WO2013023511A1 - Dérivé de triazolopyrimidine, procédé de préparation et utilisation - Google Patents

Dérivé de triazolopyrimidine, procédé de préparation et utilisation Download PDF

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WO2013023511A1
WO2013023511A1 PCT/CN2012/078798 CN2012078798W WO2013023511A1 WO 2013023511 A1 WO2013023511 A1 WO 2013023511A1 CN 2012078798 W CN2012078798 W CN 2012078798W WO 2013023511 A1 WO2013023511 A1 WO 2013023511A1
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group
mmol
dimethyl
dioxol
tetrahydro
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PCT/CN2012/078798
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English (en)
Chinese (zh)
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屠汪洋
范江
张海棠
徐国际
刘志伟
瞿健
杨方龙
董庆
孙飘扬
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上海恒瑞医药有限公司
江苏恒瑞医药股份有限公司
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Priority to CN201280003298.0A priority Critical patent/CN103221413B/zh
Publication of WO2013023511A1 publication Critical patent/WO2013023511A1/fr

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    • 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
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • Triazolopyrimidine derivatives preparation methods thereof and uses thereof
  • the present invention relates to a novel triazolopyrimidine derivative, a pharmaceutical composition containing the same, a process for the preparation thereof and use thereof as a therapeutic agent, particularly as a P2Y12 receptor antagonist. Background technique
  • Signal transduction is the process of transmitting extracellular information into cells, participating in various biological regulation processes of cells, enhancing, differentiating, integrating and transmitting the acquired information to downstream sensors to achieve various biological effects processes.
  • Signal transduction is transmitted through membrane surface receptors, which are currently the largest family of membrane surface receptors and are involved in numerous signal transduction processes.
  • G protein-coupled receptors are classified into three classes according to the downstream G-protein types: Gs protein, Gi protein, Gq protein, and G12/13 protein, four G protein subtypes to mediate signaling.
  • G-protein coupled receptors are found only in eukaryotic organisms.
  • Ligands capable of binding to G protein-coupled receptors include information hormones, neurotransmitters, polypeptides, small molecule compounds, and the like.
  • G protein-coupled receptors are involved in the formation of many diseases and are therefore important drug targets. About 30% of the drugs on the market today use G-protein coupled receptors as targets.
  • Gq/Gi-coupled receptors There are numerous subfamilies of Gq/Gi-coupled receptors, including: (1) Purinergic receptors, members including PI, P2; (2) Adenosine receptors, Members include Al, A2A, A2B, A3, which are one of the PI subfamilies of the purine receptor family.
  • the purine receptor family plays a key role in regulating cardiac muscle oxygen consumption, coronary blood flow, anti-inflammatory, vascular reactivity, apoptosis, and cytokine secretion.
  • the P2 subfamily can be further divided into five phenotypes according to pharmacological characteristics and tissue distribution: P2X, P2Y, ⁇ 2 ⁇ , P2U and ⁇ 2 ⁇ . Among them, ⁇ 2 ⁇ and ⁇ 2 ⁇ belong to ion channel type receptors, and P2Y, P2U and ⁇ 2 ⁇ belong to G protein coupled receptors.
  • the ⁇ 2 ⁇ receptor family that has been found to couple G proteins includes nine ( ⁇ 2 ⁇ 1, 2, 4, 6, 11-14) subtypes, which are widely distributed in many cells and tissues, and the subtypes have low homology. Therefore, different subtypes have high selectivity for ligands.
  • ⁇ 2 ⁇ 1, 2, 6, and 14 bind Gq and activate the PLC pathway;
  • P2Y12, 13 binds Gi to inhibit adenylate cyclase activity;
  • P2Y4 couples Gq/Gi two G proteins;
  • P2Y11 couples Gq/Gs two G proteins .
  • the P2Y receptor mediates a range of biological effects including platelet aggregation, immune regulation, and smooth muscle cell proliferation.
  • Thrombosis is formed by platelet aggregation during coagulation. Thrombosis formed in non-injury can reduce blood flow velocity or even block terminal blood vessels, causing tissue necrosis, atherosclerosis, myocardial infarction and other diseases. Platelet activation has multiple pathways and mechanisms such as collagen exposed in blood vessels, tissue factor, endogenous stimulatory factor ADP, and the like.
  • Co-activation of the P2Y1 and P2Y12 receptors is integral to platelet aggregation.
  • the P2Y1 receptor releases Ca 2+ by activating the PBK pathway to cause aggregation of platelet deformation.
  • P2Y1 gene knockout type small Rats do not respond to ADP-induced platelet aggregation and deformation [Fabre JE et al, Nat Med 5: 1199-1202 (1999)].
  • the P2Y12 receptor was first cloned in 2001 [Hollopeter G et al., Nature 409: 202-207 (2001)]. Studies have shown that the P2Y12 receptor is involved in fibrinogen receptor activation, thrombosis, thromboxane A2 production, and platelet aggregation induced by trauma.
  • the human P2Y12 receptor consists of 342 amino acids, mainly distributed in platelets and brain tissue, and is a target for antithrombotic thiophene pyridines.
  • Endogenous stimulating factors such as ADP and other binding to the P2Y12 receptor activate pathways such as PBK and activate Raplb, Akt, and ER pathways to cause activation of fibrinogen receptors in combination with fibrinogen to induce thrombosis or platelet aggregation. This process must be achieved with simultaneous activation of the P2Y1 receptor.
  • the PAR-1 receptor belongs to the G protein-coupled receptor family, and the structural extracellular N-terminal portion is cleaved by serine proteases such as thrombin to activate itself, thereby exerting coagulation.
  • Activation of the Akt pathway activation must also rely on activation of the P2Y12 receptor and amplify the signal through the G12/13 pathway. Blocking the P2Y12 receptor significantly inhibits platelet aggregation and thrombosis induced by ADP and other stimulating factors such as the PAR-1 activating peptide SFLLR, collagen, and the like.
  • P2Y12 receptor antagonists include WO1999005143, WO2000034283, and WO200103642.
  • the object of the present invention is to provide a novel triazolopyrimidine derivative represented by the formula ⁇ or a tautomer, a mesogen, a racemate, an enantiomer thereof, a diastereomer a construct, a mixture thereof, and a pharmaceutically acceptable salt thereof,
  • ⁇ is a single key or double key
  • R 1 is selected from cycloalkyl or heteroaryl
  • R 1 is selected from a cycloalkyl group
  • the cycloalkyl group is optionally further substituted with one or more of each independently R 6
  • R 1 is selected from a cycloalkyl group fused to an aryl or heteroaryl group, Wherein the fused to an aryl or heteroaryl group
  • the cycloalkyl group is optionally further selected from one or more selected from the group consisting of alkyl, halogen, alkoxy, nitro, cyano, cycloalkyl, heterocyclyl, -C(0)R 7 , -C(0) 0R 7 , -S(0) m R 7 , -NR 8 R 9 , -C(0)NR 8 R 9 , -NR 8 C(0)R 9 , -NR 8 S(0) m R 9 or - Substituted by a substituent of S(0) m NR 8 R 9 ;
  • the heteroaryl is optionally further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, alkoxy, nitro, cyano, -C(0)R 7 - C(0)OR 7 -S(0) m R 7 -NR 8 R 9 , -C(0)NR 8 R 9 -NR 8 C(0)R 9 -NR 8 S( ) m R 9 or -S Substituted by a substituent of ( ) m NR 8 R 9 ;
  • Substituting a substituent of an alkoxy group, a nitro group or a cyano group; or R 4 and R 5 are optionally a cycloalkyl group, and ring-forming is in accordance with a valence bond theory; when 1 ⁇ is a double bond, R 4 is selected from a hydrogen atom;
  • R 5 is selected from a hydrogen atom, an alkyl group, a hydroxyl group or a halogen; when 1 ⁇ is a single bond, R 5 and R 4 are optionally a cycloalkyl group, and the ring formation is in accordance with a valence bond theory;
  • R 2 is selected from unsubstituted alkyl
  • R 3 is selected from alkoxy or hydroxy, wherein alkoxy is substituted by one hydroxy group
  • R 4 is selected from a hydrogen atom
  • R 5 is selected from a hydrogen atom
  • R 1 is not a C 3 -C 8 cycloalkyl group substituted by a phenyl group
  • R 6 is selected from aryl or heteroaryl, wherein each of said aryl or heteroaryl is independently further optionally further selected from one or more selected from the group consisting of alkyl, halogen, alkoxy, nitro, cyano, cycloalkane Base, heterocyclic group, -C(0)R -C(0)0R 7 -S(0) m R 7 , -NR 8 R 9 , -C(0)NR 8 R 9 , -NR 8 C(0 Substituting a substituent of R 9 , —NR 8 S(0) m R 9 or —S(0) m NR 8 R 9 ;
  • R 7 , R 8 and R 9 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a hydroxyalkyl group, a heterocyclic group, an aryl group or a heteroaryl group;
  • n 0, 1 or 2.
  • a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer a form, a mixture thereof, and a pharmaceutically acceptable salt thereof which is a compound of the formula ( ⁇ ) or a pharmaceutically acceptable salt thereof:
  • ⁇ 11 5 is as defined above for the definition of formula (I).
  • a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer a form, a mixture thereof, and a pharmaceutically acceptable salt thereof which is a salt of the formula:
  • ⁇ 11 5 is as defined above for the definition of formula (I).
  • a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer isomers thereof, and mixtures thereof, and pharmaceutically acceptable salts thereof in which R 1 is selected from cycloalkyl, said cycloalkyl optionally further substituted with one or more R 6 each independently substituted; R 6 is defined As described above for the definition of formula (I).
  • a compound of the formula (I) or a tautomer, a mesogen, a racemate, a diastereomer thereof, and a mixture thereof, and a pharmaceutically acceptable salt thereof wherein And R 6 is selected from aryl or heteroaryl, wherein each of said aryl or heteroaryl is independently, optionally, further substituted with one or more substituents selected from alkyl or halogen.
  • R 1 is selected from cycloalkyl or heteroaryl
  • R 1 is selected from a cycloalkyl group
  • the cycloalkyl group is optionally further substituted with one or more of each independently R 6 , or R 1 is selected from a cycloalkyl group fused to an aryl or heteroaryl group
  • the cycloalkyl group described herein fused to an aryl or heteroaryl group is further further selected from one or more selected from the group consisting of an alkyl group, a halogen, an alkoxy group, a nitro group, a cyano group, a cycloalkyl group, a heterocyclic group, -C(0)R 7 , -C(0)OR 7 , -S(0) m R 7 , -NR 8 R 9 , -C(0)NR 8 R 9 , -NR 8 C(0)R 9 Substituted by a substituent of -NR 8 S(0) m R 9 or -S(0) m NR 8 R 9 ;
  • the heteroaryl is optionally further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, alkoxy, nitro, cyano, -C(0)R 7 - C(0)OR 7 -S(0) m R 7 -NR 8 R 9 , -C(0)NR 8 R 9 -NR 8 C(0)R 9 -NR 8 S( ) m R 9 or -S Substituted by a substituent of ( ) m NR 8 R 9 ;
  • R 2 is selected from an alkyl group, which is optionally further substituted with one or more cycloalkyl groups;
  • R 5 is selected from alkyl, hydroxy or halogen, or R 4 is optionally cycloalkyl, and the ring is in accordance with the valence bond theory:
  • R 3 is selected from halogen, alkyl, alkoxy or hydroxy, wherein the alkyl and alkoxy are each independently further substituted by at least two selected from the group consisting of a hydroxyl group, a halogen, a cycloalkyl group, an OR 7 group or a heterocyclic group. Substituted by
  • R 4 is selected from a hydrogen atom, or R 5 is optionally a cycloalkyl group, and the ring formation is in accordance with a valence bond theory;
  • R 3 is an alkoxy group, wherein the alkoxy group is further substituted with at least two substituents each independently selected from a hydroxyl group, a halogen, a cycloalkyl group, a hydroxyalkyl group or a heterocyclic group;
  • R 4 is a hydrogen atom
  • R 3 is absent and conforms to the valence bond theory;
  • R 4 and R 5 are selected from hydrogen atoms;
  • R 6 is selected from aryl or heteroaryl, wherein said aryl or heteroaryl is optionally further further selected from one or more selected from the group consisting of alkyl, halogen, alkoxy, nitro, cyano, cycloalkyl, Heterocyclic group, -C(0)R 7 , -C(0)OR 7 , -S(0) m R 7 , -NR 8 R 9 , -C(0)NR 8 R 9 -NR 8 C(0 Substituting a substituent of R 9 -NR 8 S(0) m R 9 or -S(0) m NR 8 R 9 ;
  • R 7 , R 8 and R 9 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group; m is 0, 1 or 2.
  • R 3 is selected from the group consisting of an alkyl group, an alkoxy group or a hydroxyl group, wherein the alkyl group and the alkoxy group are each independently optionally further selected from one or more selected from the group consisting of a hydroxyl group, a halogen, a cycloalkyl group, an OR 7 or a hetero group.
  • R 4 is selected from an alkyl group, a hydrogen atom, or R 5 is optionally a cycloalkyl group, and the ring-forming is in accordance with a valence bond theory
  • R 5 is selected from an alkyl group, a hydroxyl group or a halogen, or R 4
  • R 7 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group;
  • RR 2 is as described above for the definition of the general formula ⁇ .
  • a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer Isomers, mixtures thereof, and pharmaceutically acceptable salts thereof which are a salt of the formula (V):
  • R 3 is selected from halogen, alkyl, alkoxy or hydroxy, wherein the alkyl and alkoxy are each independently further substituted by at least two selected from the group consisting of a hydroxyl group, a halogen, a cycloalkyl group, an OR 7 group or a heterocyclic group. Substituted by
  • R 7 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group;
  • RR 2 is as described above for the definition of the general formula ⁇ .
  • a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer Isomers, mixtures thereof, and pharmaceutically acceptable salts thereof which are a salt of the formula (VI):
  • ⁇ 11 2 is as defined above for the definition of formula (I).
  • R 2 is selected from an alkyl group, and the alkyl group is further substituted with one or more cycloalkyl groups;
  • R 3 is selected from the group consisting of an alkyl group, an alkoxy group or a hydroxyl group, wherein the alkyl group and the alkoxy group are each independently optionally further selected from one or more selected from the group consisting of a hydroxyl group, a halogen, a cycloalkyl group, an OR 7 or a hetero group. Substituted by a substituent of the ring group; R 7 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a hydroxyalkyl group, a heterocyclic group, an aryl group or a heteroaryl group;
  • R 1 is as defined above for the definition of the formula ⁇ .
  • a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer And mixtures thereof, and pharmaceutically acceptable salts thereof wherein further, preferably:
  • R 1 is a cycloalkyl group, which is optionally further substituted by one or more of each independently R 6 ;
  • R 2 is selected from an alkyl group which is further substituted by one or more cycloalkyl groups
  • the cycloalkyl group is preferably a cyclopropyl group;
  • R 3 is selected from alkoxy or hydroxy, wherein said alkoxy is optionally further substituted with one or more substituents selected from hydroxy or halo;
  • R 6 is selected from aryl or heteroaryl, wherein each of said aryl or heteroaryl is independently further optionally further selected from one or more selected from the group consisting of alkyl, halogen, alkoxy, nitro, cyano, and ring.
  • Typical compounds of the invention include, but are not limited to:
  • the present invention relates to a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer, and a mixture thereof, And a preparation method thereof and a pharmaceutically acceptable salt thereof, comprising the steps of:
  • the compound of the formula (IA) is reacted with 1 ⁇ 2 , optionally further deprotecting the protecting group ⁇ and ⁇ ' of the hydroxy group to give a compound of the formula (I);
  • L is a leaving group, preferably a halogen
  • Ruthenium and P' are a protecting group or a hydrogen atom of a hydroxyl group
  • a protecting group of a hydroxyl group is selected from an alkyl group, a benzyl group, a silyl group or an acetyl group, or an anthracene and P' together with the atom to which they are attached form a 5- to 6-membered heterocyclic ring.
  • the 5- to 6-membered heterocyclic group is optionally further substituted with one or more substituents selected from alkyl, halogen, hydroxy or alkoxy;
  • the definitions of RR 2 to R 5 are as described above for the definition of the general formula (I).
  • the invention further relates to a compound of the formula (A) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer, and mixtures thereof And a preparation method of the pharmaceutically acceptable salt thereof, comprising the steps of:
  • the compound of the formula ( ⁇ ) is reacted with 1 ⁇ 2 , optionally further deprotecting the protecting group ⁇ and ⁇ ' of the hydroxy group to obtain a compound of the formula ( ⁇ );
  • L is a leaving group, preferably a halogen
  • RR 2 -R 5 The definition of RR 2 -R 5 is as described above for the definition of formula (I).
  • Another aspect of the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof, a mesogen, a racemate, an enantiomer , diastereomers, mixtures thereof, and pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers, diluents and excipients.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, a mixture thereof, and Use of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for a P2Y12 receptor antagonist.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, a mixture thereof, and A pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the manufacture of a medicament for the treatment or prevention of myocardial infarction, embolic episodes, transient ischemic attack, peripheral vascular disease or angina pectoris.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, a mixture thereof, and Use of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the preparation of a medicament for treating or preventing a disorder of platelet aggregation disorder.
  • a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, a mixture thereof and Use of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the preparation of a medicament for treating or preventing a disorder of platelet aggregation disorder.
  • Alkyl means a saturated aliphatic hydrocarbon group which is a straight chain and a branched chain group having 1 to 20 carbon atoms, preferably an alkyl group having 1 to 12 carbon atoms, and non-limiting examples include methyl group, B Base, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropane Base, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl,
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably by one or more groups independently selected from the group consisting of: alkyl, alkenyl, Block group, alkoxy group, alkylthio group, alkylamino group, halogen, thiol, hydroxy group, nitro group, cyano group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, cycloalkoxy group, hetero Cycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, -C(0)R 7 , -C(0)OR 7 , -S(0) m R 7 , -NR 8 R 9 -C(0)NR 8 R 9 , -NR 8 C(0)R 9 , -NR 8 S(0) m R 9 or -S(0) m NR 8 R 9 .
  • Cycloalkyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 5 to 10 cycloalkyl rings. One carbon atom.
  • monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Base, cyclooctyl, etc.
  • Non-limiting examples of polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.
  • “Spirocycloalkyl” means a polycyclic group of 5 to 20 members, which shares a carbon atom (referred to as a spiro atom) between monocyclic rings, which may contain one or more double bonds, but none of the rings are fully conjugated ⁇ electronic system. It is preferably from 6 to 14 members, more preferably from 7 to 10 members.
  • the spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the rings.
  • spirocycloalkyl groups include:
  • fused cycloalkyl means 5 to 20 members, each ring of the system sharing an adjacent carbon atom of an all-carbon polycyclic group with other rings in the system, wherein one or more rings may contain one or more Double keys, but no One ring has a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic ring or a tricyclic ring.
  • fused cycloalkyl groups include:
  • Bridge cycloalkyl means 5 to 20 members, any two rings sharing two carbon-free all-carbon polycyclic groups, which may contain one or more double bonds, but none of the rings have a total The ⁇ electronic system of the yoke. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring. Bridged cycloalkyl
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Base, benzocycloheptyl and the like.
  • the cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, is preferably substituted with one or more groups independently selected from the group consisting of: alkyl, alkenyl, block, alkoxy, alkane Base, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, -NR 8 R 9 , -C(0)NR 8 R 9 -NR 8 C(0)R 9 -NR 8 S(0) m R 9 , -S(0 m NR 8 R 9 , -C(O)R 10 -C(0)OR 1() or -S(O) m R 10 .
  • Alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond. For example, a vinyl group, a 1-propenyl group, a 2-propenyl group, a 1-, 2- or 3-butenyl group, and the like.
  • the alkenyl group may be substituted or unsubstituted, and when substituted, is preferably substituted with one or more groups independently selected from the group consisting of alkyl, alkenyl, block, alkoxy, alkylthio, alkane.
  • Block group refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond. For example, an ethyl group, a 1-propyl block group, a 2-propyl block group, a 1-, 2- or 3-butyl group, and the like.
  • the block group may be substituted or unsubstituted, and when substituted, is preferably substituted with one or more groups independently selected from the group consisting of: alkyl, alkenyl, block, alkoxy, alkylthio, alkane Amino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio group, -C(0)R', -C(0)OR ⁇ -S(0) m R ⁇ -NR y , -C(0)NR y , -NRT(0)R y -NR 8 S(0) m R y or -S(0) m NR 8 R 9 .
  • Heterocyclyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 ring atoms wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(0) m (wherein m is an integer from 0 to 2), but does not include a ring moiety of -0-0-, -0-S- or -SS-, and the remaining ring atoms are carbon. It preferably comprises from 3 to 12 ring atoms, wherein from 1 to 4 are heteroatoms, more preferably the heterocyclyl ring contains from 3 to 10 ring atoms.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like.
  • Non-limiting examples of polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • spiroheterocyclyl means a polycyclic heterocyclic group of 5 to 20 members in which one atom (called a spiro atom) is shared between the monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(0) m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spiroheterocyclyl group is classified into a monospiroheterocyclic group, a dispirocyclic heterocyclic group or a polyspirocyclic group according to the number of the shared spiro atoms between the rings, preferably a monospiroheterocyclic group and a dispiroheterocyclic group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospiroheterocyclic group.
  • fused heterocyclic group means 5 to 20 members, each ring in the system shares an adjacent pair of atomic polycyclic heterocyclic groups with other rings in the system, and one or more rings may contain one or more The bond, but none of the rings have a fully conjugated ⁇ -electron system in which one or more ring atoms are selected from nitrogen, oxygen or S(0) m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group may be classified according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5.
  • Non-limiting examples of fused heterocyclic groups include:
  • “Bridge heterocyclyl” refers to a polycyclic heterocyclic group of 5 to 14 members in which two rings share two atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have a complete conjugation a ⁇ -electron system in which one or more ring atoms are selected from nitrogen, oxygen or S(0) m (where m is an integer from 0 to 2), and the remaining ring atoms are Carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the heterocyclic group may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridge depending on the number of constituent rings, and is preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring.
  • bridge heterocyclic groups include:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclic ring.
  • Non-limiting examples include: with
  • the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, is preferably substituted by one or more groups independently selected from the group consisting of alkyl, alkenyl, block, alkoxy, alkanethio Base, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, -C(0)R 7 , -C(0)OR 7 -S(0) m R 7 -NR 8 R 9 , -C(0)NR 8 R 9 , -NR 8 C(0)R 9 , -NR 8 S(0) m R 9 or -S(0) m NR 8 R 9 .
  • Aryl means a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms), a polycyclic ring having a conjugated ⁇ -electron system (ie, having adjacent pairs)
  • the ring group of a carbon atom is preferably 6 to 10 members such as a phenyl group and a naphthyl group.
  • the aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, and the ring together is an aryl ring, non-limiting examples include:
  • the aryl group may be substituted or unsubstituted, and when substituted, is preferably substituted with one or more groups independently selected from the group consisting of alkyl, alkenyl, block, alkoxy, alkylthio, alkane.
  • Heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen. It is preferably 5 to 10 members, more preferably 5 or 6 members, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. .
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples include:
  • the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, is preferably substituted with one or more groups independently selected from the group consisting of alkyl, alkenyl, block, alkoxy, alkylthio.
  • Base alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, -C(0)R 7 , -C(0)OR 7 , -S(0) m R 7 , -NR 8 R 9 , -C(0)NR 8 R 9 , -NR 8 C(0)R 9 , -NR 8 S(0) m R 9 or -S(0) m NR 8 R 9 .
  • Alkoxy means -o-(indenyl) and -o-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, is preferably substituted with one or more groups independently selected from the group consisting of alkyl, alkenyl, block, alkoxy, alkylthio.
  • Haloalkyl means that the alkyl group is substituted by one or more halogens.
  • Haldroxy means an -OH group.
  • Hydroalkyl means an alkyl group substituted by a hydroxy group, wherein alkyl is as defined above.
  • Halogen means fluoro, chloro, bromo or iodo.
  • Amino means -NH 2 .
  • Neitro means -N0 2 .
  • Benzyl refers to -CH 2 - phenyl.
  • Carboxylic acid group means -C(0)OH.
  • the "carboxylate group” means -C(0)0(alkyl) or -C(0)0(cycloalkyl), wherein the alkyl group and the cycloalkyl group are as defined above.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, including the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their The possible chemical positions, those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers and excipient.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby the biological activity.
  • “Pharmaceutically-acceptable salt” means a salt of a compound of the present invention which is safe and effective for use in a mammal and which has the desired biological activity.
  • R 7 to R 9 are as defined in the compound of the formula, and m is 0, 1 or 2.
  • a process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof which comprises:
  • the aromatic compound (IB) of the formula (IB) and the compound of the formula (IC) are subjected to aromatic nucleophilic substitution reaction in a solvent to obtain a compound of the formula (ID); the compound of the formula (ID) is dissolved in a solvent, and sodium nitrite is added in an ice bath.
  • the reaction is carried out under the conditions to obtain the compound of the formula (IA); the compound of the formula (IA) is reacted with R ⁇ NH ⁇ under basic conditions to obtain the compound of the formula (IE); the compound of the formula (IE) is further dehydroxylated.
  • Protecting groups P and P' to give compound of formula (I) o Reaction solvents include, but are not limited to, ethylene glycol, ethanol, methanol, acetic acid, water, acetonitrile, methanol, tetrahydrofuran, dichloromethane, toluene, N, N-di Methylformamide or a mixed solvent thereof;
  • Reducing agents include, but are not limited to, iron powder
  • Reagents that provide basic conditions include, but are not limited to, organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, tert-butanol, and inorganic bases.
  • organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, tert-butanol
  • inorganic bases include, but are not limited to, sodium hydride, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate or cesium carbonate;
  • the reaction temperature is controlled at -80 ° C to 200 ° C, preferably 0 ° C to 100 ° C; the reaction time is generally controlled from 1 minute to 72 hours, preferably 15 minutes to 24 hours; Its towel:
  • Ri ⁇ R 5 is as defined in the general formula (; I);
  • L and L' are leaving groups, preferably halogen
  • P and P' are a protecting group or a hydrogen atom of a hydroxyl group
  • the protecting group of the hydroxyl group is selected from an alkyl group, a benzyl group, a silyl group or an acetyl group, or P and P' together with the atom to which they are attached form a 5- to 6-membered heterocyclic ring.
  • the 5- to 6-membered heterocyclic group is optionally further substituted with one or more substituents selected from the group consisting of an alkyl group, a halogen group, a hydroxyl group or an alkoxy group.
  • the 5- to 6-membered heterocyclic group described above is optionally reacted under acidic conditions, and the protecting group is removed to obtain a compound of the formula (1).
  • the aromatic compound (IB) and the compound of the formula (VIA) are subjected to aromatic nucleophilic substitution reaction in a solvent to obtain a compound of the formula (VIB); the compound of the formula (VIB) is dissolved in a solvent, and sodium nitrite is added in an ice bath.
  • the reaction is carried out under the conditions to obtain the compound of the formula (VIC); the compound of the formula (VIC) is reacted with R ⁇ NH ⁇ under basic conditions to obtain the compound of the formula (VID); the compound of the formula (VID) in triphenylphosphine And reacting with an azodicarboxylate diester (preferably diisopropyl azodicarboxylate) to obtain a compound of the formula (VIE); the compound of the formula (VIE) further deprotects the protecting groups P and P' of the hydroxyl group, Compound (VI) of the formula.
  • azodicarboxylate diester preferably diisopropyl azodicarboxylate
  • the reaction solvent includes, but is not limited to, ethylene glycol, ethanol, methanol, acetic acid, water, acetonitrile, methanol, tetrahydrofuran, dichloromethane, toluene, N,N-dimethylformamide or a mixed solvent thereof;
  • Reducing reagents include, but are not limited to, hydrogen, iron powder or zinc powder;
  • Reagents that provide basic conditions include, but are not limited to, organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, tert-butanol, and inorganic bases.
  • organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, tert-butanol
  • inorganic bases include, but are not limited to, sodium hydride, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate or cesium carbonate;
  • the reaction temperature is controlled from -80 ° C to 200 ° C, preferably from 0 ° C to 100 ° C; the reaction time is generally controlled from 1 minute to 72 hours, preferably from 15 minutes to 24 hours;
  • Ri ⁇ R 2 is as defined in the general formula (; I);
  • L and L' are leaving groups, preferably halogen;
  • P and P' are a protecting group or a hydrogen atom of a hydroxyl group, and the protecting group of the hydroxyl group is selected from an alkyl group, a benzyl group, a silyl group or an acetyl group, or P and P' together with the atom to which they are attached form a 5- to 6-membered heterocyclic ring.
  • the 5- to 6-membered heterocyclic group is optionally further substituted with one or more substituents selected from the group consisting of an alkyl group, a halogen group, a hydroxyl group or an alkoxy group.
  • the reaction solvent includes, but is not limited to, ethylene glycol, ethanol, methanol, acetic acid, water, acetonitrile, methanol, tetrahydrofuran, dichloromethane, toluene, N,N-dimethylformamide or a mixed solvent thereof;
  • Reducing agents include, but are not limited to, iron powder
  • Reagents that provide basic conditions include, but are not limited to, organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, tert-butanol, and inorganic bases.
  • organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, tert-butanol
  • inorganic bases include, but are not limited to, sodium hydride, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate or cesium carbonate;
  • the reaction temperature is controlled from -80 ° C to 200 ° C, preferably from 0 ° C to 100 ° C; the reaction time is generally controlled from 1 minute to 72 hours, preferably from 15 minutes to 24 hours;
  • Ri ⁇ R 5 is as defined in the general formula (; I);
  • L and L' are leaving groups, preferably halogen
  • P and P' are a protecting group or a hydrogen atom of a hydroxyl group
  • the protecting group of the hydroxyl group is selected from an alkyl group, a benzyl group, a silyl group or an acetyl group, or P and P' together with the atom to which they are attached form a 5- to 6-membered heterocyclic ring.
  • the 5- to 6-membered heterocyclic group is optionally further substituted with one or more substituents selected from the group consisting of an alkyl group, a halogen group, a hydroxyl group or an alkoxy group.
  • the structure of the compound is determined by nuclear magnetic resonance (1H NMR) and/or mass spectrometry (MS).
  • the iHNMR shift ( ⁇ ) is given in parts per million (ppm).
  • the 1H NMR measurement was performed on a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated methanol (CD 3 OD), deuterated chloroform (CDC1 3 ), hexamethyl dimethyl sulfoxide (OMSO-d 6 ), internal standard. It is tetramethylsilane (TMS).
  • the MS was measured using a FINMGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
  • the HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C 18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).
  • the IC 5 o value was determined using a NovoStar plate reader (BMG, Germany).
  • the silica gel plate used has a specification of 0.15 mm to 0.2 mm, and the silica gel plate used for thin layer chromatography separation and purification is 0.4 mm to 0.5 mm.
  • the silica gel column generally uses Yantai Huanghai silica gel 200 ⁇ 300 mesh silica gel as a carrier.
  • the alkaline alumina column is generally used as a carrier for FCP200 ⁇ 300 mesh basic alumina using the national medicine chromatography.
  • Known starting materials of the invention may be synthesized or synthesized according to methods known in the art, or may be
  • An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the pressurized hydrogenation reaction uses a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 hydrogen generator or a HC2-SS type hydrogenation apparatus.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
  • the solution means an aqueous solution.
  • reaction temperature is room temperature, preferably 20 ° C to 30 ° C.
  • the progress of the reaction in the examples was monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the systems used for the reaction were: dichloromethane and methanol systems, n-hexane and ethyl acetate systems, petroleum ether and ethyl acetate systems, In the acetone system, the volume ratio of the solvent is adjusted depending on the polarity of the compound.
  • the system of the eluent for column chromatography and the system of the developer for thin layer chromatography using the purified compound include:
  • A dichloromethane and methanol system
  • B n-hexane and ethyl acetate system
  • C dichloromethane and acetone system
  • D methanol system
  • E petroleum ether and ethyl acetate system
  • F ethyl acetate and methanol system
  • volume of solvent It is adjusted according to the polarity of the compound, and may be adjusted by adding a small amount of an alkaline reagent such as triethylamine or an acidic reagent such as acetic acid.
  • Ethyl (lR,2R)-2-(3,4-difluorophenyl)cyclopropylcarboxylate lc (13.8 g, 61 mmol) was dissolved in 90 mL of methanol, then 30% sodium hydroxide C. 109 mmol) solution, reacted at 65 °C for 2 hours. Concentrated under reduced pressure, adding 100 mL of toluene and 100 mL of water, layering, adjusting pH ⁇ 7 with 35% hydrochloric acid, layering, using toluene (500 After extraction with EtOAc (3 mL), EtOAc (EtOAc m. 12.1 g, yellow liquid), the product was directly subjected to the next reaction without purification.
  • [1,2-(1:3,4-(1'](([1,3]dioxole)-7-yl]pyrimidine-4,5-diamine will be 4,6-di Chloro-2-propylmercapto-pyrimidin-5-amine Is (162 mg, 0.68 mmol, prepared by the well-known method "Specialty lj WO2001092263") and (3aS, 3bS, 6aS, 7a-2, 2, 5 ,5-tetramethyltetrahydro-3aH-cyclopenta[l,2 3,4-if
  • Oxazine-6 (4H benzyl formate 2d (27.8 g, 91.06 mmol) was dissolved in 400 mL of methanol, added palladium/carbon (10%, 1.4 g), replaced with hydrogen three times, reacted at 50 °C After 40 hours.
  • 2-Mercaptopyrimidine-4,6-diol 2j (10.0 g, 69.3 mmol) was dissolved in 30 mL of water, sodium hydroxide (6.4 g, 160 mmol) was added, stirred for 40 min, 20 mL water was added, and then added 1 -methylpyrrol-2-one (20.6 g, 207.9 mmol) bromomethylcyclopropane (9.6 g, 71.4 mmol), stirred at 20 ° C for 12 h, then added 30 mL 1 M hydrochloric acid then 15 mL 6 M hydrochloric acid.
  • 2-(cyclopropylmethylhydrazino)-5-toluene azide pyrimidine-4,6-diol dissolves 4-methylaniline (6.7 g, 62 mmol) and 36% hydrochloric acid (18.7 mL, 224 mmol)
  • 4-methylaniline 6.7 mL, 224 mmol
  • 20 mL of sodium nitrite solution 4.5 g, 65 mmol
  • the solution was kept in an ice bath and the solution was reserved.
  • reaction solution was cooled to room temperature, and poured slowly into 400 mL of ice water, stirred at room temperature for 1 hour, extracted with ethyl acetate (100 mIX3), and the organic phases were combined and washed sequentially with saturated sodium chloride solution (200 mL)
  • the residue was purified by EtOAcjjjjjjjjjjj ⁇ )) pyrimidin-5-yl] toluene) ⁇ 2n (9.5 g, red solid), Yield: 69.9%.
  • Ethyl (lR,2R)-2-(5-chloro-2-thienyl)cyclopropylcarboxylate 4c (10.9 g, 0.047 mol) was dissolved in 80 mL of ethanol, and 30% sodium hydroxide solution (3.4 g) , 0.085 mol), stirring for 4.5 hours, concentrating most of the ethanol under reduced pressure, adding 100 mL of water and 100 mL of toluene, adding concentrated hydrochloric acid dropwise, adjusting pH ⁇ 7, layering, and extracting the aqueous phase with toluene (100 mL X 2 ) The organic phase was combined, washed with EtOAc EtOAc (EtOAcjjjjjjjj Cyclopropyl formic acid 4d (7.8 g, yellow liquid), Yield: 81.6%.
  • the reaction mixture was adjusted to pH ⁇ -7 with a saturated sodium hydroxide solution, and extracted with ethyl acetate (35 mL X 3 ). The organic phase was combined and washed with saturated sodium chloride solution (40 mL X 2 ), anhydrous sulfuric acid The sodium was dried, and the filtrate was concentrated under reduced pressure. 1.5 mL ethyl acetate was added to the crude mixture, and the mixture was stirred at 57 ° C for 10 minutes, then 2 mL of n-hexane was added, and the mixture was stirred at 57 ° C for 1 hour, cooled to room temperature, and filtered to give the title.
  • the crude product is 2- ⁇ [(3aS,4R,6 6aR)-6-[7-(indanyl-2-ylamino)-5-propylindolyl-triazolo[4,5-d]pyrimidine-3 -yl]-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentenyl M[l,3]dioxol-4-yl]oxy ⁇ ethanol 5h (100 mg, 0.19 mmol) dissolved in 5 mL of methanol, added with hydrochloric acid (4 mL, 2.5 M), stirred for 12 hours, and then added saturated sodium hydroxide solution to adjust ⁇ -9, ethyl acetate (30 mL) X 2), the organic phase is combined, washed with a saturated sodium chloride solution (25 mL of EtOAc), dried over anhydrous sodium sulfate, and the filtrate is concentrated under reduced pressure.
  • reaction was carried out at 0 ° C for 12 hours, 5 mL of water was added, the reaction was carried out for 8 hours, and the reaction was carried out for 5 hours at room temperature.
  • the reaction mixture was concentrated under reduced pressure to give crude title product (4,,,,,,,,,,, , 6a-dihydro-3aH-cyclopentene M[l,3]dioxol-4-amine 6f (1.7 g, colorless oil).
  • N-[(3aR,6R)-2,2-dimethyl-6,6a-dihydro-3aH-cyclopenta[l,3]dioxol-6-yl]carbamic acid benzyl Ester 6g (570 mg, 1.97 mmol) was dissolved in 10 mL of tetrahydrofuran, and N-methyl oxidized morpholine (0.94 mL, 4 mmol) and osmium tetroxide (102 mg, 0.4 mmol) were added for 12 hours.
  • heterocyclopentene-5-yl trifluoromethanesulfonate 8a (136 mg, 0.33 mmol) was dissolved in 5 mL of tetrahydrofuran, and 0.5 mL of a solution of 1 M tetrabutylammonium fluoride trihydrate in tetrahydrofuran was added and reacted for 3 hours.
  • OR,4R,5 6 6a -6-[(6-chloro-5-nitro-2-propylindolyl-pyrimidin-4-yl)amino]-5-fluoro-2,2-dimethyl
  • OR,4R,5 6 6a -6-[(5-Amino-6-chloro-2-propylindolyl-pyrimidin-4-yl)amino]-5-fluoro-2,2-dimethyl
  • Step 6 2- ⁇ [(3aS,4R,5 ⁇ 6 6a -6-[(5-Amino-6-chloro-2-propylindolyl-pyrimidin-4-yl)amino]-5-fluoro-2,2-di Methyl-4,5,6,6a-tetrahydro-3aH-cyclopentene and W][l,3]dioxol-4-yl]oxy ⁇ ethanol 2- ⁇ [0 4R, 5S,6 6a -6-[(6-chloro-5-nitro-2-propylindolyl-pyrimidin-4-yl)amino]-5-fluoro-2,2-dimethyl-4,5,6 , 6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-4-yl]oxy ⁇ ethanol 9e (0.20 g, 0.43 mmol) dissolved in 6 mL of acetic acid, iron Powder (123 mg, 2.20 mmol), EtOAc (2
  • the aqueous phase is extracted with ethyl acetate (60 mL ⁇ 2), the organic phase is combined, washed with saturated sodium chloride solution (50 mL ⁇ 2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • N-[(1R,2R/1 2 -2-(4-methylthiazol-5-yl)cyclopropane]carbamic acid tert-butyl ester (1R, 2R/1S, 2 -2-(4-methyl) Thiazol-5-yl)cyclopropanecarboxylic acid 10c (732 mg, 4 mmol) was dissolved in 20 mL of tert-butanol, followed by the addition of diphenyl azide (1.10 g, 4 mmol) and triethylamine (485.70 mg, 4.80). The reaction was carried out at a temperature of 83 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure.
  • reaction solution was concentrated under reduced pressure, water (10 m) was added, 2.5 M hydrochloric acid was added dropwise to the reaction mixture ⁇ ⁇ ⁇ 4, and the aqueous phase was extracted with ethyl acetate (15 mL ⁇ 3), and the organic phase was combined with saturated sodium chloride.
  • the solution (10 mL) was washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Ethyl (E)-3-0 pyridyl)prop-2-enoate 13b (6.90 g, 38.90 mmol) was dissolved in 50 mL of methanol and then 10 mL sodium hydroxide C 3.40 g, 85 mmol Reaction for 1.5 hours. The organic layer was extracted with ethyl acetate (200 mL ⁇ 4).

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Abstract

La présente invention concerne des dérivés de triazolopyrimidine ainsi que leur procédé de préparation et utilisation. En particulier, la présente invention concerne des dérivés de triazolopyrimidine tels que représentés par la formule générale (I), et leur utilisation en tant qu'agent thérapeutique, spécialement en tant qu'inhibiteur du récepteur P2Y12, la définition de chaque substituant dans la formule générale (I) étant la même que la définition dans la description.
PCT/CN2012/078798 2011-08-12 2012-07-18 Dérivé de triazolopyrimidine, procédé de préparation et utilisation WO2013023511A1 (fr)

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WO2023108363A1 (fr) * 2021-12-13 2023-06-22 Beijing Honghui Meditech Co., Ltd Dérivés de triazole à anneau pyrimidine et leur utilisation dans l'inhibition de l'agrégation plaquettaire
WO2023213198A1 (fr) * 2022-05-04 2023-11-09 华东师范大学 Utilisation d'un composé cyclique fusionné aromatique en tant qu'activateur de trek-1 et composition pharmaceutique et analgésique le contenant
CN115894430A (zh) * 2022-11-24 2023-04-04 四川青木制药有限公司 替格瑞洛关键中间体的制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1270590A (zh) * 1997-07-22 2000-10-18 英国阿斯特拉药品有限公司 新的化合物
CN1271359A (zh) * 1997-07-22 2000-10-25 英国阿斯特拉药品有限公司 新的化合物
CN1334816A (zh) * 1998-12-04 2002-02-06 阿斯特拉曾尼卡有限公司 新的三唑并(4,5－d)嘧啶化合物
WO2008054795A2 (fr) * 2006-10-31 2008-05-08 Janssen Pharmaceutica, N.V. Dérivés de triazolopyrimidine convenant comme antagonistes du récepteur p2y12 de l'adp

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UA100864C2 (uk) * 2007-12-03 2013-02-11 Астразенека Аб Спосіб лікування або запобігання аневризмі черевної аорти
WO2011058478A1 (fr) * 2009-11-16 2011-05-19 Pfizer Inc. Triazolopyrimidines substituées comme inhibiteurs de pde8

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1270590A (zh) * 1997-07-22 2000-10-18 英国阿斯特拉药品有限公司 新的化合物
CN1271359A (zh) * 1997-07-22 2000-10-25 英国阿斯特拉药品有限公司 新的化合物
CN1334816A (zh) * 1998-12-04 2002-02-06 阿斯特拉曾尼卡有限公司 新的三唑并(4,5－d)嘧啶化合物
WO2008054795A2 (fr) * 2006-10-31 2008-05-08 Janssen Pharmaceutica, N.V. Dérivés de triazolopyrimidine convenant comme antagonistes du récepteur p2y12 de l'adp

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SPRINGTHORPE, B. ET AL.: "From ATP to AZD6140: The discovery of an orally active reversible P2Y12 receptor antagonist for the prevention of thrombosis. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS.", vol. 17, no. 21, 2007, pages 6013 - 6018 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014154908A1 (fr) 2013-03-29 2014-10-02 Chemo Research, S.L. Alkylation sélective d'alcools cyclopentyliques
CN104974017A (zh) * 2014-04-09 2015-10-14 上海医药工业研究院 (1r,2s)-2-(3,4-二氟苯基)环丙胺·d-扁桃酸盐的制备方法
CN104974017B (zh) * 2014-04-09 2017-11-17 上海医药工业研究院 (1r,2s)‑2‑(3,4‑二氟苯基)环丙胺·d‑扁桃酸盐的制备方法
US10011605B2 (en) 2014-06-18 2018-07-03 Flamma Spa Process for the preparation of triazolo[4,5-D] pyrimidine cyclopentane compounds

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