniline was replaced with 3-amino-4-methoxy-N-phenyl-benzamide to obtain 3-[[5-chloro-4-(2 -Dimethylphosphorylanilide)pyrimidin-2-yl]amino]-4-methoxy-N-phenyl-benzamide (32.0 mg), yield: 38%. 1 H NMR: (400 MHz, CD 3 OD) δ 8.21-8.16 (m, 3H), 7.93-7.91 (m, 1H), 7.66 (d, J=8.0 Hz, 2H), 7.57-7.52 (m, 1H) ), 7.41-7.35(m, 3H), 7.26(d, J=8.5Hz, 1H), 7.18-7.15(m, 2H), 3.98(s, 3H), 1.87(s, 3H), 1.84(s, 3H).

MS-ESI计算值[M+H] +522和524，实测值522和524。 MS-ESI calculated [M+H] + 522 and 524, found 522 and 524.

实施例11Example 11

5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-[2-(2-哌啶基)乙基]苯基]嘧啶-2,4-二胺5-Chloro-N4-(2-dimethylphosphorylphenyl)-N2-[3-[2-(2-piperidinyl)ethyl]phenyl]pyrimidine-2,4-diamine

Figure PCTCN2022082343-appb-000066
Figure PCTCN2022082343-appb-000066

根据实施例1中第四步方法，将对甲氧基苯胺替换为3-[2-(2-哌啶基)乙基]苯胺，得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-[2-(2-哌啶基)乙基]苯基]嘧啶-2,4-二胺(20.0mg)，产率：26％。 1H NMR:(400MHz,CD 3OD)δ8.72-8.71(m,1H),8.55-8.50(m,1H),8.23-8.19(m,2H),7.97-7.91(m,2H),7.74-7.68(m,1H),7.55-7.51(m,1H),7.43-7.39(m,1H),7.33-7.31(m,3H),7.18-7.17(m,1H),3.41-3.37(m,2H),3.16-3.12(m,2H),1.90(s,3H),1.86(s,3H). According to the fourth step method in Example 1, p-methoxyaniline was replaced with 3-[2-(2-piperidinyl)ethyl]aniline to obtain 5-chloro-N4-(2-dimethylphosphoryl) Phenyl)-N2-[3-[2-(2-piperidinyl)ethyl]phenyl]pyrimidine-2,4-diamine (20.0 mg), yield: 26%. 1 H NMR: (400MHz, CD 3 OD) δ 8.72-8.71 (m, 1H), 8.55-8.50 (m, 1H), 8.23-8.19 (m, 2H), 7.97-7.91 (m, 2H), 7.74 -7.68(m,1H),7.55-7.51(m,1H),7.43-7.39(m,1H),7.33-7.31(m,3H),7.18-7.17(m,1H),3.41-3.37(m, 2H), 3.16-3.12(m, 2H), 1.90(s, 3H), 1.86(s, 3H).

MS-ESI计算值[M+H] +478和480，实测值478和480。 MS-ESI calculated [M+H] + 478 and 480, found 478 and 480.

实施例12Example 12

1-[3-[[5-氯-4-(2-二甲基磷酰基苯胺基)嘧啶-2-基]胺]苯基]乙酮1-[3-[[5-Chloro-4-(2-dimethylphosphorylanilino)pyrimidin-2-yl]amine]phenyl]ethanone

Figure PCTCN2022082343-appb-000067
Figure PCTCN2022082343-appb-000067

根据实施例1中第四步方法，将对甲氧基苯胺替换为1-(3-苯胺)乙酮，得到1-[3-[[5-氯-4-(2-二甲基磷酰基苯胺基)嘧啶-2-基]胺]苯基]乙酮(25.0mg)，产率：29％。According to the fourth step method in Example 1, p-methoxyaniline is replaced with 1-(3-aniline)ethanone to obtain 1-[3-[[5-chloro-4-(2-dimethylphosphoryl Anilino)pyrimidin-2-yl]amine]phenyl]ethanone (25.0 mg), yield: 29%.

1H NMR:(400MHz,CD 3OD)δ8.21(s,1H),8.15(br.s.,1H),7.99(s,1H),7.93-7.91(m,1H),7.70-7.64(m,2H),7.56-7.52(m,1H),7.43-7.40(m,2H),2.55(s,3H),1.89(s,3H),1.86(s,3H). 1 H NMR: (400MHz, CD 3 OD) δ 8.21(s, 1H), 8.15(br.s., 1H), 7.99(s, 1H), 7.93-7.91(m, 1H), 7.70-7.64( m,2H),7.56-7.52(m,1H),7.43-7.40(m,2H),2.55(s,3H),1.89(s,3H),1.86(s,3H).

MS-ESI计算值[M+H] +415和417，实测值415和417。 MS-ESI calculated [M+H] + 415 and 417, found 415 and 417.

实施例13Example 13

5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-(4-哌啶基)苯基]嘧啶-2,4-二胺5-Chloro-N4-(2-dimethylphosphorylphenyl)-N2-[3-(4-piperidinyl)phenyl]pyrimidine-2,4-diamine

Figure PCTCN2022082343-appb-000068
Figure PCTCN2022082343-appb-000068

根据实施例1中第四步方法，将对甲氧基苯胺替换为3-(4-哌啶基)苯胺，得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-(4-哌啶基)苯基]嘧啶-2,4-二胺(25.0mg,)，产率：33％。According to the fourth step method in Example 1, p-methoxyaniline is replaced with 3-(4-piperidinyl)aniline to obtain 5-chloro-N4-(2-dimethylphosphorylphenyl)-N2- [3-(4-Piperidinyl)phenyl]pyrimidine-2,4-diamine (25.0 mg, ), yield: 33%.

1H NMR:(400MHz,CD3OD)δ8.88-8.87(m,2H),8.31(d,J＝8.0Hz,2H),8.25(s,1H),8.15(br.s.,1H),8.08(s,1H),7.85(d,J＝8.0Hz,1H),7.73-7.71(m,1H),7.67-7.62(m,2H),7.35-7.31(m,1H),7.27-7.23(m,1H),1.89(s,3H),1.85(s,3H). 1 H NMR: (400MHz, CD3OD)δ8.88-8.87(m, 2H), 8.31(d, J=8.0Hz, 2H), 8.25(s, 1H), 8.15(br.s., 1H), 8.08 (s,1H),7.85(d,J=8.0Hz,1H),7.73-7.71(m,1H),7.67-7.62(m,2H),7.35-7.31(m,1H),7.27-7.23(m ,1H),1.89(s,3H),1.85(s,3H).

MS-ESI计算值[M+H] +450和452，实测值450和452。 MS-ESI calculated [M+H] + 450 and 452, found 450 and 452.

实施例14Example 14

3-((5-氯-4-((2-(二甲基磷酰基)苯基)氨基)嘧啶-2-基)氨基)-N，N-二甲基苯磺酰胺3-((5-Chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-N,N-dimethylbenzenesulfonamide

Figure PCTCN2022082343-appb-000069
Figure PCTCN2022082343-appb-000069

根据实施例1中第四步方法，将对甲氧基苯胺替换为3-氨基-N，N-二甲基苯磺酰胺，得到3-((5-氯-4-((2-(二甲基磷酰基)苯基)氨基)嘧啶-2-基)氨基)-N，N-二甲基苯磺酰胺(26.0mg)，产率：34％。 1H NMR:(400MHz,CD 3OD)δ8.37-8.36(m,1H),8.21(s,1H),7.95-7.91(m,2H),7.63-7.61(m,2H),7.51-7.48(m,2H),7.36-7.35(m,1H),2.69(s,6H),1.90-1.86(m,6H). According to the fourth step method in Example 1, p-methoxyaniline is replaced with 3-amino-N,N-dimethylbenzenesulfonamide to obtain 3-((5-chloro-4-((2-(bis Methylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-N,N-dimethylbenzenesulfonamide (26.0 mg), yield: 34%. 1 H NMR: (400 MHz, CD 3 OD) δ 8.37-8.36 (m, 1H), 8.21 (s, 1H), 7.95-7.91 (m, 2H), 7.63-7.61 (m, 2H), 7.51-7.48 (m,2H),7.36-7.35(m,1H),2.69(s,6H),1.90-1.86(m,6H).

MS-ESI计算值[M+H] +480和482，实测值480和482。 MS-ESI calculated [M+H] + 480 and 482, found 480 and 482.

实施例15Example 15

4-((5-氯-4-((2-(二甲基磷酰基)苯基)氨基)嘧啶-2-基)氨基)-N，N-二甲基苯磺酰胺4-((5-Chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-N,N-dimethylbenzenesulfonamide

Figure PCTCN2022082343-appb-000070
Figure PCTCN2022082343-appb-000070

根据实施例1中第四步方法，将对甲氧基苯胺替换为4-氨基-N，N-二甲基苯磺酰胺，得到4-((5-氯-4-((2-(二甲基磷酰基)苯基)氨基)嘧啶-2-基)氨基)-N，N-二甲基苯磺酰胺(12.0mg)，产率：16％。 1H NMR:(400MHz,CD 3OD)δ8.43-8.40(m,1H),8.21(s,1H),7.86-7.83(m,2H),7.70-7.62(m,2H),7.60-7.59(m,2H),7.36-7.35(m,1H),2.68(s,6H),1.89-1.85(m,6H). According to the fourth step method in Example 1, p-methoxyaniline is replaced with 4-amino-N,N-dimethylbenzenesulfonamide to obtain 4-((5-chloro-4-((2-(bis Methylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-N,N-dimethylbenzenesulfonamide (12.0 mg), yield: 16%. 1 H NMR: (400 MHz, CD 3 OD) δ 8.43-8.40 (m, 1H), 8.21 (s, 1H), 7.86-7.83 (m, 2H), 7.70-7.62 (m, 2H), 7.60-7.59 (m,2H),7.36-7.35(m,1H),2.68(s,6H),1.89-1.85(m,6H).

MS-ESI计算值[M+H] +480和482，实测值480和482。 MS-ESI calculated [M+H] + 480 and 482, found 480 and 482.

实施例16Example 16

(2-((5-氯-2-((3-甲氧基苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧化膦(2-((5-Chloro-2-((3-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

Figure PCTCN2022082343-appb-000071
Figure PCTCN2022082343-appb-000071

根据实施例1中第四步方法，将对甲氧基苯胺替换为3-甲氧基苯胺，得到(2-((5-氯-2-((3-甲氧基苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧化膦(21.0mg)，产率：33％。 1H NMR:(400MHz,CD 3OD)δ8.35-8.34(m,1H),8.15(s,1H),7.73-7.71(m,1H),7.57-7.56(m,1H),7.43-7.42(m,1H),7.36-7.34(m,1H),7.03(s,1H),6.99-6.97(m,1H),6.93-6.92(m,1H),3.79(s,3H),1.92-1.88(m,6H). According to the fourth step method in Example 1, p-methoxyaniline was replaced with 3-methoxyaniline to obtain (2-((5-chloro-2-((3-methoxyphenyl)amino)pyrimidine -4-yl)amino)phenyl)dimethylphosphine oxide (21.0 mg), yield: 33%. 1 H NMR: (400 MHz, CD 3 OD) δ 8.35-8.34 (m, 1H), 8.15 (s, 1H), 7.73-7.71 (m, 1H), 7.57-7.56 (m, 1H), 7.43-7.42 (m,1H),7.36-7.34(m,1H),7.03(s,1H),6.99-6.97(m,1H),6.93-6.92(m,1H),3.79(s,3H),1.92-1.88 (m,6H).

MS-ESI计算值[M+H] +403和405，实测值403和405。 MS-ESI calculated [M+H] + 403 and 405, found 403 and 405.

实施例17Example 17

3-((5-氯-4-((2-(二甲基磷酰基)苯基)氨基)嘧啶-2-基)氨基)-N，N-二甲基苯甲酰胺3-((5-Chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-N,N-dimethylbenzamide

Figure PCTCN2022082343-appb-000072
Figure PCTCN2022082343-appb-000072

根据实施例1中第四步方法，将对甲氧基苯胺替换为3-氨基-N，N-二甲基苯甲酰，得到3-((5-氯-4-((2-(二甲基磷酰基)苯基)氨基)嘧啶-2-基)氨基)-N，N-二甲基苯甲酰胺(11.0mg)，产率：16％。 1H NMR:(400MHz,CD 3OD)δ8.41-8.38(m,1H),8.15(s,1H),7.79(s,1H),7.61-7.57(m,3H),7.34-7.30(m,2H),7.02-7.00(m,1H),3.10(s,3H),2.96(s,3H),1.89-1.85(m,6H). According to the fourth step method in Example 1, p-methoxyaniline is replaced with 3-amino-N,N-dimethylbenzoyl to obtain 3-((5-chloro-4-((2-(2 Methylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-N,N-dimethylbenzamide (11.0 mg), yield: 16%. 1 H NMR: (400MHz, CD 3 OD) δ 8.41-8.38 (m, 1H), 8.15 (s, 1H), 7.79 (s, 1H), 7.61-7.57 (m, 3H), 7.34-7.30 (m ,2H),7.02-7.00(m,1H),3.10(s,3H),2.96(s,3H),1.89-1.85(m,6H).

MS-ESI计算值[M+H] +444和446，实测值444和446 MS-ESI calculated [M+H] + 444 and 446, found 444 and 446

实施例18Example 18

4-((5-氯-4-((2-(二甲基磷酰基)苯基)氨基)嘧啶-2-基)氨基)-N，N-二甲基苯甲酰胺4-((5-Chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-N,N-dimethylbenzamide

Figure PCTCN2022082343-appb-000073
Figure PCTCN2022082343-appb-000073

根据实施例1中第四步方法，将对甲氧基苯胺替换为4-氨基-N,N-二甲基苯甲酰胺，得到4-((5-氯-4-((2-(二甲基磷酰基)苯基)氨基)嘧啶-2-基)氨基)-N，N-二甲基苯甲酰胺(16.0mg)，产率：23％。 1H NMR:(400MHz,CD 3OD)δ8.45-8.42(m,1H),8.16(s,1H),7.79(s,1H),7.69-7.62(m,4H),7.34-7.32(m,3H),3.10(s,6H),1.89-1.85(m,6H). According to the fourth step method in Example 1, p-methoxyaniline is replaced with 4-amino-N,N-dimethylbenzamide to obtain 4-((5-chloro-4-(((2-(two Methylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-N,N-dimethylbenzamide (16.0 mg), yield: 23%. 1 H NMR: (400MHz, CD 3 OD) δ 8.45-8.42(m, 1H), 8.16(s, 1H), 7.79(s, 1H), 7.69-7.62(m, 4H), 7.34-7.32(m ,3H),3.10(s,6H),1.89-1.85(m,6H).

MS-ESI计算值[M+H] +444和446，实测值444和446 MS-ESI calculated [M+H] + 444 and 446, found 444 and 446

实施例19Example 19

(4-((5-氯-4-((2-(二甲基磷酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)(吗啉代)甲酮(4-((5-Chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methan ketone

Figure PCTCN2022082343-appb-000074
Figure PCTCN2022082343-appb-000074

第一步first step

(3-甲氧基-4-硝基苯基)(吗啉代)甲酮(3-Methoxy-4-nitrophenyl)(morpholino)methanone

将3-甲氧基-4-硝基苯甲酸(2.00g,10.2mmol)溶于无水二氯甲烷(30mL)中，向反应液中加入吗啡啉(1.06g,12.2mmol)，1-羟基苯并三唑(2.74g,20.3mmol)，1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(3.89g,20.3mmol)和N,N-二异丙基乙基胺(2.62g,20.3mmol)。反应液在25℃，搅拌12小时。反应液加入水(40mL)，滤液用乙酸乙酯(50mL×3)萃取。合并有机相，用饱和食盐水洗涤(40mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩，剩余物用硅胶柱色谱法分离纯化(1：1石油醚/乙酸乙酯)分离纯化得到(3-甲氧基 -4-硝基苯基)(吗啉代)甲酮(1.80g,无色油状物)，产率：67％。 1H NMR:(400MHz,DMSO-d6)δ7.96-7.93(m,1H),7.38(s,1H),7.14-7.12(m,1H),3.96(s,3H),3.67-3.56(m,6H),3.36-3.31(m,2H). 3-Methoxy-4-nitrobenzoic acid (2.00 g, 10.2 mmol) was dissolved in anhydrous dichloromethane (30 mL), and morpholine (1.06 g, 12.2 mmol), 1-hydroxyl Benzotriazole (2.74g, 20.3mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.89g, 20.3mmol) and N,N-diiso Propylethylamine (2.62 g, 20.3 mmol). The reaction solution was stirred at 25°C for 12 hours. Water (40 mL) was added to the reaction solution, and the filtrate was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine (40 mL×3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (1:1 petroleum ether/ethyl acetate) (3-Methoxy-4-nitrophenyl)(morpholino)methanone (1.80 g, colorless oil) was obtained, yield: 67%. 1 H NMR: (400MHz, DMSO-d6)δ7.96-7.93(m,1H), 7.38(s,1H), 7.14-7.12(m,1H), 3.96(s,3H), 3.67-3.56(m) ,6H),3.36-3.31(m,2H).

第二步second step

(4-氨基-3-甲氧基苯基)(吗啉代)甲酮(4-Amino-3-methoxyphenyl)(morpholino)methanone

将(3-甲氧基-4-硝基苯基)(吗啉代)甲酮(1.80g,6.76mmol)溶于甲醇(50mL)中，向反应液中加入干钯碳(10％,200mg)。反应液在25℃氢气(15psi)氛围下反应12小时。反应液过滤，滤液减压浓缩得到(4-氨基-3-甲氧基苯基)(吗啉代)甲酮(1.40g,白色固体)，产率：88％。 1H NMR:(400MHz,DMSO-d6)δ8.86(s,1H),8.82-8.80(m,1H),6.63-6.61(m,1H),5.16(s,2H),3.78(s,3H),3.60-3.58(m,4H),3.52-3.49(m,4H). (3-Methoxy-4-nitrophenyl)(morpholino)methanone (1.80 g, 6.76 mmol) was dissolved in methanol (50 mL), and dry palladium carbon (10%, 200 mg) was added to the reaction solution. ). The reaction solution was reacted under a hydrogen (15 psi) atmosphere at 25°C for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain (4-amino-3-methoxyphenyl)(morpholino)methanone (1.40 g, white solid), yield: 88%. 1 H NMR: (400MHz, DMSO-d6)δ8.86(s,1H), 8.82-8.80(m,1H), 6.63-6.61(m,1H), 5.16(s,2H), 3.78(s,3H) ),3.60-3.58(m,4H),3.52-3.49(m,4H).

MS-ESI计算值[M+H] +237，实测值237 MS-ESI calculated [M+H] + 237, found 237

第三步third step

(4-((5-氯-4-((2-(二甲基磷酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)(吗啉代)甲酮(4-((5-Chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methan ketone

根据实施例1中第四步方法，将对甲氧基苯胺替换为(4-氨基-3-甲氧基苯基)(吗啉代)甲酮，得到(4-((5-氯-4-((2-(二甲基磷酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)(吗啉代)甲酮(25.0mg)，产率：30％。 1H NMR:(400MHz,CDCl 3)δ12.39(s,1H),10.22(s,1H),8.39-8.37(m,1H),7.90-7.89(m,2H),7.50-7.48(m,1H),7.39-7.29(m,2H),7.04(s,1H),6.95-6.93(m,1H),3.95(s,3H),3.77-3.70(m,8H),1.88-1.80(m,6H). According to the fourth step method in Example 1, p-methoxyaniline was replaced with (4-amino-3-methoxyphenyl)(morpholino)methanone to obtain (4-((5-chloro-4 -((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (25.0 mg), yield: 30 %. 1 H NMR: (400 MHz, CDCl 3 ) δ 12.39 (s, 1H), 10.22 (s, 1H), 8.39-8.37 (m, 1H), 7.90-7.89 (m, 2H), 7.50-7.48 (m, 1H), 7.39-7.29(m, 2H), 7.04(s, 1H), 6.95-6.93(m, 1H), 3.95(s, 3H), 3.77-3.70(m, 8H), 1.88-1.80(m, 6H).

MS-ESI计算值[M+H] +516和518，实测值516和518。 MS-ESI calculated [M+H] + 516 and 518, found 516 and 518.

实施例20Example 20

5-氯-N2-(3,4-二甲氧基苯基)-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺5-Chloro-N2-(3,4-dimethoxyphenyl)-N4-(2-dimethylphosphonoanilino)pyrimidine-2,4-diamine

Figure PCTCN2022082343-appb-000075
Figure PCTCN2022082343-appb-000075

根据实施例1中第四步方法，将对甲氧基苯胺替换为3,4-二甲氧基苯胺，得到5-氯-N2-(3,4-二甲氧基苯基)-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺(27.0mg)，产率：36％。 1H NMR:(400MHz,CD 3OD)δ8.39(br.s,1H),8.10(br.s,1H),7.72-7.70(m,1H),7.52(br.s,1H),7.44-7.38(m,1H),7.07-7.01(m,2H),6.98-6.94(m,1H),3.89(s,3H),3.78(br.s,3H),1.93(s,3H),1.89(s,3H). According to the fourth step method in Example 1, p-methoxyaniline is replaced with 3,4-dimethoxyaniline to obtain 5-chloro-N2-(3,4-dimethoxyphenyl)-N4- (2-Dimethylphosphonoanilino)pyrimidine-2,4-diamine (27.0 mg), yield: 36%. 1 H NMR: (400MHz, CD 3 OD) δ 8.39 (br.s, 1H), 8.10 (br.s, 1H), 7.72-7.70 (m, 1H), 7.52 (br.s, 1H), 7.44 -7.38(m,1H),7.07-7.01(m,2H),6.98-6.94(m,1H),3.89(s,3H),3.78(br.s,3H),1.93(s,3H),1.89 (s,3H).

MS-ESI计算值[M+H] +433和435，实测值433和435。 MS-ESI calculated [M+H] + 433 and 435, found 433 and 435.

实施例21Example 21

5-氯-N2-(2,4-二甲氧基苯基)-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺5-Chloro-N2-(2,4-dimethoxyphenyl)-N4-(2-dimethylphosphonoanilino)pyrimidine-2,4-diamine

Figure PCTCN2022082343-appb-000076
Figure PCTCN2022082343-appb-000076

根据实施例1中第四步方法，将对甲氧基苯胺替换为2,4-二甲氧基苯胺，得到5-氯-N2-(2,4-二甲氧基苯基)-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺(20.0mg)，产率：27％。 1H NMR:(400MHz, CD 3OD)δ8.39(br.s,1H),8.07(br.s,1H),7.72-7.70(m,1H),7.56(br.s,1H),7.43-7.39(m,1H),7.33(d，J＝7.6Hz,1H),6.73(d，J＝2.4Hz,1H),6.59(d，J＝7.6Hz,1H),3.87(s,3H),3.86(s,3H),1.93(s,3H),1.89(s,3H). According to the fourth step method in Example 1, p-methoxyaniline is replaced with 2,4-dimethoxyaniline to obtain 5-chloro-N2-(2,4-dimethoxyphenyl)-N4- (2-Dimethylphosphonoanilino)pyrimidine-2,4-diamine (20.0 mg), yield: 27%. 1 H NMR: (400MHz, CD 3 OD)δ8.39(br.s,1H),8.07(br.s,1H),7.72-7.70(m,1H),7.56(br.s,1H),7.43 -7.39(m, 1H), 7.33(d, J=7.6Hz, 1H), 6.73(d, J=2.4Hz, 1H), 6.59(d, J=7.6Hz, 1H), 3.87(s, 3H) ,3.86(s,3H),1.93(s,3H),1.89(s,3H).

MS-ESI计算值[M+H] +433和435，实测值433和435。 MS-ESI calculated [M+H] + 433 and 435, found 433 and 435.

实施例22Example 22

5-氯-N2-(3,5-二甲氧基苯基)-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺5-Chloro-N2-(3,5-dimethoxyphenyl)-N4-(2-dimethylphosphonoanilino)pyrimidine-2,4-diamine

Figure PCTCN2022082343-appb-000077
Figure PCTCN2022082343-appb-000077

根据实施例1中第四步方法，将对甲氧基苯胺替换为3,5-二甲氧基苯胺，得到5-氯-N2-(3,5-二甲氧基苯基)-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺(35.0mg)，产率：47％。 1H NMR:(400MHz,CD 3OD)δ8.39(s,1H),8.13(s,1H),7.75-7.67(m,1H),7.57-7.55(m,1H),7.45-7.39(m,1H),6.60(s,2H),6.48(s,1H),3.78(s,6H),1.92(s,3H),1.89(s,3H). According to the fourth step method in Example 1, p-methoxyaniline is replaced with 3,5-dimethoxyaniline to obtain 5-chloro-N2-(3,5-dimethoxyphenyl)-N4- (2-Dimethylphosphonoanilino)pyrimidine-2,4-diamine (35.0 mg), yield: 47%. 1 H NMR: (400MHz, CD 3 OD) δ 8.39(s, 1H), 8.13(s, 1H), 7.75-7.67(m, 1H), 7.57-7.55(m, 1H), 7.45-7.39(m ,1H),6.60(s,2H),6.48(s,1H),3.78(s,6H),1.92(s,3H),1.89(s,3H).

MS-ESI计算值[M+H] +433和435，实测值433和435。 MS-ESI calculated [M+H] + 433 and 435, found 433 and 435.

实施例23Example 23

N2-[3-(三氟甲氧基)苯基]-5-氯-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺N2-[3-(Trifluoromethoxy)phenyl]-5-chloro-N4-(2-dimethylphosphonoanilino)pyrimidine-2,4-diamine

Figure PCTCN2022082343-appb-000078
Figure PCTCN2022082343-appb-000078

根据实施例1中第四步方法，将对甲氧基苯胺替换为3-三氟甲氧基苯胺，得到N2-[3-(三氟甲氧基)苯基]-5-氯-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺(18.0mg)，产率：23％。 1H NMR:(400MHz,CD 3OD)δ8.22(s,1H),8.19-8.15(m,1H),7.73-7.71(m,1H),7.58-7.56(m,1H),7.49(s,1H),7.45-7.38(m,3H),7.09-7.07(m,1H),1.88(s,3H),1.85(s,3H). According to the fourth step method in Example 1, p-methoxyaniline is replaced with 3-trifluoromethoxyaniline to obtain N2-[3-(trifluoromethoxy)phenyl]-5-chloro-N4- (2-Dimethylphosphonoanilino)pyrimidine-2,4-diamine (18.0 mg), yield: 23%. 1 H NMR: (400MHz, CD 3 OD) δ 8.22(s, 1H), 8.19-8.15(m, 1H), 7.73-7.71(m, 1H), 7.58-7.56(m, 1H), 7.49(s) ,1H),7.45-7.38(m,3H),7.09-7.07(m,1H),1.88(s,3H),1.85(s,3H).

MS-ESI计算值[M+H] +457和459，实测值457和459。 MS-ESI calculated [M+H] + 457 and 459, found 457 and 459.

实施例24Example 24

5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-(2-甲氧基乙基)苯基]嘧啶-2,4-二胺5-Chloro-N4-(2-dimethylphosphorylphenyl)-N2-[4-(2-methoxyethyl)phenyl]pyrimidine-2,4-diamine

Figure PCTCN2022082343-appb-000079
Figure PCTCN2022082343-appb-000079

根据实施例1中第四步方法，将对甲氧基苯胺替换为4-(2-甲氧基乙基)苯胺，得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-(2-甲氧基乙基)苯基]嘧啶-2,4-二胺(23.0mg)，产率：30％。 1H NMR:(400MHz,CD 3OD)δ8.35(br.s,1H),8.10(br.s,1H),7.70-7.66(m,1H),7.54(br.s,1H),7.44-7.38(m,1H),7.33(d，J＝8.8Hz, 2H),7.04(d，J＝8.0Hz,2H),4.20-4.15(m,2H),3.81-3.77(m,2H),3.46(s,3H),1.92(s,3H),1.89(s,3H). According to the fourth step method in Example 1, p-methoxyaniline is replaced with 4-(2-methoxyethyl)aniline to obtain 5-chloro-N4-(2-dimethylphosphorylphenyl)- N2-[4-(2-methoxyethyl)phenyl]pyrimidine-2,4-diamine (23.0 mg), yield: 30%. 1 H NMR: (400MHz, CD 3 OD) δ 8.35 (br.s, 1H), 8.10 (br.s, 1H), 7.70-7.66 (m, 1H), 7.54 (br.s, 1H), 7.44 -7.38(m, 1H), 7.33(d, J=8.8Hz, 2H), 7.04(d, J=8.0Hz, 2H), 4.20-4.15(m, 2H), 3.81-3.77(m, 2H), 3.46(s, 3H), 1.92(s, 3H), 1.89(s, 3H).

MS-ESI计算值[M+H] +447和449，实测值447和449。 MS-ESI calculated [M+H] + 447 and 449, found 447 and 449.

实施例25Example 25

5-氯-N2-[4-[2-(二甲基氨基)乙基]苯基]-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺5-Chloro-N2-[4-[2-(dimethylamino)ethyl]phenyl]-N4-(2-dimethylphosphonoanilino)pyrimidine-2,4-diamine

Figure PCTCN2022082343-appb-000080
Figure PCTCN2022082343-appb-000080

根据实施例1中第四步方法，将对甲氧基苯胺替换为4-(2-(二甲基氨基)乙氧基)苯胺，得到5-氯-N2-[4-[2-(二甲基氨基)乙基]苯基]-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺(25.0mg)，产率：32％。 1H NMR:(400MHz,CD 3OD)δ8.31(br.s,1H),8.15(br.s,1H),7.73-7.68(m,1H),7.57(br.s,1H),7.46-7.42(m,1H),7.42-7.38(m,2H),7.13-7.11(m,2H),4.46-4.39(m,2H),3.70-3.63(m,2H),3.03(s,6H),1.92(s,3H),1.88(s,3H). According to the fourth step method in Example 1, p-methoxyaniline is replaced with 4-(2-(dimethylamino)ethoxy)aniline to obtain 5-chloro-N2-[4-[2-(dimethyaniline) Methylamino)ethyl]phenyl]-N4-(2-dimethylphosphonoanilino)pyrimidine-2,4-diamine (25.0 mg), yield: 32%. 1 H NMR: (400MHz, CD 3 OD) δ 8.31 (br.s, 1H), 8.15 (br.s, 1H), 7.73-7.68 (m, 1H), 7.57 (br.s, 1H), 7.46 -7.42(m,1H),7.42-7.38(m,2H),7.13-7.11(m,2H),4.46-4.39(m,2H),3.70-3.63(m,2H),3.03(s,6H) ,1.92(s,3H),1.88(s,3H).

MS-ESI计算值[M+H] +460和462，实测值460和462。 MS-ESI calculated [M+H] + 460 and 462, found 460 and 462.

实施例26Example 26

5-氯-N2-[3-[2-(二甲基氨基)乙基]-4-甲氧基-苯基]-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺5-Chloro-N2-[3-[2-(dimethylamino)ethyl]-4-methoxy-phenyl]-N4-(2-dimethylphosphonoanilino)pyrimidine-2,4 -Diamine

Figure PCTCN2022082343-appb-000081
Figure PCTCN2022082343-appb-000081

根据实施例1中第四步方法，将对甲氧基苯胺替换为3-(2-(二甲氨基)乙氧基)-4-甲氧基苯胺，得到5-氯-N2-[3-[2-(二甲基氨基)乙基]-4-甲氧基-苯基]-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺(33.0mg)，产率：35％。 1H NMR:(400MHz,CD 3OD)δ8.36(br.s,1H),8.14(s,1H),7.69-7.65(m,1H),7.54-7.50(m,1H),7.43-7.36(m,1H),7.19-7.13(m,2H),7.09-7.03(m,1H),4.29-4.25(m,2H),3.93(s,3H),3.60-3.56(m,2H),3.03(s,6H),1.91(s,3H),1.88(s,3H). According to the fourth step method in Example 1, p-methoxyaniline was replaced with 3-(2-(dimethylamino)ethoxy)-4-methoxyaniline to obtain 5-chloro-N2-[3- [2-(Dimethylamino)ethyl]-4-methoxy-phenyl]-N4-(2-dimethylphosphonoanilino)pyrimidine-2,4-diamine (33.0 mg), yielded Rate: 35%. 1 H NMR: (400MHz, CD 3 OD) δ 8.36 (br.s, 1H), 8.14 (s, 1H), 7.69-7.65 (m, 1H), 7.54-7.50 (m, 1H), 7.43-7.36 (m,1H),7.19-7.13(m,2H),7.09-7.03(m,1H),4.29-4.25(m,2H),3.93(s,3H),3.60-3.56(m,2H),3.03 (s,6H),1.91(s,3H),1.88(s,3H).

MS-ESI计算值[M+H] +490和492，实测值490和492。 MS-ESI calculated [M+H] + 490 and 492, found 490 and 492.

实施例27Example 27

5-氯-N2-[3-[2-(二甲基氨基)乙基]苯基]-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺5-Chloro-N2-[3-[2-(dimethylamino)ethyl]phenyl]-N4-(2-dimethylphosphonoanilino)pyrimidine-2,4-diamine

Figure PCTCN2022082343-appb-000082
Figure PCTCN2022082343-appb-000082

根据实施例1中第四步方法，将对甲氧基苯胺替换为3-(2-(二甲基氨基)乙氧基)苯胺，得到5-氯-N2-[3-[2-(二甲基氨基)乙基]苯基]-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺(18.0mg)，产率：20％。 1H NMR: (400MHz,CD 3OD)δ8.42(br.s,1H),8.19-8.15(m,1H),7.68-7.66(m,1H),7.58-7.56(m,1H),7.37(br.s,1H),7.32-7.15(m,3H),6.78-6.75(m,1H),4.33-4.29(m,2H),3.62-3.57(m,2H),2.99(s,6H),1.91(s,3H),1.87(s,3H). According to the fourth step method in Example 1, p-methoxyaniline was replaced with 3-(2-(dimethylamino)ethoxy)aniline to obtain 5-chloro-N2-[3-[2-(dimethyaniline) Methylamino)ethyl]phenyl]-N4-(2-dimethylphosphonoanilino)pyrimidine-2,4-diamine (18.0 mg), yield: 20%. 1 H NMR: (400MHz, CD 3 OD) δ 8.42(br.s, 1H), 8.19-8.15(m, 1H), 7.68-7.66(m, 1H), 7.58-7.56(m, 1H), 7.37 (br.s,1H),7.32-7.15(m,3H),6.78-6.75(m,1H),4.33-4.29(m,2H),3.62-3.57(m,2H),2.99(s,6H) ,1.91(s,3H),1.87(s,3H).

MS-ESI计算值[M+H] +460和462，实测值460和462。 MS-ESI calculated [M+H] + 460 and 462, found 460 and 462.

实施例28Example 28

5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-(2-甲氧基乙基)苯基]嘧啶-2,4-二胺5-Chloro-N4-(2-dimethylphosphorylphenyl)-N2-[3-(2-methoxyethyl)phenyl]pyrimidine-2,4-diamine

Figure PCTCN2022082343-appb-000083
Figure PCTCN2022082343-appb-000083

根据实施例1中第四步方法，将对甲氧基苯胺替换为3-(2-甲氧基乙氧基)苯胺，得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-(2-甲氧基乙基)苯基]嘧啶-2,4-二胺(25.0mg)，产率：33％。According to the fourth step method in Example 1, p-methoxyaniline is replaced with 3-(2-methoxyethoxy)aniline to obtain 5-chloro-N4-(2-dimethylphosphorylphenyl) -N2-[3-(2-methoxyethyl)phenyl]pyrimidine-2,4-diamine (25.0 mg), yield: 33%.

1H NMR:(400MHz,CD 3OD)δ8.33(br.s,1H),8.17(s,1H),7.71-7.70(m,1H),7.60-7.58(m,1H),7.47-7.40(m,1H),7.34-7.32(m,1H),7.08(s,1H),6.95-6.94(m,2H),4.12-4.06(m,2H),3.77-3.73(m,2H),3.44(s,3H),1.92(s,3H),1.89(s,3H). 1 H NMR: (400MHz, CD 3 OD) δ 8.33 (br.s, 1H), 8.17 (s, 1H), 7.71-7.70 (m, 1H), 7.60-7.58 (m, 1H), 7.47-7.40 (m,1H),7.34-7.32(m,1H),7.08(s,1H),6.95-6.94(m,2H),4.12-4.06(m,2H),3.77-3.73(m,2H),3.44 (s,3H),1.92(s,3H),1.89(s,3H).

MS-ESI计算值[M+H] +447和449，实测值447和449。 MS-ESI calculated [M+H] + 447 and 449, found 447 and 449.

实施例29Example 29

5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-甲氧基-3-(4-甲基哌嗪-1-基)苯基]嘧啶-2,4-二胺5-Chloro-N4-(2-dimethylphosphorylphenyl)-N2-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4- Diamine

Figure PCTCN2022082343-appb-000084
Figure PCTCN2022082343-appb-000084

根据实施例1中第四步方法，将对甲氧基苯胺替换为4-甲氧基-3-(4-甲基哌嗪-1-基)苯胺，得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-甲氧基-3-(4-甲基哌嗪-1-基)苯基]嘧啶-2,4-二胺(24.0mg)，产率：30％。 1H NMR:(400MHz,CD 3OD)δ8.47-8.44(m,1H),8.05(s,1H),7.59-7.56(m,1H),7.50-7.47(m,1H),7.25-7.24(m,2H),7.06(s,1H),6.84(d,J＝9.2Hz,1H),3.86(s,3H),3.02(br.s.,4H),2.60(br.s.,4H),2.35(s,3H),1.88(s,3H),1.85(s,3H). According to the fourth step method in Example 1, p-methoxyaniline was replaced with 4-methoxy-3-(4-methylpiperazin-1-yl)aniline to obtain 5-chloro-N4-(2- Dimethylphosphorylphenyl)-N2-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine (24.0 mg), yield : 30%. 1 H NMR: (400MHz, CD 3 OD) δ 8.47-8.44 (m, 1H), 8.05 (s, 1H), 7.59-7.56 (m, 1H), 7.50-7.47 (m, 1H), 7.25-7.24 (m, 2H), 7.06(s, 1H), 6.84(d, J=9.2Hz, 1H), 3.86(s, 3H), 3.02(br.s., 4H), 2.60(br.s., 4H) ),2.35(s,3H),1.88(s,3H),1.85(s,3H).

MS-ESI计算值[M+H] +501和503，实测值501和503。 MS-ESI calculated [M+H] + 501 and 503, found 501 and 503.

实施例30Example 30

5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-(2-吗啡啉基乙基)苯基]嘧啶-2,4-二胺5-Chloro-N4-(2-dimethylphosphorylphenyl)-N2-[3-(2-morpholinylethyl)phenyl]pyrimidine-2,4-diamine

Figure PCTCN2022082343-appb-000085
Figure PCTCN2022082343-appb-000085

根据实施例1中第四步方法，将对甲氧基苯胺替换为3-(2-吗啉代乙氧基)苯胺，得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-(2-吗啡啉基乙基)苯基]嘧啶-2,4-二胺(6.0mg)，产率：8％。 1H NMR:(400MHz,CD3OD)δ8.52-8.48(m,1H),8.12(s,1H),7.67-7.55(m,2H),7.32-7.24(m,2H),7.18-7.08(m,2H),6.64-6.56(m,1H),4.08(t,J＝5.6Hz,2H),3.74-3.70(m,4H),2.79(t,J＝5.6Hz,2H),2.63-2.56(m,4H),1.89(s,3H),1.86(s,3H). According to the fourth step method in Example 1, p-methoxyaniline was replaced with 3-(2-morpholinoethoxy)aniline to obtain 5-chloro-N4-(2-dimethylphosphorylphenyl) -N2-[3-(2-Mormorpholinylethyl)phenyl]pyrimidine-2,4-diamine (6.0 mg), yield: 8%. 1 H NMR: (400MHz, CD3OD) δ 8.52-8.48(m, 1H), 8.12(s, 1H), 7.67-7.55(m, 2H), 7.32-7.24(m, 2H), 7.18-7.08(m ,2H),6.64-6.56(m,1H),4.08(t,J＝5.6Hz,2H),3.74-3.70(m,4H),2.79(t,J＝5.6Hz,2H),2.63-2.56( m,4H),1.89(s,3H),1.86(s,3H).

MS-ESI计算值[M+H] +502和504，实测值502和504。 MS-ESI calculated [M+H] + 502 and 504, found 502 and 504.

实施例31Example 31

5-氯-N4-(2-二甲基磷酰基苯基)-N2-(5-甲氧基-2-吗啡啉基-苯基)嘧啶-2,4-二胺5-Chloro-N4-(2-dimethylphosphorylphenyl)-N2-(5-methoxy-2-morpholinyl-phenyl)pyrimidine-2,4-diamine

Figure PCTCN2022082343-appb-000086
Figure PCTCN2022082343-appb-000086

第一步first step

4-(4-甲氧基-2-硝基-苯基)吗啡啉4-(4-Methoxy-2-nitro-phenyl)morpholine

将1-溴-4-甲氧基-2-硝基苯(400.0mg,1.72mmol)溶于无水二氧六环(4mL)中，向反应液中加入吗啡啉(150.2mg,1.72mmol)，碳酸铯(1.12g,3.45mmol)，醋酸钯(19.4mg,86.2umol)和4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(99.8mg,172.4umol)，反应液在100℃，搅拌3小时。反应完全，反应液冷至室温，加入水(5mL)，用乙酸乙酯(20mL×3)萃取。合并有机相，用饱和食盐水洗涤(15mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩，剩余物用制备薄层色谱法板分离纯化(10：1石油醚/乙酸乙酯，Rf＝0.12)分离纯化得到4-(4-甲氧基-2-硝基-苯基)吗啡啉(210mg,黄色固体)，产率：41％。 1H NMR:(400MHz,CD 3OD)δ7.40-7.35(m,1H),7.29(d,J＝2.8Hz,1H),7.19(dd,J＝2.8,8.8Hz,1H),3.86-3.83(m,3H),3.81-3.76(m,4H),3.01-2.93(m,4H). 1-Bromo-4-methoxy-2-nitrobenzene (400.0 mg, 1.72 mmol) was dissolved in anhydrous dioxane (4 mL), and morpholine (150.2 mg, 1.72 mmol) was added to the reaction solution. , cesium carbonate (1.12g, 3.45mmol), palladium acetate (19.4mg, 86.2umol) and 4,5-bis(diphenylphosphonium)-9,9-dimethylxanthene (99.8mg, 172.4umol) , the reaction solution was stirred at 100 °C for 3 hours. The reaction was completed, the reaction solution was cooled to room temperature, water (5 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (15 mL×3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by preparative thin layer chromatography (10:1 petroleum ether/ethyl acetate, Rf=0.12) was isolated and purified to obtain 4-(4-methoxy-2-nitro-phenyl)morpholine (210 mg, yellow solid), yield: 41%. 1 H NMR: (400MHz, CD 3 OD) δ 7.40-7.35 (m, 1H), 7.29 (d, J=2.8Hz, 1H), 7.19 (dd, J=2.8, 8.8Hz, 1H), 3.86- 3.83(m,3H),3.81-3.76(m,4H),3.01-2.93(m,4H).

MS-ESI计算值[M+H] +239，实测值239。 MS-ESI calculated [M+H] + 239, found 239.

第二步second step

5-甲氧基-2-吗啡啉基-苯胺5-Methoxy-2-morpholinyl-aniline

将4-(4-甲氧基-2-硝基-苯基)吗啡啉(100.0mg,0.462mmol)溶于乙酸乙酯(15mL)中，向反应液中加入湿钯碳(40.0mg,10％纯度)，反应液在氢气(50psi)氛围，20℃下，搅拌5小时。反应完全，过滤，滤液减压浓缩得到5-甲氧基-2-吗啡啉基-苯胺(100mg,黄色固体)。 1H NMR:(400MHz,CD 3OD)δ6.94(d,J＝8.4Hz,1H),6.38(d,J＝2.8Hz,1H),6.27(dd,J＝2.8,8.4Hz,1H),3.85-3.81(m,4H),3.72(s,3H),2.85-2.81(m,4H). 4-(4-Methoxy-2-nitro-phenyl)morpholine (100.0 mg, 0.462 mmol) was dissolved in ethyl acetate (15 mL), and wet palladium on carbon (40.0 mg, 10 mL) was added to the reaction solution. % purity), the reaction was stirred under a hydrogen (50 psi) atmosphere at 20°C for 5 hours. The reaction was completed, filtered, and the filtrate was concentrated under reduced pressure to give 5-methoxy-2-morpholinyl-aniline (100 mg, yellow solid). 1 H NMR: (400 MHz, CD 3 OD) δ 6.94 (d, J=8.4 Hz, 1H), 6.38 (d, J=2.8 Hz, 1H), 6.27 (dd, J=2.8, 8.4 Hz, 1H) ,3.85-3.81(m,4H),3.72(s,3H),2.85-2.81(m,4H).

第三步third step

5-氯-N4-(2-二甲基磷酰基苯基)-N2-(5-甲氧基-2-吗啡啉基-苯基)嘧啶-2,4-二胺5-Chloro-N4-(2-dimethylphosphorylphenyl)-N2-(5-methoxy-2-morpholinyl-phenyl)pyrimidine-2,4-diamine

根据实施例1中第四步方法，将对甲氧基苯胺替换为5-甲氧基-2-吗啉代苯胺，得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-(5-甲氧基-2-吗啡啉基-苯基)嘧啶-2,4-二胺(15.0mg)，产率：18％。 1H NMR:(400MHz,CD 3OD)δ8.31(s,2H),7.74(dd,J＝7.6,13.6Hz,1H),7.63(t,J＝7.2Hz,1H),7.51-7.42(m,1H),7.39-7.22(m,2H),6.90(d,J＝8.4Hz,1H),3.87-3.81(m,4H),3.72(s,3H),2.99(br.s.,4H),1.92(s,3H),1.89(s,3H). According to the fourth step method in Example 1, p-methoxyaniline is replaced with 5-methoxy-2-morpholinoaniline to obtain 5-chloro-N4-(2-dimethylphosphorylphenyl)- N2-(5-Methoxy-2-morpholinyl-phenyl)pyrimidine-2,4-diamine (15.0 mg), yield: 18%. 1 H NMR: (400 MHz, CD 3 OD) δ 8.31 (s, 2H), 7.74 (dd, J=7.6, 13.6 Hz, 1H), 7.63 (t, J=7.2 Hz, 1H), 7.51-7.42 ( m,1H),7.39-7.22(m,2H),6.90(d,J=8.4Hz,1H),3.87-3.81(m,4H),3.72(s,3H),2.99(br.s.,4H ),1.92(s,3H),1.89(s,3H).

MS-ESI计算值[M+H] +488和490，实测值488和490。 MS-ESI calculated [M+H] + 488 and 490, found 488 and 490.

实施例32Example 32

5-氯-N4-(2-二甲基磷酰基苯基)-N2-(4-甲氧基-2-吗啡啉基-苯基)嘧啶-2,4-二胺5-Chloro-N4-(2-dimethylphosphorylphenyl)-N2-(4-methoxy-2-morpholinyl-phenyl)pyrimidine-2,4-diamine

Figure PCTCN2022082343-appb-000087
Figure PCTCN2022082343-appb-000087

第一步first step

4-(5-甲氧基-2-硝基-苯基)吗啡啉4-(5-Methoxy-2-nitro-phenyl)morpholine

将2-氟-4-甲氧基-1-硝基苯(400.0mg,2.34mmol)溶于无水二甲基亚砜(4mL)中，向反应液中加入吗啡啉(203.9mg,2.34mmol)和碳酸钾(646.8mg,4.68mmol)，反应液在100℃，搅1小时。液相色谱和反应完全后。反应液冷至室温，加入水(5mL)，滤液用乙酸乙酯(20mL×3)萃取。合并有机相，用饱和食盐水洗涤(15mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩得到4-(5-甲氧基-2-硝基-苯基)吗啡啉(520mg)。 1H NMR:(400MHz,CD3OD)δ7.94(d,J＝8.8Hz,1H),6.69-6.62(m,2H),3.88(s,3H),3.83-3.78(m,4H),3.08-3.00(m,4H). 2-Fluoro-4-methoxy-1-nitrobenzene (400.0 mg, 2.34 mmol) was dissolved in anhydrous dimethyl sulfoxide (4 mL), and morpholine (203.9 mg, 2.34 mmol) was added to the reaction solution. ) and potassium carbonate (646.8 mg, 4.68 mmol), the reaction solution was stirred at 100° C. for 1 hour. LC and after the reaction is complete. The reaction solution was cooled to room temperature, water (5 mL) was added, and the filtrate was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (15 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 4-(5-methoxy-2-nitro-phenyl)morpholine (520 mg) . 1 H NMR: (400MHz, CD3OD) δ 7.94(d, J=8.8Hz, 1H), 6.69-6.62(m, 2H), 3.88(s, 3H), 3.83-3.78(m, 4H), 3.08- 3.00(m,4H).

MS-ESI计算值[M+H] +239，实测值239。 MS-ESI calculated [M+H] + 239, found 239.

第二步second step

5-甲氧基-2-吗啡啉基-苯胺5-Methoxy-2-morpholinyl-aniline

根据实施例31中第二步方法，将4-(4-甲氧基-2-硝基-苯基)吗啡啉替换为4-(5-甲氧基-2-硝基-苯基)吗啡啉,得到4-甲氧基-2-吗啡啉基-苯胺(420mg,黄色固体)。 1H NMR:(400MHz,CDCl 3)δ6.71(d,J＝8.4Hz,1H),6.64(d,J＝2.8Hz,1H),6.55(dd,J＝2.8,8.4Hz,1H),3.88-3.84(m,4H),3.76(s,3H),3.42(br.s.,2H),2.95-2.91(m,4H). According to the second step in Example 31, 4-(4-methoxy-2-nitro-phenyl)morphine was replaced by 4-(5-methoxy-2-nitro-phenyl)morphine morpholino to give 4-methoxy-2-morpholinyl-aniline (420 mg, yellow solid). 1 H NMR: (400MHz, CDCl 3 ) δ 6.71 (d, J=8.4Hz, 1H), 6.64 (d, J=2.8Hz, 1H), 6.55 (dd, J=2.8, 8.4Hz, 1H), 3.88-3.84(m, 4H), 3.76(s, 3H), 3.42(br.s., 2H), 2.95-2.91(m, 4H).

第三步third step

5-氯-N4-(2-二甲基磷酰基苯基)-N2-(4-甲氧基-2-吗啡啉基-苯基)嘧啶-2,4-二胺5-Chloro-N4-(2-dimethylphosphorylphenyl)-N2-(4-methoxy-2-morpholinyl-phenyl)pyrimidine-2,4-diamine

根据实施例1中第四步方法，将对甲氧基苯胺替换为4-甲氧基-2-吗啉代苯胺，得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-(4-甲氧基-2-吗啡啉基-苯基)嘧啶-2,4-二胺(11.0mg)，产率：14％。According to the fourth step method in Example 1, p-methoxyaniline is replaced with 4-methoxy-2-morpholinoaniline to obtain 5-chloro-N4-(2-dimethylphosphorylphenyl)- N2-(4-Methoxy-2-morpholinyl-phenyl)pyrimidine-2,4-diamine (11.0 mg), yield: 14%.

1H NMR:(400MHz,CD 3OD)δ8.39-8.37(m,1H),8.09(s,1H),7.81(d,J＝8.8Hz,1H),7.67-7.60(m,1H),7.55-7.54(m,1H),7.33-7.26(m,1H),6.76(s,1H),6.58-6.55(m,1H),3.86-3.82(m,4H),3.80(s,3H),2.91-2.87(m,4H),1.88(s,3H),1.85(s,3H). 1 H NMR: (400MHz, CD 3 OD) δ 8.39-8.37 (m, 1H), 8.09 (s, 1H), 7.81 (d, J=8.8Hz, 1H), 7.67-7.60 (m, 1H), 7.55-7.54(m, 1H), 7.33-7.26(m, 1H), 6.76(s, 1H), 6.58-6.55(m, 1H), 3.86-3.82(m, 4H), 3.80(s, 3H), 2.91-2.87(m, 4H), 1.88(s, 3H), 1.85(s, 3H).

MS-ESI计算值[M+H] +488和490，实测值488和490。 MS-ESI calculated [M+H] + 488 and 490, found 488 and 490.

实施例33Example 33

5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-甲氧基-2-[2-甲氧基乙基(甲基)氨基]苯基]嘧啶-2,4-二胺5-Chloro-N4-(2-dimethylphosphorylphenyl)-N2-[4-methoxy-2-[2-methoxyethyl(methyl)amino]phenyl]pyrimidine-2, 4-Diamine

Figure PCTCN2022082343-appb-000088
Figure PCTCN2022082343-appb-000088

第一步first step

5-甲氧基-N-(2-甲氧基乙基)-N-甲基-2-硝基-苯胺5-Methoxy-N-(2-methoxyethyl)-N-methyl-2-nitro-aniline

根据实施例32中第一步方法,将吗啡啉替换为N-甲基-2-甲氧基乙胺，得到5-甲氧基-N-(2-甲氧基乙基)-N-甲基-2-硝基-苯胺(512mg,黄色油状物)，粗品直接用于下一步。 1H NMR:(400MHz,CDCl 3)δ7.87(d,J＝9.2Hz,1H),6.59(d,J＝2.4Hz,1H),6.41(dd,J＝2.4,9.2Hz,1H),3.87(s,3H),3.63-3.61(m,2H),3.39-3.36(m,2H),3.36(s,3H),2.92(s,3H). According to the first step method in Example 32, morpholine was replaced with N-methyl-2-methoxyethylamine to obtain 5-methoxy-N-(2-methoxyethyl)-N-methyl yl-2-nitro-aniline (512 mg, yellow oil), which was used crude in the next step. 1 H NMR: (400MHz, CDCl 3 ) δ 7.87 (d, J=9.2Hz, 1H), 6.59 (d, J=2.4Hz, 1H), 6.41 (dd, J=2.4, 9.2Hz, 1H), 3.87(s,3H),3.63-3.61(m,2H),3.39-3.36(m,2H),3.36(s,3H),2.92(s,3H).

MS-ESI计算值[M+H] +241，实测值241。 MS-ESI calculated [M+H] + 241, found 241.

第二步second step

4-甲氧基-N2-(2-甲氧基乙基)-N2-甲基-苯-1,2-二胺4-Methoxy-N2-(2-methoxyethyl)-N2-methyl-benzene-1,2-diamine

根据实施例31中第二步方法，将4-(4-甲氧基-2-硝基-苯基)吗啡啉替换为5-甲氧基-N-(2-甲氧基乙基)-N-甲基-2-硝基-苯胺，得到4-甲氧基-N2-(2-甲氧基乙基)-N2-甲基-苯-1,2-二胺(400mg,黄色油状物)，粗品直接用于下一步。According to the second step in Example 31, substituting 4-(4-methoxy-2-nitro-phenyl)morpholine with 5-methoxy-N-(2-methoxyethyl)- N-methyl-2-nitro-aniline to give 4-methoxy-N2-(2-methoxyethyl)-N2-methyl-benzene-1,2-diamine (400 mg, yellow oil ), the crude product was used directly in the next step.

MS-ESI计算值[M+H] +211，实测值211。 MS-ESI calculated [M+H] + 211, found 211.

第三步third step

根据实施例1中第四步方法，将对甲氧基苯胺替换为5-甲氧基N1-(2-甲氧基乙基)-N1甲基苯-1,2-二胺，得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-甲氧基-2-[2-甲氧基乙基(甲基)氨基]苯基]嘧啶-2,4-二胺(29.0mg)，产率：37％。 1H NMR:(400MHz,CD 3OD)δ8.39-8.37(dd,J＝4.4,8.4Hz,1H),8.08(s,1H),7.88(d,J＝8.8Hz,1H),7.69-7.61(m,1H),7.58(t,J＝8.0Hz,1H),7.34-7.27(m,1H),6.80(d,J＝2.8Hz,1H),6.57(dd,J＝2.8,8.8Hz,1H),3.79(s,3H),3.45(t,J＝5.6Hz,2H),3.28(s,3H),3.04(t,J＝5.6Hz,2H),2.72(s,3H),1.88(s,3H),1.85(s,3H). According to the fourth step method in Example 1, p-methoxyaniline was replaced with 5-methoxy N1-(2-methoxyethyl)-N1 methylbenzene-1,2-diamine to obtain 5- Chloro-N4-(2-dimethylphosphorylphenyl)-N2-[4-methoxy-2-[2-methoxyethyl(methyl)amino]phenyl]pyrimidine-2,4- Diamine (29.0 mg), yield: 37%. 1 H NMR: (400 MHz, CD 3 OD) δ 8.39-8.37 (dd, J=4.4, 8.4 Hz, 1H), 8.08 (s, 1H), 7.88 (d, J=8.8 Hz, 1H), 7.69- 7.61(m, 1H), 7.58(t, J=8.0Hz, 1H), 7.34-7.27(m, 1H), 6.80(d, J=2.8Hz, 1H), 6.57(dd, J=2.8, 8.8Hz) ,1H),3.79(s,3H),3.45(t,J＝5.6Hz,2H),3.28(s,3H),3.04(t,J＝5.6Hz,2H),2.72(s,3H),1.88 (s,3H),1.85(s,3H).

MS-ESI计算值[M+H] +490和492，实测值490和492。 MS-ESI calculated [M+H] + 490 and 492, found 490 and 492.

实施例34Example 34

5-氯-N4-(2-二甲基磷酰基苯基)-N2-(4-甲氧基-3-吗啡啉基-苯基)嘧啶-2,4-二胺5-Chloro-N4-(2-dimethylphosphorylphenyl)-N2-(4-methoxy-3-morpholinyl-phenyl)pyrimidine-2,4-diamine

Figure PCTCN2022082343-appb-000089
Figure PCTCN2022082343-appb-000089

第一步first step

4-(2-甲氧基-5-硝基-苯基)吗啡啉4-(2-Methoxy-5-nitro-phenyl)morpholine

根据实施例31中第一步方法，将1-溴-4-甲氧基-2-硝基苯替换为2-溴-1-甲氧基-4-硝基苯，得到4-(2-甲氧基-5-硝基-苯基)吗啡啉(130mg,黄色固体)，产率：28％。 1H NMR:(400MHz,CD 3OD)δ7.99(dd,J＝2.8,8.8Hz,1H),7.80(d,J＝2.8Hz,1H),7.13(d,J＝8.8Hz,1H),4.00(s,3H),3.89-3.83(m,4H),3.15-3.05(m,4H).MS-ESI计算值[M+H] +239，实测值239。 According to the first step method in Example 31, 1-bromo-4-methoxy-2-nitrobenzene was replaced with 2-bromo-1-methoxy-4-nitrobenzene to obtain 4-(2- Methoxy-5-nitro-phenyl)morpholine (130 mg, yellow solid), yield: 28%. 1 H NMR: (400 MHz, CD 3 OD) δ 7.99 (dd, J=2.8, 8.8 Hz, 1H), 7.80 (d, J=2.8 Hz, 1H), 7.13 (d, J=8.8 Hz, 1H) , 4.00(s, 3H), 3.89-3.83(m, 4H), 3.15-3.05(m, 4H). MS-ESI calculated [M+H] + 239, found 239.

第二步second step

4-甲氧基-3-吗啡啉基-苯胺4-Methoxy-3-morpholinyl-aniline

根据实施例31中第二步方法，将4-(4-甲氧基-2-硝基-苯基)吗啡啉替换为4-(2-甲氧基-5-硝基-苯基)吗啡啉，得到4-甲氧基-3-吗啡啉基-苯胺(110mg,黄色固体)，粗品直接用于下一步。 1H NMR:(400MHz,CDCl 3)δ6.73-6.68(m,1H),6.39-6.32(m,2H),3.90-3.87(m,4H),3.80(s,3H),3.45(br.s.,2H),3.08-3.02(m,4H). According to the second step in Example 31, 4-(4-methoxy-2-nitro-phenyl)morphine was replaced by 4-(2-methoxy-5-nitro-phenyl)morphine morpholino to give 4-methoxy-3-morpholinyl-aniline (110 mg, yellow solid), the crude product was used directly in the next step. 1 H NMR: (400MHz, CDCl 3 )δ6.73-6.68(m,1H), 6.39-6.32(m,2H), 3.90-3.87(m,4H), 3.80(s,3H), 3.45(br. s.,2H),3.08-3.02(m,4H).

MS-ESI计算值[M+H] +209，实测值209。 MS-ESI calculated [M+H] + 209, found 209.

第三步third step

根据实施例1中第四步方法，将对甲氧基苯胺替换为4-甲氧基-3-吗啉代苯胺得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-(4-甲氧基-3-吗啡啉基-苯基)嘧啶-2,4-二胺(24.0mg)，产率：29％。According to the fourth step method in Example 1, p-methoxyaniline is replaced with 4-methoxy-3-morpholinoaniline to obtain 5-chloro-N4-(2-dimethylphosphorylphenyl)-N2 -(4-Methoxy-3-morpholinyl-phenyl)pyrimidine-2,4-diamine (24.0 mg), yield: 29%.

1H NMR:(400MHz,CD 3OD)δ8.24(s,1H),8.16(br.s.,1H),7.82(d,J＝2.4Hz,1H),7.76-7.69(m,1H),7.64(dd,J＝2.4,8.8Hz,1H),7.56(t,J＝7.6Hz,1H),7.48-7.42(m,1H),7.39(d,J＝8.8Hz,1H),4.13(br.s.,2H),4.11(s,3H),4.10(br.s.,2H),3.66(br.s.,4H),1.93(s,3H),1.89(s,3H). 1 H NMR: (400MHz, CD 3 OD) δ 8.24(s, 1H), 8.16(br.s., 1H), 7.82(d, J=2.4Hz, 1H), 7.76-7.69(m, 1H) ,7.64(dd,J＝2.4,8.8Hz,1H),7.56(t,J＝7.6Hz,1H),7.48-7.42(m,1H),7.39(d,J＝8.8Hz,1H),4.13( br.s., 2H), 4.11(s, 3H), 4.10(br.s., 2H), 3.66(br.s., 4H), 1.93(s, 3H), 1.89(s, 3H).

MS-ESI计算值[M+H] +488和490，实测值488和490。 MS-ESI calculated [M+H] + 488 and 490, found 488 and 490.

实施例35Example 35

5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-甲氧基-3-[2-甲氧基乙基(甲基)氨基]苯基]嘧啶-2,4-二胺5-Chloro-N4-(2-dimethylphosphorylphenyl)-N2-[4-methoxy-3-[2-methoxyethyl(methyl)amino]phenyl]pyrimidine-2, 4-Diamine

Figure PCTCN2022082343-appb-000090
Figure PCTCN2022082343-appb-000090

第一步first step

2-甲氧基-N-(2-甲氧基乙基)-N-甲基-5-硝基-苯胺2-Methoxy-N-(2-methoxyethyl)-N-methyl-5-nitro-aniline

根据实施例31中第一步方法，将1-溴-4-甲氧基-2-硝基苯和吗啡啉替换为2-溴-1-甲氧基-4-硝基苯和N-甲基-2-甲氧基乙胺，得到2-甲氧基-N-(2-甲氧基乙基)-N-甲基-5-硝基-苯胺(90mg,黄色固体)，产率：22％。According to the first step method in Example 31, 1-bromo-4-methoxy-2-nitrobenzene and morpholine were replaced by 2-bromo-1-methoxy-4-nitrobenzene and N-methyl yl-2-methoxyethylamine to give 2-methoxy-N-(2-methoxyethyl)-N-methyl-5-nitro-aniline (90 mg, yellow solid) in yield: twenty two%.

1H NMR:(400MHz,CD 3OD)δ7.92-7.87(m,1H),7.78(d,J＝2.8Hz,1H),7.10-7.06(m,1H),3.98(s,3H),3.61-3.57(m,2H),3.37-3.34(m,2H),3.32(br.s.,3H),2.92(s,3H). 1 H NMR: (400MHz, CD 3 OD) δ 7.92-7.87 (m, 1H), 7.78 (d, J=2.8Hz, 1H), 7.10-7.06 (m, 1H), 3.98 (s, 3H), 3.61-3.57(m, 2H), 3.37-3.34(m, 2H), 3.32(br.s., 3H), 2.92(s, 3H).

MS-ESI计算值[M+H] +241，实测值241。 MS-ESI calculated [M+H] + 241, found 241.

第二步second step

4-甲氧基-N3-(2-甲氧基乙基)-N3-甲基-苯-1,3-二胺4-Methoxy-N3-(2-methoxyethyl)-N3-methyl-benzene-1,3-diamine

根据实施例31中第二步方法，将4-(4-甲氧基-2-硝基-苯基)吗啡啉替换为2-甲氧基-N-(2-甲氧基乙基)-N- 甲基-5-硝基-苯胺，得到4-甲氧基-N3-(2-甲氧基乙基)-N3-甲基-苯-1,3-二胺(100mg,黄色油状物)，粗品直接用于下一步。According to the second step in Example 31, 4-(4-methoxy-2-nitro-phenyl)morpholine was replaced by 2-methoxy-N-(2-methoxyethyl)- N-methyl-5-nitro-aniline to give 4-methoxy-N3-(2-methoxyethyl)-N3-methyl-benzene-1,3-diamine (100 mg, yellow oil ), the crude product was used directly in the next step.

1H NMR:(400MHz,CDCl 3)δ6.69(d,J＝8.4Hz,1H),6.47(br.s.,1H),6.35(d,J＝8.8Hz,1H),3.80(s,3H),3.59-3.51(m,2H),3.41-3.34(m,2H),3.33(s,3H),2.89(s,3H). 1 H NMR: (400 MHz, CDCl 3 ) δ 6.69 (d, J=8.4 Hz, 1H), 6.47 (br.s., 1H), 6.35 (d, J=8.8 Hz, 1H), 3.80 (s, 3H), 3.59-3.51(m, 2H), 3.41-3.34(m, 2H), 3.33(s, 3H), 2.89(s, 3H).

第三步third step

5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-甲氧基-3-[2-甲氧基乙基(甲基)氨基]苯基]嘧啶-2,4-二胺根据实施例1中第四步方法，将对甲氧基苯胺替换为6-甲氧基N1-(2-甲氧基乙基)-N1甲基苯-1,3-二胺，得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-甲氧基-3-[2-甲氧基乙基(甲基)氨基]苯基]嘧啶-2,4-二胺(18.0mg)，产率：21％。 1H NMR:(400MHz,CD 3OD)δ8.22(s,1H),8.15(br.s.,1H),7.74-7.64(m,3H),7.56-7.49(m,1H),7.44-7.36(m,2H),4.08(s,3H),3.81-3.74(m,2H),3.50-3.34(m,2H),3.24(s,3H),3.22(s,3H),1.90(s,3H),1.86(s,3H). 5-Chloro-N4-(2-dimethylphosphorylphenyl)-N2-[4-methoxy-3-[2-methoxyethyl(methyl)amino]phenyl]pyrimidine-2, 4-Diamine According to the fourth step method in Example 1, p-methoxyaniline is replaced by 6-methoxy N1-(2-methoxyethyl)-N1 methylbenzene-1,3-diamine , to give 5-chloro-N4-(2-dimethylphosphorylphenyl)-N2-[4-methoxy-3-[2-methoxyethyl(methyl)amino]phenyl]pyrimidine- 2,4-Diamine (18.0 mg), yield: 21%. 1 H NMR: (400MHz, CD 3 OD) δ 8.22(s, 1H), 8.15(br.s., 1H), 7.74-7.64(m, 3H), 7.56-7.49(m, 1H), 7.44- 7.36(m, 2H), 4.08(s, 3H), 3.81-3.74(m, 2H), 3.50-3.34(m, 2H), 3.24(s, 3H), 3.22(s, 3H), 1.90(s, 3H),1.86(s,3H).

MS-ESI计算值[M+H] +490和492，实测值490和492。 MS-ESI calculated [M+H] + 490 and 492, found 490 and 492.

实施例36Example 36

5-氯-N4-(2-二甲基磷酰基苯基)-N2-(3-甲氧基-5-吗啡啉基-苯基)嘧啶-2,4-二胺5-Chloro-N4-(2-dimethylphosphorylphenyl)-N2-(3-methoxy-5-morpholinyl-phenyl)pyrimidine-2,4-diamine

Figure PCTCN2022082343-appb-000091
Figure PCTCN2022082343-appb-000091

第一步first step

4-(3-甲氧基-5-硝基-苯基)吗啡啉4-(3-Methoxy-5-nitro-phenyl)morpholine

根据实施例31中第一步方法，将1-溴-4-甲氧基-2-硝基苯替换为1-溴-3-甲氧基-5-硝基苯，得到4-(3-甲氧基-5-硝基-苯基)吗啡啉(115mg,黄色固体)，产率：28％。 1H NMR:(400MHz,CD 3OD)δ7.41(t,J＝2.0Hz,1H),7.23(t,J＝2.0Hz,1H),6.84(t,J＝2.0Hz,1H),3.87(s,3H),3.87-3.83(m,4H),3.26-3.22(m,4H). According to the first step method in Example 31, 1-bromo-4-methoxy-2-nitrobenzene was replaced with 1-bromo-3-methoxy-5-nitrobenzene to obtain 4-(3- Methoxy-5-nitro-phenyl)morpholine (115 mg, yellow solid), yield: 28%. 1 H NMR: (400 MHz, CD 3 OD) δ 7.41 (t, J=2.0 Hz, 1H), 7.23 (t, J=2.0 Hz, 1H), 6.84 (t, J=2.0 Hz, 1H), 3.87 (s,3H),3.87-3.83(m,4H),3.26-3.22(m,4H).

MS-ESI计算值[M+H] +239，实测值239。 MS-ESI calculated [M+H] + 239, found 239.

第二步second step

3-甲氧基-5-吗啡啉基-苯胺3-Methoxy-5-morpholinyl-aniline

根据实施例31中第二步方法，将4-(4-甲氧基-2-硝基-苯基)吗啡啉替换为4-(3-甲氧基-5-硝基-苯基)吗啡啉，得到3-甲氧基-5-吗啡啉基-苯胺(100mg,黄色油状物)，粗品直接用于下一步。 1H NMR:(400MHz,CDCl 3)δ5.94-5.91(m,1H),5.88(t,J＝2.0Hz,1H),5.84(t,J＝2.0Hz,1H),3.86-3.81(m,4H),3.76(s,3H),3.64(br.s.,2H),3.14-3.10(m,4H). According to the second step in Example 31, 4-(4-methoxy-2-nitro-phenyl)morphine was replaced by 4-(3-methoxy-5-nitro-phenyl)morphine morpholino to give 3-methoxy-5-morpholinyl-aniline (100 mg, yellow oil), the crude product was used directly in the next step. 1 H NMR: (400MHz, CDCl 3 ) δ 5.94-5.91 (m, 1H), 5.88 (t, J=2.0Hz, 1H), 5.84 (t, J=2.0Hz, 1H), 3.86-3.81 (m ,4H),3.76(s,3H),3.64(br.s.,2H),3.14-3.10(m,4H).

MS-ESI计算值[M+H] +241，实测值241。 MS-ESI calculated [M+H] + 241, found 241.

第三步third step

5-氯-N4-(2-二甲基磷酰基苯基)-N2-(3-甲氧基-5-吗啡啉基-苯基)嘧啶-2,4-二胺5-Chloro-N4-(2-dimethylphosphorylphenyl)-N2-(3-methoxy-5-morpholinyl-phenyl)pyrimidine-2,4-diamine

根据实施例1中第四步方法，将对甲氧基苯胺替换为3-甲氧基-5-吗啉代苯胺，得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-(3-甲氧基-5-吗啡啉基-苯基)嘧啶-2,4-二胺(22.0mg)，产率：25％。 1H NMR:(400MHz, CDCl 3)δ12.56(br.s.,1H),11.40(br.s.,1H),8.41(br.s.,1H),7.90(s,1H),7.80(br.s.,1H),7.55(br.s.,2H),7.42-7.33(m,2H),7.06(br.s.,1H),4.32(br.s.,4H),3.87(s,3H),3.50(br.s.,4H),1.92(s,3H),1.89(s,3H). According to the fourth step method in Example 1, p-methoxyaniline is replaced with 3-methoxy-5-morpholinoaniline to obtain 5-chloro-N4-(2-dimethylphosphorylphenyl)- N2-(3-Methoxy-5-morpholinyl-phenyl)pyrimidine-2,4-diamine (22.0 mg), yield: 25%. 1 H NMR: (400MHz, CDCl 3 )δ12.56(br.s.,1H), 11.40(br.s.,1H), 8.41(br.s.,1H), 7.90(s,1H), 7.80 (br.s.,1H),7.55(br.s.,2H),7.42-7.33(m,2H),7.06(br.s.,1H),4.32(br.s.,4H),3.87( s,3H),3.50(br.s.,4H),1.92(s,3H),1.89(s,3H).

MS-ESI计算值[M+H] +488和490，实测值488和490。 MS-ESI calculated [M+H] + 488 and 490, found 488 and 490.

实施例37Example 37

5-氯-N4-(2-二甲基磷酰基苯基)-N2-(3-甲氧基-2-吗啡啉基-苯基)嘧啶-2,4-二胺5-Chloro-N4-(2-dimethylphosphorylphenyl)-N2-(3-methoxy-2-morpholinyl-phenyl)pyrimidine-2,4-diamine

Figure PCTCN2022082343-appb-000092
Figure PCTCN2022082343-appb-000092

第一步first step

4-(2-甲氧基-6-硝基-苯基)吗啡啉4-(2-Methoxy-6-nitro-phenyl)morpholine

根据实施例31中第一步方法，将1-溴-4-甲氧基-2-硝基苯替换为2-溴-1-甲氧基-3-硝基苯,得到4-(2-甲氧基-6-硝基-苯基)吗啡啉(73.0mg,黄色固体)，产率：18％。 1H NMR:(400MHz,CD 3OD)δ6.02-5.97(m,1H),5.93-5.89(m,1H),5.82(dd,J＝1.2,8.0Hz,1H),2.63(s,3H),2.40(t,J＝4.4Hz,4H),1.80(br.s.,4H). According to the first step method in Example 31, 1-bromo-4-methoxy-2-nitrobenzene was replaced with 2-bromo-1-methoxy-3-nitrobenzene to obtain 4-(2- Methoxy-6-nitro-phenyl)morpholine (73.0 mg, yellow solid), yield: 18%. 1 H NMR: (400MHz, CD 3 OD) δ 6.02-5.97 (m, 1H), 5.93-5.89 (m, 1H), 5.82 (dd, J=1.2, 8.0Hz, 1H), 2.63 (s, 3H) ), 2.40(t, J＝4.4Hz, 4H), 1.80(br.s., 4H).

MS-ESI计算值[M+H] +239，实测值239。 MS-ESI calculated [M+H] + 239, found 239.

第二步second step

3-甲氧基-5-吗啡啉基-苯胺3-Methoxy-5-morpholinyl-aniline

根据实施例31中第二步方法，将4-(4-甲氧基-2-硝基-苯基)吗啡啉替换为4-(2-甲氧基-6-硝基-苯基)吗啡啉，得到3-甲氧基-2-吗啡啉基-苯胺(90.0mg,黄色油状物)，粗品直接用于下一步。 1H NMR:(400MHz,CDCl3) 1H NMR:(400MHz,CDCl 3)δ6.94(t,J＝8.4Hz,1H),6.40(dd,J＝1.2,8.0Hz,1H),6.28(dd,J＝1.2,8.4Hz,1H),4.29(br.s.,2H),3.94-3.87(m,2H),3.88-3.82(m,1H),3.80(s,3H),3.73-3.55(m,5H). According to the second step in Example 31, 4-(4-methoxy-2-nitro-phenyl)morphine was replaced by 4-(2-methoxy-6-nitro-phenyl)morphine morpholino to give 3-methoxy-2-morpholinyl-aniline (90.0 mg, yellow oil), the crude product was used directly in the next step. 1 H NMR: (400 MHz, CDCl 3 ) 1 H NMR: (400 MHz, CDCl 3 ) δ 6.94 (t, J=8.4 Hz, 1H), 6.40 (dd, J=1.2, 8.0 Hz, 1H), 6.28 (dd , J=1.2, 8.4Hz, 1H), 4.29(br.s., 2H), 3.94-3.87(m, 2H), 3.88-3.82(m, 1H), 3.80(s, 3H), 3.73-3.55( m,5H).

MS-ESI计算值[M+H] +241，实测值241。 MS-ESI calculated [M+H] + 241, found 241.

第三步third step

5-氯-N4-(2-二甲基磷酰基苯基)-N2-(3-甲氧基-2-吗啡啉基-苯基)嘧啶-2,4-二胺5-Chloro-N4-(2-dimethylphosphorylphenyl)-N2-(3-methoxy-2-morpholinyl-phenyl)pyrimidine-2,4-diamine

根据实施例1中第四步方法，将对甲氧基苯胺替换为3-甲氧基-2-吗啉代苯胺，得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-(3-甲氧基-2-吗啡啉基-苯基)嘧啶-2,4-二胺(8.0mg)，产率：10％。 1H NMR:(400MHz,CD 3OD)δ8.37(s,1H),8.16(dd,J＝4.0,8.0Hz,1H),7.80(dd,J＝7.6,13.6Hz,1H),7.70(t,J＝8.0Hz,1H),7.57-7.52(m,1H),7.40(d,J＝8.4Hz,1H),7.04(t,J＝8.4Hz,1H),6.89(d,J＝8.4Hz,1H),3.89(s,3H),3.36-3.34(m,4H),3.83(br.s.,4H),1.90(s,3H),1.87(s,3H). According to the fourth step method in Example 1, p-methoxyaniline is replaced with 3-methoxy-2-morpholinoaniline to obtain 5-chloro-N4-(2-dimethylphosphorylphenyl)- N2-(3-Methoxy-2-morpholinyl-phenyl)pyrimidine-2,4-diamine (8.0 mg), yield: 10%. 1 H NMR: (400 MHz, CD 3 OD) δ 8.37 (s, 1H), 8.16 (dd, J=4.0, 8.0 Hz, 1H), 7.80 (dd, J=7.6, 13.6 Hz, 1H), 7.70 ( t,J＝8.0Hz,1H),7.57-7.52(m,1H),7.40(d,J＝8.4Hz,1H),7.04(t,J＝8.4Hz,1H),6.89(d,J＝8.4 Hz,1H),3.89(s,3H),3.36-3.34(m,4H),3.83(br.s.,4H),1.90(s,3H),1.87(s,3H).

MS-ESI计算值[M+H] +488和490，实测值488和490。 MS-ESI calculated [M+H] + 488 and 490, found 488 and 490.

实施例38Example 38

5-氯-N4-(2-二甲基磷酰基苯基)-N2-[5-甲氧基-2-[2-甲氧基乙基(甲基)氨基]苯基]嘧啶-2,4-二胺5-Chloro-N4-(2-dimethylphosphorylphenyl)-N2-[5-methoxy-2-[2-methoxyethyl(methyl)amino]phenyl]pyrimidine-2, 4-Diamine

Figure PCTCN2022082343-appb-000093
Figure PCTCN2022082343-appb-000093

第一步first step

4-甲氧基-N-(2-甲氧基乙基)-N-甲基-2-硝基-苯胺4-Methoxy-N-(2-methoxyethyl)-N-methyl-2-nitro-aniline

根据实施例32中第一步方法,将吗啡啉和2-氟-4-甲氧基-1-硝基苯替换为1-氟-4-甲氧基-2-硝基苯和N-甲基-2-甲氧基乙胺，得到4-甲氧基-N-(2-甲氧基乙基)-N-甲基-2-硝基-苯胺(500mg,黄色油状物)，粗品直接用于下一步。 1H NMR:(400MHz,CDCl 3)δ7.23-7.18(m,2H),7.05(dd,J＝2.8,8.8Hz,1H),3.81(s,3H),3.54-3.49(m,2H),3.32(s,3H),3.22(t,J＝6.0Hz,2H),2.83(s,3H). According to the first step method in Example 32, morpholine and 2-fluoro-4-methoxy-1-nitrobenzene were replaced by 1-fluoro-4-methoxy-2-nitrobenzene and N-methyl benzene yl-2-methoxyethylamine to give 4-methoxy-N-(2-methoxyethyl)-N-methyl-2-nitro-aniline (500 mg, yellow oil), crude product directly for the next step. 1 H NMR: (400 MHz, CDCl 3 ) δ 7.23-7.18 (m, 2H), 7.05 (dd, J=2.8, 8.8 Hz, 1H), 3.81 (s, 3H), 3.54-3.49 (m, 2H) ,3.32(s,3H),3.22(t,J=6.0Hz,2H),2.83(s,3H).

MS-ESI计算值[M+H] +241，实测值241。 MS-ESI calculated [M+H] + 241, found 241.

第二步second step

4-甲氧基-N1-(2-甲氧基乙基)-N1-甲基-苯-1,2-二胺4-Methoxy-N1-(2-methoxyethyl)-N1-methyl-benzene-1,2-diamine

根据实施例31中第二步方法，将4-(4-甲氧基-2-硝基-苯基)吗啡啉替换为4-甲氧基-N-(2-甲氧基乙基)-N-甲基-2-硝基-苯胺，得到4-甲氧基-N1-(2-甲氧基乙基)-N1-甲基-苯-1,2-二胺(440mg,黄色油状物)，粗品直接用于下一步。 1H NMR:(400MHz,CDCl 3)δ6.97(d,J＝8.4Hz,1H),6.30-6.24(m,2H),4.28(br.s.,2H),3.75(s,3H),3.45(t,J＝5.6Hz,2H),3.37(s,3H),2.98(t,J＝5.6Hz,2H),2.69(s,3H). According to the second step in Example 31, substituting 4-(4-methoxy-2-nitro-phenyl)morpholine with 4-methoxy-N-(2-methoxyethyl)- N-methyl-2-nitro-aniline to give 4-methoxy-N1-(2-methoxyethyl)-N1-methyl-benzene-1,2-diamine (440mg, yellow oil ), the crude product was used directly in the next step. 1 H NMR: (400MHz, CDCl 3 ) δ 6.97(d, J=8.4Hz, 1H), 6.30-6.24(m, 2H), 4.28(br.s., 2H), 3.75(s, 3H), 3.45(t, J=5.6Hz, 2H), 3.37(s, 3H), 2.98(t, J=5.6Hz, 2H), 2.69(s, 3H).

MS-ESI计算值[M+H] +243，实测值243。 MS-ESI calculated [M+H] + 243, found 243.

第三步third step

5-氯-N4-(2-二甲基磷酰基苯基)-N2-[5-甲氧基-2-[2-甲氧基乙基(甲基)氨基]苯基]嘧啶-2,4-二胺根据实施例1中第四步方法，将对甲氧基苯胺替换为4-甲氧基N 1-(2-甲氧基乙基)-N 1甲基苯-1,2-二胺，得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[5-甲氧基-2-[2-甲氧基乙基(甲基)氨基]苯基]嘧啶-2,4-二胺(5.0mg)，产率：6％。 1H NMR:(400MHz,CDCl 3)δ8.76-8.69(m,2H),8.15(s,1H),8.10(d,J＝2.8Hz,1H),7.58(t,J＝8.0Hz,1H),7.35-7.27(m,1H),7.16-7.10(m,3H),6.49(dd,J＝2.8,8.4Hz,1H),3.70(s,3H),3.42(t,J＝5.6Hz,2H),3.32(s,3H),3.01(t,J＝5.6Hz,2H),2.70(s,3H),1.86(s,3H),1.83(s,3H). 5-Chloro-N4-(2-dimethylphosphorylphenyl)-N2-[5-methoxy-2-[2-methoxyethyl(methyl)amino]phenyl]pyrimidine-2, 4-Diamine According to the fourth step method in Example 1, p-methoxyaniline is replaced by 4-methoxy N 1 -(2-methoxyethyl)-N 1 methylbenzene-1,2- diamine to give 5-chloro-N4-(2-dimethylphosphorylphenyl)-N2-[5-methoxy-2-[2-methoxyethyl(methyl)amino]phenyl] Pyrimidine-2,4-diamine (5.0 mg), yield: 6%. 1 H NMR: (400MHz, CDCl 3 ) δ 8.76-8.69 (m, 2H), 8.15 (s, 1H), 8.10 (d, J=2.8Hz, 1H), 7.58 (t, J=8.0Hz, 1H) ),7.35-7.27(m,1H),7.16-7.10(m,3H),6.49(dd,J=2.8,8.4Hz,1H),3.70(s,3H),3.42(t,J=5.6Hz, 2H), 3.32(s, 3H), 3.01(t, J=5.6Hz, 2H), 2.70(s, 3H), 1.86(s, 3H), 1.83(s, 3H).

MS-ESI计算值[M+H] +490和492，实测值490和492。 MS-ESI calculated [M+H] + 490 and 492, found 490 and 492.

实施例39Example 39

5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-甲氧基-5-[2-甲氧基乙基(甲基)氨基]苯基]嘧啶-2,4-二胺5-Chloro-N4-(2-dimethylphosphorylphenyl)-N2-[3-methoxy-5-[2-methoxyethyl(methyl)amino]phenyl]pyrimidine-2, 4-Diamine

Figure PCTCN2022082343-appb-000094
Figure PCTCN2022082343-appb-000094

第一步first step

3-甲氧基-N-(2-甲氧基乙基)-N-甲基-5-硝基-苯胺3-Methoxy-N-(2-methoxyethyl)-N-methyl-5-nitro-aniline

根据实施例31中第一步方法，将1-溴-4-甲氧基-2-硝基苯和吗啡啉替换为1-溴-3-甲氧基-5-硝基苯N-甲基-2-甲氧基乙胺，得到3-甲氧基-N-(2-甲氧基乙基)-N-甲基-5-硝基-苯胺(176mg,黄色油状物)，产率：42％。According to the first step method in Example 31, 1-bromo-4-methoxy-2-nitrobenzene and morpholine were replaced by 1-bromo-3-methoxy-5-nitrobenzene N-methyl -2-Methoxyethylamine to give 3-methoxy-N-(2-methoxyethyl)-N-methyl-5-nitro-aniline (176 mg, yellow oil) in yield: 42%.

1H NMR:(400MHz,CD 3OD)δ7.20(t,J＝2.0Hz,1H),7.05(t,J＝2.0Hz,1H),6.59(t,J＝2.0Hz,1H),3.85(s,3H),3.60(s,4H),3.36(s,3H),3.04(s,3H). 1 H NMR: (400 MHz, CD 3 OD) δ 7.20 (t, J=2.0 Hz, 1H), 7.05 (t, J=2.0 Hz, 1H), 6.59 (t, J=2.0 Hz, 1H), 3.85 (s, 3H), 3.60(s, 4H), 3.36(s, 3H), 3.04(s, 3H).

MS-ESI计算值[M+H] +241，实测值241。 MS-ESI calculated [M+H] + 241, found 241.

第二步second step

5-甲氧基-N1-(2-甲氧基乙基)-N1-甲基-苯-1,3-二胺5-Methoxy-N1-(2-methoxyethyl)-N1-methyl-benzene-1,3-diamine

根据实施例31中第二步方法，将4-(4-甲氧基-2-硝基-苯基)吗啡啉替换为4-甲氧基-N-(2-甲氧基乙基)-N-甲基-2-硝基-苯胺，得到5-甲氧基-N1-(2-甲氧基乙基)-N1-甲基-苯-1,3-二胺(180mg,黄色油状物)，粗品直接用于下一步。 1H NMR:(400MHz,CD 3OD)δ5.77-5.75(m,1H),5.72-5.69(m,2H),3.76(s,3H),3.57-3.54(m,2H),3.48-3.44(m,2H),3.36(s,3H),2.94(s,3H). According to the second step in Example 31, substituting 4-(4-methoxy-2-nitro-phenyl)morpholine with 4-methoxy-N-(2-methoxyethyl)- N-methyl-2-nitro-aniline to give 5-methoxy-N1-(2-methoxyethyl)-N1-methyl-benzene-1,3-diamine (180 mg, yellow oil ), the crude product was used directly in the next step. 1 H NMR: (400 MHz, CD 3 OD) δ 5.77-5.75 (m, 1H), 5.72-5.69 (m, 2H), 3.76 (s, 3H), 3.57-3.54 (m, 2H), 3.48-3.44 (m, 2H), 3.36(s, 3H), 2.94(s, 3H).

MS-ESI计算值[M+H] +243，实测值243。 MS-ESI calculated [M+H] + 243, found 243.

第三步third step

5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-甲氧基-5-[2-甲氧基乙基(甲基)氨基]苯基]嘧啶-2,4-二胺根据实施例1中第四步方法，将对甲氧基苯胺替换为5-甲氧基N 1-(2-甲氧基乙基)-N 1甲基苯-1,3-二胺，得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-甲氧基-5-[2-甲氧基乙基(甲基)氨基]苯基]嘧啶-2,4-二胺(18.0mg)，产率：21％。 1H NMR:(400MHz,D 2O)δ8.08(s,1H),7.65-7.60(m,1H),7.60-7.56(m,1H),7.48(t,J＝7.6Hz,1H),7.45-7.39(m,1H),7.05(s,1H),6.89(d,J＝10.4Hz,2H),3.64(s,3H),3.55(d,J＝4.8Hz,2H),3.23(br.s.,2H),3.11(s,3H),3.07(s,3H),1.72(s,3H),1.68(s,3H). 5-Chloro-N4-(2-dimethylphosphorylphenyl)-N2-[3-methoxy-5-[2-methoxyethyl(methyl)amino]phenyl]pyrimidine-2, 4-Diamine According to the fourth step method in Example 1, p-methoxyaniline is replaced by 5-methoxy N 1 -(2-methoxyethyl)-N 1 methylbenzene-1,3- diamine to give 5-chloro-N4-(2-dimethylphosphorylphenyl)-N2-[3-methoxy-5-[2-methoxyethyl(methyl)amino]phenyl] Pyrimidine-2,4-diamine (18.0 mg), yield: 21%. 1 H NMR: (400MHz, D 2 O) δ 8.08(s, 1H), 7.65-7.60(m, 1H), 7.60-7.56(m, 1H), 7.48(t, J=7.6Hz, 1H), 7.45-7.39(m, 1H), 7.05(s, 1H), 6.89(d, J=10.4Hz, 2H), 3.64(s, 3H), 3.55(d, J=4.8Hz, 2H), 3.23(br .s., 2H), 3.11(s, 3H), 3.07(s, 3H), 1.72(s, 3H), 1.68(s, 3H).

MS-ESI计算值[M+H] +490和492，实测值490和492。 MS-ESI calculated [M+H] + 490 and 492, found 490 and 492.

实施例40Example 40

5-氯-N4-(2-二甲基偶磷酰基苯基)-N2-(3-甲氧基-4-吗啡啉-苯基)嘧啶-2,4-二氨基5-Chloro-N4-(2-dimethylphosphorylphenyl)-N2-(3-methoxy-4-morpholine-phenyl)pyrimidine-2,4-diamino

Figure PCTCN2022082343-appb-000095
Figure PCTCN2022082343-appb-000095

第一步first step

4-(2-甲氧基-4-硝基-苯基)吗啡啉4-(2-Methoxy-4-nitro-phenyl)morpholine

将1-氯-2-甲氧基-4-硝基-苯(500mg,2.67mmol)和吗啡啉(697.83mg,8.01mmol)的混合物加热至120℃搅拌15小时。向混合物中加入水(15mL)，并用乙酸乙酯(15mL×3)萃取。合并有机相，无水硫酸钠干燥，过滤蒸干。得到的粗品用制备薄层色谱法(石油醚：乙酸乙酯＝4:1，Rf＝0.4)分离纯化得到4-(2-甲氧基-4-硝基-苯基)吗啡啉(290mg,黄色油状)，产率：46％。 1H NMR:(400MHz,CDCl 3)δ7.81(dd,J＝2.4,8.8Hz,1H),7.66(d,J＝2.4Hz,1H),6.82(d,J＝8.8Hz,1H),3.89(s,3H),3.85-3.79(m,4H),3.21-3.13(m,4H). A mixture of 1-chloro-2-methoxy-4-nitro-benzene (500 mg, 2.67 mmol) and morpholine (697.83 mg, 8.01 mmol) was heated to 120°C and stirred for 15 hours. To the mixture was added water (15 mL), and extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The obtained crude product was separated and purified by preparative thin layer chromatography (petroleum ether:ethyl acetate=4:1, Rf=0.4) to obtain 4-(2-methoxy-4-nitro-phenyl)morpholine (290mg, Yellow oil), yield: 46%. 1 H NMR: (400 MHz, CDCl 3 ) δ 7.81 (dd, J=2.4, 8.8 Hz, 1H), 7.66 (d, J=2.4 Hz, 1H), 6.82 (d, J=8.8 Hz, 1H), 3.89(s, 3H), 3.85-3.79(m, 4H), 3.21-3.13(m, 4H).

第二步second step

4-(2-甲氧基-4-氨基-苯基)吗啡啉4-(2-Methoxy-4-amino-phenyl)morpholine

将4-(2-甲氧基-4-硝基-苯基)吗啡啉(290mg,1.22mmol)溶于乙酸乙酯(10mL)中，向反应液中加入湿钯碳(50.0mg，10％纯度)，反应液在氢气(50psi)氛围，20℃下，搅拌6小时。反应完全。反应液 过滤，滤液减压浓缩得到4-(2-甲氧基-4-氨基-苯基)吗啡啉(290.0mg，红色油状物)，粗品不经纯化直接用于下一步。 1H NMR:(400MHz,CDCl3)δ7.19(s,1H),6.75–6.65(m,1H),6.21(s,1H),3.86-3.77(m,4H),3.75(s,3H),3.00-2.79(m,4H). 4-(2-Methoxy-4-nitro-phenyl)morpholine (290 mg, 1.22 mmol) was dissolved in ethyl acetate (10 mL), and wet palladium carbon (50.0 mg, 10%) was added to the reaction solution. Purity), the reaction was stirred under a hydrogen (50 psi) atmosphere at 20°C for 6 hours. The reaction is complete. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain 4-(2-methoxy-4-amino-phenyl)morpholine (290.0 mg, red oil). The crude product was used in the next step without purification. 1 H NMR: (400MHz, CDCl3)δ7.19(s,1H), 6.75-6.65(m,1H), 6.21(s,1H), 3.86-3.77(m,4H), 3.75(s,3H), 3.00-2.79(m,4H).

第三步third step

根据实施例1中第四步方法，将对甲氧基苯胺替换为4-(2-甲氧基-4-氨基-苯基)吗啡啉，得到5-氯-N4-(2-二甲基偶磷酰基苯基)-N2-(3-甲氧基-4-吗啡啉-苯基)嘧啶-2,4-二氨基(46.0mg)，产率：54％。 1H NMR:(400MHz,CD 3OD)δ8.31(s,1H),8.25-8.12(m,1H),7.82-7.70(m,2H),7.70-7.60(m,1H),7.55-7.46(m,1H),7.42(d,J＝1.6Hz,1H),7.27(dd,J＝2.0,8.8Hz,1H),4.16(br t,J＝4.4Hz,4H),3.87(s,3H),3.80(br s,4H),1.92(s,3H),1.88(s,3H). According to the fourth step method in Example 1, p-methoxyaniline was replaced with 4-(2-methoxy-4-amino-phenyl)morpholine to obtain 5-chloro-N4-(2-dimethyl Phosphorylphenyl)-N2-(3-methoxy-4-morpholine-phenyl)pyrimidine-2,4-diamino (46.0 mg), yield: 54%. 1 H NMR: (400MHz, CD 3 OD) δ 8.31 (s, 1H), 8.25-8.12 (m, 1H), 7.82-7.70 (m, 2H), 7.70-7.60 (m, 1H), 7.55-7.46 (m, 1H), 7.42 (d, J=1.6Hz, 1H), 7.27 (dd, J=2.0, 8.8Hz, 1H), 4.16 (br t, J=4.4Hz, 4H), 3.87 (s, 3H) ),3.80(br s,4H),1.92(s,3H),1.88(s,3H).

MS-ESI计算值[M+H] +488和490，实测值488和490。 MS-ESI calculated [M+H] + 488 and 490, found 488 and 490.

实施例41Example 41

5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-甲氧基-4-[2-甲氧乙基(甲基)氨基]苯基]嘧啶-2,4-二胺5-Chloro-N4-(2-dimethylphosphorylphenyl)-N2-[3-methoxy-4-[2-methoxyethyl(methyl)amino]phenyl]pyrimidine-2,4 -Diamine

Figure PCTCN2022082343-appb-000096
Figure PCTCN2022082343-appb-000096

第一步first step

2-甲氧基-N-(2-甲氧乙基)-N-甲基-4-硝基-苯胺2-Methoxy-N-(2-methoxyethyl)-N-methyl-4-nitro-aniline

根据实施例32中第一步方法,将吗啡啉替换为2-甲氧基-N-甲基-乙二胺，得到2-甲氧基-N-(2-甲氧乙基)-N-甲基-4-硝基-苯胺(170mg,黄色油状)，产率：27％。According to the first step method in Example 32, morpholine was replaced with 2-methoxy-N-methyl-ethylenediamine to obtain 2-methoxy-N-(2-methoxyethyl)-N- Methyl-4-nitro-aniline (170 mg, yellow oil), yield: 27%.

1H NMR:(400MHz,CDCl 3)δ7.79(dd,J＝2.4,8.8Hz,1H),7.62(d,J＝2.4Hz,1H),6.74(d,J＝8.8Hz,1H),3.85(s,3H),3.59-3.45(m,4H),3.26(s,3H),2.96(s,3H)。 1 H NMR: (400 MHz, CDCl 3 ) δ 7.79 (dd, J=2.4, 8.8 Hz, 1H), 7.62 (d, J=2.4 Hz, 1H), 6.74 (d, J=8.8 Hz, 1H), 3.85(s, 3H), 3.59-3.45(m, 4H), 3.26(s, 3H), 2.96(s, 3H).

第二步second step

2-甲氧基-N1-(2-甲氧乙基)-N1-甲基-苯-1,4-二胺2-Methoxy-N1-(2-methoxyethyl)-N1-methyl-benzene-1,4-diamine

根据实施例31中第二步方法，将4-(4-甲氧基-2-硝基-苯基)吗啡啉替换为2-甲氧基-N-(2-甲氧乙基)-N-甲基-4-硝基-苯胺得到2-甲氧基-N1-(2-甲氧乙基)-N1-甲基-苯-1,4-二胺(160mg,红色油状)粗品不经纯化直接用于下一步。 1H NMR:(400MHz,CDCl 3)δ6.77(d,J＝8.0Hz,1H),6.24-6.10(m,2H),3.74(s,3H),3.43(t,J＝6.0Hz,2H),3.25(s,3H),3.07(t,J＝6.0Hz,2H),2.71(s,3H). According to the second step in Example 31, 4-(4-methoxy-2-nitro-phenyl)morpholine was replaced by 2-methoxy-N-(2-methoxyethyl)-N -Methyl-4-nitro-aniline gave 2-methoxy-N1-(2-methoxyethyl)-N1-methyl-benzene-1,4-diamine (160 mg, red oil) as crude product Purification was used directly in the next step. 1 H NMR: (400 MHz, CDCl 3 ) δ 6.77 (d, J=8.0 Hz, 1H), 6.24-6.10 (m, 2H), 3.74 (s, 3H), 3.43 (t, J=6.0 Hz, 2H) ), 3.25(s, 3H), 3.07(t, J=6.0Hz, 2H), 2.71(s, 3H).

第三步third step

5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-甲氧基-4-[2-甲氧乙基(甲基)氨基]苯基]嘧啶-2,4-二胺5-Chloro-N4-(2-dimethylphosphorylphenyl)-N2-[3-methoxy-4-[2-methoxyethyl(methyl)amino]phenyl]pyrimidine-2,4 -Diamine

根据实施例1中第四步方法，将对甲氧基苯胺替换为2-甲氧基-N1-(2-甲氧乙基)-N1-甲基-苯-1,4-二胺，得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-甲氧基-4-[2-甲氧乙基(甲基)氨基]苯基]嘧啶-2,4-二胺(27.0mg)，产率：31％。 1H NMR:(400MHz,CD 3OD)δ8.32(s,1H),8.22-8.13(m,1H),7.80-7.70(m,1H),7.68-7.56(m,2H),7.54-7.45(m,1H),7.44-7.35(m,1H),7.31-7.23(m,1H),3.86(s,5H),3.37(s,2H),3.29(s,3H),1.92(s,3H),1.89(s,3H). According to the fourth step method in Example 1, p-methoxyaniline is replaced with 2-methoxy-N1-(2-methoxyethyl)-N1-methyl-benzene-1,4-diamine to obtain 5-Chloro-N4-(2-dimethylphosphorylphenyl)-N2-[3-methoxy-4-[2-methoxyethyl(methyl)amino]phenyl]pyrimidine-2,4 - Diamine (27.0 mg), yield: 31%. 1 H NMR: (400MHz, CD 3 OD) δ 8.32 (s, 1H), 8.22-8.13 (m, 1H), 7.80-7.70 (m, 1H), 7.68-7.56 (m, 2H), 7.54-7.45 (m,1H),7.44-7.35(m,1H),7.31-7.23(m,1H),3.86(s,5H),3.37(s,2H),3.29(s,3H),1.92(s,3H) ),1.89(s,3H).

MS-ESI计算值[M+H] +490和492，实测值490和492。 MS-ESI calculated [M+H] + 490 and 492, found 490 and 492.

实施例42Example 42

5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-甲氧基-2-[2-甲氧乙基(甲基)胺]苯基]嘧啶-2,4-二胺5-Chloro-N4-(2-dimethylphosphorylphenyl)-N2-[3-methoxy-2-[2-methoxyethyl(methyl)amine]phenyl]pyrimidine-2,4 -Diamine

Figure PCTCN2022082343-appb-000097
Figure PCTCN2022082343-appb-000097

根据实施例1中第四步方法，将对甲氧基苯胺替换为3-甲氧基-N2-(2-甲氧乙基)-N2-甲基-苯-1,2-二氨基得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-甲氧基-2-[2-甲氧乙基(甲基)胺]苯基]嘧啶-2,4-二胺(7.00mg)，产率：9％。 1H NMR:(400MHz,CD 3OD)δ8.36(s,1H),7.88(br s,1H),7.75-7.58(m,2H),7.44-7.27(m,4H),4.05(s,3H),3.97-3.57(m,2H),3.51-3.34(m,2H),3.11(s,6H),1.90(s,3H),1.87(s,3H)。 According to the fourth step method in Example 1, p-methoxyaniline was replaced with 3-methoxy-N2-(2-methoxyethyl)-N2-methyl-benzene-1,2-diamino to obtain 5 -Chloro-N4-(2-dimethylphosphorylphenyl)-N2-[3-methoxy-2-[2-methoxyethyl(methyl)amine]phenyl]pyrimidine-2,4- Diamine (7.00 mg), yield: 9%. 1 H NMR: (400MHz, CD 3 OD) δ 8.36(s, 1H), 7.88(br s, 1H), 7.75-7.58(m, 2H), 7.44-7.27(m, 4H), 4.05(s, 3H), 3.97-3.57(m, 2H), 3.51-3.34(m, 2H), 3.11(s, 6H), 1.90(s, 3H), 1.87(s, 3H).

MS-ESI计算值[M+H] +490和492，实测值490和492。 MS-ESI calculated [M+H] + 490 and 492, found 490 and 492.

实施例43Example 43

5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-[2-(4-甲基哌嗪-1-基)乙氧基]苯基]嘧啶-2,4-二胺5-Chloro-N4-(2-dimethylphosphorylphenyl)-N2-[3-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]pyrimidine-2,4 -Diamine

Figure PCTCN2022082343-appb-000098
Figure PCTCN2022082343-appb-000098

根据实施例1中第四步方法，将对甲氧基苯胺替换为3-[2-(4-甲基哌嗪-1-基)乙氧基]苯胺得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-[2-(4-甲基哌嗪-1-基)乙氧基]苯基]嘧啶-2,4-二胺(16.0mg)产率：20％。 1H NMR:(400MHz,CD 3OD)δ8.54-8.48(m,1H),8.12(s,1H),7.67-7.56(m,2H),7.31-7.24(m,2H),7.17-7.08(m,2H),6.63-6.58(m,1H),4.07(t,J＝5.6Hz,2H),2.82(t,J＝5.6Hz,2H),2.76-2.41(m,8H),2.33(s,3H),1.89(s,3H),1.86(s,3H)。 According to the fourth step method in Example 1, p-methoxyaniline was replaced with 3-[2-(4-methylpiperazin-1-yl)ethoxy]aniline to obtain 5-chloro-N4-(2- Dimethylphosphorylphenyl)-N2-[3-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]pyrimidine-2,4-diamine (16.0 mg) yield : 20%. 1 H NMR: (400MHz, CD 3 OD) δ 8.54-8.48 (m, 1H), 8.12 (s, 1H), 7.67-7.56 (m, 2H), 7.31-7.24 (m, 2H), 7.17-7.08 (m,2H),6.63-6.58(m,1H),4.07(t,J=5.6Hz,2H),2.82(t,J=5.6Hz,2H),2.76-2.41(m,8H),2.33( s, 3H), 1.89 (s, 3H), 1.86 (s, 3H).

MS-ESI计算值[M+H] +515和517，实测值515和517。 MS-ESI calculated [M+H] + 515 and 517, found 515 and 517.

实施例44Example 44

5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-[2-(4甲基哌嗪-1-基)乙氧基]苯基]嘧啶-2,4-二胺5-Chloro-N4-(2-dimethylphosphorylphenyl)-N2-[4-[2-(4methylpiperazin-1-yl)ethoxy]phenyl]pyrimidine-2,4- Diamine

Figure PCTCN2022082343-appb-000099
Figure PCTCN2022082343-appb-000099

根据实施例1中第四步方法，将对甲氧基苯胺替换为4-[2-(4-甲基哌嗪-1-基)乙氧基]苯胺得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-[2-(4甲基哌嗪-1-基)乙氧基]苯基]嘧啶-2,4-二胺(35.0mg)，产率：40％。 1H NMR:(400MHz,CD 3OD)δ8.32(s,1H),8.14(s,1H),7.76-7.66(m,1H),7.60(s,1H),7.47-7.42(m,1H),7.41-7.36(m,2H),7.18-7.08(m,2H),4.55-4.48(m,2H),3.93-3.56(m,10H),3.06(s,3H),1.91(s,3H),1.88(s,3H)。MS-ESI计算值[M+H] +515和517，实测值515和517。 According to the fourth step method in Example 1, p-methoxyaniline was replaced with 4-[2-(4-methylpiperazin-1-yl)ethoxy]aniline to obtain 5-chloro-N4-(2- Dimethylphosphorylphenyl)-N2-[4-[2-(4methylpiperazin-1-yl)ethoxy]phenyl]pyrimidine-2,4-diamine (35.0 mg), yield : 40%. 1 H NMR: (400MHz, CD 3 OD) δ 8.32(s, 1H), 8.14(s, 1H), 7.76-7.66(m, 1H), 7.60(s, 1H), 7.47-7.42(m, 1H) ), 7.41-7.36(m, 2H), 7.18-7.08(m, 2H), 4.55-4.48(m, 2H), 3.93-3.56(m, 10H), 3.06(s, 3H), 1.91(s, 3H ), 1.88(s, 3H). MS-ESI calculated [M+H] + 515 and 517, found 515 and 517.

实施例45Example 45

5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-[4-[2-甲氧乙基(甲基)胺]吡唑-1-基]苯基]嘧啶-2,4-二胺5-Chloro-N4-(2-dimethylphosphorylphenyl)-N2-[4-[4-[2-methoxyethyl(methyl)amine]pyrazol-1-yl]phenyl]pyrimidine -2,4-Diamine

Figure PCTCN2022082343-appb-000100
Figure PCTCN2022082343-appb-000100

第一步first step

4-溴-1-(4-硝基苯)吡唑4-Bromo-1-(4-nitrophenyl)pyrazole

根据实施例32中第一步方法,将吗啡啉和2-氟-4-甲氧基-1-硝基苯替换为对氟硝基苯和4-溴吡唑，得到4-溴-1-(4-硝基苯)吡唑(15.0g,黄色固体)，产率：79％。1H NMR:(400MHz,CDCl 3)δ8.35(d,J＝9.2Hz,2H),8.06(s,1H),7.84(d,J＝9.2Hz,2H),7.75(s,1H)。 According to the first step method in Example 32, morpholine and 2-fluoro-4-methoxy-1-nitrobenzene were replaced by p-fluoronitrobenzene and 4-bromopyrazole to obtain 4-bromo-1- (4-Nitrobenzene)pyrazole (15.0 g, yellow solid), yield: 79%. 1H NMR: (400 MHz, CDCl3 ) δ 8.35 (d, J=9.2 Hz, 2H), 8.06 (s, 1H), 7.84 (d, J=9.2 Hz, 2H), 7.75 (s, 1H).

MS-ESI计算值[M+H] +268和270，实测值268和270。 MS-ESI calculated [M+H] + 268 and 270, found 268 and 270.

第二步second step

N-(2-甲氧乙基)-N-甲基-1-(4-硝基苯)吡唑-4-氨基N-(2-Methoxyethyl)-N-methyl-1-(4-nitrobenzene)pyrazole-4-amino

将4-溴-1-(4-硝基苯)吡唑(200mg,1.00eq)，2-甲氧基-N-甲基-二乙胺(200mg,2.24mmol)，和叔丁基醇钠(71.7mg,746umol)溶于四氢呋喃(3.00mL)中，在氮气保护下向反应液中加入甲烷磺酸(2-二-叔丁基膦基-2',4',6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯-2-基)钯(II)(30.0mg,37.3umol)，于80℃下搅拌反应16小时。反应液过滤蒸干，用制备薄层色谱法(二氯甲烷：甲醇＝10：1)纯化得到N-(2-甲氧乙基)-N-甲基-1-(4-硝基苯)吡唑-4-氨基(122mg,黄色固体)，产率：59％。1H NMR:(400MHz,CDCl 3)δ8.33-8.26(m,2H),7.81-7.73(m,2H),7.49(s,1H),7.34(d,J＝0.8Hz,1H),3.58(t,J＝5.6Hz,2H),3.38(s,3H),3.34-3.28(m,2H),2.88(s,3H). 4-Bromo-1-(4-nitrophenyl)pyrazole (200mg, 1.00eq), 2-methoxy-N-methyl-diethylamine (200mg, 2.24mmol), and sodium tert-butylate (71.7 mg, 746 umol) was dissolved in tetrahydrofuran (3.00 mL), and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropane) was added to the reaction solution under nitrogen protection base-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (30.0 mg, 37.3 umol), and the reaction was stirred at 80°C for 16 hours. The reaction solution was filtered and evaporated to dryness, and purified by preparative thin layer chromatography (dichloromethane:methanol=10:1) to obtain N-(2-methoxyethyl)-N-methyl-1-(4-nitrobenzene) Pyrazol-4-amino (122 mg, yellow solid), yield: 59%. 1H NMR: (400MHz, CDCl 3 ) δ 8.33-8.26(m, 2H), 7.81-7.73(m, 2H), 7.49(s, 1H), 7.34(d, J=0.8Hz, 1H), 3.58( t, J=5.6Hz, 2H), 3.38(s, 3H), 3.34-3.28(m, 2H), 2.88(s, 3H).

MS-ESI计算值[M+H] +277，实测值277。 MS-ESI calculated [M+H] + 277, found 277.

第三步third step

1-(4-氨基苯)-N-(2-甲氧乙基)-N-甲基-吡唑-4-胺1-(4-Aminobenzene)-N-(2-methoxyethyl)-N-methyl-pyrazol-4-amine

根据实施例31中第二步方法，将4-(4-甲氧基-2-硝基-苯基)吗啡啉替换为N-(2-甲氧乙基)-N-甲基-1-(4-硝基苯)吡唑-4-氨基得到1-(4-氨基苯)-N-(2-甲氧乙基)-N-甲基-吡唑-4-胺(110mg,黄色固体)，粗品不经纯化直接用于下一步。 1H NMR:(400MHz,CDCl3)δ7.43-7.40(m,1H),7.40-7.37(m,1H),7.33(d,J＝0.8Hz,1H),7.26(d,J＝0.8Hz,1H),6.75-6.73(m,1H),6.72-6.70(m,1H),3.58(t,J＝5.8Hz,2H),3.41-3.36(m,3H),3.24(t,J＝5.8Hz,2H),2.82(s,3H)。 According to the second step in Example 31, 4-(4-methoxy-2-nitro-phenyl)morpholine was replaced by N-(2-methoxyethyl)-N-methyl-1- (4-Nitrobenzene)pyrazol-4-amino gave 1-(4-aminobenzene)-N-(2-methoxyethyl)-N-methyl-pyrazol-4-amine (110 mg, yellow solid ), the crude product was used directly in the next step without purification. 1 H NMR: (400MHz, CDCl3)δ7.43-7.40(m,1H),7.40-7.37(m,1H),7.33(d,J=0.8Hz,1H),7.26(d,J=0.8Hz, 1H), 6.75-6.73(m, 1H), 6.72-6.70(m, 1H), 3.58(t, J=5.8Hz, 2H), 3.41-3.36(m, 3H), 3.24(t, J=5.8Hz) , 2H), 2.82(s, 3H).

第四步the fourth step

根据实施例1中第四步方法，将对甲氧基苯胺替换为1-(4-氨基苯)-N-(2-甲氧乙基)-N-甲基-吡唑-4-胺，得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-[4-[2-甲氧乙基(甲基)胺]吡唑-1-基]苯基]嘧啶-2,4-二胺(58.0mg)，产率：42％。 1H NMR:(400MHz,CD 3OD)δ8.89(s,1H),8.25(s,2H),8.06(s,1H),7.90-7.82(m,2H),7.79-7.71(m,1H),7.65-7.58(m,3H),7.51-7.44(m,1H),3.89-3.82(m,2H),3.67-3.60(m,2H),3.44(s,3H),3.42(s,3H),1.91(s,3H),1.88(s,3H). According to the fourth step method in Example 1, p-methoxyaniline is replaced with 1-(4-aminobenzene)-N-(2-methoxyethyl)-N-methyl-pyrazol-4-amine, 5-Chloro-N4-(2-dimethylphosphorylphenyl)-N2-[4-[4-[2-methoxyethyl(methyl)amine]pyrazol-1-yl]phenyl] Pyrimidine-2,4-diamine (58.0 mg), yield: 42%. 1 H NMR: (400MHz, CD 3 OD) δ 8.89(s, 1H), 8.25(s, 2H), 8.06(s, 1H), 7.90-7.82(m, 2H), 7.79-7.71(m, 1H) ),7.65-7.58(m,3H),7.51-7.44(m,1H),3.89-3.82(m,2H),3.67-3.60(m,2H),3.44(s,3H),3.42(s,3H ),1.91(s,3H),1.88(s,3H).

MS-ESI计算值[M+H] +526和528，实测值526和528。 MS-ESI calculated [M+H] + 526 and 528, found 526 and 528.

实施例46Example 46

5-氯-N2-[4-[4-[(3R)-3-(二甲氨基)吡咯烷-1-基]吡唑-1-基]苯基]-N4-(2-二甲基磷酰基苯基)嘧啶-2,4-二胺5-Chloro-N2-[4-[4-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]pyrazol-1-yl]phenyl]-N4-(2-dimethyl Phosphorylphenyl)pyrimidine-2,4-diamine

Figure PCTCN2022082343-appb-000101
Figure PCTCN2022082343-appb-000101

第一步first step

(3R)-N,N-二甲基-1-[1-(4-硝基苯)吡唑-4-基]吡咯烷-3-胺(3R)-N,N-Dimethyl-1-[1-(4-nitrophenyl)pyrazol-4-yl]pyrrolidin-3-amine

根据实施例45中第二步方法，将2-甲氧基-N-甲基-二乙胺替换为(3R)-N,N-二甲基吡唑-3-胺得到(3R)-N,N-二甲基-1-[1-(4-硝基苯)吡唑-4-基]吡咯烷-3-胺(72.0mg,黄色固体)，产率：32％。1H NMR:(400MHz,CDCl3)δ8.33-8.26(m,2H),7.80-7.74(m,2H),7.42(s,1H),7.28(s,1H),3.38-3.21(m,3H),3.09(t,J＝8.0Hz,1H),2.98-2.88(m,1H),2.32(s,6H),2.25-2.14(m,1H),2.10-1.90(m,1H)。According to the second step method in Example 45, 2-methoxy-N-methyl-diethylamine was replaced with (3R)-N,N-dimethylpyrazol-3-amine to obtain (3R)-N , N-dimethyl-1-[1-(4-nitrophenyl)pyrazol-4-yl]pyrrolidin-3-amine (72.0 mg, yellow solid), yield: 32%. 1H NMR:(400MHz,CDCl3)δ8.33-8.26(m,2H),7.80-7.74(m,2H),7.42(s,1H),7.28(s,1H),3.38-3.21(m,3H) , 3.09(t, J=8.0Hz, 1H), 2.98-2.88(m, 1H), 2.32(s, 6H), 2.25-2.14(m, 1H), 2.10-1.90(m, 1H).

MS-ESI计算值[M+H] +302，实测值302。 MS-ESI calculated [M+H] + 302, found 302.

第二步second step

(3R)-1-[1-(4-苯胺基)吡唑-4-基]-N,N-二甲基-吡咯烷-3-胺(3R)-1-[1-(4-anilino)pyrazol-4-yl]-N,N-dimethyl-pyrrolidin-3-amine

根据实施例31中第二步方法，将4-(4-甲氧基-2-硝基-苯基)吗啡啉替换为(3R)-N,N-二甲基-1-[1-(4-硝基苯)吡唑-4-基]吡咯烷-3-胺得到(3R)-1-[1-(4-苯胺基)吡唑-4-基]-N,N-二甲基-吡咯烷-3-胺(60.0mg,黄色油状)，产率：87％。 1H NMR:(400MHz,CDCl 3)δ7.43-7.41(m,1H),7.40-7.38(m,1H),7.26(d,J＝0.8Hz,1H),7.19(d,J＝0.8Hz,1H),6.75-6.72(m,1H),6.72-6.70(m,1H),3.31(dd,J＝7.2,8.0Hz,1H),3.25-3.18(m,2H),3.02(t,J＝8.0Hz,1H),2.96-2.86(m,1H),2.30(s,6H),2.22-2.12(m,1H),1.98-1.85(m,1H). According to the second step method in Example 31, 4-(4-methoxy-2-nitro-phenyl)morpholine was replaced by (3R)-N,N-dimethyl-1-[1-( 4-Nitrophenyl)pyrazol-4-yl]pyrrolidin-3-amine gives (3R)-1-[1-(4-anilino)pyrazol-4-yl]-N,N-dimethyl -pyrrolidin-3-amine (60.0 mg, yellow oil), yield: 87%. 1 H NMR: (400MHz, CDCl 3 ) δ 7.43-7.41 (m, 1H), 7.40-7.38 (m, 1H), 7.26 (d, J=0.8Hz, 1H), 7.19 (d, J=0.8Hz) ,1H),6.75-6.72(m,1H),6.72-6.70(m,1H),3.31(dd,J=7.2,8.0Hz,1H),3.25-3.18(m,2H),3.02(t,J =8.0Hz,1H),2.96-2.86(m,1H),2.30(s,6H),2.22-2.12(m,1H),1.98-1.85(m,1H).

MS-ESI计算值[M+H] +272，实测值272。 MS-ESI calculated [M+H] + 272, found 272.

第三步third step

5-氯-N2-[4-[4-[(3R)-3-(二甲氨基)吡咯烷-1-基]吡唑-1-基]苯基]-N4-(2-二甲基磷酰基苯基)嘧啶-2,4-二胺根据实施例1中第四步方法，将对甲氧基苯胺替换为(3R)-1-[1-(4-苯胺基)吡唑-4-基]-N,N-二甲基-吡咯烷-3-胺，得到5-氯-N2-[4-[4-[(3R)-3-(二甲氨基)吡咯烷-1-基]吡唑-1-基]苯基]-N4-(2-二甲基磷酰基苯基)嘧啶-2,4-二胺(12.0mg)产率：18％。 1H NMR:(400MHz,DMSO-d 6)δ7.99(s,1H),7.85-7.79(m,1H),7.71(s,1H),7.58-7.40(m,5H),7.35-7.26(m,3H),3.93-3.85(m,1H),3.36-3.24(m,3H),3.04-2.97(m,1H),2.76(d,J＝2.3Hz,6H),2.42-2.30(m,1H),2.10-2.01(m,1H),1.68(s,3H),1.65(s,3H)。 5-Chloro-N2-[4-[4-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]pyrazol-1-yl]phenyl]-N4-(2-dimethyl Phosphorylphenyl)pyrimidine-2,4-diamine According to the fourth step method in Example 1, p-methoxyaniline was replaced by (3R)-1-[1-(4-anilino)pyrazole-4 -yl]-N,N-dimethyl-pyrrolidin-3-amine to give 5-chloro-N2-[4-[4-[(3R)-3-(dimethylamino)pyrrolidin-1-yl ]pyrazol-1-yl]phenyl]-N4-(2-dimethylphosphorylphenyl)pyrimidine-2,4-diamine (12.0 mg) Yield: 18%. 1 H NMR: (400MHz, DMSO-d 6 )δ7.99(s, 1H), 7.85-7.79(m, 1H), 7.71(s, 1H), 7.58-7.40(m, 5H), 7.35-7.26( m, 3H), 3.93-3.85(m, 1H), 3.36-3.24(m, 3H), 3.04-2.97(m, 1H), 2.76(d, J=2.3Hz, 6H), 2.42-2.30(m, 1H), 2.10-2.01(m, 1H), 1.68(s, 3H), 1.65(s, 3H).

MS-ESI计算值[M+H] +551和553，实测值551和553。 MS-ESI calculated [M+H] + 551 and 553, found 551 and 553.

实施例47Example 47

5-氯-N2-[4-[4-[(3S)-3-(二甲氨基)吡咯烷-1-基]吡唑-1-基]苯基]-N4-(2-二甲基磷酰基苯基)嘧啶-2,4-二胺5-Chloro-N2-[4-[4-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]pyrazol-1-yl]phenyl]-N4-(2-dimethyl Phosphorylphenyl)pyrimidine-2,4-diamine

Figure PCTCN2022082343-appb-000102
Figure PCTCN2022082343-appb-000102

第一步first step

(3S)-N,N-二甲基-1-[1-(4-硝基苯)吡唑-4-基]吡咯烷-3-胺(3S)-N,N-Dimethyl-1-[1-(4-nitrophenyl)pyrazol-4-yl]pyrrolidin-3-amine

根据实施例45中第二步方法，将2-甲氧基-N-甲基-二乙胺替换为(3S)-N,N-二甲基吡唑-3-胺得到(3S)-N,N-二甲基-1-[1-(4-硝基苯)吡唑-4-基]吡咯烷-3-胺(100mg,黄色固体)，产率：44％。1H NMR:(400MHz,CDCl 3)δ8.32-8.27(m,2H),7.79-7.75(m,2H),7.42(s,1H),7.29(s,1H),3.36-3.24(m,3H),3.09(t,J＝8.0Hz,1H),2.98-2.90(m,1H),2.32(s,6H),2.25-2.16(m,1H),1.99-1.92(m,1H). According to the second step method in Example 45, 2-methoxy-N-methyl-diethylamine was replaced with (3S)-N,N-dimethylpyrazol-3-amine to obtain (3S)-N , N-dimethyl-1-[1-(4-nitrophenyl)pyrazol-4-yl]pyrrolidin-3-amine (100 mg, yellow solid), yield: 44%. 1H NMR: (400MHz, CDCl 3 ) δ 8.32-8.27(m, 2H), 7.79-7.75(m, 2H), 7.42(s, 1H), 7.29(s, 1H), 3.36-3.24(m, 3H) ),3.09(t,J=8.0Hz,1H),2.98-2.90(m,1H),2.32(s,6H),2.25-2.16(m,1H),1.99-1.92(m,1H).

MS-ESI计算值[M+H] +302，实测值302。 MS-ESI calculated [M+H] + 302, found 302.

第二步second step

(3S)-1-[1-(4-苯胺基)吡唑-4-基]-N,N-二甲基-吡咯烷-3-胺(3S)-1-[1-(4-anilino)pyrazol-4-yl]-N,N-dimethyl-pyrrolidin-3-amine

根据实施例31中第二步方法，将4-(4-甲氧基-2-硝基-苯基)吗啡啉替换为(3S)-N,N-二甲基-1-[1-(4-硝基苯)吡唑-4-基]吡咯烷-3-胺得到(3S)-1-[1-(4-苯胺基)吡唑-4-基]-N,N-二甲基-吡咯烷-3-胺(65.0mg,黄色固体)，粗品。 1H NMR:(400MHz,CDCl 3)δ7.43-7.41(m,1H),7.41-7.38(m,1H),7.26(d,J＝0.8Hz,1H),7.19(d,J＝0.8Hz,1H),6.75-6.73(m,1H),6.72-6.70(m,1H),3.31(dd,J＝7.2,8.0Hz,1H),3.25-3.19(m,2H),3.02(t,J＝8.0Hz,1H),2.96-2.86(m,1H),2.30(s,6H),2.21-2.12(m,1H),1.98-1.85(m,1H). According to the second step method in Example 31, 4-(4-methoxy-2-nitro-phenyl)morpholine was replaced by (3S)-N,N-dimethyl-1-[1-( 4-Nitrophenyl)pyrazol-4-yl]pyrrolidin-3-amine gives (3S)-1-[1-(4-anilino)pyrazol-4-yl]-N,N-dimethyl -pyrrolidin-3-amine (65.0 mg, yellow solid), crude. 1 H NMR: (400MHz, CDCl 3 ) δ 7.43-7.41 (m, 1H), 7.41-7.38 (m, 1H), 7.26 (d, J=0.8Hz, 1H), 7.19 (d, J=0.8Hz) ,1H),6.75-6.73(m,1H),6.72-6.70(m,1H),3.31(dd,J=7.2,8.0Hz,1H),3.25-3.19(m,2H),3.02(t,J =8.0Hz,1H),2.96-2.86(m,1H),2.30(s,6H),2.21-2.12(m,1H),1.98-1.85(m,1H).

MS-ESI计算值[M+H] +272，实测值272。 MS-ESI calculated [M+H] + 272, found 272.

第三步third step

5-氯-N2-[4-[4-[(3S)-3-(二甲氨基)吡咯烷-1-基]吡唑-1-基]苯基]-N4-(2-二甲基磷酰基苯基)嘧啶-2,4-二胺根据实施例1中第四步方法，将对甲氧基苯胺替换为(3S)-1-[1-(4-苯胺基)吡唑-4-基]-N,N-二甲基-吡咯烷-3-胺的得到5-氯-N2-[4-[4-[(3S)-3-(二甲氨基)吡咯烷-1-基]吡唑-1-基]苯基]-N4-(2-二甲基磷酰基苯基)嘧啶-2,4-二胺(36.0mg)，产率：52％。 1H NMR:(400MHz,D 2O)δ7.90(s,1H),7.63-7.58(m,1H),7.57-7.49(m,2H),7.41-7.34(m,2H),7.32-7.27(m,1H),7.22-7.17(m,2H),7.15-7.09(m,2H),4.00-3.89(m,1H),3.41-3.28(m,3H),3.10-2.98(m,1H),2.85(d,J＝2.8Hz,6H),2.49-2.37(m,1H),2.15-2.08(m,1H),1.69(s,3H),1.66(s,3H)。 5-Chloro-N2-[4-[4-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]pyrazol-1-yl]phenyl]-N4-(2-dimethyl Phosphorylphenyl)pyrimidine-2,4-diamine According to the fourth step method in Example 1, p-methoxyaniline was replaced by (3S)-1-[1-(4-anilino)pyrazole-4 -yl]-N,N-dimethyl-pyrrolidin-3-amine to give 5-chloro-N2-[4-[4-[(3S)-3-(dimethylamino)pyrrolidin-1-yl ]pyrazol-1-yl]phenyl]-N4-(2-dimethylphosphorylphenyl)pyrimidine-2,4-diamine (36.0 mg), yield: 52%. 1 H NMR: (400MHz, D 2 O) δ 7.90 (s, 1H), 7.63-7.58 (m, 1H), 7.57-7.49 (m, 2H), 7.41-7.34 (m, 2H), 7.32-7.27 (m,1H),7.22-7.17(m,2H),7.15-7.09(m,2H),4.00-3.89(m,1H),3.41-3.28(m,3H),3.10-2.98(m,1H) , 2.85(d, J=2.8Hz, 6H), 2.49-2.37(m, 1H), 2.15-2.08(m, 1H), 1.69(s, 3H), 1.66(s, 3H).

MS-ESI计算值[M+H] +551和553，实测值551和553。 MS-ESI calculated [M+H] + 551 and 553, found 551 and 553.

实施例48Example 48

Figure PCTCN2022082343-appb-000103
Figure PCTCN2022082343-appb-000103

第一步first step

根据实施例45中第二步方法，将2-甲氧基-N-甲基-二乙胺替换为1-甲基哌嗪得到1-甲基-4-[1-(3-硝基苯)吡唑-4-基]哌嗪(98.0mg,黄色固体)，产率：46％。1H NMR:(400MHz,CDCl 3)δ8.38(t,J＝2.4Hz,1H),8.01-7.94(m,2H),7.52(t,J＝8.4Hz,1H),7.45(s,1H),7.41(s,1H),3.07-2.98(m,4H),2.60-2.47(m,4H),2.30(s,3H). According to the second step method in Example 45, 2-methoxy-N-methyl-diethylamine was replaced with 1-methylpiperazine to obtain 1-methyl-4-[1-(3-nitrobenzene ) pyrazol-4-yl]piperazine (98.0 mg, yellow solid), yield: 46%. 1H NMR: (400MHz, CDCl 3 ) δ 8.38 (t, J=2.4Hz, 1H), 8.01-7.94 (m, 2H), 7.52 (t, J=8.4Hz, 1H), 7.45 (s, 1H) ,7.41(s,1H),3.07-2.98(m,4H),2.60-2.47(m,4H),2.30(s,3H).

MS-ESI计算值[M+H] +288，实测值288。 MS-ESI calculated [M+H] + 288, found 288.

第二步second step

4-[4-(4-甲基哌嗪-1-基)吡唑-1-基]苯胺4-[4-(4-Methylpiperazin-1-yl)pyrazol-1-yl]aniline

根据实施例31中第二步方法，将4-(4-甲氧基-2-硝基-苯基)吗啡啉替换为1-甲基-4-[1-(3-硝基苯)吡唑-4-基]哌嗪得到4-[4-(4-甲基哌嗪-1-基)吡唑-1-基]苯胺(90.00mg,黄色油状)，粗品。 1H NMR:(400MHz,CDCl 3)δ7.43-7.37(m,3H),7.33(d,J＝0.8Hz,1H),6.73(s,1H),6.71(s,1H),3.09-3.00(m,4H),2.64-2.55(m,4H),2.35(s,3H)。 According to the second step method in Example 31, 4-(4-methoxy-2-nitro-phenyl)morpholine was replaced by 1-methyl-4-[1-(3-nitrophenyl)pyridine oxazol-4-yl]piperazine gave 4-[4-(4-methylpiperazin-1-yl)pyrazol-1-yl]aniline (90.00 mg, yellow oil) as crude product. 1 H NMR: (400MHz, CDCl 3 ) δ 7.43-7.37(m, 3H), 7.33(d, J=0.8Hz, 1H), 6.73(s, 1H), 6.71(s, 1H), 3.09-3.00 (m, 4H), 2.64-2.55 (m, 4H), 2.35 (s, 3H).

MS-ESI计算值[M+H] +258，实测值258。 MS-ESI calculated [M+H] + 258, found 258.

第三步third step

根据实施例1中第四步方法，将对甲氧基苯胺替换为4-[4-(4-甲基哌嗪-1-基)吡唑-1-基]苯胺5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-[4-(4-甲基哌嗪-1-基)吡唑-1-基]苯基]嘧啶-2,4-二胺(50.0mg)，产率：49％。 1H NMR:(400MHz,D 2O)δ7.87(s,1H),7.67(s,1H),7.61-7.55(m,1H),7.53-7.45(m,2H),7.32-7.22(m,2H),7.18-7.05(m,4H),3.53(t,J＝14.4Hz,4H),3.25-3.14(m,2H),3.03-2.91(m,2H),2.87(s,3H),1.69(s,3H),1.65(s,3H). According to the fourth step method in Example 1, p-methoxyaniline was replaced with 4-[4-(4-methylpiperazin-1-yl)pyrazol-1-yl]aniline 5-chloro-N4-( 2-Dimethylphosphorylphenyl)-N2-[4-[4-(4-methylpiperazin-1-yl)pyrazol-1-yl]phenyl]pyrimidine-2,4-diamine ( 50.0 mg), yield: 49%. 1 H NMR: (400MHz, D 2 O) δ 7.87(s, 1H), 7.67(s, 1H), 7.61-7.55(m, 1H), 7.53-7.45(m, 2H), 7.32-7.22(m ,2H),7.18-7.05(m,4H),3.53(t,J＝14.4Hz,4H),3.25-3.14(m,2H),3.03-2.91(m,2H),2.87(s,3H), 1.69(s, 3H), 1.65(s, 3H).

MS-ESI计算值[M+H] +537和539，实测值537和539。 MS-ESI calculated [M+H] + 537 and 539, found 537 and 539.

实施例49Example 49

5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-(4-吗啡啉吡唑-1-基)苯基]嘧啶-2,4-二胺5-Chloro-N4-(2-dimethylphosphorylphenyl)-N2-[4-(4-morpholinopyrazol-1-yl)phenyl]pyrimidine-2,4-diamine

Figure PCTCN2022082343-appb-000104
Figure PCTCN2022082343-appb-000104

第一步first step

4-[1-(4-硝基苯)吡唑-4-基]吗啡啉4-[1-(4-Nitrophenyl)pyrazol-4-yl]morpholine

根据实施例45中第二步方法，将2-甲氧基-N-甲基-二乙胺替换为吗啡啉得到4-[1-(4-硝基苯)吡唑-4-基]吗啡啉(102mg,黄色固体)，产率：50％。1H NMR:(400MHz,CDCl 3)δ8.35-8.28(m,2H),7.82-7.77(m,2H),7.57(s,1H),7.48(d,J＝0.8Hz,1H),3.93-3.82(m,4H),3.06-3.03(m,4H)。 According to the second step method in Example 45, 2-methoxy-N-methyl-diethylamine was replaced by morpholine to obtain 4-[1-(4-nitrophenyl)pyrazol-4-yl]morphine phenoline (102 mg, yellow solid), yield: 50%. 1H NMR: (400MHz, CDCl 3 ) δ 8.35-8.28(m, 2H), 7.82-7.77(m, 2H), 7.57(s, 1H), 7.48(d, J=0.8Hz, 1H), 3.93- 3.82 (m, 4H), 3.06-3.03 (m, 4H).

MS-ESI计算值[M+H] +275，实测值275。 MS-ESI calculated [M+H] + 275, found 275.

第二步second step

4-(4-吗啡啉吡唑-1-基)苯胺4-(4-Mormorpholinpyrazol-1-yl)aniline

根据实施例31中第二步方法，将4-(4-甲氧基-2-硝基-苯基)吗啡啉替换为4-[1-(4-硝基苯)吡唑-4-基]吗啡啉得到4-(4-吗啡啉吡唑-1-基)苯胺(80.0mg,黄色固体)，产率：90％。 1H NMR:(400MHz,CDCl 3)δ7.45 7.38(m,3H),7.34(s,1H),6.73(d,J＝8.8Hz,2H),3.92-3.80(m,4H),3.04-2.94(m,4H)。 According to the second step method in Example 31, 4-(4-methoxy-2-nitro-phenyl)morpholine was replaced by 4-[1-(4-nitrophenyl)pyrazol-4-yl ] morpholine gave 4-(4-morpholinepyrazol-1-yl)aniline (80.0 mg, yellow solid), yield: 90%. 1 H NMR: (400 MHz, CDCl 3 ) δ 7.45 7.38 (m, 3H), 7.34 (s, 1H), 6.73 (d, J=8.8Hz, 2H), 3.92-3.80 (m, 4H), 3.04- 2.94 (m, 4H).

MS-ESI计算值[M+H] +245，实测值245。 MS-ESI calculated [M+H] + 245, found 245.

第三步third step

5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-(4-吗啡啉吡唑-1-基)苯基]嘧啶-2,4-二胺5-Chloro-N4-(2-dimethylphosphorylphenyl)-N2-[4-(4-morpholinopyrazol-1-yl)phenyl]pyrimidine-2,4-diamine

根据实施例1中第四步方法，将对甲氧基苯胺替换为4-(4-吗啡啉吡唑-1-基)苯胺得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-(4-吗啡啉吡唑-1-基)苯基]嘧啶-2,4-二胺(36.0mg)，产率：39％。 1H NMR:(400MHz,CD 3OD)δ8.50(s,1H),8.29-8.20(m,2H),7.92(s,1H),7.81(d,J＝8.8Hz,2H),7.77-7.69(m,1H),7.64-7.54(m,3H),7.49-7.42(m,1H),4.06-3.98(m,4H),3.54-3.47(m,4H),1.91(s,3H),1.88(s,3H)。 According to the fourth step method in Example 1, p-methoxyaniline was replaced with 4-(4-morpholinopyrazol-1-yl)aniline to obtain 5-chloro-N4-(2-dimethylphosphorylphenyl) )-N2-[4-(4-morpholinopyrazol-1-yl)phenyl]pyrimidine-2,4-diamine (36.0 mg), yield: 39%. 1 H NMR: (400MHz, CD 3 OD) δ 8.50 (s, 1H), 8.29-8.20 (m, 2H), 7.92 (s, 1H), 7.81 (d, J=8.8Hz, 2H), 7.77- 7.69(m,1H),7.64-7.54(m,3H),7.49-7.42(m,1H),4.06-3.98(m,4H),3.54-3.47(m,4H),1.91(s,3H), 1.88(s, 3H).

MS-ESI计算值[M+H] +524和526，实测值524和526。 MS-ESI calculated [M+H] + 524 and 526, found 524 and 526.

实施例50Example 50

5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-[4-[[6-(4-甲基哌嗪-1-基)-3-吡啶]胺]吡唑-1-基]苯基]嘧啶-2,4-胺5-Chloro-N4-(2-dimethylphosphorylphenyl)-N2-[4-[4-[[6-(4-methylpiperazin-1-yl)-3-pyridin]amine]pyridine azol-1-yl]phenyl]pyrimidin-2,4-amine

Figure PCTCN2022082343-appb-000105
Figure PCTCN2022082343-appb-000105

第一步first step

6-(4-甲基哌嗪-1-基)-N-[1-(4-硝基苯)吡唑-4-基]吡啶-3-胺6-(4-Methylpiperazin-1-yl)-N-[1-(4-nitrophenyl)pyrazol-4-yl]pyridin-3-amine

根据实施例45中第二步方法，将2-甲氧基-N-甲基-二乙胺替换为6-(4-甲基哌嗪-1-基)吡啶-3-氨基得到6-(4-甲基哌嗪-1-基)-N-[1-(4-硝基苯)吡唑-4-基]吡啶-3-胺(222mg,黄色固体)，产率：78％。1H NMR:(400MHz,CDCl 3)δ8.24(d,J＝8.4Hz,2H),7.96(d,J＝2.8Hz,1H),7.74-7.67(m,3H),7.56(s,1H),7.19-7.16(m,1H),6.60(d,J＝8.8Hz,1H),3.45-3.39(m,4H),2.51-2.48(m,4H),2.31-2.27(m,3H)。 According to the second step method in Example 45, 2-methoxy-N-methyl-diethylamine was replaced with 6-(4-methylpiperazin-1-yl)pyridine-3-amino to obtain 6-( 4-Methylpiperazin-1-yl)-N-[1-(4-nitrophenyl)pyrazol-4-yl]pyridin-3-amine (222 mg, yellow solid), yield: 78%. 1H NMR: (400MHz, CDCl 3 ) δ 8.24 (d, J=8.4Hz, 2H), 7.96 (d, J=2.8Hz, 1H), 7.74-7.67 (m, 3H), 7.56 (s, 1H) , 7.19-7.16(m, 1H), 6.60(d, J=8.8Hz, 1H), 3.45-3.39(m, 4H), 2.51-2.48(m, 4H), 2.31-2.27(m, 3H).

MS-ESI计算值[M+H] +380，实测值380。 MS-ESI calculated [M+H] + 380, found 380.

第二步second step

N-[1-(4-氨基苯)吡唑-4-基]-6-(4-甲基哌嗪-1-基)吡啶-3-胺N-[1-(4-Aminophenyl)pyrazol-4-yl]-6-(4-methylpiperazin-1-yl)pyridin-3-amine

根据实施例31中第二步方法，将4-(4-甲氧基-2-硝基-苯基)吗啡啉替换为6-(4-甲基哌嗪-1-基)-N-[1-(4-硝基苯)吡唑-4-基]吡啶-3-胺得到N-[1-(4-氨基苯)吡唑-4-基]-6-(4-甲基哌嗪-1-基)吡啶-3-胺(200mg,浅黄色固体)，产率：99％。 1H NMR:(400MHz,CDCl 3)δ7.96(d,J＝2.8Hz,1H),7.64(s,1H),7.52(s,1H),7.44-7.37(m,2H),7.17(dd,J＝3.0,8.8Hz,1H),6.77-6.70(m,2H),6.63(d,J＝8.8Hz,1H),3.50-3.41(m,4H),2.59-2.53(m,4H),2.35(s,3H). According to the second step in Example 31, 4-(4-methoxy-2-nitro-phenyl)morpholine was replaced by 6-(4-methylpiperazin-1-yl)-N-[ 1-(4-Nitrobenzene)pyrazol-4-yl]pyridin-3-amine gives N-[1-(4-aminobenzene)pyrazol-4-yl]-6-(4-methylpiperazine -1-yl)pyridin-3-amine (200 mg, pale yellow solid), yield: 99%. 1 H NMR: (400 MHz, CDCl 3 ) δ 7.96 (d, J=2.8 Hz, 1H), 7.64 (s, 1H), 7.52 (s, 1H), 7.44-7.37 (m, 2H), 7.17 (dd , J=3.0, 8.8Hz, 1H), 6.77-6.70(m, 2H), 6.63(d, J=8.8Hz, 1H), 3.50-3.41(m, 4H), 2.59-2.53(m, 4H), 2.35(s,3H).

MS-ESI计算值[M+H] +350，实测值350。 MS-ESI calculated [M+H] + 350, found 350.

第三步third step

5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-[4-[[6-(4-甲基哌嗪-1-基)-3-吡啶]胺]吡唑-1-基]苯基]嘧啶-2,4-胺根据实施例1中第四步方法，将对甲氧基苯胺替换为N-[1-(4-氨基苯)吡唑-4-基]-6-(4-甲基哌嗪-1-基)吡啶-3-胺得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-[4-[[6-(4-甲基哌嗪-1-基)-3-吡啶]胺]吡唑-1-基]苯基]嘧啶-2,4-胺(52.0mg)，产率：27％。 1H NMR:(400MHz,CD 3OD)δ8.39(s,1H),8.31-8.20(m,2H),7.98-7.92(m,1H),7.84(d,J＝8.8Hz,2H),7.78-7.69(m,2H),7.66-7.59(m,2H),7.58-7.53(m,2H),7.52-7.43(m,2H),4.35-4.24(m,2H),3.79-3.69(m,2H),3.68-3.57(m,2H),3.43-3.34(m,2H),3.03(s,3H),1.92(s,3H),1.88(s,3H). 5-Chloro-N4-(2-dimethylphosphorylphenyl)-N2-[4-[4-[[6-(4-methylpiperazin-1-yl)-3-pyridin]amine]pyridine Azol-1-yl]phenyl]pyrimidin-2,4-amine According to the fourth step method in Example 1, p-methoxyaniline was replaced with N-[1-(4-aminophenyl)pyrazole-4- yl]-6-(4-methylpiperazin-1-yl)pyridin-3-amine to give 5-chloro-N4-(2-dimethylphosphorylphenyl)-N2-[4-[4-[ [6-(4-Methylpiperazin-1-yl)-3-pyridin]amine]pyrazol-1-yl]phenyl]pyrimidin-2,4-amine (52.0 mg), yield: 27%. 1 H NMR: (400MHz, CD 3 OD) δ 8.39 (s, 1H), 8.31-8.20 (m, 2H), 7.98-7.92 (m, 1H), 7.84 (d, J=8.8Hz, 2H), 7.78-7.69(m, 2H), 7.66-7.59(m, 2H), 7.58-7.53(m, 2H), 7.52-7.43(m, 2H), 4.35-4.24(m, 2H), 3.79-3.69(m ,2H),3.68-3.57(m,2H),3.43-3.34(m,2H),3.03(s,3H),1.92(s,3H),1.88(s,3H).

MS-ESI计算值[M+H] +629和631，实测值629和631。 MS-ESI calculated [M+H] + 629 and 631, found 629 and 631.

实施例51Example 51

5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-[4-(4-甲基哌嗪-1-基)吡唑-1-基]苯基]嘧啶-2,4-二胺5-Chloro-N4-(2-dimethylphosphorylphenyl)-N2-[3-[4-(4-methylpiperazin-1-yl)pyrazol-1-yl]phenyl]pyrimidine- 2,4-Diamine

Figure PCTCN2022082343-appb-000106
Figure PCTCN2022082343-appb-000106

第一步first step

4-溴-1-(3-硝基苯基)吡唑4-Bromo-1-(3-nitrophenyl)pyrazole

根据实施例32中第一步方法，将吗啡啉和2-氟-4-甲氧基-1-硝基苯替换为三氟硝基苯得到4-溴-1-(3-硝基苯基)吡唑(8.00g,黄色固体)，产率：84％。1H NMR:(400MHz,CDCl 3)δ8.51(t,J＝2.0Hz,1H),8.19-8.13(m,1H),8.05-8.01(m,2H),7.72(s,1H),7.65(t,J＝8.4Hz,1H) According to the first step method in Example 32, morpholine and 2-fluoro-4-methoxy-1-nitrobenzene were replaced by trifluoronitrobenzene to obtain 4-bromo-1-(3-nitrophenyl ) pyrazole (8.00 g, yellow solid), yield: 84%. 1H NMR: (400MHz, CDCl 3 ) δ 8.51(t, J=2.0Hz, 1H), 8.19-8.13(m, 1H), 8.05-8.01(m, 2H), 7.72(s, 1H), 7.65( t,J=8.4Hz,1H)

第二步second step

1-甲基-4-[1-(3-硝基苯基)吡唑-4-基]哌嗪1-Methyl-4-[1-(3-nitrophenyl)pyrazol-4-yl]piperazine

根据实施例45中第二步方法，将2-甲氧基-N-甲基-二乙胺替换为4-溴-1-(3-硝基苯基)吡唑得到1-甲基-4-[1-(3-硝基苯基)吡唑-4-基]哌嗪(98.0mg,黄色固体)，产率：46％。1H NMR:(400MHz,CDCl 3)δ8.38(t,J＝2.4Hz,1H),8.01-7.94(m,2H),7.52(t,J＝8.4Hz,1H),7.45(s,1H),7.41(s,1H),3.07- 2.98(m,4H),2.60-2.47(m,4H),2.30(s,3H)。 According to the second step method in Example 45, 2-methoxy-N-methyl-diethylamine was replaced with 4-bromo-1-(3-nitrophenyl)pyrazole to obtain 1-methyl-4 -[1-(3-Nitrophenyl)pyrazol-4-yl]piperazine (98.0 mg, yellow solid), yield: 46%. 1H NMR: (400MHz, CDCl 3 ) δ 8.38 (t, J=2.4Hz, 1H), 8.01-7.94 (m, 2H), 7.52 (t, J=8.4Hz, 1H), 7.45 (s, 1H) , 7.41(s, 1H), 3.07-2.98(m, 4H), 2.60-2.47(m, 4H), 2.30(s, 3H).

第三步third step

3-[4-(4-甲基哌嗪-1-基)吡唑-1-基]苯胺3-[4-(4-Methylpiperazin-1-yl)pyrazol-1-yl]aniline

根据实施例31中第二步方法，将4-(4-甲氧基-2-硝基-苯基)吗啡啉替换为1-甲基-4-[1-(3-硝基苯基)吡唑-4-基]哌嗪得到3-[4-(4-甲基哌嗪-1-基)吡唑-1-基]苯胺(50.0mg,白色固体)，产率：57％。 1H NMR:(400MHz,CDCl 3)δ7.35(d,J＝7.6Hz,2H),7.11(t,J＝8.0Hz,1H),6.98-6.93(m,1H),6.89-6.82(m,1H),6.52-6.46(m,1H),3.03-2.93(m,4H),2.57-2.48(m,4H),2.28(s,3H)。 According to the second step in Example 31, 4-(4-methoxy-2-nitro-phenyl)morpholine was replaced by 1-methyl-4-[1-(3-nitrophenyl) Pyrazol-4-yl]piperazine gave 3-[4-(4-methylpiperazin-1-yl)pyrazol-1-yl]aniline (50.0 mg, white solid), yield: 57%. 1 H NMR: (400 MHz, CDCl 3 ) δ 7.35 (d, J=7.6 Hz, 2H), 7.11 (t, J=8.0 Hz, 1H), 6.98-6.93 (m, 1H), 6.89-6.82 (m , 1H), 6.52-6.46 (m, 1H), 3.03-2.93 (m, 4H), 2.57-2.48 (m, 4H), 2.28 (s, 3H).

第四步the fourth step

5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-[4-(4-甲基哌嗪-1-基)吡唑-1-基]苯基]嘧啶-2,4-二胺5-Chloro-N4-(2-dimethylphosphorylphenyl)-N2-[3-[4-(4-methylpiperazin-1-yl)pyrazol-1-yl]phenyl]pyrimidine- 2,4-Diamine

根据实施例1中第四步方法，将对甲氧基苯胺替换为3-[4-(4-甲基哌嗪-1-基)吡唑-1-基]苯胺得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-[4-(4-甲基哌嗪-1-基)吡唑-1-基]苯基]嘧啶-2,4-二胺(75.0mg)产率：67％。 1H NMR:(400MHz,CD 3OD)δ8.23(s,2H),7.99(s,1H),7.89-7.87(m,1H),7.71-7.61(m,3H),7.51(t,J＝8.0Hz,1H),7.33-7.22(m,3H),3.73-3.59(m,4H),3.37(s,2H),3.09-2.96(m,5H),1.91(s,3H),1.87(s,3H)。 According to the fourth step method in Example 1, p-methoxyaniline was replaced with 3-[4-(4-methylpiperazin-1-yl)pyrazol-1-yl]aniline to obtain 5-chloro-N4- (2-Dimethylphosphorylphenyl)-N2-[3-[4-(4-methylpiperazin-1-yl)pyrazol-1-yl]phenyl]pyrimidine-2,4-diamine (75.0 mg) Yield: 67%. 1 H NMR: (400MHz, CD 3 OD) δ 8.23(s, 2H), 7.99(s, 1H), 7.89-7.87(m, 1H), 7.71-7.61(m, 3H), 7.51(t, J =8.0Hz,1H),7.33-7.22(m,3H),3.73-3.59(m,4H),3.37(s,2H),3.09-2.96(m,5H),1.91(s,3H),1.87( s, 3H).

MS-ESI计算值[M+H] +538和540，实测值538和540。 MS-ESI calculated [M+H] + 538 and 540, found 538 and 540.

实施例52Example 52

5-氯-N2-[3-[4-[(3R)-3-(二甲胺基)吡咯烷-1-基]吡唑-1-基]苯基]-N4-(2-二甲基磷酰基苯基)嘧啶-2,4-二胺5-Chloro-N2-[3-[4-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]pyrazol-1-yl]phenyl]-N4-(2-dimethyl (phosphorylphenyl)pyrimidine-2,4-diamine

Figure PCTCN2022082343-appb-000107
Figure PCTCN2022082343-appb-000107

第一步first step

(3R)-N,N-二甲基-1-[1-(3-硝基苯)吡唑-4-基]吡咯烷-3-胺(3R)-N,N-Dimethyl-1-[1-(3-nitrophenyl)pyrazol-4-yl]pyrrolidin-3-amine

参照实施例1第二步将甲基哌嗪替换为(3R)-N,N-二甲基吡咯烷-3-胺，得到(3R)-N,N-二甲基-1-[1-(3-硝基苯)吡唑-4-基]吡咯烷-3-胺(33.0mg,黄色固体)，产率：15％。1H NMR:(400MHz,CDCl 3)δ8.29(t,J＝2.0Hz,1H),7.88(dd,J＝2.0,8.0Hz,2H),7.44-7.39(m,1H),7.23-7.10(m,3H),3.23-3.07(m,3H),2.94(t,J＝8.0Hz,1H),2.84-2.76(m,1H),2.19-2.14(m,6H)。 With reference to the second step of Example 1, methylpiperazine was replaced with (3R)-N,N-dimethylpyrrolidin-3-amine to obtain (3R)-N,N-dimethyl-1-[1- (3-Nitrophenyl)pyrazol-4-yl]pyrrolidin-3-amine (33.0 mg, yellow solid), yield: 15%. 1H NMR: (400MHz, CDCl 3 ) δ 8.29 (t, J=2.0Hz, 1H), 7.88 (dd, J=2.0, 8.0Hz, 2H), 7.44-7.39 (m, 1H), 7.23-7.10 ( m, 3H), 3.23-3.07 (m, 3H), 2.94 (t, J=8.0Hz, 1H), 2.84-2.76 (m, 1H), 2.19-2.14 (m, 6H).

第二步second step

(3R)-1-[1-(3-胺基苯基)吡唑-4-基]-N,N-二甲基-吡咯烷-3-胺(3R)-1-[1-(3-Aminophenyl)pyrazol-4-yl]-N,N-dimethyl-pyrrolidin-3-amine

根据实施例31中第二步方法，将4-(4-甲氧基-2-硝基-苯基)吗啡啉替换为(3R)-N,N-二甲基-1-[1-(3-硝基苯)吡唑-4-基]吡咯烷-3-胺得到(3R)-1-[1-(3-胺基苯基)吡唑-4-基]-N,N-二甲基-吡咯烷-3-胺(30.0mg,白色固体，粗品)。According to the second step method in Example 31, 4-(4-methoxy-2-nitro-phenyl)morpholine was replaced by (3R)-N,N-dimethyl-1-[1-( 3-Nitrophenyl)pyrazol-4-yl]pyrrolidin-3-amine gives (3R)-1-[1-(3-aminophenyl)pyrazol-4-yl]-N,N-di Methyl-pyrrolidin-3-amine (30.0 mg, white solid, crude).

第三步third step

5-氯-N2-[3-[4-[(3R)-3-(二甲胺基)吡咯烷-1-基]吡唑-1-基]苯基]-N4-(2-二甲基磷酰基苯基)嘧啶-2,4-二胺 根据实施例1中第四步方法，将对甲氧基苯胺替换为(3R)-1-[1-(3-胺基苯基)吡唑-4-基]-N,N-二甲基-吡咯烷-3-胺得到5-氯-N2-[3-[4-[(3R)-3-(二甲胺基)吡咯烷-1-基]吡唑-1-基]苯基]-N4-(2-二甲基磷酰基苯基)嘧啶-2,4-二胺(19.0mg)，产率：29％。 1H NMR:(400MHz,CD 3OD)δ8.32-8.08(m,3H),7.91(s,1H),7.72-7.63(m,3H),7.51(t,J＝8.4Hz,1H),7.35-7.17(m,3H),4.26-4.14(m,1H),3.85-3.74(m,1H),3.73-3.62(m,2H),3.42-3.34(m,1H),2.68-2.56(m,1H),2.48-2.35(m,1H),1.92(s,3H),1.88(s,3H). 5-Chloro-N2-[3-[4-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]pyrazol-1-yl]phenyl]-N4-(2-dimethyl According to the fourth step method in Example 1, p-methoxyaniline was replaced by (3R)-1-[1-(3-aminophenyl)pyridine Azol-4-yl]-N,N-dimethyl-pyrrolidin-3-amine gives 5-chloro-N2-[3-[4-[(3R)-3-(dimethylamino)pyrrolidine- 1-yl]pyrazol-1-yl]phenyl]-N4-(2-dimethylphosphorylphenyl)pyrimidine-2,4-diamine (19.0 mg), yield: 29%. 1 H NMR: (400MHz, CD 3 OD) δ 8.32-8.08 (m, 3H), 7.91 (s, 1H), 7.72-7.63 (m, 3H), 7.51 (t, J=8.4Hz, 1H), 7.35-7.17(m, 3H), 4.26-4.14(m, 1H), 3.85-3.74(m, 1H), 3.73-3.62(m, 2H), 3.42-3.34(m, 1H), 2.68-2.56(m ,1H),2.48-2.35(m,1H),1.92(s,3H),1.88(s,3H).

MS-ESI计算值[M+H] +551和553，实测值551和553。 MS-ESI calculated [M+H] + 551 and 553, found 551 and 553.

实施例53Example 53

N4-(2-二甲基磷酰基苯基)-N2-(4-甲氧基苯基)-5-(三氟甲基)嘧啶-2,4-二胺N4-(2-Dimethylphosphorylphenyl)-N2-(4-methoxyphenyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine

Figure PCTCN2022082343-appb-000108
Figure PCTCN2022082343-appb-000108

第一步first step

N-[2-(1-氨基-1-甲基-乙基)苯基]-2,5-二氯-嘧啶-4-胺N-[2-(1-Amino-1-methyl-ethyl)phenyl]-2,5-dichloro-pyrimidin-4-amine

将2-(二氟甲氧基)苯胺(100mg,0.591mmol)和2,4-二氯嘧啶-5-(三氟甲基)嘧啶(128.3mg,0.591mmol)溶于二甲基甲酰胺(2mL)中，然后向反应液加入二异丙基乙胺(229mg,1.77mmol)。反应液在30℃，搅拌16小时。液相色谱和反应完全后。反应液冷至室温，加入水(10mL)，滤液用乙酸乙酯(20mL×3)萃取。合并有机相，用饱和食盐水洗涤(15mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩，剩余物用制备薄层色谱法纯化(乙酸乙酯，Rf＝0.20)分离纯化得到混合物2-氯-N-(2-二甲基磷酰基苯基)-5-(三氟甲基)嘧啶-4-胺(50.0mg,黄色固体)，产率：24％。 1H NMR:(400MHz,CD 3OD)δ8.72(s,1H),8.49(m,1H),7.66-7.74(m,1H),7.60-7.65(m,1H),7.26-7.33(m,1H),1.91(s,3H),1.87(s,3H). 2-(Difluoromethoxy)aniline (100 mg, 0.591 mmol) and 2,4-dichloropyrimidine-5-(trifluoromethyl)pyrimidine (128.3 mg, 0.591 mmol) were dissolved in dimethylformamide ( 2 mL), and then diisopropylethylamine (229 mg, 1.77 mmol) was added to the reaction solution. The reaction solution was stirred at 30°C for 16 hours. LC and after the reaction is complete. The reaction solution was cooled to room temperature, water (10 mL) was added, and the filtrate was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (15 mL×3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography (ethyl acetate, Rf=0.20) to obtain a mixture 2-Chloro-N-(2-dimethylphosphorylphenyl)-5-(trifluoromethyl)pyrimidin-4-amine (50.0 mg, yellow solid), yield: 24%. 1 H NMR: (400MHz, CD 3 OD) δ 8.72 (s, 1H), 8.49 (m, 1H), 7.66-7.74 (m, 1H), 7.60-7.65 (m, 1H), 7.26-7.33 (m ,1H),1.91(s,3H),1.87(s,3H).

MS-ESI计算值[M+H] +350和352，实测值350和352。 MS-ESI calculated [M+H] + 350 and 352, found 350 and 352.

第二步second step

根据实施例1中第四步方法，将(2-((2,5-二氯嘧啶-4-基)氨基)苯基)二甲基氧化膦替换为2-氯-N-(2-二甲基磷酰基苯基)-5-(三氟甲基)嘧啶-4-胺，得到N4-(2-二甲基磷酰基苯基)-N2-(4-甲氧基苯基)-5-(三氟甲基)嘧啶-2,4-二胺(6.00mg)，产率：10％。 1H NMR:(400MHz,CD 3OD)δ8.45(s,1H),7.82(d,J＝3.6Hz,1H),7.61(dd,J＝4.4,9.2Hz,1H),7.31(d,J＝8.8Hz,4H),7.01(d,J＝8.8Hz,2H),3.88(s,3H),1.88(s,3H),1.84(s,3H). According to the fourth step in Example 1, replace (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide with 2-chloro-N-(2-di Methylphosphorylphenyl)-5-(trifluoromethyl)pyrimidin-4-amine to give N4-(2-dimethylphosphorylphenyl)-N2-(4-methoxyphenyl)-5 -(trifluoromethyl)pyrimidine-2,4-diamine (6.00 mg), yield: 10%. 1 H NMR: (400 MHz, CD 3 OD) δ 8.45 (s, 1H), 7.82 (d, J=3.6 Hz, 1H), 7.61 (dd, J=4.4, 9.2 Hz, 1H), 7.31 (d, J=8.8Hz, 4H), 7.01(d, J=8.8Hz, 2H), 3.88(s, 3H), 1.88(s, 3H), 1.84(s, 3H).

MS-ESI计算值[M+H] +437和439，实测值437和439。 MS-ESI calculated [M+H] + 437 and 439, found 437 and 439.

实施例54Example 54

2-(二甲基氨基)-1-[6-[[4-(2-二甲基磷酰基苯氨基)-5-氟-嘧啶-2-基]氨基]-5-甲氧基-吲哚-1-基]乙酮2-(Dimethylamino)-1-[6-[[4-(2-dimethylphosphorylanilino)-5-fluoro-pyrimidin-2-yl]amino]-5-methoxy-indium Indol-1-yl]ethanone

Figure PCTCN2022082343-appb-000109
Figure PCTCN2022082343-appb-000109

第一步first step

2-氯-N-(2-二甲基磷酰基苯基)-5-氟-嘧啶-4-胺2-Chloro-N-(2-dimethylphosphorylphenyl)-5-fluoro-pyrimidin-4-amine

将2-二甲基磷酰基苯胺(200mg,1.18mmol)溶于二甲基甲酰胺(4mL)中，然后在10摄氏度下向反应液中加入2,4-二氯-5-氟-嘧啶(197mg,1.18mmol)和碳酸钾(490mg,3.55mmol)。反应液在60℃，搅拌16小时。液相色谱和反应完全后。反应液用饱和氯化铵(10mL)淬灭，乙酸乙酯(20mL×3)萃取，合并有机相后用饱和食盐水洗(10mL×2)，无水硫酸钠干燥、过滤、浓缩后用制备TLC板(乙酸乙酯/甲醇＝10:1，Rf＝0.26)分离纯化得到2-氯-N-(2-二甲基磷酰基苯基)-5-氟-嘧啶-4-胺(55mg,黄色固体)，产率：15.5％。 1H NMR:(400MHz,CD3OD)δ8.63(m,1H),8.22(m,1H),7.70-7.58(m,2H),7.34-7.26(m,1H),1.92(s,3H),1.89(s,3H). 2-Dimethylphosphoranilide (200 mg, 1.18 mmol) was dissolved in dimethylformamide (4 mL), and 2,4-dichloro-5-fluoro-pyrimidine ( 197 mg, 1.18 mmol) and potassium carbonate (490 mg, 3.55 mmol). The reaction solution was stirred at 60°C for 16 hours. LC and after the reaction is complete. The reaction solution was quenched with saturated ammonium chloride (10 mL), extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated, and used for preparative TLC Plate (ethyl acetate/methanol=10:1, Rf=0.26) was isolated and purified to give 2-chloro-N-(2-dimethylphosphorylphenyl)-5-fluoro-pyrimidin-4-amine (55mg, yellow solid), yield: 15.5%. 1 H NMR: (400MHz, CD3OD)δ8.63(m,1H), 8.22(m,1H), 7.70-7.58(m,2H), 7.34-7.26(m,1H), 1.92(s,3H), 1.89(s,3H).

MS-ESI计算值[M+H] +300和302，实测值300和302。 MS-ESI calculated [M+H] + 300 and 302, found 300 and 302.

第二步second step

2-(二甲基氨基)-1-[6-[[4-(2-二甲基磷酰基苯氨基)-5-氟-嘧啶-2-基]氨基]-5-甲氧基-吲哚-1-基]乙酮根据实施例1中第四步方法，将对甲氧基苯胺替换为1-(6-氨基-5-甲氧基吲哚-1-基)-2-(甲基氨基)乙酮，得到2-(二甲基氨基)-1-[6-[[4-(2-二甲基磷酰基苯氨基)-5-氟-嘧啶-2-基]氨基]-5-甲氧基-吲哚-1-基]乙酮(22.0mg)，产率：19.1％。 1H NMR:(400MHz,CD 3OD)δ8.48(d，J＝7.6Hz,1H),8.31(s,1H),8.04(d，J＝4.8Hz,1H),7.67(dd，J＝7.6,13.8Hz,1H),7.48(t，J＝8.0Hz,1H),7.38-7.32(m,1H),7.17(s,1H),4.34(s,2H),4.15(t，J＝8.4Hz,2H),3.87(s,3H),3.40-3.37(m,2H),3.00(s,6H),1.94(s,3H),1.91(s,3H). 2-(Dimethylamino)-1-[6-[[4-(2-dimethylphosphorylanilino)-5-fluoro-pyrimidin-2-yl]amino]-5-methoxy-indium Indol-1-yl]ethanone According to the fourth step method in Example 1, p-methoxyaniline was replaced with 1-(6-amino-5-methoxyindol-1-yl)-2-(methyl ylamino)ethanone to give 2-(dimethylamino)-1-[6-[[4-(2-dimethylphosphorylanilino)-5-fluoro-pyrimidin-2-yl]amino]- 5-Methoxy-indol-1-yl]ethanone (22.0 mg), yield: 19.1%. 1 H NMR: (400 MHz, CD 3 OD) δ 8.48 (d, J=7.6 Hz, 1H), 8.31 (s, 1H), 8.04 (d, J=4.8 Hz, 1H), 7.67 (dd, J= 7.6, 13.8Hz, 1H), 7.48(t, J=8.0Hz, 1H), 7.38-7.32(m, 1H), 7.17(s, 1H), 4.34(s, 2H), 4.15(t, J=8.4 Hz, 2H), 3.87(s, 3H), 3.40-3.37(m, 2H), 3.00(s, 6H), 1.94(s, 3H), 1.91(s, 3H).

MS-ESI计算值[M+H] +513，实测值513。 MS-ESI calculated [M+H] + 513, found 513.

实施例55Example 55

1-[6-[[5-氯-4-(2-二甲基磷酰基苯胺)嘧啶-2-基]氨基]-5-甲氧基-二氢吲哚-1-基]-2-(二甲氨基)乙酰基1-[6-[[5-Chloro-4-(2-dimethylphosphoranilide)pyrimidin-2-yl]amino]-5-methoxy-indoline-1-yl]-2- (Dimethylamino)acetyl

Figure PCTCN2022082343-appb-000110
Figure PCTCN2022082343-appb-000110

第一步first step

5-甲氧基二氢吲哚5-Methoxyindoline

0℃下向5-甲氧基吲哚(40.00g,0.272mol)的乙酸(200mL)溶液中分批加入氰基硼氢化钠(34.16g,0.544mol)，并在20℃下搅拌4小时，反应完全后，向反应液中加入20％的氢氧化钠溶液调节pH至13，然后向其中加入乙酸乙酯(300mL)，分液，水相用乙酸乙酯(300.00mL×2)萃取，合并有机相经无水硫酸钠干燥、过滤、减压浓缩，再经色谱硅胶柱(0-25％乙酸乙酯/石油醚)分离纯化得到5-甲氧基二氢吲哚(25.00g,淡黄色油状物)，产率：62％。 1H NMR:(400MHz,CDCl 3)δ6.77(s,1H),6.61-6.60(m,2H),3.76(s,3H),3.54(t,J＝8.0Hz,2H),3.02(t,J＝8.0Hz,2H). To a solution of 5-methoxyindole (40.00 g, 0.272 mol) in acetic acid (200 mL) at 0 °C was added sodium cyanoborohydride (34.16 g, 0.544 mol) in portions, and stirred at 20 °C for 4 hours, After the reaction was completed, 20% sodium hydroxide solution was added to the reaction solution to adjust the pH to 13, then ethyl acetate (300 mL) was added to it, the liquid was separated, the aqueous phase was extracted with ethyl acetate (300.00 mL×2), and the combined The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (0-25% ethyl acetate/petroleum ether) to obtain 5-methoxyindoline (25.00 g, pale yellow). oil), yield: 62%. 1 H NMR: (400MHz, CDCl 3 ) δ 6.77(s, 1H), 6.61-6.60(m, 2H), 3.76(s, 3H), 3.54(t, J=8.0Hz, 2H), 3.02(t ,J=8.0Hz,2H).

第二步second step

2-(二甲氨基)-1-(5-甲氧基二氢吲哚-1-基)乙酰基(盐酸盐)2-(Dimethylamino)-1-(5-methoxyindoline-1-yl)acetyl (hydrochloride)

室温条件下，向5-甲氧基二氢吲哚(25.00g,0.168mol)的二氯甲烷(500mL)溶液中加入2-二甲胺乙酸(25.92g,0.251mol)，PyBOP(139.52g,0.268mol)和二异丙基乙胺(64.97g,0.503mol)并在20℃下搅拌10小时，反应完全后，向反应液中加入2N的盐酸(120mL)，并搅拌30分钟(pH＝3)，此时析出大量的白色固体，过滤，干燥得2-(二甲氨基)-1-(5-甲氧基二氢吲哚-1-基)乙酰基(盐酸盐)(40.00g,白色固体)，产率：88％。 1H NMR:(400MHz,CDCl 3)δ8.06-8.03(m,1H),6.87(s,1H),6.76-6.75(m,1H),4.26(s,2H),4.08-4.04(m,2H),3.78(s,3H),3.26-3.22(m,2H),3.01(s,6H). At room temperature, to a solution of 5-methoxyindoline (25.00g, 0.168mol) in dichloromethane (500mL) was added 2-dimethylaminoacetic acid (25.92g, 0.251mol), PyBOP (139.52g, 0.268mol) and diisopropylethylamine (64.97g, 0.503mol) and stirred at 20°C for 10 hours. After the reaction was completed, 2N hydrochloric acid (120mL) was added to the reaction solution and stirred for 30 minutes (pH=3 ), a large amount of white solid was precipitated at this time, filtered and dried to obtain 2-(dimethylamino)-1-(5-methoxyindoline-1-yl)acetyl (hydrochloride) (40.00g, white solid), yield: 88%. 1 H NMR: (400MHz, CDCl 3 ) δ 8.06-8.03(m, 1H), 6.87(s, 1H), 6.76-6.75(m, 1H), 4.26(s, 2H), 4.08-4.04(m, 2H), 3.78(s, 3H), 3.26-3.22(m, 2H), 3.01(s, 6H).

第三步third step

2-(二甲氨基)-1-(5-甲氧基-6-硝基-二氢吲哚-1-基)乙酰基2-(Dimethylamino)-1-(5-methoxy-6-nitro-indoline-1-yl)acetyl

0℃下向硝酸钠(13.81g,0.163mol)的三氟乙酸(100mL)溶液中加入2-(二甲氨基)-1-(5-甲氧基二氢吲哚-1-基)乙酰基(盐酸盐)(40.00g,0.148mol)的三氟乙酸(100mL)溶液，并在0℃下搅拌1.5小时，反应完全后，向反应液中加入2N的氢氧化钠溶液调节pH至11(过程中保证温度在10℃以下)，此时析出大量的黄色固体,过滤，干燥得2-(二甲氨基)-1-(5-甲氧基-6-硝基-二氢吲哚-1-基)乙酰基(36.00g,黄色固体)，产率：87％。 1H NMR:(400MHz,CDCl 3)δ8.70(s,1H),6.93(s,1H),4.26(t,J＝8.0Hz,2H),3.93(s,3H),3.26(t,J＝8.0Hz,2H),3.20(s,2H),2.37(s,6H). To a solution of sodium nitrate (13.81 g, 0.163 mol) in trifluoroacetic acid (100 mL) at 0°C was added 2-(dimethylamino)-1-(5-methoxyindoline-1-yl)acetyl (hydrochloride) (40.00 g, 0.148 mol) in trifluoroacetic acid (100 mL), and stirred at 0 °C for 1.5 hours. After the reaction was completed, 2N sodium hydroxide solution was added to the reaction solution to adjust the pH to 11 ( During the process, ensure that the temperature is below 10 ° C), at this time, a large amount of yellow solid is precipitated, filtered and dried to obtain 2-(dimethylamino)-1-(5-methoxy-6-nitro-indoline-1 -yl)acetyl (36.00 g, yellow solid), yield: 87%. 1 H NMR: (400 MHz, CDCl 3 ) δ 8.70 (s, 1H), 6.93 (s, 1H), 4.26 (t, J=8.0 Hz, 2H), 3.93 (s, 3H), 3.26 (t, J =8.0Hz, 2H), 3.20(s, 2H), 2.37(s, 6H).

第四步the fourth step

1-(6-氨基-5-甲氧基-二氢吲哚-1-基)-2-(二甲氨基)乙酰基1-(6-Amino-5-methoxy-indoline-1-yl)-2-(dimethylamino)acetyl

将2-(二甲氨基)-1-(5-甲氧基-6-硝基-二氢吲哚-1-基)乙酰基(5.00g,17.90mmol)溶于乙酸乙酯(100mL)和甲醇(15mL)中，向反应液中加入湿钯碳(10％,600mg)。反应液在20℃氢气(50psi)氛围下反应4小时。反应液过滤，滤液减压浓缩得到黄色固体，用少量乙酸乙酯冲洗，得到1-(6-氨基-5-甲氧基-二氢吲哚-1-基)-2-(二甲氨基)乙酰基(2.50g,淡黄色固体)，产率：56％。 1H NMR:(400MHz,CDCl 3)δ7.68(s,1H),6.62(s,1H),4.01(t,J＝8.0Hz,2H),3.79(s,3H),3.17(s,2H),3.06(t,J＝8.0Hz,2H),2.36(s,6H). 2-(Dimethylamino)-1-(5-methoxy-6-nitro-indoline-1-yl)acetyl (5.00 g, 17.90 mmol) was dissolved in ethyl acetate (100 mL) and In methanol (15 mL), wet palladium on carbon (10%, 600 mg) was added to the reaction solution. The reaction solution was reacted under a hydrogen (50 psi) atmosphere at 20°C for 4 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 1-(6-amino-5-methoxy-indoline-1-yl)-2-(dimethylamino) Acetyl (2.50 g, pale yellow solid), yield: 56%. 1 H NMR: (400 MHz, CDCl 3 ) δ 7.68 (s, 1H), 6.62 (s, 1H), 4.01 (t, J=8.0 Hz, 2H), 3.79 (s, 3H), 3.17 (s, 2H) ), 3.06(t, J=8.0Hz, 2H), 2.36(s, 6H).

第五步the fifth step

1-[6-[[5-氯-4-(2-二甲基磷酰基苯胺)嘧啶-2-基]氨基]-5-甲氧基-二氢吲哚-1-基]-2-(二甲氨基)乙酰基根据实施例1中第四步方法，将对甲氧基苯胺替换为1-(6-氨基-5-甲氧基-二氢吲哚-1-基)-2-(二甲氨基)乙酰基，得到1-[6-[[5-氯-4-(2-二甲基磷酰基苯胺)嘧啶-2-基]氨基]-5-甲氧基-二氢吲哚-1-基]-2-(二甲氨基)乙酰基(45.00mg)，产率：13％。 1H NMR:(400MHz,CD 3OD)δ8.33-8.29(m,1H),8.20(s,1H),8.11(s, 1H),7.68-7.63(m,1H),7.46-7.42(m,1H),7.38-7.34(m,1H),7.16(s,1H),4.34(s,2H),4.14(t,J＝8.0Hz,2H),3.85(s,3H),3.36(t,J＝8.0Hz,2H),2.99(s,6H),1.92(s,3H),1.88(s,3H). 1-[6-[[5-Chloro-4-(2-dimethylphosphoranilide)pyrimidin-2-yl]amino]-5-methoxy-indoline-1-yl]-2- (Dimethylamino)Acetyl According to the fourth step method in Example 1, p-methoxyaniline is replaced with 1-(6-amino-5-methoxy-indoline-1-yl)-2- (Dimethylamino)acetyl to give 1-[6-[[5-chloro-4-(2-dimethylphosphoranilide)pyrimidin-2-yl]amino]-5-methoxy-indoline Indol-1-yl]-2-(dimethylamino)acetyl (45.00 mg), yield: 13%. 1 H NMR: (400MHz, CD 3 OD) δ 8.33-8.29(m, 1H), 8.20(s, 1H), 8.11(s, 1H), 7.68-7.63(m, 1H), 7.46-7.42(m ,1H),7.38-7.34(m,1H),7.16(s,1H),4.34(s,2H),4.14(t,J=8.0Hz,2H),3.85(s,3H),3.36(t, J=8.0Hz, 2H), 2.99(s, 6H), 1.92(s, 3H), 1.88(s, 3H).

MS-ESI计算值[M+H] +529；531，实测值529；531。 MS-ESI calculated [M+H] + 529; 531, found 529; 531.

实施例56Example 56

5-[[5-氯-4-(2-二甲基磷酰基苯胺)嘧啶-2-基]氨基]-6-甲基-1,3-二氢苯并咪唑-2-羰基5-[[5-Chloro-4-(2-dimethylphosphorylanilide)pyrimidin-2-yl]amino]-6-methyl-1,3-dihydrobenzimidazole-2-carbonyl

Figure PCTCN2022082343-appb-000111
Figure PCTCN2022082343-appb-000111

根据实施例1中第四步方法，将对甲氧基苯胺替换为5-氨基-6-甲基-1,3-二氢苯并咪唑-2-羰基，得到5-[[5-氯-4-(2-二甲基磷酰基苯胺)嘧啶-2-基]氨基]-6-甲基-1,3-二氢苯并咪唑-2-羰基(7.00mg)，产率：7.2％。 1H NMR:(400MHz,CD3OD)δ8.21-7.78(m,2H),7.76-7.69(m,2H),7.37(br.s.,1H),7.06-7.04(m,2H),2.28(s,3H),1.90-1.87(m,6H). According to the fourth step method in Example 1, p-methoxyaniline was replaced with 5-amino-6-methyl-1,3-dihydrobenzimidazole-2-carbonyl to obtain 5-[[5-chloro- 4-(2-Dimethylphosphorylanilino)pyrimidin-2-yl]amino]-6-methyl-1,3-dihydrobenzimidazole-2-carbonyl (7.00 mg), yield: 7.2%. 1 H NMR:(400MHz,CD3OD)δ8.21-7.78(m,2H),7.76-7.69(m,2H),7.37(br.s.,1H),7.06-7.04(m,2H),2.28( s,3H),1.90-1.87(m,6H).

MS-ESI计算值[M+H] +443和445，实测值443和445。 MS-ESI calculated [M+H] + 443 and 445, found 443 and 445.

实施例57Example 57

6-[[5-氯-4-(2-二甲基磷酰基苯胺)嘧啶-2-基]氨基]-2,3-二氢酞嗪-1,4-二羰基6-[[5-Chloro-4-(2-dimethylphosphorylanilide)pyrimidin-2-yl]amino]-2,3-dihydrophthalazine-1,4-dicarbonyl

Figure PCTCN2022082343-appb-000112
Figure PCTCN2022082343-appb-000112

根据实施例1中第四步方法，将对甲氧基苯胺替换为6-氨基-2,3-二氢酞嗪-1,4-二酮，得到6-[[5-氯-4-(2-二甲基磷酰基苯胺)嘧啶-2-基]氨基]-2,3-二氢酞嗪-1,4-二羰基(3.60mg)，产率：3.8％。 1H NMR:(400MHz,CD 3OD)δ8.29(s,1H),8.15-8.09(m,3H),7.95-7.92(m,1H),7.72-7.67(m,1H),7.55-7.52(m,1H),7.44-7.40(m,1H),1.89(s,3H),1.86(s,3H). According to the fourth step method in Example 1, p-methoxyaniline was replaced with 6-amino-2,3-dihydrophthalazine-1,4-dione to obtain 6-[[5-chloro-4-( 2-Dimethylphosphorylanilide)pyrimidin-2-yl]amino]-2,3-dihydrophthalazine-1,4-dicarbonyl (3.60 mg), yield: 3.8%. 1 H NMR: (400MHz, CD 3 OD) δ 8.29 (s, 1H), 8.15-8.09 (m, 3H), 7.95-7.92 (m, 1H), 7.72-7.67 (m, 1H), 7.55-7.52 (m,1H),7.44-7.40(m,1H),1.89(s,3H),1.86(s,3H).

MS-ESI计算值[M+H] +457和459，实测值457和459。 MS-ESI calculated [M+H] + 457 and 459, found 457 and 459.

实施例58Example 58

N5-[5-氯-4-(2-二甲基磷酰基苯胺)嘧啶-2-基]-N,N-二甲基-1氢-苯并咪唑-2,5-二胺N5-[5-Chloro-4-(2-dimethylphosphorylanilide)pyrimidin-2-yl]-N,N-dimethyl-1hydro-benzimidazole-2,5-diamine

Figure PCTCN2022082343-appb-000113
Figure PCTCN2022082343-appb-000113

根据实施例1中第四步方法，将对甲氧基苯胺替换为N,N-二甲基-1H-苯并咪唑-2,5-二胺，得到N5-[5-氯-4-(2-二甲基磷酰基苯胺)嘧啶-2-基]-N,N-二甲基-1氢-苯并咪唑-2,5-二胺(14.00mg,)，产率：12％。 1H NMR:(400MHz,CD 3OD):：δ8.01(s,1H),7.79(br.s.,1H),7.61-7.59(m,1H),7.45-7.34(m,2H),7.21- 7.18(m,2H),7.13-7.11(m,1H),3.20(s,6H),1.78(s,3H),1.74(s,3H). According to the fourth step method in Example 1, p-methoxyaniline is replaced with N,N-dimethyl-1H-benzimidazole-2,5-diamine to obtain N5-[5-chloro-4-( 2-Dimethylphosphorylanilide)pyrimidin-2-yl]-N,N-dimethyl-lhydro-benzimidazole-2,5-diamine (14.00 mg, ), yield: 12%. 1 H NMR: (400MHz, CD 3 OD):: δ 8.01(s, 1H), 7.79(br.s., 1H), 7.61-7.59(m, 1H), 7.45-7.34(m, 2H), 7.21- 7.18(m, 2H), 7.13-7.11(m, 1H), 3.20(s, 6H), 1.78(s, 3H), 1.74(s, 3H).

MS-ESI计算值[M+H] +456；458，实测值456；458。 MS-ESI calculated [M+H] + 456; 458, found 456; 458.

实施例59Example 59

4-[[5-氯-4-(2-二甲基磷酰基苯胺)嘧啶-2-基]氨基]异吲哚啉4-[[5-Chloro-4-(2-dimethylphosphorylanilide)pyrimidin-2-yl]amino]isoindoline

Figure PCTCN2022082343-appb-000114
Figure PCTCN2022082343-appb-000114

根据实施例1中第四步方法，将对甲氧基苯胺替换为4-氨基异吲哚啉，得到4-[[5-氯-4-(2-二甲基磷酰基苯胺)嘧啶-2-基]氨基]异吲哚啉(17.0mg)，产率：19％。 1H NMR:(400MHz,CD 3OD)δ8.21(s,1H),7.93(br.s.,1H),7.82-7.80(m,1H),7.68-7.59(m,3H),7.34-7.33(m,2H),4.38(s,2H),1.86(s,3H),1.83(s,3H). According to the fourth step method in Example 1, p-methoxyaniline was replaced with 4-aminoisoindoline to obtain 4-[[5-chloro-4-(2-dimethylphosphorylanilide)pyrimidine-2 -yl]amino]isoindoline (17.0 mg), yield: 19%. 1 H NMR: (400MHz, CD 3 OD) δ 8.21(s, 1H), 7.93(br.s., 1H), 7.82-7.80(m, 1H), 7.68-7.59(m, 3H), 7.34- 7.33(m, 2H), 4.38(s, 2H), 1.86(s, 3H), 1.83(s, 3H).

MS-ESI计算值[M+H] +428和430，实测值428和430。 MS-ESI calculated [M+H] + 428 and 430, found 428 and 430.

实施例60Example 60

6-((5-氯-4-((2-(二甲基磷酰基)苯基)氨基)嘧啶-2-基)氨基)苯并[b]噻吩-1,1-二氧化物6-((5-Chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)benzo[b]thiophene-1,1-dioxide

Figure PCTCN2022082343-appb-000115
Figure PCTCN2022082343-appb-000115

根据实施例1中第四步方法，将对甲氧基苯胺替换为6-氨基苯并[b]噻吩-1,1-二氧化物，得到6-((5-氯-4-((2-(二甲基磷酰基)苯基)氨基)嘧啶-2-基)氨基)苯并[b]噻吩-1,1-二氧化物(20.0mg)，产率：27％。 1H NMR:(400MHz,CD 3OD)δ8.29(s,1H),8.11-8.10(m,1H),7.98(s,1H),7.74-7.71(m,2H),7.60-7.57(m,1H),7.49-7.45(m,3H),7.01-6.99(m,1H),1.91-1.88(m,6H). According to the fourth step method in Example 1, p-methoxyaniline was replaced with 6-aminobenzo[b]thiophene-1,1-dioxide to obtain 6-((5-chloro-4-(((2 -(Dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)benzo[b]thiophene-1,1-dioxide (20.0 mg), yield: 27%. 1 H NMR: (400MHz, CD 3 OD) δ 8.29(s, 1H), 8.11-8.10(m, 1H), 7.98(s, 1H), 7.74-7.71(m, 2H), 7.60-7.57(m ,1H),7.49-7.45(m,3H),7.01-6.99(m,1H),1.91-1.88(m,6H).

MS-ESI计算值[M+H] +461和463，实测值461和463。 MS-ESI calculated [M+H] + 461 and 463, found 461 and 463.

实施例61Example 61

(2-((5-氯-2-((2-甲基苯并[d]噻唑-5-基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧化膦(2-((5-Chloro-2-((2-methylbenzo[d]thiazol-5-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

Figure PCTCN2022082343-appb-000116
Figure PCTCN2022082343-appb-000116

根据实施例1中第四步方法，将对甲氧基苯胺替换为2-甲基苯并[d]噻唑-5-胺，得到(2-((5-氯-2-((2-甲基苯并[d]噻唑-5-基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧化膦(30.0mg)，产率：43％。 1H NMR:(400MHz,CD 3OD)δ8.31(s,1H),8.17-8.15(m,2H),8.05(s,1H),7.78-7.69(m,2H),7.48-7.43(m,2H),3.11(s,3H),1.92-1.88(m,6H). According to the fourth step method in Example 1, p-methoxyaniline was replaced with 2-methylbenzo[d]thiazol-5-amine to obtain (2-((5-chloro-2-(((2-methyl) ylbenzo[d]thiazol-5-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (30.0 mg), yield: 43%. 1 H NMR: (400MHz, CD 3 OD) δ 8.31(s, 1H), 8.17-8.15(m, 2H), 8.05(s, 1H), 7.78-7.69(m, 2H), 7.48-7.43(m ,2H),3.11(s,3H),1.92-1.88(m,6H).

MS-ESI计算值[M+H] +444和446，实测值444和446。 MS-ESI calculated [M+H] + 444 and 446, found 444 and 446.

实施例62Example 62

(2-((5-氯-2-((1-甲基-1H-吲唑-6-基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧化膦2-甲基苯并[d]噻唑-5-胺(2-((5-Chloro-2-((1-methyl-1H-indazol-6-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide 2-methylbenzene [d]thiazol-5-amine

Figure PCTCN2022082343-appb-000117
Figure PCTCN2022082343-appb-000117

根据实施例1中第四步方法，将对甲氧基苯胺替换为1-甲基-1H-吲唑-6-胺，得到(2-((5-氯-2-((1-甲基-1H-吲唑-6-基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧化膦2-甲基苯并[d]噻唑-5-胺(21.0mg)，产率：31％。 1H NMR:(400MHz,CD 3OD)δ8.28-8.27(m,1H),8.22(s,1H),8.11(s,1H),7.86-7.84(m,1H),7.73-7.68(m,2H),7.40-7.38(m,2H),7.23-7.21(m,1H),3.97(s,3H),1.92-1.88(m,6H). According to the fourth step method in Example 1, p-methoxyaniline was replaced with 1-methyl-1H-indazol-6-amine to obtain (2-((5-chloro-2-(((1-methyl) -1H-Indazol-6-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide 2-methylbenzo[d]thiazol-5-amine (21.0 mg), yield: 31%. 1 H NMR: (400MHz, CD 3 OD) δ 8.28-8.27(m, 1H), 8.22(s, 1H), 8.11(s, 1H), 7.86-7.84(m, 1H), 7.73-7.68(m ,2H),7.40-7.38(m,2H),7.23-7.21(m,1H),3.97(s,3H),1.92-1.88(m,6H).

MS-ESI计算值[M+H] +427和429，实测值427和429。 MS-ESI calculated [M+H] + 427 and 429, found 427 and 429.

实施例63Example 63

5-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-2-甲基异-1-酮5-((5-Chloro-4-((2-(dimethylphosphono)phenyl)amino)pyrimidin-2-yl)amino)-2-methyliso-1-one

Figure PCTCN2022082343-appb-000118
Figure PCTCN2022082343-appb-000118

根据实施例1中第四步方法，将对甲氧基苯胺替换为5-氨基-2-甲基异-1-酮，得到5-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-2-甲基异-1-酮(25.0mg)，产率：29％。 1HNMR:(400MHz,CD 3OD)δ8.38-8.35(m,1H),8.18(s,1H),7.96(s,1H),7.72-7.65(m,2H),7.60-7.55(m,2H),7.40-7.39(m,1H),4.38(s,2H),3.20(s,3H),1.88(s,3H),1.84(s,3H). According to the fourth step method in Example 1, p-methoxyaniline is replaced with 5-amino-2-methyl iso-1-one to obtain 5-((5-chloro-4-((2-(dimethyl (25.0 mg), yield: 29%. 1 HNMR: (400MHz, CD 3 OD) δ 8.38-8.35(m, 1H), 8.18(s, 1H), 7.96(s, 1H), 7.72-7.65(m, 2H), 7.60-7.55(m, 2H), 7.40-7.39(m, 1H), 4.38(s, 2H), 3.20(s, 3H), 1.88(s, 3H), 1.84(s, 3H).

MS-ESI计算值[M+H] +442和444，实测值442和444。 MS-ESI calculated [M+H] + 442 and 444, found 442 and 444.

实施例64Example 64

5-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-2-甲基异-1-酮5-((5-Chloro-4-((2-(dimethylphosphono)phenyl)amino)pyrimidin-2-yl)amino)-2-methyliso-1-one

Figure PCTCN2022082343-appb-000119
Figure PCTCN2022082343-appb-000119

根据实施例1中第四步方法，将对甲氧基苯胺替换为6-氨基-2-甲基异-1-酮，得到5-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-2-甲基异-1-酮(25.0mg)，产率：29％。 1HNMR:(400MHz,DMSO-d6)δ11.23(s,1H),9.62(s,1H),8.63(s,1H),8.25(s,1H),8.02-8.01(m,1H),7.82-7.81(m,1H),7.80-7.79(m,1H),7.61-7.57(m,1H),7.55-7.43(m,1H),7.19-7.17(m,1H),4.39(s,2H),3.07(s,3H),1.80(s,3H),1.77(s,3H). According to the fourth step method in Example 1, p-methoxyaniline is replaced with 6-amino-2-methyl iso-1-one to obtain 5-((5-chloro-4-((2-(dimethyl (25.0 mg), yield: 29%. 1 HNMR: (400MHz, DMSO-d6)δ11.23(s,1H), 9.62(s,1H), 8.63(s,1H), 8.25(s,1H), 8.02-8.01(m,1H), 7.82 -7.81(m,1H),7.80-7.79(m,1H),7.61-7.57(m,1H),7.55-7.43(m,1H),7.19-7.17(m,1H),4.39(s,2H) ,3.07(s,3H),1.80(s,3H),1.77(s,3H).

MS-ESI计算值[M+H] +442和444，实测值442和444。 MS-ESI calculated [M+H] + 442 and 444, found 442 and 444.

实施例65Example 65

4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-2-甲基异-1-酮4-((5-Chloro-4-((2-(dimethylphosphono)phenyl)amino)pyrimidin-2-yl)amino)-2-methyliso-1-one

Figure PCTCN2022082343-appb-000120
Figure PCTCN2022082343-appb-000120

根据实施例1中第四步方法，将对甲氧基苯胺替换为4-氨基-2-甲基异-1-酮，得到4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-2-甲基异-1-酮(25.0mg)，产率：29％。 1HNMR:(400MHz,CD 3OD)δ8.16-8.15(m,1H),8.10(s,1H),7.75-7.73(m,1H),7.57-7.55(m,2H),7.47-7.43(m,1H),7.29-7.28(m,1H),7.20-7.19(m,1H),4.40(s,2H),3.04(s,3H),1.85(s,3H),1.82(s,3H). According to the fourth step method in Example 1, p-methoxyaniline is replaced with 4-amino-2-methyliso-1-one to obtain 4-((5-chloro-4-(((2-(dimethylene) (25.0 mg), yield: 29%. 1 HNMR: (400MHz, CD3OD )δ8.16-8.15(m,1H), 8.10(s,1H), 7.75-7.73(m,1H), 7.57-7.55(m,2H), 7.47-7.43( m,1H),7.29-7.28(m,1H),7.20-7.19(m,1H),4.40(s,2H),3.04(s,3H),1.85(s,3H),1.82(s,3H) .

MS-ESI计算值[M+H] +442和444，实测值442和444。 MS-ESI calculated [M+H] + 442 and 444, found 442 and 444.

实施例67Example 67

5-氯-N4-(2-甲基磷酰基苯基)-N2-(2-甲基异吲哚啉-5-基)嘧啶-2,4-二胺5-Chloro-N4-(2-methylphosphorylphenyl)-N2-(2-methylisoindolin-5-yl)pyrimidine-2,4-diamine

Figure PCTCN2022082343-appb-000121
Figure PCTCN2022082343-appb-000121

第一步first step

2-甲基异吲哚啉-5-胺2-Methylisoindolin-5-amine

将四氢铝锂(198.14mg,5.22mmol)溶于四氢呋喃(10mL)中，然后在10摄氏度下向反应液中加入5-氨基-2-甲基-异吲哚啉-1,3-二酮(400mg,2.27mmol)的四氢呋喃(10mL)。反应液在80℃，搅拌3小时。反应完全后，在冰浴条件下，向反应液中缓慢的依次加入水(0.2mL)，15％NaOH水溶液(0.2mL)和水(0.6mL)，室温搅拌30分钟后过滤，滤液减压浓缩后用制备薄层色谱法分离纯化(乙酸乙酯，Rf＝0.1)分离纯化得到2-甲基异吲哚啉-5胺(100mg,黄色油状物)，产率：30％。 1H NMR:(400MHz,CD 3OD)δ6.97(d，J＝8.0Hz,1H),6.66-6.59(m,2H),3.82(d，J＝8.0Hz,4H),2.57(s,3H). 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. After the reaction was completed, water (0.2 mL), 15% NaOH aqueous solution (0.2 mL) and water (0.6 mL) were slowly added to the reaction solution under ice bath conditions, stirred at room temperature for 30 minutes, filtered, and the filtrate was concentrated under reduced pressure After separation and purification by preparative thin layer chromatography (ethyl acetate, Rf=0.1), 2-methylisoindolin-5amine (100 mg, yellow oil) was obtained, yield: 30%. 1 H NMR: (400 MHz, CD 3 OD) δ 6.97 (d, J=8.0 Hz, 1H), 6.66-6.59 (m, 2H), 3.82 (d, J=8.0 Hz, 4H), 2.57 (s, 3H).

MS-ESI计算值[M+H] +149，实测值149。 MS-ESI calculated [M+H] + 149, found 149.

第二步second step

5-氯-N4-(2-甲基磷酰基苯基)-N2-(2-甲基异吲哚啉-5-基)嘧啶-2,4-二胺5-Chloro-N4-(2-methylphosphorylphenyl)-N2-(2-methylisoindolin-5-yl)pyrimidine-2,4-diamine

根据实施例1中第四步方法，将对甲氧基苯胺替换为2-甲基异吲哚啉-5-胺，得到5-氯-N4-(2-甲基磷酰基苯基)-N2-(2-甲基异吲哚啉-5-基)嘧啶-2,4-二胺(12.0mg)，产率：16％。 1H NMR:(400MHz,CD3OD)δ8.25(s,1H),8.16(br.s,1H),7.78(dd，J＝7.6Hz,1H),7.69(t，J＝7.6Hz,1H),7.56-7.43(m,4H),4.85-4.82(m,2H),4.58-4.44(m,2H),3.17(s,3H),1.90(s,3H),1.87(s,3H). According to the fourth step method in Example 1, p-methoxyaniline was replaced with 2-methylisoindolin-5-amine to obtain 5-chloro-N4-(2-methylphosphorylphenyl)-N2 -(2-Methylisoindolin-5-yl)pyrimidine-2,4-diamine (12.0 mg), yield: 16%. 1 H NMR: (400MHz, CD3OD) δ 8.25 (s, 1H), 8.16 (br.s, 1H), 7.78 (dd, J=7.6Hz, 1H), 7.69 (t, J=7.6Hz, 1H) ,7.56-7.43(m,4H),4.85-4.82(m,2H),4.58-4.44(m,2H),3.17(s,3H),1.90(s,3H),1.87(s,3H).

MS-ESI计算值[M+H] +428和430，实测值428和430。 MS-ESI calculated [M+H] + 428 and 430, found 428 and 430.

实施例68Example 68

(2-((5-氯-2-((4-甲氧基苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧化膦(2-((5-Chloro-2-((4-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

Figure PCTCN2022082343-appb-000122
Figure PCTCN2022082343-appb-000122

根据实施例1中第四步方法，将对甲氧基苯胺替换为7-氨基—2,3-二氢-2-甲基-1H-异吲哚-1-酮，得到7-[[5-氯-4-(2-二甲基膦酰基苯胺基)嘧啶-2-基]氨基]-2-甲基-异吲哚-1-酮(33.0mg)，产率：43％。 1H NMR:(400MHz,CD 3OD)δ8.36(s,1H),8.07(br.s,1H),7.86-7.79(m,2H),7.72(t，J＝7.8Hz,1H),7.57(t，J＝6.8Hz,1H),7.35-7.31(m,1H),7.29-7.25(m,1H),4.48(s,2H),3.17(s,3H),1.89(s,3H),1.86(s,3H). According to the fourth step method in Example 1, p-methoxyaniline was replaced with 7-amino-2,3-dihydro-2-methyl-1H-isoindol-1-one to obtain 7-[[5 -Chloro-4-(2-dimethylphosphonoanilino)pyrimidin-2-yl]amino]-2-methyl-isoindol-1-one (33.0 mg), yield: 43%. 1 H NMR: (400MHz, CD 3 OD) δ 8.36 (s, 1H), 8.07 (br.s, 1H), 7.86-7.79 (m, 2H), 7.72 (t, J=7.8Hz, 1H), 7.57(t, J=6.8Hz, 1H), 7.35-7.31(m, 1H), 7.29-7.25(m, 1H), 4.48(s, 2H), 3.17(s, 3H), 1.89(s, 3H) ,1.86(s,3H).

MS-ESI计算值[M+H] +442和444，实测值442和444。 MS-ESI calculated [M+H] + 442 and 444, found 442 and 444.

实施例69Example 69

N2-(1,3-苯并二氧戊环-5-基)-5-氯-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺N2-(1,3-Benzodioxolan-5-yl)-5-chloro-N4-(2-dimethylphosphonoanilino)pyrimidine-2,4-diamine

Figure PCTCN2022082343-appb-000123
Figure PCTCN2022082343-appb-000123

根据实施例1中第四步方法，将对甲氧基苯胺替换为苯并[d][1,3]二氧杂环戊烯-5-胺，得到N2-(1,3-苯并二氧戊环-5-基)-5-氯-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺(26.0mg)，产率：36％。 1H NMR:(400MHz,CD 3OD)δ8.37(br.s,1H),8.10(br.s,1H),7.70(dd，J＝7.6,14.0Hz,1H),7.59(br.s,1H),7.45-7.39(m,1H),6.97(s,1H),6.92-6.88(m,1H),6.87-6.83(m,1H),6.05(s,2H),1.92(s,3H),1.89(s,3H).MS-ESI计算值[M+H] +417和419，实测值417和419。 According to the fourth step method in Example 1, p-methoxyaniline is replaced with benzo[d][1,3]dioxol-5-amine to obtain N2-(1,3-benzodiol Oxolan-5-yl)-5-chloro-N4-(2-dimethylphosphonoanilino)pyrimidine-2,4-diamine (26.0 mg), yield: 36%. 1 H NMR: (400 MHz, CD 3 OD) δ 8.37 (br.s, 1H), 8.10 (br.s, 1H), 7.70 (dd, J=7.6, 14.0 Hz, 1H), 7.59 (br.s ,1H),7.45-7.39(m,1H),6.97(s,1H),6.92-6.88(m,1H),6.87-6.83(m,1H),6.05(s,2H),1.92(s,3H ), 1.89 (s, 3H). MS-ESI calculated [M+H] + 417 and 419, found 417 and 419.

实施例70Example 70

5-氯-N2-(2,3-二氢-1,4-苯并二氧杂苯-6-基)-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺5-Chloro-N2-(2,3-dihydro-1,4-benzodioxan-6-yl)-N4-(2-dimethylphosphonoanilino)pyrimidine-2,4-di amine

Figure PCTCN2022082343-appb-000124
Figure PCTCN2022082343-appb-000124

根据实施例1中第四步方法，将对甲氧基苯胺替换为2,3-二氢苯并[b][1,4]二氧杂环己烯-6-胺，得到5-氯-N2-(2,3-二氢-1,4-苯并二氧杂苯-6-基)-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺(21.0mg)，产率：28％。 1H NMR:(400MHz,CD 3OD)δ8.38(br.s,1H),8.09(br.s,1H),7.73-7.67(m,1H),7.58-7.57(t，J＝7.2Hz,1H),7.45-7.39(m,1H),6.97(d，J＝2.4Hz,1H),6.93-6.87(m,1H),6.86-6.82(m,1H),4.29(s,4H),1.92(s,3H),1.89(s,3H). According to the fourth step method in Example 1, p-methoxyaniline was replaced with 2,3-dihydrobenzo[b][1,4]dioxene-6-amine to obtain 5-chloro- N2-(2,3-Dihydro-1,4-benzodioxan-6-yl)-N4-(2-dimethylphosphonoanilino)pyrimidine-2,4-diamine (21.0 mg ), yield: 28%. 1 H NMR: (400MHz, CD 3 OD) δ 8.38 (br.s, 1H), 8.09 (br.s, 1H), 7.73-7.67 (m, 1H), 7.58-7.57 (t, J=7.2Hz ,1H),7.45-7.39(m,1H),6.97(d,J=2.4Hz,1H),6.93-6.87(m,1H),6.86-6.82(m,1H),4.29(s,4H), 1.92(s, 3H), 1.89(s, 3H).

MS-ESI计算值[M+H] +431和433，实测值431和433。 MS-ESI calculated [M+H] + 431 and 433, found 431 and 433.

实施例71Example 71

5-氯-N2-(2,2-二氟-1,3-苯并二氧戊环-5-基)-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺5-Chloro-N2-(2,2-difluoro-1,3-benzodioxolan-5-yl)-N4-(2-dimethylphosphonoanilino)pyrimidine-2,4-di amine

Figure PCTCN2022082343-appb-000125
Figure PCTCN2022082343-appb-000125

根据实施例1中第四步方法，将对甲氧基苯胺替换为2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-胺，得到5-氯-N2-(2,2-二氟-1,3-苯并二氧戊环-5-基)-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺(10.0mg)，产率：36％。 1H NMR:(400MHz,CD3OD)δ8.38-8.36(m,1H),8.13(s,1H),7.70-7.67(m,3H),7.33-7.32(m,1H),7.15-7.13(m,1H),,7.08-7.04(m,1H),1.88(s,3H),1.85(s,3H). According to the fourth step method in Example 1, p-methoxyaniline was replaced with 2,2-difluorobenzo[d][1,3]dioxol-5-amine to obtain 5-chloro- N2-(2,2-Difluoro-1,3-benzodioxolan-5-yl)-N4-(2-dimethylphosphonoanilino)pyrimidine-2,4-diamine (10.0 mg ), yield: 36%. 1 H NMR: (400MHz, CD3OD)δ8.38-8.36(m,1H), 8.13(s,1H), 7.70-7.67(m,3H), 7.33-7.32(m,1H), 7.15-7.13(m ,1H),,7.08-7.04(m,1H),1.88(s,3H),1.85(s,3H).

MS-ESI计算值[M+H] +453和455，实测值453和455。 MS-ESI calculated [M+H] + 453 and 455, found 453 and 455.

实施例72Example 72

N2-(1,3-苯并二氧戊环-4-基)-5-氯-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺N2-(1,3-Benzodioxolan-4-yl)-5-chloro-N4-(2-dimethylphosphonoanilino)pyrimidine-2,4-diamine

Figure PCTCN2022082343-appb-000126
Figure PCTCN2022082343-appb-000126

根据实施例1中第四步方法，将对甲氧基苯胺替换为苯并[d][1,3]二氧杂环戊烯-4-胺，得到N2-(1,3-苯并二氧戊环-4-基)-5-氯-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺(20.0mg)，产率：28％。 1H NMR:(400MHz,CD 3OD)δ8.37(br.s,1H),8.17(s,1H),7.71-7.68(m,1H),7.53(br.s,1H),7.44-7.34(m,1H),6.98-6.86(m,3H),5.98(s,2H),1.92(s,3H),1.89(s,3H). According to the fourth step method in Example 1, p-methoxyaniline is replaced with benzo[d][1,3]dioxol-4-amine to obtain N2-(1,3-benzodiol Oxolan-4-yl)-5-chloro-N4-(2-dimethylphosphonoanilino)pyrimidine-2,4-diamine (20.0 mg), yield: 28%. 1 H NMR: (400MHz, CD 3 OD)δ8.37(br.s,1H),8.17(s,1H),7.71-7.68(m,1H),7.53(br.s,1H),7.44-7.34 (m,1H),6.98-6.86(m,3H),5.98(s,2H),1.92(s,3H),1.89(s,3H).

MS-ESI计算值[M+H] +417和419，实测值417和419。 MS-ESI calculated [M+H] + 417 and 419, found 417 and 419.

实施例73Example 73

N2-(1,3-苯并噁唑-5-基)-5-氯-N4-(2-二甲基磷酰基苯基)嘧啶-2,4-二胺N2-(1,3-Benzoxazol-5-yl)-5-chloro-N4-(2-dimethylphosphorylphenyl)pyrimidine-2,4-diamine

Figure PCTCN2022082343-appb-000127
Figure PCTCN2022082343-appb-000127

根据实施例1中第四步方法，将对甲氧基苯胺替换为苯并[d]恶唑-5-胺，得到N2-(1,3-苯并噁唑-5-基)-5-氯-N4-(2-二甲基磷酰基苯基)嘧啶-2,4-二胺(9.0mg)，产率：14％。 1H NMR:(400MHz,CD 3OD)δ8.51-8.48(m,1H),8.44(s,1H),8.15-8.04(m,2H),7.65-7.58(m,1H),7.57-7.52(m,3H),7.30-7.23(m,1H),1.89(s,3H),1.85(s,3H). According to the fourth step method in Example 1, p-methoxyaniline was replaced with benzo[d]oxazol-5-amine to obtain N2-(1,3-benzoxazol-5-yl)-5- Chloro-N4-(2-dimethylphosphorylphenyl)pyrimidine-2,4-diamine (9.0 mg), yield: 14%. 1 H NMR: (400 MHz, CD 3 OD) δ 8.51-8.48 (m, 1H), 8.44 (s, 1H), 8.15-8.04 (m, 2H), 7.65-7.58 (m, 1H), 7.57-7.52 (m,3H),7.30-7.23(m,1H),1.89(s,3H),1.85(s,3H).

MS-ESI计算值[M+H] +414和416，实测值414和416。 MS-ESI calculated [M+H] + 414 and 416, found 414 and 416.

实施例74Example 74

1-[6-[[5-氯-4-[(2-二甲基磷酰基苯基)甲氨基]嘧啶-2-基]氨基]-5-甲氧基-二氢吲哚-1-基]-2-(二甲氨基)乙酰基1-[6-[[5-Chloro-4-[(2-dimethylphosphorylphenyl)methylamino]pyrimidin-2-yl]amino]-5-methoxy-indoline-1- yl]-2-(dimethylamino)acetyl

Figure PCTCN2022082343-appb-000128
Figure PCTCN2022082343-appb-000128

第一步first step

2-二甲基磷酰基苯腈2-Dimethylphosphoryl benzonitrile

氮气条件下，将2-碘苯氰(300.0mg,1.31mmol)溶于无水二氧六环(5mL)中，向反应液中加入二甲基氧化磷(102.24mg,1.31mmol)，碳酸铯(0.854g,2.62mmol)，4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(7.6mg,0.013mmol)和三(二亚苄基丙酮)二钯(12.0mg,0.013mmol)，反应液在90℃下搅拌12小时。反应完全后，过滤，减压浓缩，向其中加入10mL水和10mL乙酸乙酯，水相经乙酸乙酯(10mL×3)萃取，有机相经无水硫酸钠干燥、过滤、减压浓缩后，将反应液浓缩，经硅胶柱色谱法(20-50％乙酸乙酯/石油醚)分离纯化得到2-二甲基磷酰基苯腈(90.0mg,白色固体)，产率：38％。 1H NMR:(400MHz,CDCl3)δ8.34-8.29(m,1H),7.83-7.79(m,2H),7.69-7.66(m,1H),1.99(s,3H),1.95(s,3H). Under nitrogen, 2-iodobenzonitrile (300.0 mg, 1.31 mmol) was dissolved in anhydrous dioxane (5 mL), and dimethyl phosphorus oxide (102.24 mg, 1.31 mmol) was added to the reaction solution, cesium carbonate (0.854g, 2.62mmol), 4,5-bis(diphenylphosphorus)-9,9-dimethylxanthene (7.6mg, 0.013mmol) and tris(dibenzylideneacetone)dipalladium (12.0 mg, 0.013 mmol), and the reaction solution was stirred at 90° C. for 12 hours. After the reaction is complete, filter and concentrate under reduced pressure, add 10 mL of water and 10 mL of ethyl acetate, the aqueous phase is extracted with ethyl acetate (10 mL×3), the organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, The reaction solution was concentrated, separated and purified by silica gel column chromatography (20-50% ethyl acetate/petroleum ether) to obtain 2-dimethylphosphoryl benzonitrile (90.0 mg, white solid), yield: 38%. 1 H NMR: (400MHz, CDCl3) δ 8.34-8.29(m, 1H), 7.83-7.79(m, 2H), 7.69-7.66(m, 1H), 1.99(s, 3H), 1.95(s, 3H) ).

第二步second step

2-二甲基磷酰基苄胺2-Dimethylphosphorylbenzylamine

将2-二甲基磷酰基苯腈(70.0mg,0.391mmol)溶于甲醇(10mL)中，向反应液中加入湿钯碳(10％,20mg)。反应液在20℃氢气(50psi)氛围下反应16小时。反应液过滤，滤液减压浓缩得到黄色固体，用少量乙酸乙酯冲洗，得到粗产物2-二甲基磷酰基苄胺(70.0mg,黄色固体)。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).

MS-ESI计算值[M+H] +184，实测值184。 MS-ESI calculated [M+H] + 184, found 184.

第三步third step

2,5-二氯-N-[(2-二甲基磷酰基苯基)甲基]嘧啶-4-胺2,5-Dichloro-N-[(2-dimethylphosphorylphenyl)methyl]pyrimidin-4-amine

室温条件下，向2,4,5-三氯嘧啶(0.105g,0.573mmol)的二氯甲烷(8mL)溶液中加入2-二甲基磷酰基苄胺(0.07g,0.382mmol)和三乙胺(0.097g,0.955mmol)并在20℃下搅拌16小时，反应完全后，用二氯甲烷(10.00mL×3)萃取，有机相经无水硫酸钠干燥、过滤、减压浓缩后，将反应液浓缩，经薄层色谱法(15/1二氯甲烷/甲醇)分离纯化得到2,5-二氯-N-[(2-二甲基磷酰基苯基)甲基]嘧啶-4-胺(0.1g,黄色固体，产率：66％)。To a solution of 2,4,5-trichloropyrimidine (0.105 g, 0.573 mmol) in dichloromethane (8 mL) was added 2-dimethylphosphorylbenzylamine (0.07 g, 0.382 mmol) and triethyl at room temperature Amine (0.097 g, 0.955 mmol) was stirred at 20 °C for 16 hours. After the reaction was complete, it was extracted with dichloromethane (10.00 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The 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%).

1H NMR:(400MHz,CDCl3)δ8.26-8.23(m,1H),7.93(s,1H),7.75-7.72(m,1H),7.55-7.52(m,1H),7.44-7.39(m,2H),4.97-4.95(m,2H),1.87(s,3H),1.84(s,3H). 1 H NMR: (400MHz, CDCl3) δ 8.26-8.23(m, 1H), 7.93(s, 1H), 7.75-7.72(m, 1H), 7.55-7.52(m, 1H), 7.44-7.39(m ,2H),4.97-4.95(m,2H),1.87(s,3H),1.84(s,3H).

第四步the fourth step

1-[6-[[5-氯-4-[(2-二甲基磷酰基苯基)甲氨基]嘧啶-2-基]氨基]-5-甲氧基-二氢吲哚-1-基]-2-(二甲氨基)乙酰基1-[6-[[5-Chloro-4-[(2-dimethylphosphorylphenyl)methylamino]pyrimidin-2-yl]amino]-5-methoxy-indoline-1- yl]-2-(dimethylamino)acetyl

将1-(6-氨基-5-甲氧基-吲哚-1-基)-2-(二甲氨基)乙酰基(75.51mg,0.303mmol)溶于叔丁醇(5mL)中，然后向反应液加入2,5-二氯-N-[(2-二甲基磷酰基苯基)甲基]嘧啶-4-胺(100.00mg,0.303mmol)和甲烷磺酸(87.33mg,0.909mmol)。反应液在90℃条件下搅拌16小时。反应液减压浓缩，剩余物经高效液相色谱法分离纯化得到1-[6-[[5-氯-4-[(2-二甲基磷酰基苯基)甲氨基]嘧啶-2-基]氨基]-5-甲氧基-二氢吲哚-1-基]-2-(二甲氨基)乙酰基(40.00mg)，产率：23％。 1H NMR:(400MHz,CD 3OD)δ8.91(br.s.,1H),8.01(s,1H),7.68-7.65(m,1H),7.46(s,3H),7.16(s,1H),5.25(s,2H),4.33(s,2H),4.17-4.12(m,2H),3.91(s,3H),3.35-3.33(m,2H),2.93(s,6H),1.94(s,3H),1.91(s,3H). 1-(6-Amino-5-methoxy-indol-1-yl)-2-(dimethylamino)acetyl (75.51 mg, 0.303 mmol) was dissolved in tert-butanol (5 mL) and added to The reaction solution was added with 2,5-dichloro-N-[(2-dimethylphosphorylphenyl)methyl]pyrimidin-4-amine (100.00 mg, 0.303 mmol) and methanesulfonic acid (87.33 mg, 0.909 mmol) . The reaction solution was stirred at 90°C for 16 hours. The 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%. 1 H NMR: (400MHz, CD 3 OD) δ 8.91(br.s., 1H), 8.01(s, 1H), 7.68-7.65(m, 1H), 7.46(s, 3H), 7.16(s, 1H), 5.25(s, 2H), 4.33(s, 2H), 4.17-4.12(m, 2H), 3.91(s, 3H), 3.35-3.33(m, 2H), 2.93(s, 6H), 1.94 (s,3H),1.91(s,3H).

MS-ESI计算值[M+H] +543和545，实测值543和545。 MS-ESI calculated [M+H] + 543 and 545, found 543 and 545.

实验例1：体外评价LRRK2激酶抑制活性Experimental Example 1: In vitro evaluation of LRRK2 kinase inhibitory activity

实验目的：通过均相时间分辨荧光检测磷酸化Fluorescein-ERM(LRRKtide)peptide的磷酸基团与

Figure PCTCN2022082343-appb-000129
Tb-pERM(pLRRKtide)Antibody抗体结合后产生的能量信号转移(520nM/485nM荧光信号比值)。计算待测化合物的LRRK2激酶抑制IC 50值。 Objective: To detect the phosphate group of phosphorylated Fluorescein-ERM(LRRKtide)peptide by homogeneous time-resolved fluorescence.
Figure PCTCN2022082343-appb-000129
Energy signal transfer after Tb-pERM(pLRRKtide) Antibody antibody binding (520nM/485nM fluorescence signal ratio). Calculate the LRRK2 kinase inhibition IC50 values of the test compounds.

实验材料:Experimental Materials:

1.反应溶液：10mM羟乙基哌嗪乙磺酸(PH7.5)；2mM氯化镁；0.5mM乙二醇二乙醚二胺四乙酸；0.002％聚氧乙烯脂肪醇醚；1mM二硫苏糖醇和1％DMSO；1. 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;

2.检测溶液：TR-FRET Dilution Buffer；2. Detection solution: TR-FRET Dilution Buffer;

3.LRRK2 Recombinant Human Protein：使用GST标签用杆状病毒在昆虫Sf9细胞中表达重组全长人LRRK2 Protein；.3. LRRK2 Recombinant Human Protein: express recombinant full-length human LRRK2 Protein in insect Sf9 cells with baculovirus using GST tag;.

4.底物：0.4uM Fluorescein-ERM(LRRKtide)peptide；57uM ATP。4. Substrate: 0.4uM Fluorescein-ERM (LRRKtide)peptide; 57uM ATP.

检测方法:Detection method:

均相时间分辨荧光技术(HTRF)；Homogeneous time-resolved fluorescence (HTRF);

Fluorescein-ERM(LRRKtide)peptide多肽与

Figure PCTCN2022082343-appb-000130
Tb-pERM(pLRRKtide)Antibody抗体在485nM和520nM之间的能量共振转移。 Fluorescein-ERM (LRRKtide) peptide with
Figure PCTCN2022082343-appb-000130
Energy resonance transfer of Tb-pERM(pLRRKtide) Antibody antibody between 485nM and 520nM.

实验操作:Experimental operation:

1.通过Echo550非接触式纳升级声波移液系统加入待测化合物的DMSO溶液；1. Add the DMSO solution of the compound to be tested through the Echo550 non-contact nano-liter sonic pipetting system;

2.用新鲜制备的反应溶液配置酶和多肽混合溶液，加入到反应孔穴中，室温下预温育20分钟；2. Prepare a mixed solution of enzyme and polypeptide with freshly prepared reaction solution, add it to the reaction hole, and pre-incubate it at room temperature for 20 minutes;

3.加入57uM ATP引发反应，室温反应90分钟；3. Add 57uM ATP to initiate the reaction, and react at room temperature for 90 minutes;

4.加入检测系统(Fluorescein-ERM(LRRKtide)peptide多肽，

Figure PCTCN2022082343-appb-000131
Tb-pERM(pLRRKtide)Antibody抗体及10mM乙二胺四乙酸)，室温反应60分钟，用Em/Ex 520/485检测荧光信号； 4. Add the detection system (Fluorescein-ERM (LRRKtide) peptide polypeptide,
Figure PCTCN2022082343-appb-000131
Tb-pERM (pLRRKtide) Antibody antibody and 10 mM ethylenediaminetetraacetic acid), react at room temperature for 60 minutes, and use Em/Ex 520/485 to detect the fluorescent signal;

5.通过信号比值计算相对DMSO空白的相对酶活性抑制，利用软件XLfit5拟合曲线计算IC 50值。 实验结果： 5. Calculate the relative enzyme activity inhibition relative to the DMSO blank by the signal ratio, and use the software XLfit5 to fit the curve to calculate the IC 50 value. Experimental results:

表1-LRRK2磷酸二酯酶抑制活性测试结果Table 1-LRRK2 phosphodiesterase inhibitory activity test results

供试品(各实施例所制得的化合物)Test sample (compound prepared in each example) LRRK2激酶抑制活性LRRK2 kinase inhibitory activity 化合物1Compound 1 ++++++ 化合物2Compound 2 ++++++ 化合物3Compound 3 ++++++ 化合物4Compound 4 ++++++ 化合物5Compound 5 ++++++ 化合物6Compound 6 ++++++ 化合物7Compound 7 ++++++ 化合物8Compound 8 ++++++ 化合物9Compound 9 ++++++ 化合物10Compound 10 ++++++ 化合物11Compound 11 ++++++ 化合物12Compound 12 ++++++ 化合物13Compound 13 ++++++ 化合物14Compound 14 ++++++ 化合物15Compound 15 ++++++ 化合物16Compound 16 ++++++ 化合物17Compound 17 ++++++ 化合物18Compound 18 ++++++ 化合物19Compound 19 ++++++ 化合物20Compound 20 ++++++ 化合物21Compound 21 ++++++ 化合物22Compound 22 ++++++ 化合物23Compound 23 ++++++ 化合物24Compound 24 ++++++ 化合物25Compound 25 ++++++ 化合物26Compound 26 ++++++ 化合物27Compound 27 ++++++ 化合物28Compound 28 ++++++ 化合物29Compound 29 ++++++ 化合物30Compound 30 ++++++ 化合物31Compound 31 ++ 化合物32Compound 32 ++ 化合物33Compound 33 ++++ 化合物34Compound 34 ++++++ 化合物35Compound 35 ++++++ 化合物36Compound 36 ++++++ 化合物37Compound 37 ++++

化合物38Compound 38 ++ 化合物39Compound 39 ++++++ 化合物40Compound 40 ++++++ 化合物41Compound 41 ++++++ 化合物42Compound 42 ++ 化合物43Compound 43 ++++++ 化合物44Compound 44 ++++++ 化合物45Compound 45 ++++++ 化合物46Compound 46 ++++++ 化合物47Compound 47 ++++++ 化合物48Compound 48 ++++++ 化合物49Compound 49 ++++++ 化合物50Compound 50 ++++++ 化合物51Compound 51 ++++++ 化合物52Compound 52 ++++++ 化合物53Compound 53 ++++++ 化合物54Compound 54 ++++ 化合物55Compound 55 ++++++ 化合物56Compound 56 ++++++ 化合物57Compound 57 ++++++ 化合物58Compound 58 ++++++ 化合物59Compound 59 ++++++ 化合物60Compound 60 ++++++ 化合物61Compound 61 ++++++ 化合物62Compound 62 ++++++ 化合物63Compound 63 ++++++ 化合物64Compound 64 ++++++ 化合物65Compound 65 ++++++ 化合物67Compound 67 ++++++ 化合物68Compound 68 ++++ 化合物69Compound 69 ++++++ 化合物70Compound 70 ++++++ 化合物71Compound 71 ++++ 化合物72Compound 72 ++++++ 化合物73Compound 73 ++++++ 化合物74Compound 74 ++

注：100nM≦“+”＜1000nM；10nM≦“++”＜100nM；1nM≦“+++”＜10nM；Note: 100nM≦“+”＜1000nM; 10nM≦“++”＜100nM; 1nM≦“+++”＜10nM;

结论：本发明化合物具有显著甚至意料不到的LRRK2激酶抑制活性。Conclusion: The compounds of the present invention have significant and even unexpected LRRK2 kinase inhibitory activity.

Claims (24)

式(Ⅰ)所示化合物、其药学上可接受的盐，A compound represented by formula (I), or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022082343-appb-100001
Figure PCTCN2022082343-appb-100001
 其中，in, W选自
Figure PCTCN2022082343-appb-100002
W is selected from
Figure PCTCN2022082343-appb-100002
 L选自单键和-CH 2-； L is selected from a single bond and -CH 2 -; R 1和R 2分别独立地选自H、F、Cl、Br、I、OH、CN、NH 2和COOH，或分别独立地选自任选被1、2或3个R取代的：C 1-6烷基、C 1-6杂烷基、4～6元杂环烷基和R a-L 1-，且R 1、R 2不选自：
Figure PCTCN2022082343-appb-100003
Figure PCTCN2022082343-appb-100004
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:
Figure PCTCN2022082343-appb-100003
Figure PCTCN2022082343-appb-100004
 R a选自H、苯基、5～6元杂芳基、C 4-6环烷基和4～6元杂环烷基； R a is selected from H, phenyl, 5-6 membered heteroaryl, C 4-6 cycloalkyl and 4-6 membered heterocycloalkyl; L 1选自-C(＝O)-、-C(＝O)NH-、-S(＝O)-、-S(＝O) 2-、-CH 2-和-CH 2CH 2-； L 1 is selected from -C(=O)-, -C(=O)NH-, -S(=O)-, -S(=O) 2 -, -CH 2 - and -CH 2 CH 2 -; 或者，R 1与R 2连接在一起，结构单元
Figure PCTCN2022082343-appb-100005
选自任选被1、2或3个R取代的
Figure PCTCN2022082343-appb-100006
Alternatively, R 1 and R 2 are linked together, building blocks
Figure PCTCN2022082343-appb-100005
is selected from optionally substituted with 1, 2 or 3 R
Figure PCTCN2022082343-appb-100006
 或者，R 1与
Figure PCTCN2022082343-appb-100007
连接在一起，结构单元
Figure PCTCN2022082343-appb-100008
选自任选被1、2或3个R取代的：
Figure PCTCN2022082343-appb-100009
Alternatively, R 1 with
Figure PCTCN2022082343-appb-100007
connected together, structural units
Figure PCTCN2022082343-appb-100008
Selected from optionally substituted with 1, 2 or 3 Rs:
Figure PCTCN2022082343-appb-100009
 R 3选自F、Cl、Br、I、OH、CN、CF 3和NH 2； R 3 is selected from F, Cl, Br, I, OH, CN, CF 3 and NH 2 ; R 4分别独立地分别独立地选自H、F、Cl、Br和I； R 4 are each independently independently selected from H, F, Cl, Br and I; R 5和R 6分别独立地选自H、卤素、OH、CN、NH 2、NO 2、COOH和R b-L 2-L 3-L 4-，或分别独立地选自任选被1、2或3个R取代的：C 1-6烷基、C 1-6杂烷基、C 4-6环烷基、4～6元杂环烷基、苯基和5～6元杂芳基，且R 5和R 6不选自任选被1、2或3个卤素取代的
Figure PCTCN2022082343-appb-100010
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
Figure PCTCN2022082343-appb-100010
 R b选自H、卤素、OH、CN、NH 2、NO 2、COOH，或选自任选被1、2或3个R取代的：C 1-6烷基、C 1- 6杂烷基、C 4-6环烷基、4～6元杂环烷基和5～6元杂芳基； 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; L 2、L 3和L 4分别独立地选自单键、O、S、NH、-C(＝O)-、-C(＝O)NH-、-S(＝O)-、-S(＝O) 2-、-(CH 2) 1-3-、苯基、5～6元杂芳基和4～6元杂环烷基，且L 2、L 3和L 4不同时选自单键； L 2 , L 3 and L 4 are each independently selected from single bond, O, S, NH, -C(=O)-, -C(=O)NH-, -S(=O)-, -S( =O) 2 -, -(CH 2 ) 1-3 -, phenyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl, and L 2 , L 3 and L 4 are not simultaneously selected from mono- key; 或者，R 5和R 6连接在一起，结构单元
Figure PCTCN2022082343-appb-100011
选自形成一个任选被1、2或3个R取代的： Alternatively, R 5 and R 6 are linked together, building blocks
Figure PCTCN2022082343-appb-100011
is selected to form an optionally substituted with 1, 2 or 3 Rs:
Figure PCTCN2022082343-appb-100012
Figure PCTCN2022082343-appb-100012
 R 7选自H、卤素、OH、CN、NH 2、NO 2和COOH，或选自任选被1、2或3个R取代的：NH 2和C 1-3烷基； R 7 is selected from H, halogen, OH, CN, NH 2 , NO 2 and COOH, or from optionally substituted with 1, 2 or 3 R: NH 2 and C 1-3 alkyl; R 8选自F、Cl、Br、I、OH、CN和NH 2； R 8 is selected from F, Cl, Br, I, OH, CN and NH 2 ; R选自卤素、OH、CN、NH 2、COOH，或选自任选被1、2或3个R’取代的：C 1-3烷基和C 1-3杂烷基； 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’选自F、Cl、Br、I、OH、CN、NH 2、COOH、Me、Et、CF 3、CHF 2、CH 2F、NHCH 3和N(CH 3) 2；所述C 1-6杂烷基、C 1-3杂烷基、4～6元杂环烷基和5～6元杂芳基之杂原子或杂原子团，选自-C(＝O)NH-、-NH-、-C(＝NH)-、-S(＝O) 2NH-、-S(＝O)NH-、-N＝、-O-、-S-、-O-N＝、-C(＝O)O-、-C(＝O)-、-S(＝O)-、 -S(＝O) 2-和-NHC(＝O)NH-； R' is selected from F, Cl, Br, I, OH, CN, NH 2 , COOH, Me, Et, CF 3 , CHF 2 , CH 2 F, NHCH 3 and N(CH 3 ) 2 ; the C 1- The heteroatom or heteroatom group of 6 -heteroalkyl, C 1-3 -heteroalkyl, 4-6-membered heterocycloalkyl and 5-6-membered heteroaryl, selected from -C(=O)NH-, -NH- , -C(=NH)-, -S(=O) 2 NH-, -S(=O)NH-, -N=, -O-, -S-, -ON=, -C(=O) O-, -C(=O)-, -S(=O)-, -S(=O) 2 - and -NHC(=O)NH-; 以上任何一种情况下，杂原子或杂原子团的数目分别独立地选自1、2或3。In any of the above cases, the number of heteroatoms or heteroatomic groups is independently selected from 1, 2 or 3, respectively. 根据权利要求1所述化合物、其药学上可接受的盐及其互变异构体，其中，R选自F、Cl、Br、I、OH、CN、NH 2和COOH，或选自任选被1、2或3个R’取代的：C 1-3烷基、C 1-3烷氧基和C 1-3烷基-C(＝O)-；具体地，R选自F、Cl、Br、I、OH、CN、NH 2和COOH，或选自任选被1、2或3个R’取代的：Me、Et、
Figure PCTCN2022082343-appb-100013
The compound according to claim 1, its pharmaceutically acceptable salt and its tautomer, wherein, R is selected from F, Cl, Br, I, OH, CN, NH 2 and COOH, or selected from optional Substituted by 1, 2 or 3 R': C 1-3 alkyl, C 1-3 alkoxy and C 1-3 alkyl-C(=O)-; specifically, R is selected from F, Cl , Br, I, OH, CN, NH and COOH, or selected from : Me, Et,
Figure PCTCN2022082343-appb-100013
 更具体地，R选自F、Cl、Br、I、OH、CN、NH 2、-N(CH 3) 2、COOH、Me、Et、CF 3、CHF 2、CH 2F、
Figure PCTCN2022082343-appb-100014
More specifically, R is selected from F, Cl, Br, I, OH, CN, NH2 , -N( CH3 ) 2 , COOH, Me, Et, CF3 , CHF2 , CH2F ,
Figure PCTCN2022082343-appb-100014
 根据权利要求1或2所述化合物、其药学上可接受的盐及其互变异构体，其中，Ra选自H、苯基和6元杂环烷基。The compound according to claim 1 or 2, its pharmaceutically acceptable salt and its tautomer, wherein Ra is selected from H, phenyl and 6-membered heterocycloalkyl. 根据权利要求3所述化合物、其药学上可接受的盐及其互变异构体，其中，Ra选自H、苯基和吗啉基；The compound according to claim 3, its pharmaceutically acceptable salt and its tautomer, wherein, Ra is selected from H, phenyl and morpholinyl; 具体地，Ra选自H、
Figure PCTCN2022082343-appb-100015
Specifically, Ra is selected from H,
Figure PCTCN2022082343-appb-100015
 根据权利要求1或2所述化合物、其药学上可接受的盐及其互变异构体，其中，Ra-L 1-选自任选被1、2或3个R取代的：
Figure PCTCN2022082343-appb-100016
The compound according to claim 1 or 2, its pharmaceutically acceptable salts and its tautomers, wherein Ra-L 1 - is selected from optionally substituted with 1, 2 or 3 Rs:
Figure PCTCN2022082343-appb-100016
 根据权利要求1或2所述化合物、其药学上可接受的盐及其互变异构体，其中，R 1和R 2分别独立地选自H、F、Cl、Br、I、OH、CN、NH 2和COOH，或分别独立地选自任选被1、2或3个R取代的：C 1-3烷基、C 1-3烷氧基、C 1-3烷硫基、C 1-3烷氨基、N,N’-二(C 1-2烷基)氨基-和5～6元杂环烷基。 The compound according to claim 1 or 2, its pharmaceutically acceptable salt and its tautomer, wherein R 1 and R 2 are independently selected from H, F, Cl, Br, I, OH, CN , NH 2 and COOH, or each independently selected from optionally substituted with 1, 2 or 3 R: 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. 根据权利要求6所述化合物、其药学上可接受的盐及其互变异构体，其中，R 1和R 2分别独立地选自H、F、Cl、Br、I、OH、CN、NH 2、COOH，或分别独立地选自任选被1、2或3个R取代的：Me、
Figure PCTCN2022082343-appb-100017
The compound according to claim 6, its pharmaceutically acceptable salt and its tautomer, wherein R 1 and R 2 are independently selected from H, F, Cl, Br, I, OH, CN, NH 2 , COOH, or independently selected from: Me,
Figure PCTCN2022082343-appb-100017
 具体地，R 1和R 2分别独立地选自H、F、Cl、Br、I、OH、CN、NH 2、COOH、CF 3、
Figure PCTCN2022082343-appb-100018
Figure PCTCN2022082343-appb-100019
Specifically, R 1 and R 2 are each independently selected from H, F, Cl, Br, I, OH, CN, NH 2 , COOH, CF 3 ,
Figure PCTCN2022082343-appb-100018
Figure PCTCN2022082343-appb-100019
 根据权利要求1或2所述化合物、其药学上可接受的盐及其互变异构体，其中，结构单元
Figure PCTCN2022082343-appb-100020
选自
Figure PCTCN2022082343-appb-100021
The compound according to claim 1 or 2, its pharmaceutically acceptable salt and its tautomer, wherein the structural unit
Figure PCTCN2022082343-appb-100020
selected from
Figure PCTCN2022082343-appb-100021
 根据权利要求1或2所述化合物、其药学上可接受的盐及其互变异构体，其中，R 1与R 2连接在一起，结构单元
Figure PCTCN2022082343-appb-100022
选自
Figure PCTCN2022082343-appb-100023
The compound according to claim 1 or 2, its pharmaceutically acceptable salt and its tautomer, wherein, R 1 and R 2 are linked together, and the structural unit
Figure PCTCN2022082343-appb-100022
selected from
Figure PCTCN2022082343-appb-100023
 根据权利要求1或2所述化合物、其药学上可接受的盐及其互变异构体，其中，R 1与
Figure PCTCN2022082343-appb-100024
连接在一起，结构单元
Figure PCTCN2022082343-appb-100025
选自
Figure PCTCN2022082343-appb-100026
The compound according to claim 1 or 2, its pharmaceutically acceptable salt and its tautomer, wherein R 1 and
Figure PCTCN2022082343-appb-100024
connected together, structural units
Figure PCTCN2022082343-appb-100025
selected from
Figure PCTCN2022082343-appb-100026
 根据权利要求1或2所述化合物、其药学上可接受的盐及其互变异构体，其中，Rb选自H、卤素、OH、CN、NH 2、NO 2和COOH，或选自任选被1、2或3个R取代的：C 1-3烷氨基、C 1-3烷氧基、C 1-3烷硫基、N,N’-二(C 1-2烷基)氨基、吡咯烷基、吗啉基、哌嗪基、吡啶基和嘧啶基。 The compound according to claim 1 or 2, its pharmaceutically acceptable salt and its tautomer, wherein Rb is selected from H, halogen, OH, CN, NH 2 , NO 2 and COOH, or selected from any Optionally substituted with 1, 2 or 3 Rs: C 1-3 alkylamino, C 1-3 alkoxy, C 1-3 alkylthio, N,N'-bis(C 1-2 alkyl)amino , pyrrolidinyl, morpholinyl, piperazinyl, pyridyl and pyrimidinyl. 根据权利要求11所述化合物、其药学上街接受的盐及其互变异构体，其中，Rb选自H、卤素、OH、CN、NH 2、NO 2和COOH，或选自任选被1、2或3个R取代的：
Figure PCTCN2022082343-appb-100027
Figure PCTCN2022082343-appb-100028
The compound of claim 11, its pharmaceutically acceptable salts and its tautomers, wherein Rb is selected from H, halogen, OH, CN, NH2 , NO2 and COOH, or is selected from the group consisting of 1, 2 or 3 R substitutions:
Figure PCTCN2022082343-appb-100027
Figure PCTCN2022082343-appb-100028
 具体地，Rb选自：H、卤素、OH、CN、NH 2、NO 2、COOH、
Figure PCTCN2022082343-appb-100029
Figure PCTCN2022082343-appb-100030
Specifically, Rb is selected from: H, halogen, OH, CN, NH 2 , NO 2 , COOH,
Figure PCTCN2022082343-appb-100029
Figure PCTCN2022082343-appb-100030
 根据权利要求1或2所述化合物、其药学上可接受的盐及其互变异构体，其中，L 2、L 3和L 4分别独立地选自：单键、O、S、NH、-C(＝O)-、-C(＝O)NH-、-S(＝O)-、-S(＝O) 2-、-CH 2-、-CH 2CH 2-、苯基、吡 啶基、吡唑基、咪唑基、吡啶基、嘧啶基、噻吩基、恶唑基、噻唑基、异恶唑基和异噻唑基。 The compound according to claim 1 or 2, its pharmaceutically acceptable salt and its tautomer, wherein, L 2 , L 3 and L 4 are independently selected from: single bond, O, S, NH, -C(=O)-, -C(=O)NH-, -S(=O)-, -S(=O) 2 -, -CH 2 -, -CH 2 CH 2 -, phenyl, pyridine pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, thienyl, oxazolyl, thiazolyl, isoxazolyl and isothiazolyl. 根据权利要求13所述化合物、其药学上可接受的盐及其互变异构，其中，L 2、L 3和L 4分别独立地选自：单键、O、S、NH、-C(＝O)-、-C(＝O)NH-、-S(＝O)-、-S(＝O) 2-、-CH 2-、-CH 2CH 2-、
Figure PCTCN2022082343-appb-100031
The compound according to claim 13, its pharmaceutically acceptable salt and its tautomerism, wherein, L 2 , L 3 and L 4 are independently selected from: single bond, O, S, NH, -C( =O)-, -C(=O)NH-, -S(=O)-, -S(=O) 2 -, -CH 2 -, -CH 2 CH 2 -,
Figure PCTCN2022082343-appb-100031
 根据权利要求9或10所述化合物、其药学上可接受的盐及其互变异构体，其中，Rb-L 2-L 3-L 4-选自： The compound according to claim 9 or 10, its pharmaceutically acceptable salt and its tautomer, wherein Rb-L 2 -L 3 -L 4 - is selected from:
Figure PCTCN2022082343-appb-100032
Figure PCTCN2022082343-appb-100032
 根据权利要求1或2所述化合物、其药学上可接受的盐及其互变异构体，其中，R 5和R 6分别独立地选自H、卤素、OH、CN、NH 2、NO 2和COOH，或分别独立地选自任选被1、2或3个R取代的：C 1- 3杂烷基、噻唑基、嘧啶基、吡啶基、噻吩基、哌啶基、吗啉基和哌嗪基。 The compound according to claim 1 or 2, its pharmaceutically acceptable salt and its tautomer, wherein R 5 and R 6 are independently selected from H, halogen, OH, CN, NH 2 , NO 2 and COOH, or independently selected from C 1-3 heteroalkyl, thiazolyl, pyrimidinyl, pyridyl, thienyl, piperidinyl , morpholinyl and Piperazinyl. 根据权利要求16所述化合物、其药学上可接受的盐及其互变异构体，其中，R 5、R 6分别独立地选自H、F、Cl、Br、I、OH、CN、NH 2、NO 2和COOH，或分别独立地选自任选被1、2或3个R取代的：
Figure PCTCN2022082343-appb-100033
The compound according to claim 16, its pharmaceutically acceptable salt and its tautomer, wherein R 5 and R 6 are independently selected from H, F, Cl, Br, I, OH, CN, NH 2 , NO 2 and COOH, or each independently selected from optionally substituted with 1, 2 or 3 Rs:
Figure PCTCN2022082343-appb-100033
 根据权利要求17所述化合物、其药学上可接受的盐及其互变异构体，其中，R 5和R 6分别独立地选自H、F、Cl、Br、I、OH、CN、NH 2、NO 2、COOH、
Figure PCTCN2022082343-appb-100034
Figure PCTCN2022082343-appb-100035
The compound according to claim 17, its pharmaceutically acceptable salt and its tautomer, wherein R 5 and R 6 are independently selected from H, F, Cl, Br, I, OH, CN, NH 2 , NO2 , COOH,
Figure PCTCN2022082343-appb-100034
Figure PCTCN2022082343-appb-100035
 根据权利要求1或2所述化合物、其药学上可接受的盐及其互变异构体，其中，R 7选自H，或选自 任选被1、2或3个R取代的：NH 2、CH 3和
Figure PCTCN2022082343-appb-100036
The compound of claim 1 or 2, its pharmaceutically acceptable salts and its tautomers, wherein R 7 is selected from H, or from optionally substituted with 1, 2 or 3 Rs: NH 2 , CH3 and
Figure PCTCN2022082343-appb-100036
 根据权利要求19所述化合物、其药学上可接受的盐及其互变异构体，其中，R 7选自H、-N(CH 3) 2、和CH 3。 The compound of claim 19, a pharmaceutically acceptable salt thereof, and a tautomer thereof, wherein R 7 is selected from the group consisting of H, -N(CH 3 ) 2 , and CH 3 . 根据权利要求1或2所述化合物、其药学上可接受的盐及其互变异构体，R 5和R 6连接在一起，结构单元
Figure PCTCN2022082343-appb-100037
选自：
Figure PCTCN2022082343-appb-100038
Figure PCTCN2022082343-appb-100039
According to the compound of claim 1 or 2, its pharmaceutically acceptable salt and its tautomer, R 5 and R 6 are linked together, and the structural unit
Figure PCTCN2022082343-appb-100037
Selected from:
Figure PCTCN2022082343-appb-100038
Figure PCTCN2022082343-appb-100039
 根据权利要求1-21任意一项所述的化合物、其药学上可接受的盐及其互变异构体，其中，化合物选自The compound according to any one of claims 1-21, its pharmaceutically acceptable salt and its tautomer, wherein the compound is selected from
Figure PCTCN2022082343-appb-100040
Figure PCTCN2022082343-appb-100040
 R 1、R 2、R 3和R 4如权利要求1-21任意一项所定义。 R 1 , R 2 , R 3 and R 4 are as defined in any one of claims 1-21. 化合物、其药学上可接受的盐或其互变异构体，其选自：A compound, a pharmaceutically acceptable salt thereof, or a tautomer thereof, selected from the group consisting of:
Figure PCTCN2022082343-appb-100041
Figure PCTCN2022082343-appb-100041
Figure PCTCN2022082343-appb-100042
Figure PCTCN2022082343-appb-100042
Figure PCTCN2022082343-appb-100043
Figure PCTCN2022082343-appb-100043
Figure PCTCN2022082343-appb-100044
Figure PCTCN2022082343-appb-100044
 根据权利要求23所述的化合物、其药学上可接受的盐或其互变异构体，其选自：The compound of claim 23, a pharmaceutically acceptable salt thereof, or a tautomer thereof, selected from the group consisting of:
Figure PCTCN2022082343-appb-100045
Figure PCTCN2022082343-appb-100045
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