CN108658855A - A kind of nitrogenous dicyclic compound and its preparation method and application - Google Patents

A kind of nitrogenous dicyclic compound and its preparation method and application Download PDF

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Publication number
CN108658855A
CN108658855A CN201710191188.6A CN201710191188A CN108658855A CN 108658855 A CN108658855 A CN 108658855A CN 201710191188 A CN201710191188 A CN 201710191188A CN 108658855 A CN108658855 A CN 108658855A
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base
alkyl
aliphatic
amino
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邵长伦
牟晓凤
魏美燕
姜瑶瑶
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Ocean University of China
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Ocean University of China
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
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    • 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
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    • 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
    • C07D401/10—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 carbon chain containing aromatic rings
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    • 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
    • C07D401/14—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 three or more hetero rings
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    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • 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
    • C07D471/04—Ortho-condensed systems
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    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
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    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/23—Heterocyclic radicals containing two or more heterocyclic rings condensed among themselves or condensed with a common carbocyclic ring system, not provided for in groups C07H19/14 - C07H19/22

Abstract

A kind of nitrogenous dicyclic compound and its preparation method and application, the present invention relates to a kind of alkaloid compounds, or non-equal amount of mixture, geometric isomer, solvate, pharmaceutically acceptable salt or the prodrug of its tautomer, stereoisomer, racemic modification, enantiomter, and the pharmaceutical composition comprising the compound.The invention also discloses this kind of compound and its pharmaceutical composition as drug especially as the purposes of antiviral drugs.

Description

A kind of nitrogenous dicyclic compound and its preparation method and application
Technical field
The invention belongs to drug fields, and more particularly to a kind of nitrogenous dicyclic compound and its pharmaceutical composition and It is as drug especially as the purposes of antiviral drugs.
Background technology
It can be simply divided into no togavirus by whether its shell is wrapped in the film rich in lipid in virus and have cyst membrane sick Malicious two classes.No togavirus mainly enters infected cell by pinocytosis under clathrin mediation;There is togavirus Invasion be mainly virus envelope and host cell membrane fusion process.The research and development of anti-virus formulation are based primarily upon two at present Aspect designs, first, from viral dip dyeing level, second is that from host cell defense level.It has listed at present most of antiviral Drug is based on virus itself, i.e. action receptor is virus itself.Interferon (IFN) is that the generation developed earliest is disease-resistant Cytotoxic drug is named because it has the ability of " interference " virus replication.More and more antiviral drugs are developed in recent years Come, and is widely used in clinical treatment.Such as another kind of after interferon can interfere virus transcription or duplication Nucleoside medicine, Ribavirin (ribavirin), acyclovir (acyclovir), Valaciclovir (valacyclovir), Zidovudine (zidovudine), Sebivo (telbivudine) etc..
Although many antiviral drugs are effectively used in clinic successively, drug-resistant virus also day by day floats in recent years It is existing.Drug resistance Producing reason is mainly that the gene of virus generates mutation and antiviral drugs is made to lose the target spot institute of its effect It causes.Such as:The thymidine kinase gene of HSV mutates, can not be by acyclovir (acyclovir) and Ganciclovir (ganciclovir) etc. it is converted to effective composition in the cell, therefore develops immunity to drugs to those drugs;Influenza A virus M2 protein gene mutations, then can develop immunity to drugs to amantadine or Rimantadine (rimantadine);HIV is reversed The variation of record enzyme or protease gene is also the main cause for causing drug resistance to generate;The unstructuredness 5A and env gene 2- sugar of HCV The genetic mutation of albumen can make HCV develop immunity to drugs interferon.In summary, exploitation novel antiviral drug is extremely urgent.
WO2014044615, which discloses compound as follows, has insecticidal activity.
China 201510918196.7 discloses the anti-HSV-1 virus activities of compound as follows.
Chinese patent 201510150071.4 and patent 201510150737.6 disclose compound as follows and all have anti-RSV Virus activity.
United States Patent (USP) US20150291531, which discloses compound as follows, has anti-H1N1 virus activities.
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Patent 201510918373.1 discloses a series of anti-HSV-1 virus activities of quinolinones compounds.
For the present invention on the basis of the above patent, a kind of nitrogenous dicyclic compound of research is in terms of preparing antiviral drugs Application, in the prior art, though disclosed compound has certain similarity, institute of the present invention with the compounds of this invention The compound shown and the prior art have a significant difference, and the antiviral activity of nitrogenous dicyclic compound obtains pole in the present invention Big raising, and toxicity reduces, and has good application prospect.
Invention content
A kind of nitrogenous dicyclic compound of Formulas I-II structures, tautomer, stereoisomer, racemic modification, mapping The non-equal amount of mixture of isomers, the solvate of geometric isomer, solvate, pharmaceutically acceptable salt or its salt, It is characterized in that Formulas I and Formula II compound have the following structure：, R1, R2, R3, R4And shown in A, Y be defined as follows：
The aromatic ring or hetero-aromatic ring that A is five yuan or hexa-atomic, saturated or unsaturated carbocyclic ring or carbon heterocyclic, condensed-bicyclic or condensed miscellaneous Bicyclic, Y is O or S; “" it is singly-bound or to be not present;N=0,1,2,3 or 4;In Formulas I, A is phenyl ring, when Y is O, R2Cannot be H;
Each R1Can be identical or different, it is each independently hydrogen, halogen, hydroxyl, amino, nitro, cyano, carboxyl, alkane Base, halogenated alkyl, alkoxy, alkylamino, alkyl acyl, hydroxy alkoxy base, Hydroxyalkylamino, hydroxyalkanoyl, Halogenated alkoxy, halogenated alkylamino, ohaloalkanoyl, aminoalkoxy, naphthenic base, cycloalkyl oxy, naphthenic base ammonia Base, cycloalkanoyl, alkenyl, alkenylalkoxy, alkenyl alkylamino, alkenyl alkanoyl, alkynyl, alkynyl alkoxy, Alkynyl alkylamino, alkynyl alkanoyl, aryl, aryloxy group, aroyl, fragrant amino, alkoxy aryl, aryl alkane amino, Heteroaryl, heteroaryloxy, 4-hetaroylpyrazol, heteroaryl amino, heteroarylalkoxy, heteroarylalkylamino, heterocycle alkane acyl Base, Heterocyclylalkyl, heterocycle oxygroup, heterocyclylamino group, heterocyclylacyl, heterocyclylalkoxy, heterocycle alkylamino, Heterocycle alkanoyl, azido alkoxy, condensed-bicyclic base condense miscellaneous bicyclic group, and condensed-bicyclic base aliphatic condenses Miscellaneous bicyclic group aliphatic, condensed-bicyclic base oxygroup condense miscellaneous bicyclic group oxygroup, and condensed-bicyclic base amino condenses miscellaneous bicyclic Base amino, condensed-bicyclic base alkoxy condense miscellaneous bicyclic group alkoxy, and condensed-bicyclic base alkylamino condenses miscellaneous bicyclic group Alkylamino, condensed-bicyclic base oxygroup alkoxy, condensed miscellaneous bicyclic group oxygroup alkoxy, condensed-bicyclic base aminoalkoxy, Miscellaneous bicyclic group aminoalkoxy is condensed, condensed-bicyclic base-C (=O)-, condensed-bicyclic base-C (=O) O- condense miscellaneous bicyclic group-C (=O)-, miscellaneous bicyclic group-C (=O) O-, condensed-bicyclic base amino-C (=O)-are condensed, miscellaneous bicyclic group amino-C (=O)-is condensed, Condensed-bicyclic base-C (=O) N (R5)-, condenses miscellaneous bicyclic group-C (=O) N (R5)-, spiral shell bicyclic group, the miscellaneous bicyclic group of spiral shell, spiral shell are bicyclic Base aliphatic, the miscellaneous bicyclic group aliphatic of spiral shell, spiral shell bicyclic group oxygroup, the miscellaneous bicyclic group oxygroup of spiral shell, spiral shell bicyclic group amino, spiral shell are miscellaneous Bicyclic group amino, spiral shell bicyclic group alkoxy, the miscellaneous bicyclic group alkoxy of spiral shell, spiral shell bicyclic group alkylamino, the miscellaneous bicyclic group alkane ammonia of spiral shell Base, spiral shell bicyclic group oxygroup alkoxy, the miscellaneous bicyclic group oxygroup alkoxy of spiral shell, spiral shell bicyclic group aminoalkoxy, the miscellaneous bicyclic group of spiral shell Aminoalkoxy, spiral shell bicyclic group-C (=O)-, spiral shell bicyclic group-C (=O) O-, the miscellaneous bicyclic group-C of spiral shell (=O)-, the miscellaneous bicyclic group-of spiral shell C (=O) O-, spiral shell bicyclic group amino-C (=O)-, the miscellaneous bicyclic group amino-C of spiral shell (=O)-, spiral shell bicyclic group-C (=O) N (R5)-, spiral shell Miscellaneous bicyclic group-C (=O) N (R5)-, R6R5N-, -C(=O)NR5R6, -OC(=O)NR5R6, -OC(=O)OR5, -N(R5)C(=O) NR5R6, -N(R5)C(=O)OR6, -N(R5)C(=O)-R6, R5R6N-S(=O)t-, R5S(=O)t-, R5S(=O)tN(R6)-, R6R5N- alkyl, R5S(=O)tAlkyl, R5R6N-C (=O)-alkyl, R6R5N- alkoxies, R5S(=O)tAlkoxy, R5R6N-C (=O)-alkoxy, aryl-(CH2)p-G-(CH2)m, heteroaryl-(CH2)p-G-(CH2)m, heterocycle-(CH2)p- G-(CH2)m, or naphthenic base-(CH2)p-G-(CH2)m, wherein G is O, S, NR7, S(=O), S(=O)2,C(=O), -C (=O)N(R5)-, -OC(=O)N(R5)-, -OC(=O)-, -N(R5)C(=O)N(R5)-, -(R5)N-S(=O)t-, -OS(= O)t, or-OS (=O)tN(R5)-;T is l or 2;P and m is each independently 0, l, 2,3 or 4;Or wherein aryl- (CH2)p-G-(CH2)m, heteroaryl-(CH2)p-G-(CH2)m, heterocycle-(CH2)p-G-(CH2)m, or naphthenic base- (CH2)p-G-(CH2)mCan F, Cl, Br, I, alkyl, alkenyl, alkynyl, alkoxy or cyanogen be selected from by one or more The substituent group of base replaces;
Each R2Can be identical or different, it is each independently hydrogen, alkyl, halogenated alkyl, alkyl acyl, hydroxyalkanoyl, Ohaloalkanoyl, naphthenic base, cycloalkanoyl, alkenyl, alkenyl alkanoyl, alkynyl, alkynyl alkanoyl, aryl, virtue Acyl group, heteroaryl, 4-hetaroylpyrazol, heterocycle alkanoyl, Heterocyclylalkyl, heterocyclylacyl, heterocycle alkanoyl are folded Nitrogen base alkyl, condensed-bicyclic base condense miscellaneous bicyclic group, and condensed-bicyclic base-C (=O)-condenses miscellaneous bicyclic group-C (=O)-, Condensed-bicyclic base amino-C (=O)-, condensed miscellaneous bicyclic group amino-C (=O)-, spiral shell bicyclic group, the miscellaneous bicyclic group of spiral shell, spiral shell are bicyclic Base aliphatic, the miscellaneous bicyclic group aliphatic of spiral shell, spiral shell bicyclic group-C (=O)-, the miscellaneous bicyclic group-C of spiral shell (=O)-, spiral shell bicyclic group amino- C (=O)-, the miscellaneous bicyclic group amino-C of spiral shell (=O)-,-C (=O) NR5R6, R5R6N-S(=O)t-, R5S(=O)t-, R6R5N- alkane Base, R5S(=O)tAlkyl, R5R6N-C (=O)-alkyl, aryl-(CH2)p-G-(CH2)m, heteroaryl-(CH2)p-G- (CH2)m, heterocycle-(CH2)p-G-(CH2)m, or naphthenic base-(CH2)p-G-(CH2)m, wherein G is O, S, NR7, S (=O), S(=O)2,C(=O), -C(=O)N(R5)-, -OC(=O)N(R5)-, -OC(=O)-, -N(R5)C(=O)N(R5)-, - (R5)N-S(=O)t-, -OS(=O)t, or-OS (=O)tN(R5)-;T is l or 2;P and m is each independently 0, l, 2,3 Or 4;Or aryl-(CH therein2)p-G-(CH2)m, heteroaryl-(CH2)p-G-(CH2)m, heterocycle-(CH2)p-G- (CH2)m, or naphthenic base-(CH2)p-G-(CH2)mCan by one or more be selected from F, Cl, Br, I, cyano, alkyl, Alkenyl, alkynyl, alkoxy, aryl, heteroaryl, carbocylic radical, the substituent group substitution of heterocycle;
Each R3And R4Can be identical or different, it is each independently hydrogen, halogen, hydroxyl, amino, nitro, cyano, carboxylic Base, alkyl, halogenated alkyl, alkoxy, alkylamino, alkyl acyl, hydroxy alkoxy base, Hydroxyalkylamino, hydroxyl alkane acyl Base, halogenated alkoxy, halogenated alkylamino, ohaloalkanoyl, aminoalkoxy, naphthenic base, cycloalkyl oxy, cycloalkanes Base amino, cycloalkanoyl, alkenyl, alkenylalkoxy, alkenyl alkylamino, alkenyl alkanoyl, alkynyl, alkynyl alcoxyl Base, alkynyl alkylamino, alkynyl alkanoyl, aryl, aryloxy group, aroyl, fragrant amino, alkoxy aryl, aryl alkane Amino, heteroaryl, heteroaryloxy, 4-hetaroylpyrazol, heteroaryl amino, heteroarylalkoxy, heteroarylalkylamino, heterocycle Base alkanoyl, Heterocyclylalkyl, heterocycle oxygroup, heterocyclylamino group, heterocyclylacyl, heterocyclylalkoxy, heterocycle Alkylamino, heterocycle alkanoyl, azido alkoxy, condensed-bicyclic base condense miscellaneous bicyclic group, condensed-bicyclic base fat Race condenses miscellaneous bicyclic group aliphatic, and condensed-bicyclic base oxygroup condenses miscellaneous bicyclic group oxygroup, and condensed-bicyclic base amino is thick Miscellaneous bicyclic group amino is closed, condensed-bicyclic base alkoxy condenses miscellaneous bicyclic group alkoxy, and condensed-bicyclic base alkylamino condenses Miscellaneous bicyclic group alkylamino, condensed-bicyclic base oxygroup alkoxy condense miscellaneous bicyclic group oxygroup alkoxy, condensed-bicyclic base amino Alkoxy, condenses miscellaneous bicyclic group aminoalkoxy, and condensed-bicyclic base-C (=O)-, condensed-bicyclic base-C (=O) O- are condensed miscellaneous Bicyclic group-C (=O)-condenses miscellaneous bicyclic group-C (=O) O-, condensed-bicyclic base amino-C (=O)-, condenses miscellaneous bicyclic group amino- C (=O)-, condensed-bicyclic base-C (=O) N (R5)-, condenses miscellaneous bicyclic group-C (=O) N (R5)-, spiral shell bicyclic group, spiral shell are miscellaneous bicyclic Base, spiral shell bicyclic group aliphatic, the miscellaneous bicyclic group aliphatic of spiral shell, spiral shell bicyclic group oxygroup, the miscellaneous bicyclic group oxygroup of spiral shell, spiral shell bicyclic group Amino, the miscellaneous bicyclic group amino of spiral shell, spiral shell bicyclic group alkoxy, the miscellaneous bicyclic group alkoxy of spiral shell, spiral shell bicyclic group alkylamino, spiral shell are miscellaneous Bicyclic group alkylamino, spiral shell bicyclic group oxygroup alkoxy, the miscellaneous bicyclic group oxygroup alkoxy of spiral shell, spiral shell bicyclic group aminoalkoxy, The miscellaneous bicyclic group aminoalkoxy of spiral shell, spiral shell bicyclic group-C (=O)-, spiral shell bicyclic group-C (=O) O-, the miscellaneous bicyclic group-C of spiral shell (=O)-, Miscellaneous bicyclic group-the C of spiral shell (=O) O-, spiral shell bicyclic group amino-C (=O)-, the miscellaneous bicyclic group amino-C of spiral shell (=O)-, spiral shell bicyclic group-C (= O)N(R5Miscellaneous bicyclic group-the C of)-, spiral shell (=O) N (R5)-, R6R5N-, -C(=O)NR5R6, -OC(=O)NR5R6, -OC(=O)OR5, -N(R5)C(=O)NR5R6, -N(R5)C(=O)OR6, -N(R5)C(=O)-R6, R5R6N-S(=O)t-, R5S(=O)t-, R5S(= O)tN(R6)-, R6R5N- alkyl, R5S(=O)tAlkyl, R5R6N-C (=O)-alkyl, R6R5N- alkoxies, R5S(=O)tAlkane Oxygroup, R5R6N-C (=O)-alkoxy, aryl-(CH2)p-G-(CH2)m, heteroaryl-(CH2)p-G-(CH2)m, heterocycle- (CH2)p-G-(CH2)m, or naphthenic base-(CH2)p-G-(CH2)m, wherein G is O, S, NR7, S(=O), S(=O)2,C(= O), -C(=O)N(R5)-, -OC(=O)N(R5)-, -OC(=O)-, -N(R5)C(=O)N(R5)-, -(R5)N-S(=O)t-, - OS(=O)t, or-OS (=O)tN(R5)-;T is l or 2;P and m is each independently 0, l, 2,3 or 4;Or it is wherein fragrant Base-(CH2)p-G-(CH2)m, heteroaryl-(CH2)p-G-(CH2)m, heterocycle-(CH2)p-G-(CH2)m, or naphthenic base- (CH2)p-G-(CH2)mCan F, Cl, Br, I, alkyl, alkenyl, alkynyl, alkoxy or cyanogen be selected from by one or more The substituent group of base replaces;
R7Can be identical or different, it is each independently hydrogen, R5R6NC(=O)-, R5OC(=O)-, R5C(=O)-, R5R6NS (=O)-, R5OS(=O)-, R5S(=O)-, R5R6NS(=O)2-, R5OS(=O)2-, R5S(=O)2, aliphatic, halogenated fat Fat race, hydroxyl group aliphatic, amino aliphatic, alkoxy aliphatic, alkylamino aliphatic, alkylthio group aliphatic, aryl Aliphatic, heteroaryl aliphatic, heterocycle aliphatic, naphthenic base aliphatic, aryloxy group aliphatic, heterocycle oxygroup fat Fat race, cycloalkyl oxy aliphatic, fragrant amino aliphatic, heterocyclylamino group aliphatic, cycloalkyl amino aliphatic, virtue Base, heteroaryl, heterocycle or carbocylic radical;
Each R5And R6It independently is hydrogen, aliphatic, halogenated aliphatic, hydroxyl group aliphatic, amino aliphatic, alkoxy fat Fat race, alkylamino aliphatic, alkylthio group aliphatic, aromatic yl aliphat, heteroaryl aliphatic, heterocycle aliphatic, ring Alkyl fatty race, aryloxy group aliphatic, heterocycle oxygroup aliphatic, cycloalkyl oxy aliphatic, fragrant amino aliphatic, Heterocyclylamino group aliphatic, cycloalkyl amino aliphatic, aryl, heteroaryl, heterocycle or naphthenic base;Work as R5And R6It is connected in On the same nitrogen-atoms, R5, R6Can be randomly formed substituted or non-substituted 3-7 membered rings with nitrogen-atoms, condensed-bicyclic or Spiral shell is bicyclic;The hetero atom in heterocycle, heteroaryl, condensed miscellaneous bicyclic group, the miscellaneous bicyclic group of spiral shell involved in above-mentioned group is independent 1-5 hetero atom of the ground in N, O, S, Se;
Above-mentioned R1, R2, R3, R4, R5, R6, R7Group can appoint by deuterium, halogen, hydroxyl, methylol, carboxyl, acetyl Amino, alkyl（Such as methyl, ethyl, propyl）, alkoxy（Such as methoxyl group, ethyoxyl, tert-butoxy）, alkylamino, cycloalkanes Base, alkenyl, alkynyl, trifluoromethyl, trifluoroacetyl group, sulfydryl, halogen, nitro, amino, azido (- N3), Guanidine radicals, cyano, tertbutyloxycarbonyl (- Boc), carbonyl (- C=O), oxo (=O) is thio (=S), sulfonyl, virtue Base, heteroaryl, the substitution of one or more of heterocycle.
In other embodiments, the compound of the present invention is general formula III-X compounds represented, or general formula III- The stereoisomer geometric isomer of compound shown in X, tautomer, nitrogen oxides, raceme, hydrate, solvate, Metabolite, pharmaceutically acceptable salt or prodrug：
,
Wherein Y is O or S; T1, T2, T3, T4, T5, T6Separate is CR1, C（R1）2Or N, NR8, wherein T1, T2, T3, T4, T5, T6At most there are three can be N; V, V1, V2Separate is O, S, N or CR1Or NR8; “" indicate singly-bound or be not present;Each R1, R2, R3, R4, R8As follows：
Each R1Can be identical or different, it is each independently H, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, Carboxyl, C1-C20 alkyl, C1-C20 halogenated alkyls, C1-C20 alkoxies, C1-C20 alkylaminos, C1-C20 alkyl acyls, Hydroxyl C1-C20 alkoxies, hydroxyl C1-C20 alkylaminos, hydroxyl C1-C20 alkanoyls, C1-C20 halogenated alkoxies, C1- The halogenated alkylaminos of C20, C1-C20 ohaloalkanoyls, C1-C20 aminoalkoxies, C3-C10 naphthenic base, C3-C10 naphthenic base Oxygroup, C3-C10 cycloalkyl aminos, C3-C10 cycloalkanoyls, C2-C7 alkenyls, C2-C7 alkynyls, C5-C10 aryl, C5-C10 aryloxy group, C5-C10 aroyls, C5-C10 fragrant aminos, C5-C10 aryl C1-C5 alkoxies, C5-C10 aryl alkane Amino, C5-C12 heteroaryls, C5-C12 heteroaryloxies, C5-C12 4-hetaroylpyrazols, C5-C12 heteroaryl amino, C5-C12 are miscellaneous Aryl C1-C5 alkoxies, C5-C12 heteroaryl C1-C5 alkylaminos, C4-C12 heterocycle C1-C5 alkanoyls, C4-C12 heterocycles Alkyl, C4-C12 heterocycle oxygroups, C4-C12 heterocyclylamino groups, C4-C12 heterocyclylacyls, C4-C12 heterocycles C1-C5 Alkoxy, C4-C12 heterocycle C1-C5 alkylaminos, C4-C12 heterocycle C1-C5 alkanoyls, R6R5N-, -C(=O)NR5R6, -OC(=O)NR5R6, -OC(=O)OR5, -N(R5)C(=O)NR5R6, -N(R5)C(=O)OR6, -N(R5)C(=O)-R6, R5R6N-S(=O)t-, R5S(=O)t-, R5S(=O)tN(R6)-, R6R5N- C1-C5 alkyl, R5S(=O)t- C1-C5 alkyl, R5R6N-C (=O)-C1-C5 alkyl, R6R5N- C1-C5 alkoxies, R5S(=O)t- C1-C5 alkoxies, R5R6N-C(=O)- C1-C5 alkoxies, C5-C10 aryl-(CH2)p-G-(CH2)m, C5-C12 heteroaryls-(CH2)p-G-(CH2)m-, C4-C12 Heterocycle-(CH2)p-G-(CH2)m, or C3-C10 naphthenic base-(CH2)p-G-(CH2)m, wherein G is O, S, NR7, S(= O), S(=O)2,C(=O), -C(=O)N(R5)-, -OC(=O)N(R5)-, -OC(=O)-, -N(R5)C(=O)N(R5)-, - (R5)N-S(=O)t-, -OS(=O)t, or-OS (=O)tN(R5)-;T is l or 2;P and m is each independently 0, l, 2,3 Or 4;Or wherein C5-C10 aryl-(CH2)p-G-(CH2)m, C5-C12 heteroaryls-(CH2)p-G-(CH2)m-, C4-C12 Heterocycle-(CH2)p-G-(CH2)m, or C3-C1 naphthenic base-(CH2)p-G-(CH2)mCan F be selected from by one or more, The substituent group of Cl, Br, I, alkyl, alkenyl, alkynyl, alkoxy or cyano replaces.
Wherein each R2, R8It is each independently H, C1-C20 alkyl, C1-C20 halogenated alkyls, C1-C20 alkyl acyls, C1-C20 hydroxyalkanoyls, C1-C20 ohaloalkanoyls, C3-C10 naphthenic base, C3-C10 cycloalkanoyls, C2-C7 alkene Base, C2-C7 alkenyl alkanoyls, C2-C7 alkynyls, C2-C7 alkynyl alkanoyls, C5-C10 aryl, C5-C10 aroyls, C5-C12 heteroaryls, C5-C12 4-hetaroylpyrazols, C4-C12 heterocycle alkanoyls, C4-C12 Heterocyclylalkyls, C4-C12 heterocycles Base acyl group, C4-C12 heterocycle C1-C5 alkanoyls, C5-C12 condensed-bicyclic bases, C5-C12 condense miscellaneous bicyclic group ,-C (=O) NR5R6, R5R6N-S(=O)t-, R5S(=O)t-, R6R5N-C1-C5 alkyl, R5S(=O)t- C1-C5 alkyl, R5R6N-C(= O)-C1-C5 alkyl, C5-C10 aryl-(CH2)p-G-(CH2)m, C5-C12 heteroaryls-(CH2)p-G-(CH2)m-, C4-C12 Heterocycle-(CH2)p-G-(CH2)m, or C3-C10 naphthenic base-(CH2)p-G-(CH2)m, wherein G is O, S, NR7, S(= O), S(=O)2,C(=O), -C(=O)N(R5)-, -OC(=O)N(R5)-, -OC(=O)-, -(R5)N-S(=O)t-, -OS(= O)t, or-OS (=O)tN(R5)-;T is l or 2;P and m is each independently 0, l, 2,3 or 4;Or wherein C5-C10 Aryl-(CH2)p-G-(CH2)m, C5-C12 heteroaryls-(CH2)p-G-(CH2)m, C4-C12 heterocycles-(CH2)p-G- (CH2)m, or C3-C10 naphthenic base-(CH2)p-G-(CH2)mCan by one or more be selected from F, Cl, Br, I, cyano, Alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, carbocylic radical, the substituent group substitution of heterocycle.
R3, R4It is each independently H, F, Cl, Br, I, C1-C20 alkyl, C1-C20 halogenated alkyls, C1-C20 Alkyl acyl, C1-C20 hydroxyalkanoyls, C1-C20 ohaloalkanoyls, C3-C10 naphthenic base, C3-C10 cycloalkanoyls, C2-C7 alkenyls, C2-C7 alkenyl alkanoyls, C2-C7 alkynyls, C2-C7 alkynyl alkanoyls, C5-C10 aryl, C5-C10 virtues Acyl group, C5-C12 heteroaryls, C5-C12 4-hetaroylpyrazols, C4-C12 heterocycle alkanoyls, C4-C12 Heterocyclylalkyls, C4- C12 heterocyclylacyls, C4-C12 heterocycle C1-C5 alkanoyls, C5-C12 condensed-bicyclic bases, C5-C12 condense miscellaneous bicyclic group, -C(=O)NR5R6, R5R6N-S(=O)t-, R5S(=O)t-, R6R5N-C1-C5 alkyl, R5S(=O)t- C1-C5 alkyl, R5R6N-C (=O)-C1-C5 alkyl, C5-C10 aryl-(CH2)p-G-(CH2)m, C5-C12 heteroaryls-(CH2)p-G- (CH2)m, C4-C12 heterocycles-(CH2)p-G-(CH2)m, or C3-C10 naphthenic base-(CH2)p-G-(CH2)m, wherein G is O, S, NR7, S(=O), S(=O)2,C(=O), -C(=O)N(R5)-, -OC(=O)N(R5)-, -OC(=O)-, -N(R5)C (=O)N(R5)-, -(R5)N-S(=O)t-, -OS(=O)t, or-OS (=O)tN(R5)-;T is l or 2;P and m is respectively independent Ground is 0, l, 2,3 or 4;Or wherein C5-C10 aryl-(CH2)p-G-(CH2)m, C5-C12 heteroaryls-(CH2)p-G- (CH2)m, C4-C12 heterocycles-(CH2)p-G-(CH2)m, or C3-C10 naphthenic base-(CH2)p-G-(CH2)mIt can be by one It is a or multiple selected from F, Cl, Br, I, cyano, alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, carbocyclic ring Base, the substituent group substitution of heterocycle.
In some embodiments, wherein each R of compound of the present invention1Can be identical or different, it is each independently H, D, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, butyl, Tertiary butyl, C5H11, C6H13, C8H17, trifluoromethyl, hydroxymethyl, amino methyl, methoxyl group, ethyoxyl, tertiary fourth Oxygroup, methylamino, ethylamino, isopropylamino, 3- hydroxyl-propyls, acetyl group, trifluoroacetyl group, Cyanoacetyl, Methylamino acetyl group, propiono, iso-propionyl, 2- hydroxypropanoyls, 2- aminopropionyls, 2- chlorine propionos, 2- Bromine propiono, valeryl, caproyl, heptanoyl group, methacrylyl, phenyl, benzoyl, p-nitrophenyl are right Methyl benzoyl, fluoro benzoyl, p-benzoyl base, to methoxybenzoyl base, 2,4- dimethyl benzene first Acyl group, azidobenzoyl, benzyl, p-chlorobenzyl, vinyl, acrylic, allyl, n-butene base are different The hydro carbons and its containing oxygen derivative of the multiple of cyclobutenyl, n-pentene base, isopentene group, isoprene or isoprene unit (monoterpene or sequiterpene substituent group), cyclopropyl, ring propiono, ring valeryl, cyclohexanoyl, 3- picolinoyls, naphthalene Base, phenethyl imidazole radicals, pyridyl group, pyrrole radicals, oxazolyl, isoxazolyl, triazol radical, tetrazole base, furans Base, thienyl, thiazolyl, piperidyl, piperazinyl, indyl, carbazyl, benzofuranyl tetrahydrofuran base, four Hydrogen pyranose, pyrimidine bases, purine bases ,-N (CH3)2,-C (C=O) NH-C1-C4 alkyl ,-OC (C=O)-NH-C1-C4 Alkyl ,-OC (O=O) O-C1-C4 alkyl ,-NHC (=O) NH-C1-C4 alkyl ,-NHC (=O) O-C1-C4 alkyl ,-NHC (= O)-C1-C4 alkyl, C1-C4 alkyl-NH-S (=O)2, C1-C4 alkyl S (=O)2, C1-C4 alkyl S (=O)2NH-, benzene Base-(CH2)P-G-(CH2)m, difluorophenyl-(CH2)P-G-(CH2)m, thiazolyl-(CH2)p-G-(CH2)m, pyridyl group- (CH2)p-G-(CH2)m, phenylethyl, cyclohexyl-(CH2)p-G-(CH2)m, wherein G is O, S, S (=O), S (= O)2, C(=O);P and m is each independently 0,1,2 or 3;Or wherein C5-C10 aryl-(CH2)P-G-(CH2)mIt can be with F, Cl, Br, I, methyl, ethyl, propyl, acetenyl, propinyl, butynyl, methoxy are selected from by one or more The substituent group of base, ethyoxyl or cyano replaces;Or above-mentioned R1It is welcome by D, F, Cl, Br, I, hydroxyl, hydroxyl first Base, carboxyl, acetylamino, alkyl（Such as methyl, ethyl, propyl）, alkoxy（Such as methoxyl group, ethyoxyl, tert-butoxy）, Alkylamino, naphthenic base, alkenyl, alkynyl, trifluoromethyl, trifluoroacetyl group, sulfydryl, halogen, nitro, amino are folded Nitrogen base (- N3), guanidine radicals, cyano, tertbutyloxycarbonyl (- Boc), carbonyl (- C=O), oxo (=O) is thio (=S), Sulfonyl, aryl, heteroaryl, the substitution of one or more of heterocycle.
Wherein each R2, R8Can be identical or different, it is each independently H, methyl, ethyl, propyl, isopropyl, Butyl, tertiary butyl, C5H11, C6H13, C8H17, trifluoromethyl, hydroxymethyl, amino methyl, 3- hydroxyl-propyls, second Acyl group, trifluoroacetyl group, Cyanoacetyl, methylamino acetyl group, propiono, iso-propionyl, 2- hydroxypropanoyls, 2- aminopropionyls, 2- chlorine propionos, 2- bromine propionos, valeryl, caproyl, heptanoyl group, methacrylyl, benzene Base, benzoyl, p-nitrophenyl, to methyl benzoyl, fluoro benzoyl, p-benzoyl base, to first Oxygroup benzoyl, 2,4- dimethylbenzoyls, azidobenzoyl, benzyl, p-chlorobenzyl, vinyl, Acrylic, allyl, n-butene base, isobutenyl, n-pentene base, isopentene group, cyclopropyl, ring propiono, ring Valeryl, cyclohexanoyl, 3- picolinoyls, naphthalene, phenethyl imidazole radicals, pyridyl group, pyrrole radicals, oxazolyls, Isoxazolyl, triazol radical, tetrazole base, furyl, pyranose, thienyl, thiazolyl, piperidyl, piperazinyl, Indyl, carbazyl, benzofuranyl tetrahydrofuran base, THP trtrahydropyranyl, pyrimidine bases, purine bases, pentose Base, hexose base ,-(C=O) NH-C1-C4 alkyl, C1-C4 alkyl-NH-S (=O)2, C1-C4 alkyl S (=O)2, benzene Base-(CH2)P-G-(CH2)m, difluorophenyl-(CH2)P-G-(CH2) m, thiazolyl-(CH2)p-G-(CH2)m, pyridyl group- (CH2)p-G-(CH2)m, phenylethyl, cyclohexyl-(CH2)p-G-(CH2)m, wherein G is O, S, S (=O), S (= O)2, C(=O);P and m is each independently 0,1,2 or 3;Or wherein C5-C10 aryl-(CH2)P-G-(CH2)mIt can be with F, Cl, Br, I, methyl, ethyl, propyl, acetenyl, propinyl, butynyl, methoxy are selected from by one or more The substituent group of base, ethyoxyl or cyano replaces;Or above-mentioned R2, R8It is welcome by D, F, Cl, Br, I, hydroxyl, Hydroxyl, methylol, carboxyl, acetylamino, C1-C5 alkyl（Such as methyl, ethyl, propyl）, C1-C5 alkoxies, C1-C5 Alkylamino, trifluoromethyl, trifluoroacetyl group, sulfydryl, nitro, amino, azido (- N3), guanidine radicals, cyano, uncle Butoxy carbonyl (- Boc), carbonyl (- C=O), oxo (=O) is thio (=S), sulfonyl, one or more of phenyl Substitution.
Each R3, R4Can be identical or different, it is each independently H, D, F, Cl, Br, I, hydroxyl, amino, nitre Base, cyano, methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, C5H11, C6H13, C8H17, trifluoromethyl, Hydroxymethyl, amino methyl, methoxyl group, ethyoxyl, tert-butoxy, methylamino, ethylamino, isopropylamino, 3- hydroxyls Base-propyl, acetyl group, trifluoroacetyl group, Cyanoacetyl, methylamino acetyl group, propiono, iso-propionyl, 2- Hydroxypropanoyl, 2- aminopropionyls, 2- chlorine propionos, 2- bromine propionos, valeryl, caproyl, heptanoyl group are different Crotonyl, phenyl, benzoyl, p-nitrophenyl, to methyl benzoyl, fluoro benzoyl, p-aminophenyl Formoxyl, to methoxybenzoyl base, 2,4- dimethylbenzoyls, azidobenzoyl, benzyl, to benzyl chloride Base, vinyl, acrylic, allyl, n-butene base, isobutenyl, n-pentene base, isopentene group, isoprene Or the hydro carbons and its containing oxygen derivative (monoterpene or sequiterpene substituent group) of the multiple of isoprene unit, cyclopropyl, ring propionyl Base, ring valeryl, cyclohexanoyl, 3- picolinoyls, naphthalene, phenethyl imidazole radicals, pyridyl group, pyrrole radicals are disliked Oxazolyl, isoxazolyl, triazol radical, tetrazole base, furyl, thienyl, thiazolyl, piperidyl, piperazinyl, Indyl, carbazyl, benzofuranyl tetrahydrofuran base, THP trtrahydropyranyl, pyrimidine bases, purine bases ,-N (CH3)2,-C (C=O) NH-C1-C4 alkyl ,-OC (C=O)-NH-C1-C4 alkyl ,-OC (O=O) O-C1-C4 alkyl ,-NHC (=O) NH-C1-C4 alkyl ,-NHC (=O) O-C1-C4 alkyl ,-NHC (=O)-C1-C4 alkyl, C1-C4 alkyl-NH-S (= O)2, C1-C4 alkyl S (=O)2, C1-C4 alkyl S (=O)2NH-, phenyl-(CH2)P-G-(CH2)m, difluorophenyl- (CH2)P-G-(CH2)m, thiazolyl-(CH2)p-G-(CH2)m, pyridyl group-(CH2)p-G-(CH2)m, phenylethyl, ring Hexyl-(CH2)p-G-(CH2)m, wherein G is O, S, S (=O), S (=O)2, C(=O);P and m are each independently 0, 1,2 or 3;Or wherein C5-C10 aryl-(CH2)P-G-(CH2)mCan F, Cl, Br, I be selected from by one or more, The substituent group of methyl, ethyl, propyl, acetenyl, propinyl, butynyl, methoxyl group, ethyoxyl or cyano replaces; Or above-mentioned R3, R4It is welcome by D, F, Cl, Br, I, hydroxyl, methylol, carboxyl, acetylamino, alkyl（Such as first Base, ethyl, propyl）, alkoxy（Such as methoxyl group, ethyoxyl, tert-butoxy）, alkylamino, naphthenic base, alkenyl, alkynyl, Trifluoromethyl, trifluoroacetyl group, sulfydryl, halogen, nitro, amino, azido (- N3), guanidine radicals, cyano, tertiary fourth Oxygen carbonyl (- Boc), carbonyl (- C=O), oxo (=O) is thio (=S), sulfonyl, aryl, heteroaryl, heterocycle One or more of base replaces.
Wherein each R7Can be identical or different, it is each independently H, R5R6NC(=O)-, R5OC(=O)-, R5C(= O)-, R5R6NS(=O)-, R5OS(=O)-, R5S(=O)-, R5R6NS(=O)2-, R5OS(=O)2-, R5S(=O)2-, C1-C3 Aliphatic, C1-C3 halogenated aliphatics, C1-C3 hydroxyl group aliphatics, C1-C3 amino aliphatic, C1-C3 alkoxy C 1-C3 fat Fat race, C1-C3 alkylamino C1-C3 aliphatic, C1-C3 alkylthio group C1-C3 aliphatic, C5-C10 aryl C1-C3 aliphatic, C5-C9 heteroaryl C1-C3 aliphatic, C4-C10 heterocycle C1-C3 aliphatic, C3-C10 naphthenic base C1-C3 aliphatic, C5- C10 aryloxy group C1-C3 aliphatic, C4-C10 heterocycle oxygroup C1-C3 aliphatic, C3-C10 cycloalkyl oxies C1-C3 fat Race, C5-C10 fragrant amino C1-C3 aliphatic, C4-C10 heterocyclylamino group C1-C3 aliphatic, C3-C10 cycloalkyl aminos C1- C3 aliphatic, C5-C10 aryl, C5-C10 heteroaryls, C4-C10 heterocycles or C3-C10 naphthenic base.
Wherein each R5And R6It independently is H, D, C1-C3 aliphatic, C1-C3 halogenated aliphatics, C1-C3 hydroxy aliphatics Race, C1-C3 amino aliphatic, C1-C3 alkoxy C 1-C3 aliphatic, C1-C3 alkylamino C1-C3 aliphatic, C1-C3 alkane Sulfenyl C1-C3 aliphatic, C5-C10 aryl C1-C3 aliphatic, C5-C9 heteroaryl C1-C3 aliphatic, C4-C10 heterocycles C1-C3 aliphatic, C3-C10 naphthenic base C1-C3 aliphatic, C5-C10 aryloxy group C1-C3 aliphatic, C4-C10 heterocyclyloxies Base C1-C3 aliphatic, C3-C10 cycloalkyl oxy C1-C3 aliphatic, C5-C10 fragrant amino C1-C3 aliphatic, C4-C10 are miscellaneous Ring group amino C1-C3 aliphatic, C3-C10 cycloalkyl amino C1-C3 aliphatic, C5-C10 aryl, C5-C10 heteroaryls, C4-C10 heterocycles or C3-C10 naphthenic base;Work as R5And R6It is connected on the same nitrogen-atoms, R5, R6It can be arbitrary with nitrogen-atoms Ground forms substituted or non-substituted 3-7 membered rings.
Above-mentioned R1, R2, R3, R4, R5, R6, R7, R8Group can appoint by deuterium, halogen, hydroxyl, methylol, carboxylic Base, acetylamino, alkyl（Such as methyl, ethyl, propyl）, alkoxy（Such as methoxyl group, ethyoxyl, tert-butoxy）, alkane ammonia Base, naphthenic base, alkenyl, alkynyl, trifluoromethyl, trifluoroacetyl group, sulfydryl, halogen, nitro, amino, azido (-N3), guanidine radicals, cyano, tertbutyloxycarbonyl (- Boc), carbonyl (- C=O), oxo (=O) is thio (=S), sulphonyl Base, aryl, heteroaryl, the substitution of one or more of heterocycle.
In some embodiments, wherein each R of compound of the present invention1Can be identical or different, it is each independently H, D, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, butyl, Tertiary butyl, C5H11, C6H13, C8H17, trifluoromethyl, hydroxymethyl, amino methyl, methoxyl group, ethyoxyl, tertiary fourth Oxygroup, methylamino, ethylamino, isopropylamino, 3- hydroxyl-propyls, acetyl group, trifluoroacetyl group, Cyanoacetyl, Methylamino acetyl group, propiono, iso-propionyl, 2- hydroxypropanoyls, 2- aminopropionyls, 2- chlorine propionos, 2- Bromine propiono, valeryl, caproyl, heptanoyl group, methacrylyl, phenyl, benzoyl, p-nitrophenyl are right Methyl benzoyl, fluoro benzoyl, p-benzoyl base, to methoxybenzoyl base, 2,4- dimethyl benzene first Acyl group, azidobenzoyl, benzyl, p-chlorobenzyl, vinyl, acrylic, allyl, n-butene base are different The hydro carbons and its containing oxygen derivative of the multiple of cyclobutenyl, n-pentene base, isopentene group, isoprene or isoprene unit (monoterpene or sequiterpene substituent group), cyclopropyl, ring propiono, ring valeryl, cyclohexanoyl, 3- picolinoyls, naphthalene Base, phenethyl imidazole radicals, pyridyl group, pyrrole radicals, oxazolyl, isoxazolyl, triazol radical, tetrazole base, furans Base, thienyl, thiazolyl, piperidyl, piperazinyl, indyl, carbazyl, benzofuranyl tetrahydrofuran base, four Hydrogen pyranose, pyrimidine bases, purine bases ,-N (CH3)2,-C (C=O) NH-C1-C4 alkyl ,-OC (C=O)-NH-C1-C4 Alkyl ,-OC (O=O) O-C1-C4 alkyl ,-NHC (=O) NH-C1-C4 alkyl ,-NHC (=O) O-C1-C4 alkyl ,-NHC (= O)-C1-C4 alkyl, C1-C4 alkyl-NH-S (=O)2, C1-C4 alkyl S (=O)2, C1-C4 alkyl S (=O)2NH-, benzene Base-(CH2)P-G-(CH2)m, difluorophenyl-(CH2)P-G-(CH2)m, thiazolyl-(CH2)p-G-(CH2)m, pyridyl group- (CH2)p-G-(CH2)m, phenylethyl, cyclohexyl-(CH2)p-G-(CH2)m, wherein G is O, S, S (=O), S (= O)2, C(=O);P and m is each independently 0,1,2 or 3;Or wherein C5-C10 aryl-(CH2)P-G-(CH2)mIt can be with F, Cl, Br, I, methyl, ethyl, propyl, acetenyl, propinyl, butynyl, methoxy are selected from by one or more The substituent group of base, ethyoxyl or cyano replaces;Or above-mentioned R1It is welcome by D, F, Cl, Br, I, hydroxyl, hydroxyl first Base, carboxyl, acetylamino, alkyl（Such as methyl, ethyl, propyl）, alkoxy（Such as methoxyl group, ethyoxyl, tert-butoxy）, Alkylamino, naphthenic base, alkenyl, alkynyl, trifluoromethyl, trifluoroacetyl group, sulfydryl, halogen, nitro, amino are folded Nitrogen base (- N3), guanidine radicals, cyano, tertbutyloxycarbonyl (- Boc), carbonyl (- C=O), oxo (=O) is thio (=S), Sulfonyl, aryl, heteroaryl, the substitution of one or more of heterocycle.
Wherein each R2, R8Can be identical or different, it is each independently H, methyl, ethyl, propyl, isopropyl, Butyl, tertiary butyl, C5H11, C6H13, C8H17, trifluoromethyl, hydroxymethyl, amino methyl, 3- hydroxyl-propyls, second Acyl group, trifluoroacetyl group, Cyanoacetyl, methylamino acetyl group, propiono, iso-propionyl, 2- hydroxypropanoyls, 2- aminopropionyls, 2- chlorine propionos, 2- bromine propionos, valeryl, caproyl, heptanoyl group, methacrylyl, benzene Base, benzoyl, p-nitrophenyl, to methyl benzoyl, fluoro benzoyl, p-benzoyl base, to first Oxygroup benzoyl, 2,4- dimethylbenzoyls, azidobenzoyl, benzyl, p-chlorobenzyl, vinyl, Acrylic, allyl, n-butene base, isobutenyl, n-pentene base, isopentene group, cyclopropyl, ring propiono, ring Valeryl, cyclohexanoyl, 3- picolinoyls, naphthalene, phenethyl imidazole radicals, pyridyl group, pyrrole radicals, oxazolyls, Isoxazolyl, triazol radical, tetrazole base, furyl, pyranose, thienyl, thiazolyl, piperidyl, piperazinyl, Indyl, carbazyl, benzofuranyl tetrahydrofuran base, THP trtrahydropyranyl, pyrimidine bases, purine bases, pentose Base, hexose base ,-(C=O) NH-C1-C4 alkyl, C1-C4 alkyl-NH-S (=O)2, C1-C4 alkyl S (=O)2, benzene Base-(CH2)P-G-(CH2)m, difluorophenyl-(CH2)P-G-(CH2) m, thiazolyl-(CH2)p-G-(CH2)m, pyridyl group- (CH2)p-G-(CH2)m, phenylethyl, cyclohexyl-(CH2)p-G-(CH2)m, wherein G is O, S, S (=O), S (= O)2, C(=O);P and m is each independently 0,1,2 or 3;Or wherein C5-C10 aryl-(CH2)P-G-(CH2)mIt can be with F, Cl, Br, I, methyl, ethyl, propyl, acetenyl, propinyl, butynyl, methoxy are selected from by one or more The substituent group of base, ethyoxyl or cyano replaces;Or above-mentioned R2, R8It is welcome by D, F, Cl, Br, I, hydroxyl, Hydroxyl, methylol, carboxyl, acetylamino, C1-C5 alkyl（Such as methyl, ethyl, propyl）, C1-C5 alkoxies, C1-C5 Alkylamino, trifluoromethyl, trifluoroacetyl group, sulfydryl, nitro, amino, azido (- N3), guanidine radicals, cyano, uncle Butoxy carbonyl (- Boc), carbonyl (- C=O), oxo (=O) is thio (=S), sulfonyl, one or more of phenyl Substitution.
Each R3, R4Can be identical or different, it is each independently H, D, F, Cl, Br, I, hydroxyl, amino, nitre Base, cyano, methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, C5H11, C6H13, C8H17, trifluoromethyl, Hydroxymethyl, amino methyl, methoxyl group, ethyoxyl, tert-butoxy, methylamino, ethylamino, isopropylamino, 3- hydroxyls Base-propyl, acetyl group, trifluoroacetyl group, Cyanoacetyl, methylamino acetyl group, propiono, iso-propionyl, 2- Hydroxypropanoyl, 2- aminopropionyls, 2- chlorine propionos, 2- bromine propionos, valeryl, caproyl, heptanoyl group are different Crotonyl, phenyl, benzoyl, p-nitrophenyl, to methyl benzoyl, fluoro benzoyl, p-aminophenyl Formoxyl, to methoxybenzoyl base, 2,4- dimethylbenzoyls, azidobenzoyl, benzyl, to benzyl chloride Base, vinyl, acrylic, allyl, n-butene base, isobutenyl, n-pentene base, isopentene group, isoprene Or the hydro carbons and its containing oxygen derivative (monoterpene or sequiterpene substituent group) of the multiple of isoprene unit, cyclopropyl, ring propionyl Base, ring valeryl, cyclohexanoyl, 3- picolinoyls, naphthalene, phenethyl imidazole radicals, pyridyl group, pyrrole radicals are disliked Oxazolyl, isoxazolyl, triazol radical, tetrazole base, furyl, thienyl, thiazolyl, piperidyl, piperazinyl, Indyl, carbazyl, benzofuranyl tetrahydrofuran base, THP trtrahydropyranyl, pyrimidine bases, purine bases ,-N (CH3)2,-C (C=O) NH-C1-C4 alkyl ,-OC (C=O)-NH-C1-C4 alkyl ,-OC (O=O) O-C1-C4 alkyl ,-NHC (=O) NH-C1-C4 alkyl ,-NHC (=O) O-C1-C4 alkyl ,-NHC (=O)-C1-C4 alkyl, C1-C4 alkyl-NH-S (= O)2, C1-C4 alkyl S (=O)2, C1-C4 alkyl S (=O)2NH-, phenyl-(CH2)P-G-(CH2)m, difluorophenyl- (CH2)P-G-(CH2)m, thiazolyl-(CH2)p-G-(CH2)m, pyridyl group-(CH2)p-G-(CH2)m, phenylethyl, ring Hexyl-(CH2)p-G-(CH2)m, wherein G is O, S, S (=O), S (=O)2, C(=O);P and m are each independently 0, 1,2 or 3;Or wherein C5-C10 aryl-(CH2)P-G-(CH2)mCan F, Cl, Br, I be selected from by one or more, The substituent group of methyl, ethyl, propyl, acetenyl, propinyl, butynyl, methoxyl group, ethyoxyl or cyano replaces; Or above-mentioned R3, R4It is welcome by D, F, Cl, Br, I, hydroxyl, methylol, carboxyl, acetylamino, alkyl（Such as first Base, ethyl, propyl）, alkoxy（Such as methoxyl group, ethyoxyl, tert-butoxy）, alkylamino, naphthenic base, alkenyl, alkynyl, Trifluoromethyl, trifluoroacetyl group, sulfydryl, halogen, nitro, amino, azido (- N3), guanidine radicals, cyano, tertiary fourth Oxygen carbonyl (- Boc), carbonyl (- C=O), oxo (=O) is thio (=S), sulfonyl, aryl, heteroaryl, heterocycle One or more of base replaces.
In further embodiments, the compounds of this invention includes the change of the structure or following one structure of following one Isomers, stereoisomer, racemic modification, the non-equal amount of mixture of enantiomter, geometric isomer, solvate, pharmacy The solvate of upper acceptable salt or its salt, or prodrug:
。
One aspect of the present invention is related to pharmaceutical composition, including the compound of the present invention, or its stereoisomer, geometry Isomers, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or Their prodrug, or optional pharmaceutically acceptable carrier, excipient, diluent, adjuvant, medium, or they Combination.
One aspect of the present invention is related to the method for preventing, handling, treating or mitigate patient's various diseases caused by virus, Including using the pharmaceutically acceptable effective dose of the pharmaceutical composition of the compounds of this invention to be administered patient.
One aspect of the present invention is related to the method for preventing, handling, treating or mitigate patient's various diseases caused by virus, Including using the pharmaceutically acceptable effective dose of the compounds of this invention to be administered patient.
Another aspect of the present invention is related to the compound of the present invention and is used to prepare for preventing, handling, treat or mitigating patient The purposes of the drug of various diseases caused by virus.
Another aspect of the present invention, which is related to being used to prepare using a kind of pharmaceutical composition comprising the compound of the present invention, to be used for The purposes for the drug prevent, handle, treating or mitigate patient's various diseases caused by virus.
On the other hand, preventing or treating to move using the compounds of this invention or its pharmaceutical composition the present invention relates to a kind of The method for application of object or human body various diseases caused by virus, the purposes include to use the compound of the present invention or its drug Pharmaceutically acceptable effective therapeutic dose of composition is administered human body or animal.
Some of embodiments are, of the present invention by RSV, HSV, EV71, H1N1, H3N2, H5N1, H7N9, Cox- Application in the drug of disease caused by B3, HBV, HIV, FMDV, SARS etc., the disease select breathing problem, pneumonia, gum Fash, bleb and the herpetic pharynx at the positions such as stomatitis, keratoconjunctivitis, encephalitis, hepatitis, genital system infection, hand, foot, oral cavity Gorge inflammation, hand-foot-and-mouth disease, immunity disease, inflammatory disease etc..
Some of embodiments are that drug of the present invention is for treating Respiratory Syncytial Virus(RSV)（RSV), simple blister Exanthema virus（HSV）, hepatitis B（HBV）, Enterovirus 71 (EV71), influenza virus (H1N1, H3N2, H5N1, H7N9), mouth Disease caused by aphtovirus (FMDV), human immunodeficiency virus (HIV), SARS virus.
Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspect and its The content of his aspect will make more specific complete description below.
Definition and general terms
The present invention will be corresponding to the content determining materialization document list in detail, embodiment is all accompanied by structural formula With the explanation of chemical formula.The present invention, which has, expectedly covers all choices, variant and coordinate, these possible pictures Existing invention field is included in defined in claim like that.Those skilled in the art will identify many similar or equivalent In method described herein and substance, these can be applied to the practice of the present invention.The present invention be limited to absolutely not method and The description of substance.There are many documents and similar substance to distinguish or contradict with the present patent application, including but not limited to The definition of term, the usage of term, the technology of description, or the range that is controlled as the present patent application.
The present invention will apply defined below unless other aspects show.Purpose according to the present invention, chemical element is according to member Plain periodic table, CAS versions and chemicals handbook, 75,thEd, 1994 define.In addition, organic chemistry General Principle is shown in “Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry,” by Michael B. Smith and Jerry March, John. Wiley&Sons, New York:2007, therefore all contents have all merged bibliography.
As described in the invention, the compound of the present invention can optionally be replaced by one or more substituent groups, Such as general formula compound above, or as example special inside embodiment, subclass, and one kindization that the present invention is included Close object.It should be appreciated that this term can exchange use to " optionally replacing " this term with " substituted or non-substituted ".It is general and Speech, term " optionally " whether it is before the term " replaced ", indicate that one or more of given structure hydrogen is former Son is replaced by specific substituent group.Unless other aspects show, one optional substituent group can there are one substituent groups in base The each commutable position of group is replaced.When more than one position can be by one for specific group in given structural formula Or multiple substituent groups are replaced, then substituent group can replace at various locations identical or differently.The wherein substituent group It can be, but be not limited to, halogenated alkyl, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, Alkylamino, alkylthio group, alkyl, alkenyl, alkynyl, heterocycle, sulfydryl, nitro, aryloxy group, heteroaryloxy, oxo (=O), carboxyl, the alkoxy of hydroxyl substitution, the alkyl-C (=O)-of hydroxyl substitution, alkyl-C (=O)-, alkyl-S (= O)-, alkyl-S (=O)2, the alkyl-S (=O)-of hydroxyl substitution, the alkyl-S (=O) of hydroxyl substitution2, Carboxyalkoxy etc. Deng.
Terminology used in the present invention " aliphatic " or " aliphatic group " indicate straight chain（It is i.e. non-branched）Or branch, it takes Generation or non-substituted fully saturated or containing one or more degrees of unsaturation hydrocarbon chain.Unless otherwise detailed instructions, fatty group 1-20 carbon atom is contained in group, and some of embodiments are that aliphatic group contains 1-10 carbon atom, and other is real Applying example is, aliphatic group contains 1-8 carbon atom, and other embodiment is that it is former that aliphatic group contains 1-6 carbon Son, other embodiment are that aliphatic group contains 1-4 carbon atom, and other embodiment is aliphatic group Contain 1-3 carbon atom.Suitable aliphatic group is including but not limited to linear chain or branched chain is substituted or non-substituted Alkyl, alkenyl or alkynyl, such as methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, hexyl, isobutyl group are secondary Butyl, vinyl etc..
Terminology used in the present invention " halogenated aliphatic " indicates aliphatic group by one or more identical or different halogen Atom is replaced, wherein aliphatic group have meaning as described in the present invention, halogen atom, that is, fluorine, chlorine, bromine or iodine, in this way Example including but not limited to trifluoromethyl, trifluoroethyl, chloromethyl, 2- chlorovinyls etc..
Terminology used in the present invention " hydroxyl group aliphatic " indicates that aliphatic group is replaced by one or more hydroxyl groups, Wherein aliphatic group has meaning as described in the present invention, and such example is including but not limited to ethoxy, 2- hydroxyls Base propyl, methylol etc..
Terminology used in the present invention " amino aliphatic " indicates that aliphatic group is replaced by one or more amino groups, Wherein aliphatic group has meaning as described in the present invention, and such example is including but not limited to amino methyl, 2- Amino-ethyl, 2- amino isopropyls etc..
Terminology used in the present invention " alkyl " includes 1-20 carbon atom, or 1-10 carbon atom, or 1-6 carbon original Son, or 1-4 carbon atom, or 1-3 carbon atom saturated straight chain or branch univalence hydrocarbyl, wherein alkyl can independently appoint Selection of land is replaced by one or more substituent groups described in the invention.The further example of alkyl includes, but and unlimited In methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-propyl (n-Pr ,-CH2CH2CH3), isopropyl (i-Pr ,- CH(CH3)2), normal-butyl (n-Bu ,-CH2CH2CH2CH3), isobutyl group (i-Bu ,-CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tertiary butyl (t-Bu ,-C (CH3)3), n-pentyl (- CH2CH2CH2CH2CH3), 2- amyls (- CH (CH3)CH2CH2CH3), 3- amyls (- CH (CH2CH3)2), 2- methyl -2- butyl (- C (CH3)2CH2CH3), 3- methyl -2- fourths Base (- CH (CH3)CH(CH3)2), 3- methyl-1s-butyl (- CH2CH2CH(CH3)2), 2-methyl-1-butene base (- CH2CH(CH3) CH2CH3), n-hexyl (- CH2CH2CH2CH2CH2CH3), 2- hexyls (- CH (CH3)CH2CH2CH2CH3), 3- hexyls (- CH (CH2CH3)(CH2CH2CH3)), 2- methyl -2- amyls (- C (CH3)2CH2CH2CH3), 3- methyl -2- amyls (- CH (CH3)CH (CH3)CH2CH3), 4- methyl -2- amyls (- CH (CH3)CH2CH(CH3)2), 3- methyl -3- amyls (- C (CH3) (CH2CH3)2), 2- methyl -3- amyls (- CH (CH2CH3)CH(CH3)2), 2,3- dimethyl -2- butyl (- C (CH3)2CH (CH3)2), 3,3- dimethyl -2- butyl (- CH (CH3)C(CH3)3), n-heptyl, n-octyl, etc..Term " alkyl " and Its prefix " alkane " uses here, all includes the saturated carbon chains of straight chain and branch.
Term " alkenyl " indicates 2-12 carbon atom, or 2-8 carbon atom, or 2-6 carbon atom, or 2-4 carbon original The monovalent hydrocarbon of sub- linear chain or branched chain, wherein at least one position are undersaturated condition, i.e., a C-C is sp2Double bond, The group of alkenyl groups can be replaced by one or more substituent groups described in the invention individually optionally, including group Have negation " just " or " E ∥ Z " positioning, wherein specific example is including but not limited to vinyl (- CH=CH2), alkene Propyl (- CH2CH=CH2), etc..
Term " alkynyl " indicates 2-12 carbon atom, or 2-8 carbon atom, or 2-6 carbon atom, or 2-4 carbon original The monovalent hydrocarbon of sub- linear chain or branched chain, wherein at least one position are undersaturated condition, i.e., a C-C is tri- keys of sp, wherein Alkynyl group can be replaced by one or more substituent groups described in the invention individually optionally, and specific example includes, But it is not limited to, acetenyl (three CH of-C), propargyl (- CH2Tri- CH of C), etc..
Term " alkyl of hydroxyl substitution " indicates that alkyl group is replaced by one or more hydroxyl groups, wherein alkyl Group has meaning of the present invention.Such example includes, but is not limited to methylol, ethoxy, l, 2- dihydroxies Base ethyl etc..
Term " carbocyclic ring ", " carbocylic radical ", " naphthenic base " refer to monovalence or multivalence, non-aromatic, saturation or part insatiable hunger And ring, and do not include hetero atom, two rings or tricyclic of monocycle or 7-12 carbon atom including 3-12 carbon atom.Tool The bicyclic carbocyclic ring of 7-12 atom can be two rings [4,5], [5,5], [5,6] or [6,6] system, at the same have 9 or The bicyclic carbocyclic ring of 10 atoms can be two rings [5,6] or [6,6] system.Suitable cyclic aliphatic group includes, but not It is limited to, naphthenic base, cycloalkenyl group and cycloalkynyl radical.The example of cyclic aliphatic group further comprises, but is not limited to, ring third Base, cyclobutyl, cyclopenta, 1- cyclopenta -1- alkenyls, 1- cyclopenta -2- alkenyls, 1- cyclopenta -3- alkenyls, hexamethylene Base, 1- cyclohexyl -1- alkenyls, 1- cyclohexyl -2- alkenyls, 1- cyclohexyl -3- alkenyls, cyclohexadienyl, suberyl, ring Octyl, cyclononyl, cyclodecyl, ring undecyl, cyclo-dodecyl, adamantyl etc..And " carbocyclic ring ", " carbon Ring group ", " naphthenic base " can be substituted or non-substituted, and wherein substituent group can be, but be not limited to, halogenated alkyl, Hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocycle Base, sulfydryl, nitro, aryloxy group, the alkoxy of hydroxyl substitution, alkyl-C (=O)-, the alkyl-C (=O)-of hydroxyl substitution, Alkyl-S (=O)-, alkyl-S (=O)2, the alkyl-S (=O)-of hydroxyl substitution, the alkyl-S (=O) of hydroxyl substitution2, carboxyl Alkoxy etc..
Term " cycloalkyl oxy " or " carbocylic radical oxygroup " include the naphthenic base optionally replaced or carbocylic radical, such as present invention It is defined, it is connected on oxygen atom, and be connected with remaining molecule by oxygen atom, such example includes, but not It is limited to cyclopropyl oxygroup, cyclopentyloxy, cyclohexyl oxygroup, the cyclopropyl oxygroup etc. of hydroxyl substitution.
Term " cycloalkyl amino " indicates that amino group is replaced by one or two group of naphthene base, wherein naphthenic base With meaning as described in the present invention, such example is including but not limited to cyclopropylamino, clopentylamino, ring Hexylamino, the cyclopropylamino of hydroxyl substitution, dicyclohexyl amino, Bicyclopropyl amino etc..
Term " cycloalkyl oxy aliphatic " indicates that aliphatic group is replaced by one or more cycloalkyl oxy groups, Wherein aliphatic group and cycloalkyl oxy group have meaning as described in the present invention, and such example includes, but not It is limited to cyclopropyl oxygroup methyl, cyclopropyl oxygroup ethyl, cyclopentyloxymethyl, cyclopentyloxy ethyl, cyclohexyl oxygen Base ethyl, halogenated cyclopropyl oxygroup ethyl etc..
Term " cycloalkyl amino aliphatic " indicates that aliphatic group is replaced by one or more cycloalkylamino groups, Wherein aliphatic group and cycloalkylamino group have meaning as described in the present invention, and such example includes, but not It is limited to Cyclopropylaminomethyl, cyclopropylamino hexyl, clopentylamino methyl, clopentylamino ethyl, cyclohexyl ammonia Base ethyl, halogenated cyclopropyl amino-ethyl etc..
Term " naphthenic base aliphatic " or " carbocylic radical aliphatic " indicate that aliphatic group can be by one or more naphthenic base Group or carbocylic radical group are replaced, wherein naphthenic base, or carbocylic radical and aliphatic group have and contain as described in the present invention Justice, such example is including but not limited to Cvclopropvlmethvl, cyclopropylethyl, Cyclopropylpropyl, cyclopentyl-methyl, Cyclohexyl-ethyl etc..
Term " heterocycle ", " heterocycle ", " heteroalicyclic " or " heterocycle " are used interchangeably here, all refer to list Ring, bicyclic, or three-ring system, one or more atoms are replaced by hetero atom individually optionally in beanstalk middle ring, and ring can be with It is fully saturated or comprising one or more degrees of unsaturation, but definitely not aromatic, is only connected to there are one tie point Other molecules get on.One or more ring hydrogen atoms are individually optionally by one or more substituent groups described in the invention Replaced.Some of embodiments are that " heterocycle " " heterocycle " " heteroalicyclic " or " heterocycle " group are the lists of 3-7 membered rings Ring（1-6 carbon atom and be N, O, P, the 1-3 hetero atom of S, in this S or P optionally by one or more oxygen atom institutes Substitution is obtained as SO, SO2, PO, PO2Group, when the ring is a three-membered ring, only one of which hetero atom), Or 7-10 members is bicyclic（4-9 carbon atom and be N, O, P, the 1-3 hetero atom of S, in this S or P optionally by one or Multiple oxygen atoms replace to obtain as SO, SO2, PO, PO2Group）.
Heterocycle can be carbon-based or heteroatom group." heterocycle " equally also includes heterocyclic group and saturation or part insatiable hunger With ring or heterocycle and close be formed by group.The example of heterocycle is including but not limited to, pyrrolidinyl, tetrahydrofuran base, Dihydrofuryl, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, Sulfydryl morpholinyl, thioalkyls, piperazinyl, high piperazine base, azelidinyl, oxetanylmethoxy, thietanyl, Piperidyl, homopiperidinyl, glycidyl, azacycloheptyl, oxetane, thiocycloheptyl, 4- methoxyl groups-piperazine Pyridine -1- bases, l, 2,3,6- tetrahydropyridine -1- bases, oxygen azatropylidene base, diazepine base, sulphur azatropylidene base, pyrroles Quinoline -1- bases, 2- pyrrolinyls, 3- pyrrolinyls, indolinyl, dihydro pyranyl, THP trtrahydropyranyl, dioxane Hexyl, l, 3- dioxymyls, pyrazolinyl, dithianyl, dithienyl group, dihydrothiophene, pyrazolidinyl imidazoles Quinoline base, imidazolidinyl, l, 2,3,4- tetrahydro isoquinolyls, l, 2,6- thiadiazine alkane l, 1- dioxy -2- bases, 4- hydroxyls Base-l, 4- azepine phosphine 4- oxide -1- bases, 2- hydroxyls -1-（Piperazine -1- bases）Ethyl ketone -4- bases, 2- hydroxyls -1-（5, 6- Dihydro-l, 2,4- triazine-l（4H）Base）Ethyl ketone -4- bases, 5,6- dihydros -4H- 1,2,4- oxadiazine -4- bases, 2- hydroxyls Base -1-（5,6- dihydropyridines-l（2H）Base）Ethyl ketone -4- bases, 3- azabicyclos [3.1.0] hexyl, 3- azabicyclos [4.1.0] heptyl, azabicyclo [2.2.2] hexyl, 2- methyl -5,6,7,8- tetrahydrochysenes-[1,2,4] triazole [1,5-c] Pyrimidine -6- bases, 4,5,6,7 1 tetrahydrochysene isoxazoles [4,3-c] pyridine -5- bases, 3HIndyl 2- oxygen -5- azabicyclos [2.2.1] heptane -5- bases, 2- oxygen -5- azabicyclos [2.2.2] octane -5- bases, quinazinyl and N- pyridyl ureas.Heterocycle The example of group further includes l, 1- dioxy sulfydryl morpholinyls, and two carbon atoms are replaced by oxygen atom as phonetic in its middle ring Pyridine diketo.And the heterocycle can be substituted or non-substituted, and wherein substituent group can be, but be not limited to, halogen Substituted alkyl, oxo (=O), hydroxyl, amino, halogen, cyano, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, Alkynyl, heterocycle, sulfydryl, nitro, aryloxy group, the alkoxy of hydroxyl substitution, the alkyl-C (=O)-of hydroxyl substitution, alkane Base-C (=O)-, alkyl-S (=O)-, alkyl-S (=O)2Alkyl-the S (=O)-of hydroxyl substitution, the alkyl-S of hydroxyl substitution (=O)2, Carboxyalkoxy etc..
Term " heterocycle aliphatic " indicates the aliphatic group of heterocycle substitution, wherein heterocycle and aliphatic group With meaning as described in the present invention, such example is including but not limited to pyrroles's -2- methyl, piperidines -2- ethyls, Piperazine -2- ethyls, piperidines -2- methyl etc..
Term " heterocycle oxygroup " includes that the heterocycle optionally replaced is connected to oxygen atom as defined herein On, wherein oxygen atom is connected with the rest part of molecule, and such example is including but not limited to pyrroles's -2- oxygroups, pyrrole Cough up -3- oxygroups, piperidines -2- oxygroups, piperidines -3- oxygroups, piperazine -2- oxygroups, piperidines -4- oxygroups etc..
Term " heterocyclylamino group " indicates that amino group is replaced by one or two heterocyclyl groups, wherein nitrogen-atoms It is connected with the rest part of molecule, and heterocycle has meaning as described in the present invention, such example includes, but simultaneously It is not limited to pyrroles's -2- amino, pyrroles's -3- amino, piperidines -2- amino, piperidines -3- amino, piperidines -4- amino, piperazine - 2- amino, two pyrroles's -2- amino etc..
Term " heterocycle oxygroup aliphatic " indicates that aliphatic group is replaced by one or more heterocycle oxygroup groups, Wherein aliphatic group and heterocycle oxygroup group have meaning as described in the present invention, and such example includes, but not It is limited to pyrroles's-2- oxygroup methyl, piperazine-3- oxygroup ethyls, piperazine-2- oxygroup ethyls, morpholine -2-oxygroup methyl, piperidines- 2- oxygroup ethyls etc..Term " heterocyclylamino group aliphatic " indicates aliphatic group by one or more heterocyclylamino group group institutes Replace, wherein aliphatic group and heterocyclylamino group group include with meaning as described in the present invention, such example, But pyrroles's -2- amino methyls are not limited to, piperazine -3- amino-ethyls, piperazine -2- amino-ethyls, piperidines -2- amino-ethyls, Morpholine -2-amino methyl etc..
Term " hetero atom " indicates one or more O, S, N, P and Se, includes the shape of any oxidation state of N, S and P Formula;The form of primary, secondary, tertiary amine and quaternary ammonium salt;Or the substituted form of hydrogen in heterocycle on nitrogen-atoms, such as, N (as 3,4- dihydros -2HN in pyrrole radicals), NH (as the NH in pyrrolidinyl) or NR are (in the pyrrolidinyl replaced as N- NR)。
Term " halogen " refers to F, Cl, Br or I.
Contain one or more degrees of unsaturation in " undersaturated " the expression part of term as used in the present invention.
Term " alkoxy " used in the present invention, is related to alkyl, as defined in the present invention, passes through oxygen original Son（" alkoxy "）It being connected in main carbochain, such example is including but not limited to methoxyl group, ethyoxyl, and third Oxygroup, butoxy etc..And the alkoxy can be substituted or non-substituted, and wherein substituent group can be, but and unlimited In, hydroxyl, amino, halogen, cyano, alkoxy, alkyl, alkenyl, alkynyl, sulfydryl, nitro etc..
Term " alkoxy of hydroxyl substitution " or " hydroxy alkoxy base " indicate alkoxy base by one or more hydroxyl bases Group is replaced, and wherein alkoxy has meaning as described in the present invention, and such example is including but not limited to hydroxyl methoxy Base, 2- hydroxyl-oxethyls, 2- hydroxy propyloxy groups, 2- hydroxyl isopropyl oxygen etc..
Term " aminoalkoxy " indicates that alkoxy base is replaced by one or more amino groups, wherein alkoxy With meaning as described in the present invention, such example is including but not limited to ammonia methoxyl group, 2- amino ethoxies, 2- Amino propoxyl group, 2- amino isopropoxies etc..
Term " halogenated alkyl " " halogenated alkenyl " and " halogenated alkoxy " indicate alkyl, and alkenyl or alkoxy can be by one The case where a or multiple halogen atoms are replaced, such example is including but not limited to trifluoromethyl, the chloro- ethylene of 2- Base, trifluoromethoxy etc..
Term " aryl " indicates monocycle altogether containing 6-14 membered rings, bicyclic, and tricyclic carbocyclic ring system, wherein, until Few member ring systems are aromatic, and wherein each member ring systems includes 3-7 membered rings, and only there are one attachment point and molecules Rest part is connected.Term " aryl " can be exchanged with term " aromatic rings " and be used, if aromatic rings may include phenyl, naphthalene And anthracene.And the aryl can be substituted or non-substituted, and wherein substituent group can be, but be not limited to, alkyl halide Base, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, Heterocycle, sulfydryl, nitro, aryloxy group, the alkoxy of hydroxyl substitution, the alkyl-C (=O)-of hydroxyl substitution, alkyl-C (= O)-, alkyl-S (=O)-, alkyl-S (=O)2, the alkyl-S (=O)-of hydroxyl substitution, alkyl-the S (=O of hydroxyl substitution )2, Carboxyalkoxy etc..
Term " difluorophenyl " indicates that phenyl group is replaced by one or more fluorine atoms.
Term " aromatic yl aliphat " indicates that aliphatic group is replaced by one or more aryl groups, wherein aliphatic Group and aryl group have meaning as described in the present invention, and such example is including but not limited to phenethyl, benzene first Base, to methylphenylethyl, styryl etc..
Term " aryloxy group " or " aryloxy " include that the aryl optionally replaced is connected to as defined herein On oxygen atom, and it is connected with molecule rest part by oxygen atom, wherein aryl group has meaning as described in the present invention, Such example is including but not limited to phenoxy group, toloxyl, ethylbenzene oxygroup etc..
Term " fragrant amino " indicates that amino group is replaced by one or two aryl group, and wherein aryl has such as this The invention meaning, such example is including but not limited to phenyl amino, p-fluorophenyl amino, diphenyl amino, Xylyl amino, di-p-tolyl amino etc..
Term " aryloxy group aliphatic " indicates that aliphatic group is replaced by one or more aryloxy groups, wherein virtue Oxygroup and aliphatic group have a meaning as described in the present invention, such example including but not limited to phenoxymethyl, Phenoxyethyl, tolyloxyethyl, phenoxy propyl etc..
Term " heteroaryloxy aliphatic " indicates that aliphatic group is replaced by one or more heteroaryloxy groups, Middle heteroaryloxy and aliphatic group have meaning as described in the present invention, and such example is including but not limited to furans Oxygroup methyl, 2-pyrimidinyl oxy ethyl etc..
Term " fragrant amino aliphatic " indicates that aliphatic group is replaced by one or more fragrant amino groups, Middle fragrant amino and aliphatic group have meaning as described in the present invention, and such example is including but not limited to phenylamino Methyl, phenylaminoethyl, toluidino ethyl, phenylamino propyl, phenylamino allyl etc..
Term " alkoxy aryl " indicates that alkoxy base is replaced by one or more aryl, wherein aryl and alcoxyl Base has meaning of the present invention, and for such example including but not limited to Phenylmethoxy, phenyl ethoxy is right Methylphenylmethoxy, phenyl-propoxy etc..And the aryl can be substituted or non-substituted, and wherein substituent group can be with It is, but is not limited to, halogenated alkyl, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkane ammonia Base, alkyl, alkenyl, alkynyl, heterocycle, sulfydryl, nitro, aryloxy group, the alkoxy of hydroxyl substitution, hydroxyl substitution Alkyl-C (=O)-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O)2, the alkyl-S (=O)-of hydroxyl substitution, Alkyl-the S (=O) of hydroxyl substitution2, Carboxyalkoxy etc..
Term " aryl alkane amino " indicate alkylamino radicals replaced by one or more aryl groups, wherein aryl and Alkoxy has meaning of the present invention, and such example is including but not limited to phenyl methylamino, phenylethylamino, Phenylpropylamino, p-methylphenyl methylamino etc..
Term " heteroaryl " can be used alone or as most of " heteroaryl alkyl " or " heteroarylalkoxy ", Indicate the monocycle altogether containing 5-14 membered rings, it is bicyclic, and three-ring system, wherein at least one member ring systems are aromatic, and At least one member ring systems include one or more hetero atoms, and wherein each member ring systems includes 3-7 membered rings, and only there are one attached Point with molecule rest part to be connected.Term " heteroaryl " can be exchanged with term " heteroaromatic " or " heteroaromatics " to be made With.And the heteroaryl can be substituted or non-substituted, and wherein substituent group can be, but be not limited to, alkyl halide Base, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, Heterocycle, sulfydryl, nitro, aryloxy group, the alkoxy of hydroxyl substitution, the alkyl-C (=O)-of hydroxyl substitution, alkyl-C (= O)-, alkyl-S (=O)-, alkyl-S (=O)2, the alkyl-S (=O)-of hydroxyl substitution, alkyl-the S (=O of hydroxyl substitution )2, Carboxyalkoxy etc..
Other embodiment is that heteroaromatic includes monocycle below, but is not limited to these monocycles：2- furyls, 3- furyls, TMSIM N imidazole base, 2- imidazole radicals, 4- imidazole radicals, 5- imidazole radicals, 3- isoxazolyls, 4- isoxazolyls, 5- Isoxazolyl, 2- oxazolyls, 4- oxazolyls, 5- oxazolyls, 4- methyl-isoxazole -5- bases, N- pyrrole radicals, 2- pyrroles Base, 3- pyrrole radicals, 2- pyridyl groups, 3- pyridyl groups, 4- pyridyl groups, 2- pyrimidine radicals, 4- pyrimidine radicals, pyrimidine -5- bases are rattled away Piperazine base（Such as 3- pyridazinyls）, 2- thiazolyls, 4- thiazolyls, 5- thiazolyls, tetrazole radical（Such as 5- tetrazole radicals）, triazolyl（Such as 2- triazolyls and 5- triazolyls）, 2- thienyls, 3- thienyls, pyrazolyl（Such as 2- pyrazolyls）, isothiazolyl, l, 2, 3- oxadiazolyls, l, 2,5- oxadiazolyls, l, 2,4- oxadiazolyls, l, 2,3- triazolyls, l, 2,3- sulfydryls Di azoly, l, 3,4- sulfydryl di azolies, l, 2,5- sulfydryl di azolies, l, 3,4- thiadiazoles -2- bases, pyrazinyl, Pyrazine -2- bases, l, 3,5- triazine radicals, benzo [d] thiazol-2-yl, imidazo [1,5-a] pyridine -6- bases;Also include It is below bicyclic, but it is bicyclic to be not limited to these：Benzimidazolyl, benzofuranyl, benzothienyl, benzothiazole Base, indyl（Such as 2- indyls）, purine radicals, quinolyl（Such as 2- quinolyls, 3- quinolyls, 4- quinolyls）, and it is different Quinolyl（Such as 1- isoquinolyls, 3- isoquinolyls or 4- isoquinolyls）.
Term " heteroaryl oxygroup " includes that the heteroaryl optionally replaced is connected to oxygen atom as defined herein On, and be connected with molecule rest part by oxygen atom, wherein heteroaryl groups have meaning as described in the present invention, this The example of sample is including but not limited to pyridine -2- oxygroups, thiazole -2- oxygroups, imidazoles -2- oxygroups, pyrimidine -2- oxygroups etc..
Term " Carboxyalkoxy " indicates that alkoxy base is replaced by one or more carboxylic groups, wherein alkoxy There is meaning as described in the present invention with carboxylic group, such example is including but not limited to Carboxvmethoxv, carboxyl Ethyoxyl etc..
Term " alkylthio group " includes that the alkyl of Cl-C10 linear chain or branched chains is connected on the sulphur atom of divalent.It is some of real Applying example is, alkylthio group is the C1-C3 alkylthio groups of lower level, and such example is including but not limited to methyl mercapto（CH3S-）. Term " halogenated alkylthio " includes that the halogenated alkyl of Cl-C10 is connected on bivalent sulfur atom.Some of embodiments are, halogenated Alkylthio group is the C1-C3 halogenated alkylthios of lower level, and such example is including but not limited to trifluoromethylthio.
Term " alkyl amino ", or " alkylamino ", including " N- alkyl aminos " and " N, N- dialkyl amido ", wherein Amine groups separately drive generation by one or two alkyl group.Some of embodiments are, alkyl amino be one or Two C1-C6 alkyl are connected to the alkylamino group of the lower level on nitrogen-atoms.Other embodiment is alkyl amino It is the alkylamino group of the lower level of C1-C3.Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, Such example is including but not limited to, N- methylaminos, N- ethylaminos, N, N- dimethylaminos, N, N- lignocaines Etc..
Term " heteroaryl amino " indicates that amine groups are replaced by one or two heteroaryl, and wherein heteroaryl has this The invention meaning, such example is including but not limited to N- thienyl amino etc..Some of embodiments are, miscellaneous Hetero-aromatic ring on arylamino can be further substituted.
Term " heteroaryl aliphatic " indicates that aliphatic group is replaced by one or more heteroaryls, wherein heteroaryl There is meaning of the present invention with aliphatic group, such example is including but not limited to thiophene -2- acrylic, pyrrole Pyridine -4- ethyls, imidazoles -2- methyl, furans -2- ethyls, indoles -3- methyl etc..
Term " heteroaryl alkyl " indicates that alkyl group is replaced by one or more heteroaryls, wherein heteroaryl and alkane There is base group meaning of the present invention, such example to include but be not limited to imidazoles -2- methyl, furans -2- second Base, indoles -3- methyl etc..
Term " heteroarylalkylamino " includes that the heteroarylalkyl group containing nitrogen-atoms is connected to other by nitrogen-atoms On group, wherein heteroaryl alkyl has meaning as described in the present invention, and such example is including but not limited to pyridine- 2- base methylaminos, thiazol-2-yl ethylamino, imidazoles -2- base ethylaminos, the third amino of pyrimidine -2-base, pyrimidine -2-base first ammonia Base etc..
Term " heteroarylalkoxy " includes that the heteroarylalkyl group containing oxygen atom is connected to other by oxygen atom On group, wherein heteroaryl alkyl has meaning as described in the present invention, and such example is including but not limited to pyridine- 2- ylmethoxies, thiazol-2-yl ethyoxyl, imidazoles -2- base oxethyls, pyrimidine -2-base propoxyl group, pyrimidine -2-base first ammonia Base.
Term " condensed-bicyclic ", " condensed ring ", " condensed-bicyclic base ", " condensed ring radical " indicate saturated or unsaturated condensed ring System is related to the bicyclic system of non-aromatic.Such system can include independent or conjugation undersaturated condition, but Its nuclear structure does not include aromatic rings or heteroaromatic（But aromatic series can be as substituent group thereon）.It is every in condensed-bicyclic One ring is either carbocyclic ring or is heteroalicyclic, and such example is including but not limited to, hexahydro furyl simultaneously [3,2- B] furans, 2,3,3a, 4,7,6- hexahydros -1HIndenes, 7- azabicyclos [2.3.0] heptane, condensed-bicyclic [3.3.0] Octane, condensed-bicyclic [3.1.0] hexane, l, 2,3,4,4a, 5,8,8a- octahydro naphthalenes, these are included in condensed Within bicyclic system.And the condensed-bicyclic base can be substituted or non-substituted, and wherein substituent group can be, but simultaneously It is not limited to, halogenated alkyl, oxo (=O), hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkane Amino, alkyl, alkenyl, alkynyl, heterocycle, sulfydryl, nitro, aryloxy group, the alkoxy of hydroxyl substitution, hydroxyl take Alkyl-the C (=O)-in generation, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O)2, hydroxyl substitution alkyl-S (= O)-, the alkyl-S (=O) of hydroxyl substitution2, Carboxyalkoxy etc..
Term " condensing miscellaneous bicyclic group " indicates saturated or unsaturated fused ring system, is related to the bicyclic body of non-aromatic System.Such system can include independent or conjugation undersaturated condition, but its nuclear structure does not include aromatic rings or virtue is miscellaneous Ring（But aromatic series can be as substituent group thereon）.And at least one member ring systems include one or more hetero atoms, wherein Each member ring systems include 3-7 membered rings, that is, include 1-6 carbon atom and be N, O, P, the 1-3 hetero atom of S, in this S Or P optionally is replaced to obtain as SO, SO by one or more oxygen atoms2, PO, PO2Group, such example includes, But it is not limited to hexahydro furyl simultaneously [3,2-b] furans, 7- azabicyclos [2.3.0] heptane etc..And it is described condensed miscellaneous bicyclic Base can be substituted or non-substituted, and wherein substituent group can be, but be not limited to, halogenated alkyl, oxo (=O), hydroxyl Base, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocycle, Sulfydryl, nitro, aryloxy group, the alkoxy of hydroxyl substitution, the alkyl-C (=O)-of hydroxyl substitution, alkyl-C (=O)-, alkane Base-S (=O)-, alkyl-S (=O)2, the alkyl-S (=O)-of hydroxyl substitution, the alkyl-S (=O) of hydroxyl substitution2, carboxyl Alkoxy etc..
Term " condensed-bicyclic base aliphatic " indicates that aliphatic group is replaced by one or more condensed-bicyclic base groups, Wherein aliphatic group and condensed-bicyclic base group have meaning as described in the present invention, and such example includes, but not It is limited to l, 2,3,4,4a, 5,8,8a- octahydro naphtylethyl groups, l, 2,3,4,4a, 5,8,8a- octahydro naphthalenes Methyl, l, 2,3,4,4a, 5,8,8a- octahydro naphthylpropyls, condensed-bicyclic [3.3.0] octane ylmethyl condense Bicyclic [3.1.0] hexyl ethyl etc..
Term " condensing miscellaneous bicyclic group aliphatic " indicates that aliphatic group condenses miscellaneous bicyclic group group institute by one or more Replace, wherein aliphatic group and condensed miscellaneous bicyclic group group include with meaning as described in the present invention, such example, But hexahydro furyl simultaneously [3,2-b] furans -2- base ethyls are not limited to, hexahydro furyl simultaneously [3,2-b] furans -2- ylmethyls, 7- azabicyclos [2.3.0] heptane -2- ylmethyls, 7- azabicyclos [2.3.0] heptane -2- base ethyls, 7- azabicyclos [2.3.0] heptane -4- ylmethyls etc..
Term " condensed-bicyclic base oxygroup " includes the condensed-bicyclic base optionally replaced, as defined in the present invention, connection It is connected with molecule rest part onto oxygen atom, and by oxygen atom, such example is including but not limited to l, and 2, 3,4,4a, 5,8,8a- octahydro naphthalene oxygroup, condensed-bicyclic [3.3.0] octane -2- oxygroups, condensed-bicyclic [3.1.0] Hexane -2- oxygroups etc..
Term " condensing miscellaneous bicyclic group oxygroup " includes the condensed miscellaneous bicyclic group optionally replaced, as defined in the present invention, It is connected on oxygen atom, and is connected with molecule rest part by oxygen atom, such example is including but not limited to six Hydrogen-furans simultaneously [3,2-b] furans -2- base oxygroups, 7- azabicyclos [2.3.0] heptane -2- base oxygroups, 7- azabicyclos [2.3.0] heptane -4- base oxygroups etc..
Term " condensed-bicyclic base amino " indicates that amino group is replaced by one or two condensed-bicyclic base, wherein thick Closing bicyclic group has meaning as described in the present invention, such example including but not limited to l, 2,3,4,4a, 5, 8,8a- octahydro naphthyl-aminos, two（1,2,3,4,4a, 5,8,8a- octahydro naphthalene）Amino, condensed-bicyclic [3.3.0] octyl amino, condensed-bicyclic [3.1.0] hexyl amino etc..
Term " condensing miscellaneous bicyclic group amino " indicates that amino group condenses miscellaneous bicyclic group by one or two and replaces, In condense miscellaneous bicyclic group have meaning as described in the present invention, such example including but not limited to hexahydro-furans simultaneously [3,2-b] furans -2- base amino, -2 base amino of 7- azabicyclos [2.3.0] heptane, 7- azabicyclos [2.3.0] heptane - 4- base amino etc..
Term " condensed-bicyclic base alkylamino " indicates that alkylamino radicals are replaced by one or more condensed-bicyclic bases, Middle condensed-bicyclic base has meaning as described in the present invention, such example including but not limited to l, 2,3,4,4a, 5,8,8a- octahydro napthylmethylaminos, two（1,2,3,4,4a, 5,8,8a- octahydro naphthalene）Methylamino condenses double Ring [3.3.0] octyl methylamino, condensed-bicyclic [3.1.0] hexyl methylamino etc..
Term " condensing miscellaneous bicyclic group alkylamino " indicates that alkylamino radicals condense miscellaneous bicyclic group by one or more and replace, Wherein condense miscellaneous bicyclic group have meaning as described in the present invention, such example including but not limited to hexahydro-furans simultaneously [3,2-b] furans -2- base methylaminos, 7- azabicyclos [2.3.0] heptane -2- base methylaminos, 7- azabicyclos [2.3.0] Heptane -4- base methylaminos etc..
Term " condensed-bicyclic base alkoxy " indicates that alkoxy is replaced by one or more condensed-bicyclic base groups, Middle alkoxy and condensed-bicyclic base have a meaning as described in the present invention, and such example is including but not limited to l, and 2, 3,4,4a, 5,8,8a- octahydro naphthylmethoxy, l, 2,3,4,4a, 5,8,8a- octahydro naphthalene ethyoxyls, Condensed-bicyclic [3.3.0] octane ethyoxyl, condensed-bicyclic [3.1.0] hexane-propoxyl group etc..
Term " condensing miscellaneous bicyclic group alkoxy " indicates that alkoxy condenses miscellaneous bicyclic group group by one or more and replaces, Wherein alkoxy and condensed miscellaneous bicyclic group has meaning as described in the present invention, and such example is including but not limited to six Simultaneously [3,2-b] furans -2- base propoxyl group, 7- azabicyclos [2.2.1] heptane -2- base oxethyls, 7- azepines are double for hydrogen-furans Ring [2.3.0] heptane -4- base propoxyl group, hexahydro-furans simultaneously [3,2-b] furans -2- base oxethyls, 7- azabicyclos [2.3.0] heptane -2- base propoxyl group, 7- azabicyclos [2.3.0] heptane -4- base oxethyls etc..
Term " condensed-bicyclic base oxygroup alkoxy " indicates alkoxy by one or more condensed-bicyclic base oxygroup groups institute Replace, wherein alkoxy and condensed-bicyclic base oxygroup include with meaning as described in the present invention, such example, but simultaneously It is not limited to l, 2,3,4,4a, 5,8,8a- octahydro naphthalene Oxymethoxies, l, 2,3,4,4a, 5,8,8a- Octahydro naphthalene oxygroup ethyoxyl, condensed-bicyclic [3.3.0] octane -2- oxygroup ethyoxyls, condensed-bicyclic [3.1.0] hexane -2- Oxygroup propoxyl group etc..
Term " condensing miscellaneous bicyclic group oxygroup alkoxy " indicates that alkoxy condenses miscellaneous bicyclic group oxygroup base by one or more Group is replaced, and wherein alkoxy and condensed miscellaneous bicyclic group oxygroup include with meaning as described in the present invention, such example, But it is not limited to hexahydro-furans simultaneously [3,2-b] furans -2- base oxygroup propoxyl group, 7- azabicyclos [2.2.1] heptane -2- bases Oxygroup ethyoxyl, 7- azabicyclos [2.3.0] heptane -4- base oxygroup propoxyl group, hexahydro-furans simultaneously [3,2-b] furans -2- Base oxygroup ethyoxyl, 7- azabicyclos [2.3.0] heptane -2- base oxygroup propoxyl group, 7- azabicyclos [2.3.0] heptane -4- Base oxygroup ethyoxyl etc..
Term " condensed-bicyclic base aminoalkoxy " indicates that alkoxy is replaced by one or more condensed-bicyclic base amino, Wherein alkoxy and condensed-bicyclic base amino have meaning as described in the present invention, such example including but not limited to L, 2,3,4,4a, 5,8,8a- octahydro naphthyl-amino ethyoxyl, l, 2,3,4,4a, 5,8,8a- octahydro naphthalenes Base amino propoxyl group, two（1,2,3,4,4a, 5,8,8a- octahydro naphthalene）Amino propoxyl group, condensed-bicyclic [3.3.0] octane -2- amino ethoxies, condensed-bicyclic [3.1.0] hexane -2- amino propoxyl group etc..
Term " condensing miscellaneous bicyclic group aminoalkoxy " indicates that alkoxy condenses miscellaneous bicyclic group amino institute by one or more Replace, wherein alkoxy and condensed miscellaneous bicyclic group amino include with meaning as described in the present invention, such example, but It is not limited to 7- azabicyclos [2.2.1] heptane -2- base amino ethoxies, 7- azabicyclos [2.3.0] heptane -4- base amino Propoxyl group, hexahydro-furans simultaneously [3,2-b] furans -2- base amino ethoxies, hexahydro-furans simultaneously [3,2-b] furans -2- bases Amino propoxyl group, hexahydro-furans simultaneously [3,2-b] furans -2- base aminomethoxies etc..
Term " loop coil base ", " loop coil ", " spiral shell bicyclic group ", " spiral shell is bicyclic " indicate a ring originating from another ring Particularly ring-shaped carbon.Such as disclosed below, the bridged-ring system of a saturation（Ring B and B '）It is referred to as " condensed double Ring ", otherwise a shared carbon atom in the member ring systems that be saturateds at two of ring A and ring B, then be referred to as " loop coil ".Inside loop coil Each ring be either carbocyclic ring or be heteroalicyclic.Such example is including but not limited to 2,7- diaza spiros [4.4] nonane -2- bases, 7- oxygen -2- azaspiros [4.5] decane -2- bases, 4- azaspiros [2.4] heptane -5- bases, 4- oxaspiros [2.4] heptane -5- bases, 5- azaspiros [2.4] heptane -5- bases, spiral shell [2.4] heptane base, spiral shell [4.4] nonyl, 7- hydroxyls - 5- azaspiros [2.4] heptane -5- bases etc..And the spiral shell bicyclic group can be substituted or non-substituted, and wherein substituent group can be with It is, but is not limited to, halogenated alkyl, oxo (=O), hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkane Oxygroup, alkylamino, alkyl, alkenyl, alkynyl, heterocycle, sulfydryl, nitro, aryloxy group, the alkoxy of hydroxyl substitution, Alkyl-the C (=O)-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O) of hydroxyl substitution2, the alkane of hydroxyl substitution Base-S (=O)-, the alkyl-S (=O) of hydroxyl substitution2, Carboxyalkoxy etc..
Term " the miscellaneous bicyclic group of spiral shell " indicates a ring originating from particularly ring-shaped carbon on another ring.Such as institute above Description, the bridged-ring system of a saturation（Ring B and B '）It is referred to as " condensed-bicyclic ", on the contrary what ring A and ring B was saturated at two A carbon atom is shared in member ring systems, then is referred to as " loop coil ".And at least one member ring systems include one or more hetero atoms, Wherein each member ring systems include 3-7 membered rings, that is, include 1-6 carbon atom and be N, O, P, the 1-3 hetero atom of S, This S or P optionally is replaced to obtain as SO, SO by one or more oxygen atoms2, PO, PO2, group, such example Including but not limited to 4- azaspiros [2.4] heptane -5- bases, 4- oxaspiros [2.4] heptane -5- bases, 5- azaspiros [2.4] Heptane -5- bases, 7- hydroxyl -5- azaspiros [2.4] heptane -5- bases etc..And the miscellaneous bicyclic group of spiral shell can be substitution or non-take Generation, wherein substituent group can be, but be not limited to, halogenated alkyl, oxo (=O), hydroxyl, amino, halogen, cyanogen Base, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocycle, sulfydryl, nitro, fragrant oxygen Base, the alkoxy of hydroxyl substitution, the alkyl-C (=O)-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S of hydroxyl substitution (=O)2, the alkyl-S (=O)-of hydroxyl substitution, the alkyl-S (=O) of hydroxyl substitution2, Carboxyalkoxy etc..
Term " spiral shell bicyclic group aliphatic " indicates that aliphatic group is replaced by one or more spiral shell bicyclic group groups, Middle aliphatic group and spiral shell bicyclic group group have a meaning as described in the present invention, such example including but not limited to Spiral shell [2.4] heptane ylmethyl, spiral shell [2.4] heptane base ethyl, spiral shell [2.4] heptane base propyl, spiral shell [4.4] nonane ylmethyl, Spiral shell 4.4] nonyl ethyl, 4- azaspiros [2.4] heptane -5- ylmethyls, 4- azaspiros [2.4] heptane -5- base ethyls, 4- Oxaspiro [2.4] heptane -5- base ethyls, 5- azaspiros [2.4] heptane -5- base propyl, 7- hydroxyl -5- azaspiros [2.4] heptan Alkane -5- base propyl etc..
Term " the miscellaneous bicyclic group aliphatic of spiral shell " indicates that aliphatic group is replaced by the miscellaneous bicyclic group group of one or more spiral shells, Wherein the miscellaneous bicyclic group group of aliphatic group and spiral shell has meaning as described in the present invention, and such example includes, but not It is limited to 4- azaspiros [2.4] heptane -5- ylmethyls, 4- azaspiros [2.4] heptane -5- base ethyls, 4- oxaspiros [2.4] heptan Alkane -5- base ethyls, 5- azaspiros [2.4] heptane -5- base propyl, 7- hydroxyl -5- azaspiros [2.4] heptane -5- base propyl etc..
Term " spiral shell bicyclic group oxygroup " includes that the spiral shell bicyclic group optionally replaced is connected to oxygen as defined in the present invention On atom, and it is connected with molecule rest part by oxygen atom, such example is including but not limited to spiral shell [2.4] heptan Alkane -2- oxygroups, spiral shell [2.4] heptane -3- oxygroups, spiral shell [2.4] heptane -4- oxygroups, spiral shell [4.4] nonane -2- oxygroups, spiral shell [4.4] nonane -4- oxygroups, 4- azaspiros [2.4] heptane -5- oxygroups etc..
Term " the miscellaneous bicyclic group oxygroup of spiral shell " includes the miscellaneous bicyclic group of spiral shell optionally replaced, as defined in the present invention, connection It is connected with molecule rest part onto oxygen atom, and by oxygen atom, such example is including but not limited to 4- azepines Spiral shell [2.4] heptane -5- base oxygroups, 4- oxaspiros [2.4] heptane -5- base oxygroups, 5- azaspiros [2.4] heptane -5- base oxygroups Deng.
Term " spiral shell bicyclic group amino " indicates that amino group is replaced by one or two spiral shell bicyclic group group, wherein spiral shell Bicyclic group has meaning as described in the present invention, such example including but not limited to spiral shell [2.4] heptane -2- amino, Spiral shell [2.4] heptane -3- amino, spiral shell [2.4] heptane -4- amino, spiral shell [4.4] nonane -2- amino, spiral shell [4.4] nonane -4- ammonia Base, 4- azaspiros [2.4] heptane -5- amino etc..
Term " the miscellaneous bicyclic group amino of spiral shell " indicates that amino group is replaced by the miscellaneous bicyclic group group of one or two spiral shell, The middle miscellaneous bicyclic group of spiral shell has meaning as described in the present invention, and such example is including but not limited to 4- azaspiros [2.4] heptan Alkane -5- base amino, 4- azaspiros [2.4] heptane -2- base amino, 4- oxaspiros [2.4] heptane -5- base amino, 5- azaspiros [2.4] heptane -5- bases amino etc..
Term " spiral shell bicyclic group alkoxy " indicates that alkoxy base is replaced by one or more spiral shell bicyclic groups, wherein spiral shell Bicyclic group and alkoxy base have meaning as described in the present invention, and such example is including but not limited to spiral shell [2.4] heptan Alkane -2- methoxyl groups, spiral shell [2.4] heptane -3- ethyoxyls, spiral shell [2.4] heptane -4- ethyoxyls, spiral shell [4.4] nonane -2- methoxies Base, spiral shell [4.4] nonane -4- propoxyl group, 4- azaspiros [2.4] heptane -5- methoxyl groups etc..
Term " the miscellaneous bicyclic group alkoxy of spiral shell " indicates that alkoxy base is replaced by the miscellaneous bicyclic group of one or more spiral shells, The miscellaneous bicyclic group of middle spiral shell and alkoxy base have meaning as described in the present invention, and such example is including but not limited to 4- Azaspiro [2.4] heptane -5- ylmethoxies, 4- azaspiros [2.4] heptane -2- base oxethyls, 4- oxaspiros [2.4] heptane - 5- base oxethyls, 5- azaspiros [2.4] heptane -5- base propoxyl group etc..
Term " spiral shell bicyclic group alkylamino " indicates that alkylamino radicals are replaced by one or more spiral shell bicyclic groups, wherein spiral shell Bicyclic group and alkylamino radicals have meaning as described in the present invention, and such example is including but not limited to spiral shell [2.4] heptan Alkane -2- methylaminos, spiral shell [2.4] heptane -3- ethylaminos, spiral shell [2.4] heptane -4- ethylaminos, spiral shell [4.4] nonane -2- first ammonia Base, spiral shell [4.4] third amino of nonane -4-, 4- azaspiros [2.4] heptane -5- methylaminos etc..
Term " the miscellaneous bicyclic group alkylamino of spiral shell " alkylamino radicals are replaced by the miscellaneous bicyclic group of one or more spiral shells, wherein spiral shell Miscellaneous bicyclic group and alkylamino radicals have meaning as described in the present invention, and such example is including but not limited to 4- azepines Spiral shell [2.4] heptane -5- base methylaminos, 4- azaspiros [2.4] heptane -2- base ethylaminos, 4- oxaspiros [2.4] heptane -5- bases Ethylamino, 5- azaspiros [2.4] heptane -5- third amino of base etc..
Term " spiral shell bicyclic group oxygroup alkoxy " indicates that alkoxy is replaced by one or more spiral shell bicyclic group oxygroup groups, Wherein spiral shell bicyclic group oxygroup and alkoxy base have meaning as described in the present invention, and such example includes, but and unlimited In spiral shell [2.4] heptane -2- oxygroup ethyoxyls, spiral shell [2.4] heptane -3- oxygroup propoxyl group, spiral shell [2.4] heptane -4- the third oxygen of oxygroup Base, spiral shell [4.4] nonane -2- oxygroup ethyoxyls, spiral shell [4.4] nonane -4- oxygroup propoxyl group, 4- azaspiros [2.4] heptane -5- Oxygroup propoxyl group etc..
Term " the miscellaneous bicyclic group oxygroup alkoxy of spiral shell " indicates alkoxy by the miscellaneous bicyclic group oxygroup group institute of one or more spiral shells Replace, wherein the miscellaneous bicyclic group oxygroup of spiral shell and alkoxy base include with meaning as described in the present invention, such example, But 4- azaspiros [2.4] heptane -5- base oxygroup ethyoxyls are not limited to, 4- oxaspiros [2.4] heptane -5- base oxygroup ethyoxyls, 5- azaspiros [2.4] heptane -5- base oxygroup ethyoxyls, 4- azaspiros [2.4] heptane -5- base oxygroup propoxyl group, 4- oxaspiros [2.4] heptane -5- bases oxygroup propoxyl group, 5- azaspiros [2.4] heptane -5- base oxygroup propoxyl group etc..
Term " spiral shell bicyclic group aminoalkoxy " indicates that alkoxy is replaced by one or more spiral shell bicyclic group amino, Middle alkoxy and spiral shell bicyclic group amino have meaning as described in the present invention, and such example is including but not limited to spiral shell [2.4] heptane -2- amino ethoxies, spiral shell [2.4] heptane -3- amino propoxyl group, spiral shell [2.4] heptane -4- amino ethoxies, Spiral shell [4.4] nonane -2- amino ethoxies, spiral shell [4.4] nonane -4- amino propoxyl group, 4- azaspiros [2.4] heptane -5- amino Propoxyl group etc..
Term " the miscellaneous bicyclic group aminoalkoxy of spiral shell " indicates that alkoxy is replaced by the miscellaneous bicyclic group amino of one or more spiral shells, Wherein the miscellaneous bicyclic group amino of alkoxy and spiral shell have meaning as described in the present invention, such example including but not limited to 4- azaspiros [2.4] heptane -5- base amino ethoxies, two oxygroup of 4- azaspiros [2.4] heptane -2- bases amino, 4- oxaspiros [2.4] heptane -5- bases amino ethoxy, 5- azaspiros [2.4] heptane -5- base amino propoxyl group etc..
Unless other aspects show that structural formula described in the invention includes all isomeric forms（As mapping is different Structure, diastereo-isomerism, and geometrical isomerism（Or conformational isomerism））：Such as R, S configuration containing asymmetric center, double bond (Z), (E) isomers, and (Z), (E) rotamer.Therefore, the single three-dimensional chemical isomer of the compound of the present invention Or its enantiomter, diastereoisomer, or geometric isomer（Or rotamer）Mixture belong to the present invention Range.
Term " prodrug " used in the present invention represents a compound and is converted into chemical combination shown in formula (I) in vivo Object.Such conversion is hydrolyzed by pro-drug or is influenced for precursor structure through enzymatic conversion in blood or tissue in blood. Pro-drug compounds of the present invention can be ester, and ester can have phenyl ester class as pro-drug in existing invention, Aliphatic (Cl-C24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as this A compound in invention includes hydroxyl, can be acylated to obtain the compound of prodrug form.Other precursors Medicament forms include phosphate, if these phosphate compounds are being obtained through the di on parent.About precursor Drug, which completely discusses, can refer to following documents：T. Higuchi and V.Stella, Pro-drugsas Novel Delivery Systems, Vol. 140f the A.C.S.Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and S.J. Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.
Unless other aspects show, all tautomeric forms of the compound of the present invention be included in the scope of the present invention it It is interior.In addition, unless other aspects show, the structural formula of compound described in the invention includes one or more different originals The enriched isotope of son.
" metabolite " refers to specific compound or its salt product obtained by metabolic action in the body.One The metabolite of compound can be identified that activity can be by such as of the invention by technology well-known in the art Described adopt like that is experimentally characterized.Such product can be by, by aoxidizing, being gone back to drug compound Original, hydrolysis, amidated, deamidation, esterification, degreasing, the methods of enzymatic lysis etc. obtain.Correspondingly, this hair The bright metabolite for including compound, including the compound of the present invention and mammal were come into full contact with produced by a period of time Metabolite.
The compound of the present invention can include asymmetric center or chiral centre, therefore there are different stereoisomers. All stereoisomeric forms in any ratio of the compound of the present invention, including but not limited to, diastereomer, enantiomter, resistance turn Isomers, and their mixture, such as racemic mixture constitute the part of the present invention.Many organic compounds are all Exist with optical active forms, i.e. the plane of their capable Plane of rotation polarised lights.When describing optically active compound, Prefix D, L or R, S are used for indicating the absolute configuration at molecular chiral center.Prefix D, L or (+),（One）For naming compound flat The symbol of plane polarized light rotation,（One）Or it is left-handed that L, which refers to compound, it is dextrorotation that prefix (+) or D, which refer to compound,. The chemical constitution of these stereoisomers is identical, but their stereochemical structure is different.Specific stereoisomer can To be enantiomer, the mixture of isomers is commonly referred to as enantiomeric mixture.50：50 mixture of enantiomers is referred to as Racemic mixture or racemic modification, this may lead to do not have stereoselectivity or stereoselectivity in chemical reaction process.Art Language " racemic mixture " and " racemic modification " refer to the mixture of equimolar two enantiomters, lack optical activity.
Term " tautomer " or " tautomeric form " refer to that the isomer of the structure of different-energy can be with Pass through the mutual inversion of phases of low energy barrier.Such as proton tautomer（I.e. prototropic tautomer）Including passing through proton transfer Change, such as the isomerization of one enol form of keto-acid and sub- one enamine of limb.Valence（Chemical valence）Tautomer packet Include the change of recombination bonding electrons.
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in fields on, such as document：S. M. Berge et al., describe pharmaceutically acceptable salts in detail. J. Pharmaceutical Sciences, 66： Recorded in 1-19,1977.The salt that pharmaceutically acceptable nontoxic acid is formed is including but not limited to amino group The inorganic acid salt that reaction is formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate, and acylate such as Acetate, oxalates, maleate, tartrate, citrate, succinate, malonate, or pass through books Recorded other methods such as ion-exchange obtains these salt on document.Other pharmaceutically acceptable salts include adipic acid Salt, alginates, ascorbate, aspartate, benzene sulfonate, benzoate, bisulphate, borate, fourth Hydrochlorate, camphor hydrochlorate, camsilate, cyclopentyl propionate, digluconate, lauryl sulfate, second sulphur Hydrochlorate, formates, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, heptan Hydrochlorate, caproate, hydriodate, 2- hydroxy-ethanesulfonate salts, lactobionate, lactate, laruate, lauryl Sulfate, malate, malonate, mesylate, 2- naphthalene sulfonates, nicotinate, nitrate, oleate, palm fibre Palmitic acid hydrochlorate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, picrate, pivalate, propionate, Stearate, rhodanate, tosilate, undecylate, valerate, etc..Salt obtained by an appropriate base Including alkali metal, alkaline-earth metal, ammonium and N+(C1-C4 alkyl)4Salt.The present invention is also intended to contemplate the base of any included N The compound of group is formed by quaternary ammonium salt.Water-soluble or oil-soluble or dispersion product can be obtained by quaternization.Alkali gold Belong to or alkali salt includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further comprise it is appropriate, The amine cation that nontoxic ammonium, quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylate, sulfuric acid Compound, phosphoric acid compound, nitric acid compound, C1-C8 azochlorosulfonate acid compounds and aromatic sulphonic acid compound.
The salt of the part of compounds of the present invention can be illustrated with the salt for the particular compound listed as follows, but not limited The present invention：
。
" solvate " of the present invention refers to that one or more solvent molecules are formed by association with the compound of the present invention Object.The solvent of solvate is formed including but not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, acetic acid Ethyl ester, acetic acid, ethylaminoethanol.Term " hydrate " refers to that solvent molecule is that water is formed by associated matter.
The solvate of part of compounds or the solvate of its salt of the present invention can use the specific chemical combination listed as follows The salt of object illustrates, but does not limit the present invention：
。
The present invention includes the application of the compounds of this invention and its pharmaceutically acceptable salt, is controlled for producing medical product Treat patient's disease caused by virus, including those diseases described in the invention.The present invention includes pharmaceutical composition, the medicine Compositions include compound representated by Formulas I-X and at least one pharmaceutically acceptable carrier, excipient, diluent, Adjuvant, effective therapeutic dose needed for the combination of medium.
The present invention equally includes to treat or mitigate patient's disease caused by virus, or the method sensitive to this illness, This method includes to be treated to patient using the therapeutically effective amount of compound representated by Formulas I-X.
Unless other aspects show, all stereoisomers of the compound of the present invention, geometric isomer mutually makes a variation Structure body, nitrogen oxides hydrates, solvate, metabolite, salt and pharmaceutically acceptable prodrug belong to the present invention Range.
Specifically, salt is pharmaceutically acceptable salt.Term " pharmaceutically acceptable " includes substance or composition must Must be suitble to chemistry or toxicologically, it is related with the other components of composition preparation and mammal for treatment.
The salt of the compound of the present invention further includes being used to prepare or purifying the intermediate of compound or Formulas I-X shown in Formulas I-X The salt of the enantiomter of shown compound separation, but it is not necessarily pharmaceutically acceptable salt.
If the compound of the present invention is alkaline, then conceivable salt can be by provided in the literature any suitable Method be prepared, for example with inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid etc..Or make With organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, hydroxyl second Acid and salicylic acid;Pyrans saccharic acid, such as glucuronic acid and galacturonic acid;Alpha-hydroxy acid, such as citric acid and tartaric acid;Ammonia Base acid, such as asparatate and glutamic acid;Aromatic acid, such as benzoic acid and cinnamic acid;Sulfonic acid, such as p-methyl benzenesulfonic acid, Ethanesulfonic acid, etc..
If the compound of the present invention is acid, then conceivable salt can be prepared by suitable method, Such as, using inorganic base or organic base, such as ammonia（Primaquine, parahelium, tertiary ammonia）, alkali metal hydroxide or alkaline-earth metal hydrogen-oxygen Compound, etc..Suitable salt is including but not limited to, organic salt obtained from amino acids, such as glycine and arginine, Ammonia, such as primaquine, parahelium and tertiary ammonia, and ring-type ammonia, such as piperidines, morpholine and piperazine etc., and from sodium, calcium, potassium, magnesium, Manganese, iron, copper, zinc, aluminium and lithium obtain inorganic salts.
According on the other hand, the characteristics of pharmaceutical composition of the invention includes the compound of Formulas I-X, listed by the present invention Compound, or embodiment compound represented, and pharmaceutically acceptable carrier, adjuvant, or excipient.The present invention's Patient's disease caused by virus effectively can detectably be treated or be mitigated to the amount of compound in composition.
There are free forms for the compound of the present invention, or it is suitable, as pharmaceutically acceptable derivates.According to this Invention, pharmaceutically acceptable derivates are including but not limited to, pharmaceutically acceptable prodrug, salt, ester, esters Salt, or other any adducts or derivative that can be directly or indirectly administered according to the needs of patient, the present invention other Compound described in aspect, metabolite or his residue.
As described in the invention, the pharmaceutically acceptable composition of the present invention further includes pharmaceutically acceptable Carrier, adjuvant, or excipient, these are applied as the present invention, including any solvent, diluent, or other liquid Excipient, dispersant or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid adhesion Agent or lubricant, etc., it is suitable for distinctive target formulation.As described in following documents：In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D. B. Troy, Lippincott Williams&Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York, the content of comprehensive document herein, show different carriers can be applied to pharmaceutically acceptable composition preparation and Their well known preparation methods.In addition to any conventional carrier medium range incompatible with the compound of the present invention, such as institute Any undesirable biological effect of generation is produced in harmful manner with any other component of pharmaceutically acceptable composition Raw interaction, their purposes are also the range that the present invention is considered.
The substance of pharmaceutically acceptable carrier be can be used as including but not limited to, ion-exchanger, aluminium, stearic acid Aluminium, lecithin, haemocyanin, such as human albumin, buffer substance such as phosphate, glycine, sorbic acid, sorbic acid Potassium, the partial glyceride mixtures of saturated vegetable fatty acid, water, salt or electrolyte, such as protamine sulfate, phosphoric acid hydrogen Disodium, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silicon, magnesium trisilicate, polyvinylpyrrolidone, polyacrylate, Wax, polyethylene-polyoxypropylene-blocking condensate, lanolin, sugar, such as lactose, dextrose and saccharose;Starch such as corn Starch and potato starch;Cellulose and its derivative such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; Gum powder;Malt;Gelatin;Talcum powder;Auxiliary material such as cocoa butter and suppository wax;Oil such as peanut oil, cotton seed oil, Safflower oil, sesame oil, olive oil, corn oil and soya-bean oil;Glycol compound, such as propylene glycol and polyethylene glycol;Esters are such as Ethyl oleate and ethyl laurate;Agar;Buffer such as magnesium hydroxide and aluminium hydroxide;Alginic acid;It is pyrogen-free Water;Isotonic salt;Lin Ge（Family name）Solution;Ethyl alcohol, phosphate buffer solution, and other nontoxic suitable lubricant such as bays Sodium sulphate and magnesium stearate, colorant, releasing agent, coating agents, sweetener, flavoring agent and fragrance, preservative and anti- Oxidant.
The pharmaceutical composition of the present invention can be oral medication, drug administration by injection, Aerosol inhalation, local administration, warp Rectally, nose administration, buccal administration or are administered vagina administration by implantable medicine box.Can be capsule, tablet, Pill, pulvis, granula and water suspension or solution.Oral medication can use following form：Tablet, capsule, can divide pill Scattered powder, particle or suspension, syrup and elixir, or be administered in a manner of external application：Ointment, gel, drug containing adhesive plaster etc., Or parenteral routes are carried out with sterile injectable solution or suspension form.The compounds of this invention also can parenteral or intraperitoneal Administration.Also surfactant can properly mixed（Such as hydroxypropyl cellulose, polyvinylpyrrolidone）Water in prepare these Reactive compound（As free alkali or pharmaceutically acceptable salt）Solution or suspension.It can also be in glycerine, liquid, poly- second two Dispersion liquid is prepared in alcohol and its mixture in the oil.Under conventional storage and use condition, contain preservative in these preparations To prevent microorganism from growing.
Medicament forms suitable for injection include：Aseptic aqueous solution or dispersion liquid and aseptic powder（It is noted for extemporaneous preparation of sterile Penetrate solution or dispersion liquid）.In all cases, these forms must be sterile and must be that fluid is arranged with being easy to syringe Go out fluid.It must be stable under conditions of manufacture and storage, and must be able to prevent microorganism（Such as bacterium and fungi）Pollution It influences.Carrier can be solvent or decentralized medium, wherein containing such as water, alcohol（Such as glycerine, propylene glycol and liquid polyethylene glycol）、 They properly mix object and vegetable oil.
Compound can be applied with local mode, without being applied with system mode.Such as usually to dilute preparation or continue The form of delivery formulations will be in compound direct injection to organ.In addition, the pharmaceutical composition containing the compounds of this invention can be with It uses in targeted drug delivery system, such as is delivered in the liposome being coated with organ specific antibody.The liposome The organ will be targeted and absorbed by the Organic selection.In addition, the composition containing the compounds of this invention can be with fast quick-release The form for putting preparation, timed release preparations or IR formulation provides.
Sucking is applied, the compound of the present invention can be aerosol, aerosol or powder type.Chemical combination of the present invention The pharmaceutical composition of object can be delivered easily in the form of aerosol spray, and the aerosol spray can be mounted in pressure In container or atomizer, suitable propellant such as dicholorodifluoromethane, Arcton 11, dichlorotetra-fluoroethane, dioxy are used Change carbon or other suitable gases.In the case of pressurized aerosol, dosage unit can be determined by valve to deliver Metered amount.Such as by taking capsule and cylindrantherae as an example, it can be prepared as containing describedization for the gelatin of inhalator or insufflator Close the mixture of powders of object and appropriate powdered substrate such as lactose or starch.
The compounds of this invention can also be prepared as rectal compositions such as enema, Gel in rectal administered, rectal foams agent, straight Intestines aerosol, suppository, gel suppository（gel suppository）Or enema,retention（retention enema）, wherein containing There is conventional suppository base such as cocoa butter or other glyceride and synthetic polymer such as polyvinylpyrrolidone, PEG. In the suppository form of composition, it is optionally first with the mixture of cocoa butter that low melt wax is such as, but not limited to fatty glyceride First it is melted.
In addition, the compounds of this invention can be also combined with other antiviral drugs.It is specifically including but not limited to, virazole, Rimantadine hydrochloride, amantadine hydrochloride, acyclovir, Valaciclovir, Ganciclovir, interferon, Zidovudine, arabinose gland Glycosides, Ribavirin, Sebivo etc..
Pharmaceutical composition can be prepared according to the usual manner acceptable carrier of one or more physiology, wherein wrapping Include the excipient and adjuvant that can help that reactive compound is processed as to pharmaceutical preparations.Selected administration method determines appropriate Dosage form.Technology, carrier and excipient known to any can understand use appropriate according in the prior art.Contain this hair The pharmaceutical composition of bright compound can be prepared according to conventional methods, for example, by conventional mixing, dissolving, pelletize, ingot processed, It is prepared by grinding, emulsification, packing, encapsulating or pressing process.
Pharmaceutical composition will include at least one pharmaceutical acceptable carrier, diluent or excipient and free acid, free alkali or can The compound of the present invention of acceptable salt is as active constituent.In addition, pharmaceutical composition may also include other medicine or pharmacy Activating agent, carrier, adjuvant, such as preservative, stabilizer, wetting agent or emulsifier, dissolution accelerator, adjust osmotic pressure salt or Buffer.In addition, pharmaceutical composition also contains other substances for having therapeutic value.
The preparation method of composition containing compound described herein include by compound with it is one or more it is inert can Pharmaceutical excipient or carrier are prepared as solid, semisolid or liquid form together.Solid composite includes but not limited to powder, piece Agent, dispersible granule, capsule, cachet and suppository.Liquid composition includes wherein being dissolved with the solution of compound, containing Emulsion, the solution containing the liposome comprising compound disclosed herein, micelle or nano-particle for having compound.Semisolid group It includes but not limited to gelling agent, suspension and cream to close object.Composition can be aqueous agent or suspended form, be suitble to In the solid form or emulsion form that are dissolved or suspended in before use in liquid.These compositions can also contain a small amount of nontoxic Adjuvant, such as wetting agent or emulsifier, pH buffer etc..
The compound of the present invention is preferably prepared into dosage unit form to mitigate the equal of dosage and dosage by pharmaceutical formulation Even property.Term " dosage " unit type " obtains suitably treating the physical dispersion unit of required drug referred to herein as patient.However It should be appreciated that the compound of the present invention or the daily total usage of composition will be judged by attending physician according to reliable medicine range To determine.Specific effective dose level will include quilt depending on many factors for any one special patient or organism The illness for the treatment of and the seriousness of illness, the activity of particular compound, concrete composition used, the age of patient, body Weight, health status, gender and eating habit, administration time, the discharge rate of administration route and particular compound used are controlled The duration for the treatment of, medicinal application is combined in drug combination or with specific compound, and some other pharmaceutical field Well known factor.
The compounds of this invention can be modified by the functional group of additional suitable to improve selectivity organism characteristic.This The modification of sample is that this field is known and include to biological lacuna（Such as blood, lymphatic system, central nervous system）Infiltration, It improves Oral Availability, improve dissolubility so as to which the modification of excretion is metabolized and changed by drug administration by injection, change.It can incite somebody to action The compounds of this invention is modified by the functional group of additional suitable to improve selectivity organism characteristic.Such modification is ability Domain is known and includes to biological lacuna（Such as blood, lymphatic system, central nervous system）Infiltration, raising are oral effective Property, improve dissolubility so as to pass through drug administration by injection, change metabolism and change excretion modification.
Disease caused by virus of the present invention is by RSV, HSV, EV71, H1N1, H3N2, H5N1, H7N9, Cox- Disease caused by the virus such as B3, HBV, FMDV, SARS, including breathing problem, liver diseases, hand-foot-and-mouth disease, immunity disease Disease, inflammatory disease etc..
General, the method that the compound of the present invention can say description through the invention is prepared, unless there are into one The explanation of step, the wherein definition of substituent group are as shown in Formulas I-X, and reaction scheme and embodiment below is for further illustrating Bright present disclosure.
Those skilled in the art will realize that：Chemical reaction described in the invention can be used for suitable prepare originally Other compounds of invention, and other methods for the preparation of the compounds of the present invention are considered as in the scope of the present invention Within.Such as can successfully it be led to by those skilled in the art according to the synthesis of the compound of those non-illustrations of the invention Method of modifying completion, such as protection interference group appropriate are crossed, by using other known reagent in addition to described in the invention , or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also public That recognizes is suitable for the preparation of other compounds of the invention.
Solvent for use of the present invention, such as anhydrous tetrahydro furan, dioxane, toluene, ether are dry by sodium metal reflux It is dry to obtain.Anhydrous methylene chloride and chloroform are dried to obtain by calcium hydride reflux.Ethyl acetate, petroleum ether, n-hexane, N, N- Dimethylacetylamide and N,N-dimethylformamide are used by anhydrous sodium sulfate is dry in advance.The protics such as methanol, ethyl alcohol Solvent is used after being dried again with anhydrous sodium sulfate after being repeatedly evaporated under reduced pressure.
Reaction is usually to cover a drying tube under positive pressure of nitrogen or argon or on anhydrous solvents below（Unless other aspects Show）, reaction bulb all by syringe squeezed into beyond the Great Wall by suitable rubber band, substrate.Glassware is by dry.
1. 3- methoxyl group -1- pentyls -4- of embodiment（2- pyridyl groups）- 1,6- naphthyridines -2 (1H) -one
Step 1) under nitrogen protection, by 3-（4-aminopyridine）- 2- pyridinyl methanones (2 mmol), methoxyacetyl chloride (3.8 mmol) and N, N- diisopropylethylamine (8 mmol) are dissolved in dichloromethane (5 mL), and room temperature reaction 3 is small When.Contact plate finds that raw material reaction finishes, and reaction solution is diluted with water rear ethyl acetate and extracts, after organic phase removed under reduced pressure solvent, Residue obtains 3- with silica gel chromatography（4- methoxyl acetamide bases）- 2- pyridinyl methanones.
Step 2）Under nitrogen protection, 3-（4- methoxyl acetamide bases）- 2- pyridinyl methanones (1.0 mmol) are dissolved in four In hydrogen furans (10 mL), t-BuOK (10 mmol) is added and reacts at room temperature 5 hours.Reaction solution saturated ammonium chloride solution Extraction, ethyl acetate extraction.After removed under reduced pressure organic phase, residue obtains 4- hydroxyl -3- methoxies with silica gel chromatography Base -4- (2- pyridines) -3,4- dihydro -1,6- naphthyridines -2 (1H) -one.
Step 3）Under an atmosphere of hydrogen, 4- hydroxy-3-methoxies -4- (2- pyridines) -3,4- dihydro -1,6- naphthyridines -2 (1H) -one is dissolved in MeOH (10 mL), 10%Pd/C (0.1 mmol) and potassium carbonate (8 mmol) afterwards 50 is addedoC is anti- It should stay overnight.After removed under reduced pressure solvent, residue obtains 3- methoxyl groups -4 with silica gel chromatography（2- pyridyl groups）- 1,6- naphthalenes Pyridine -2 (1H) -one.
Step 4）Under nitrogen protection, CuI (l mmol), Cs2CO3(20 mmol) and 2- oxocyclohexyl formic acid second Ester（2 mmol) it is added in DMSO (10 mL), 30 min are stirred at room temperature.3- methoxyl groups -4（2- pyridyl groups）- 1,6- naphthyridines -2 (1H) -one (10 mmol) and bromo pentane（10 mmol) DMSO (12 mL) solution, injection be added.It is heated to 100 °C of mistakes Night.It is cooled to room temperature, filters, water is added（50 mL) and dichloromethane（50 mL × 3), organic phase is collected, decompression boils off Solvent, crude product purify to obtain 3- methoxyl groups -4 through column chromatography（2- pyridyl groups）- 1,6- naphthyridines -2 (1H) -one.
ESI-MS (m/z): 324.24[M+H]+。
2. 1- pentamethylene base -3- methoxyl groups -4- of embodiment（4- methoxyphenyls）- 7- propiono -1,6- naphthyridines -2 (1H) -one
Step 1) under nitrogen protection, by 1- (4- amino -5- (4- methoxybenzoyls base)-pyridine -2- propyl -1- ketone (2 mmol), methoxyacetyl chloride (3.8 mmol) and N, N- diisopropylethylamine (8 mmol) are dissolved in dichloromethane (5 ML it in), reacts at room temperature 3 hours.Contact plate finds that raw material reaction finishes, and reaction solution is diluted with water rear ethyl acetate extraction, has After machine phase removed under reduced pressure solvent, residue obtains 1- (4- methoxyacetamidos -5- (4- methoxies with silica gel chromatography Base benzoyl)-pyridine -2- propyl -1- ketone.
Step 2）Under nitrogen protection, 1- (4- methoxyacetamidos -5- (4- methoxybenzoyls base)-pyridine -2- Propyl -1- ketone (1.0 mmol) is dissolved in tetrahydrofuran (10 mL), and t-BuOK (10 mmol) is added and reacts at room temperature 5 Hour.Reaction solution is extracted with saturated ammonium chloride solution, ethyl acetate extraction.After removed under reduced pressure organic phase, residue silica gel Column chromatography purifies to obtain 4- hydroxy-3-methoxies -4-（4- methoxyphenyls）- 7- propiono -3,4- dihydro -1,6- naphthyridines -2 (1H) -one.
Step 3）Under an atmosphere of hydrogen, 4- hydroxy-3-methoxies -4-（4- methoxyphenyls）- 7- propionos -3,4- two Hydrogen -1,6- naphthyridines -2 (1H) -one is dissolved in MeOH (10 mL), 10%Pd/C (0.1 mmol) and potassium carbonate (8 is added Mmol) afterwards 50oC reactions are overnight.After removed under reduced pressure solvent, residue obtains 3- methoxyl groups -4- with silica gel chromatography（4- Methoxyphenyl）- 7- propiono -1,6- naphthyridines -2 (1H) -one.
Step 4）Under nitrogen protection, CuI (1 mmol), Cs2CO3(20 mmol) and 2- oxocyclohexyl formic acid second Ester（2 mmol) it is added in DMSO (10 mL), 30 min are stirred at room temperature.3- methoxyl groups -4-（4- methoxyphenyls）- 7- third Acyl group -1,6- naphthyridines -2 (1H) -one (10 mmol) and bromocyclopentane（10 mmol) DMSO (12 mL) solution, injection It is added.It is heated to 100 °C overnight.It is cooled to room temperature, filters, water is added（50 mL) and dichloromethane（50 mL × 3), it receives Collect organic phase, decompression boils off solvent, and crude product purifies to obtain 1- pentamethylene base -3- methoxyl groups -4- through column chromatography（4- methoxybenzenes Base）- 7- propiono -1,6- naphthyridines -2 (1H) -one.
ESI-MS (m/z): 407.48 [M+H]+。
3. N of embodiment, N- dimethylglycines -3- (3- methoxyl groups 4-（3- methoxyphenyls) -2- oxygen quinoline -1 (2H)- Base）Propyl ester
Step 1）3- methoxyl groups -4-（3- methoxyphenyls）Quinoline -2 (1H) -one synthetic method reference implementation example 1 and 2.
Step 2）Under nitrogen protection, CuI (1 mmol), Cs2CO3(20 mmol) and 2- oxocyclohexyl formic acid second Ester（2 mmol) it is added in DMSO (10 mL), 30 min are stirred at room temperature.3- methoxyl groups -4-（3- methoxyphenyls）Quinoline -2 (1H) -one (10 mmol) and 3- bromos-N, N- dimethylglycine propyl ester（10 mmol) DMSO (12 mL) solution, note Penetrate addition.It is heated to 100 °C overnight.It is cooled to room temperature, filters, water is added（50 mL) and dichloromethane（50 mL×3), Organic phase is collected, decompression boils off solvent, and crude product purifies to obtain N, N- dimethylglycines -3- (3- methoxyl groups 4- through column chromatography （3- methoxyphenyls) -2- oxygen quinoline -1 (2H)-base）Propyl ester.
ESI-MS (m/z): 425.23[M+H]+。
4. 1- of embodiment (3- (N, N- dimethylamino) propyl) -3- methoxyl group -4- phenyl -1,6- naphthyridines -2 (1H) -one
Step 1）3- methoxyl group -4- phenyl -1,6- naphthyridines -2 (1H) -one synthetic method reference implementation example 1 and 2.
Step 2）Under nitrogen protection, CuI (l mmol), Cs2CO3(20 mmol) and 2- oxocyclohexyl formic acid second Ester（2 mmol) it is added in DMSO (10 mL), 30 min are stirred at room temperature.3- methoxyl group -4- phenyl -1,6- naphthyridines -2 (1H)- Ketone (10 mmol) and bromo pentane（10 mmol) DMSO (12 mL) solution, injection be added.It is heated to 100 °C overnight.It is cold But to room temperature, water is added in filtering（50 mL) and dichloromethane（50 mL × 3), organic phase is collected, decompression boils off solvent, Crude product purifies to obtain 1- (3- (N, N- dimethylamino) propyl) -3- methoxyl group -4- phenyl -1,6- naphthyridines -2 (1 through column chromatographyH)- Ketone.
ESI-MS (m/z):338.42[M+H]+。
Embodiment 5
Antiviral activity is tested
Compound test antiviral activity is that the method for foundation cytopathic effect carries out, and Ribavirin is as positive control Drug.Specific experiment scheme is as follows.
Virus multiplication is carried out first
Test Virus is inoculated on the sensitive cells of the virus, cell is placed in 1640 culture solutions of serum-free, so The cell after inoculation is allowed to be cultivated at a temperature of 5% carbon dioxide, 37 oC afterwards, until virus infection occurs in 90% cell Lesion, it is spare by -80 oC refrigerators of cold presence after the cell quantification packing after lesion.
Secondly virus virulence measurement is carried out
Being serially diluted for 10 times of ratios is carried out to the virus of proliferation using cell maintenance medium.By virus inoculation in 96 orifice plates Hep-2 on, and longitudinally repeat 3 times as a control test.Then allow the cell after being inoculated in 5% carbon dioxide, 37 It is cultivated at a temperature of oC, to observe cytopathy situation daily.After two to three days, the cell maintenance medium suction in orifice plate is abandoned, And it is added 100 in orifice plate again againμ1% dimethyl diaminophenazine chloride of L, dyes 2 hours at a temperature of 37 oC, and rear inhale is abandoned Its dyeing liquor is used in combination eluent to decolourize 10 minutes at a temperature of 37 oC.With enzyme mark under the wavelength of 540 nm or so Instrument measures its OD value, be used in combination formula calculate cell lesion rate and cell ratio away from by its cell than away from thin higher than 50% The index of the dilution of born of the same parents' lesion rate sums it up, and the TCID50 values that virus is calculated with Reed-Muench methods are 10-5.5/ mL。
Cell survival rate=(each group OD values-blank control OD values)/(normal cell OD values-blank control OD Value)
Cytopathy variability=1-cell survival rate
Cell ratio higher than 50% lesion rate-away from=(being higher than 50% lesion rate -50%)/(being less than 50% lesion rate)
Finally carry out the HIV suppression activity test of compound
First prepare cell monolayer：The degradation of cell pancreatin is placed in 96 microwell plates, its culture can be made to become cell monolayer With spare.
HIV suppression activity experiment：By test-compound according to specification be 100μG/ pipes are prepared, spare.According to The archives for testing compound, with suitable solvent 10μOften pipe tests compound for L dissolvings.With 2% cell culture fluid (200μL the dilution that continuous 10 times 2 times of ratios) are carried out to compound, need to dilute 10 gradients altogether.Then it is inoculated with In 96 microwell plates containing cell monolayer.And its 11st row is set as viral blank control group, the 12nd row are set as Cell blank control group.It is cultivated at a temperature of 5% carbon dioxide, 37 oC.Cytopathy situation is observed daily.Wait for disease Cell maintenance medium suction in orifice plate is abandoned, and is added 100 in orifice plate again again by poison control lesion 90%μThe 1% of L is neutral It is red, 2 hours are dyed at a temperature of 37 oC, rear inhale abandons its dyeing liquor, be used in combination eluent at a temperature of 37 oC Decoloration 10 minutes.Under the wavelength of 540 nm or so its OD value is measured with microplate reader.Finally, cytopathy is calculated with formula Rate and cell survival rate calculate the half-inhibition concentration (EC of compounds on viral with Reed-Muench methods50) and change Close median toxic concentration (TC of the object to cell50), and by the median toxic concentration (TC of compound on intracellular50) divided by change Close half-inhibition concentration (EC of the object to virus50) obtain the malicious index (TI) of suppression, as test the inhibition of compounds on viral Activity.
HIV suppression activity data is as follows：
" A " indicates that compound concentration is 0.05-2.0 in tableμM, " B " indicate that compound concentration is 10-25μM, " C " are indicated Compound concentration is 50-75μM, " D " indicate that compound concentration is 90-120μM;" ++++" indicate TI 500-1000 it Between, " +++ " indicates TI between 350-450, and " ++ " indicates TI between 200-300, and "+" indicates TI between 50-150.

Claims (12)

1. a kind of nitrogenous dicyclic compound of Formulas I-II structures, tautomer, stereoisomer, racemic modification, mapping are different The non-equal amount of mixture of structure body, the solvate of geometric isomer, solvate, pharmaceutically acceptable salt or its salt, it is special Sign is that Formulas I and Formula II compound have the following structure：, R1, R2, R3, R4And shown in A, Y be defined as follows：
The aromatic ring or hetero-aromatic ring that A is five yuan or hexa-atomic, saturated or unsaturated carbocyclic ring or carbon heterocyclic, condensed-bicyclic or condensed miscellaneous Bicyclic, Y is O or S; “" it is singly-bound or to be not present;N=0,1,2,3 or 4;In Formulas I, A is phenyl ring, when Y is O, R2Cannot be H;
Each R1Can be identical or different, it is each independently hydrogen, halogen, hydroxyl, amino, nitro, cyano, carboxyl, alkane Base, halogenated alkyl, alkoxy, alkylamino, alkyl acyl, hydroxy alkoxy base, Hydroxyalkylamino, hydroxyalkanoyl, Halogenated alkoxy, halogenated alkylamino, ohaloalkanoyl, aminoalkoxy, naphthenic base, cycloalkyl oxy, naphthenic base ammonia Base, cycloalkanoyl, alkenyl, alkenylalkoxy, alkenyl alkylamino, alkenyl alkanoyl, alkynyl, alkynyl alkoxy, Alkynyl alkylamino, alkynyl alkanoyl, aryl, aryloxy group, aroyl, fragrant amino, alkoxy aryl, aryl alkane amino, Heteroaryl, heteroaryloxy, 4-hetaroylpyrazol, heteroaryl amino, heteroarylalkoxy, heteroarylalkylamino, heterocycle alkane acyl Base, Heterocyclylalkyl, heterocycle oxygroup, heterocyclylamino group, heterocyclylacyl, heterocyclylalkoxy, heterocycle alkylamino, Heterocycle alkanoyl, azido alkoxy, condensed-bicyclic base condense miscellaneous bicyclic group, and condensed-bicyclic base aliphatic condenses Miscellaneous bicyclic group aliphatic, condensed-bicyclic base oxygroup condense miscellaneous bicyclic group oxygroup, and condensed-bicyclic base amino condenses miscellaneous bicyclic Base amino, condensed-bicyclic base alkoxy condense miscellaneous bicyclic group alkoxy, and condensed-bicyclic base alkylamino condenses miscellaneous bicyclic group Alkylamino, condensed-bicyclic base oxygroup alkoxy, condensed miscellaneous bicyclic group oxygroup alkoxy, condensed-bicyclic base aminoalkoxy, Miscellaneous bicyclic group aminoalkoxy is condensed, condensed-bicyclic base-C (=O)-, condensed-bicyclic base-C (=O) O- condense miscellaneous bicyclic group-C (=O)-, miscellaneous bicyclic group-C (=O) O-, condensed-bicyclic base amino-C (=O)-are condensed, miscellaneous bicyclic group amino-C (=O)-is condensed, Condensed-bicyclic base-C (=O) N (R5)-, condenses miscellaneous bicyclic group-C (=O) N (R5)-, spiral shell bicyclic group, the miscellaneous bicyclic group of spiral shell, spiral shell are bicyclic Base aliphatic, the miscellaneous bicyclic group aliphatic of spiral shell, spiral shell bicyclic group oxygroup, the miscellaneous bicyclic group oxygroup of spiral shell, spiral shell bicyclic group amino, spiral shell are miscellaneous Bicyclic group amino, spiral shell bicyclic group alkoxy, the miscellaneous bicyclic group alkoxy of spiral shell, spiral shell bicyclic group alkylamino, the miscellaneous bicyclic group alkane ammonia of spiral shell Base, spiral shell bicyclic group oxygroup alkoxy, the miscellaneous bicyclic group oxygroup alkoxy of spiral shell, spiral shell bicyclic group aminoalkoxy, the miscellaneous bicyclic group of spiral shell Aminoalkoxy, spiral shell bicyclic group-C (=O)-, spiral shell bicyclic group-C (=O) O-, the miscellaneous bicyclic group-C of spiral shell (=O)-, the miscellaneous bicyclic group-of spiral shell C (=O) O-, spiral shell bicyclic group amino-C (=O)-, the miscellaneous bicyclic group amino-C of spiral shell (=O)-, spiral shell bicyclic group-C (=O) N (R5)-, spiral shell Miscellaneous bicyclic group-C (=O) N (R5)-, R6R5N-, -C(=O)NR5R6, -OC(=O)NR5R6, -OC(=O)OR5, -N(R5)C(=O) NR5R6, -N(R5)C(=O)OR6, -N(R5)C(=O)-R6, R5R6N-S(=O)t-, R5S(=O)t-, R5S(=O)tN(R6)-, R6R5N- alkyl, R5S(=O)tAlkyl, R5R6N-C (=O)-alkyl, R6R5N- alkoxies, R5S(=O)tAlkoxy, R5R6N-C (=O)-alkoxy, aryl-(CH2)p-G-(CH2)m, heteroaryl-(CH2)p-G-(CH2)m, heterocycle-(CH2)p- G-(CH2)m, or naphthenic base-(CH2)p-G-(CH2)m, wherein G is O, S, NR7, S(=O), S(=O)2,C(=O), -C (=O)N(R5)-, -OC(=O)N(R5)-, -OC(=O)-, -N(R5)C(=O)N(R5)-, -(R5)N-S(=O)t-, -OS(= O)t, or-OS (=O)tN(R5)-;T is l or 2;P and m is each independently 0, l, 2,3 or 4;Or wherein aryl- (CH2)p-G-(CH2)m, heteroaryl-(CH2)p-G-(CH2)m, heterocycle-(CH2)p-G-(CH2)m, or naphthenic base- (CH2)p-G-(CH2)mCan F, Cl, Br, I, alkyl, alkenyl, alkynyl, alkoxy or cyanogen be selected from by one or more The substituent group of base replaces;
R2Can be identical or different, it is each independently hydrogen, alkyl, halogenated alkyl, alkyl acyl, hydroxyalkanoyl, halogen For alkanoyl, naphthenic base, cycloalkanoyl, alkenyl, alkenyl alkanoyl, alkynyl, alkynyl alkanoyl, aryl, fragrant acyl Base, heteroaryl, 4-hetaroylpyrazol, heterocycle alkanoyl, Heterocyclylalkyl, heterocyclylacyl, heterocycle alkanoyl, nitrine Base alkyl, condensed-bicyclic base condense miscellaneous bicyclic group, and condensed-bicyclic base-C (=O)-condenses miscellaneous bicyclic group-C (=O)-, thick Bicyclic group amino-C (=O)-is closed, miscellaneous bicyclic group amino-C (=O)-, spiral shell bicyclic group, the miscellaneous bicyclic group of spiral shell, spiral shell bicyclic group are condensed Aliphatic, the miscellaneous bicyclic group aliphatic of spiral shell, spiral shell bicyclic group-C (=O)-, the miscellaneous bicyclic group-C of spiral shell (=O)-, spiral shell bicyclic group amino-C (=O)-, the miscellaneous bicyclic group amino-C of spiral shell (=O)-,-C (=O) NR5R6, R5R6N-S(=O)t-, R5S(=O)t-, R6R5N- alkyl, R5S(=O)tAlkyl, R5R6N-C (=O)-alkyl, aryl-(CH2)p-G-(CH2)m, heteroaryl-(CH2)p-G-(CH2)m-, Heterocycle-(CH2)p-G-(CH2)m, or naphthenic base-(CH2)p-G-(CH2)m, wherein G is O, S, NR7, S(=O), S(= O)2,C(=O), -C(=O)N(R5)-, -OC(=O)N(R5)-, -OC(=O)-, -N(R5)C(=O)N(R5)-, -(R5)N-S(= O)t-, -OS(=O)t, or-OS (=O)tN(R5)-;T is l or 2;P and m is each independently 0, l, 2,3 or 4;Or Person aryl-(CH therein2)p-G-(CH2)m, heteroaryl-(CH2)p-G-(CH2)m, heterocycle-(CH2)p-G-(CH2)m-, Or naphthenic base-(CH2)p-G-(CH2)mCan by one or more be selected from F, Cl, Br, I, cyano, alkyl, alkenyl, Alkynyl, alkoxy, aryl, heteroaryl, carbocylic radical, the substituent group substitution of heterocycle;
Each R3And R4Can be identical or different, it is each independently hydrogen, halogen, alkyl, halogenated alkyl, alkyl acyl, hydroxyl Base alkanoyl, ohaloalkanoyl, naphthenic base, cycloalkanoyl, alkenyl, alkenyl alkanoyl, alkynyl, alkynyl alkanoyl, Aryl, aroyl, heteroaryl, 4-hetaroylpyrazol, heterocycle alkanoyl, Heterocyclylalkyl, heterocyclylacyl, heterocycle alkane Acyl group, azido alkyl, condensed-bicyclic base condense miscellaneous bicyclic group, and condensed-bicyclic base-C (=O)-condenses miscellaneous bicyclic group-C (=O)-, condensed-bicyclic base amino-C (=O)-, condensed miscellaneous bicyclic group amino-C (=O)-, spiral shell bicyclic group, the miscellaneous bicyclic group of spiral shell, Spiral shell bicyclic group aliphatic, the miscellaneous bicyclic group aliphatic of spiral shell, spiral shell bicyclic group-C (=O)-, the miscellaneous bicyclic group-C of spiral shell (=O)-, spiral shell is bicyclic Base amino-C (=O)-, the miscellaneous bicyclic group amino-C of spiral shell (=O)-,-C (=O) NR5R6, R5R6N-S(=O)t-, R5S(=O)t-, R6R5N- alkyl, R5S(=O)tAlkyl, R5R6N-C (=O)-alkyl, aryl-(CH2)p-G-(CH2)m, heteroaryl- (CH2)p-G-(CH2)m, heterocycle-(CH2)p-G-(CH2)m, or naphthenic base-(CH2)p-G-(CH2)m, wherein G is O, S, NR7, S(=O), S(=O)2,C(=O), -C(=O)N(R5)-, -OC(=O)N(R5)-, -OC(=O)-, -N(R5)C(=O) N(R5)-, -(R5)N-S(=O)t-, -OS(=O)t, or-OS (=O)tN(R5)-;T is l or 2;P and m are each independently 0, l, 2,3 or 4;Or aryl-(CH therein2)p-G-(CH2)m, heteroaryl-(CH2)p-G-(CH2)m, heterocycle- (CH2)p-G-(CH2)m, or naphthenic base-(CH2)p-G-(CH2)mCan F, Cl, Br, I, cyanogen be selected from by one or more Base, alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, carbocylic radical, the substituent group substitution of heterocycle;
R7Can be identical or different, it is each independently hydrogen, R5R6NC(=O)-, R5OC(=O)-, R5C(=O)-, R5R6NS(= O)-, R5OS(=O)-, R5S(=O)-, R5R6NS(=O)2-, R5OS(=O)2-, R5S(=O)2, aliphatic, halogenated aliphatic Race, hydroxyl group aliphatic, amino aliphatic, alkoxy aliphatic, alkylamino aliphatic, alkylthio group aliphatic, aryl fat Fat race, heteroaryl aliphatic, heterocycle aliphatic, naphthenic base aliphatic, aryloxy group aliphatic, heterocycle oxygroup fat Race, cycloalkyl oxy aliphatic, fragrant amino aliphatic, heterocyclylamino group aliphatic, cycloalkyl amino aliphatic, aryl, Heteroaryl, heterocycle or carbocylic radical;
Each R5And R6It independently is hydrogen, aliphatic, halogenated aliphatic, hydroxyl group aliphatic, amino aliphatic, alkoxy fat Race, alkylamino aliphatic, alkylthio group aliphatic, aromatic yl aliphat, heteroaryl aliphatic, heterocycle aliphatic, cycloalkanes Base aliphatic, aryloxy group aliphatic, heterocycle oxygroup aliphatic, cycloalkyl oxy aliphatic, fragrant amino aliphatic are miscellaneous Ring group amino aliphatic, cycloalkyl amino aliphatic, aryl, heteroaryl, heterocycle or naphthenic base;Work as R5And R6It is connected in same On one nitrogen-atoms, R5, R6It can be randomly formed substituted or non-substituted 3-7 membered rings, condensed-bicyclic or spiral shell with nitrogen-atoms It is bicyclic;The hetero atom in heterocycle, heteroaryl, condensed miscellaneous bicyclic group, the miscellaneous bicyclic group of spiral shell involved in above-mentioned group is independently The 1-5 hetero atom in N, O, S, Se;
Above-mentioned R1, R2, R3, R4, R5, R6, R7Group can appoint by deuterium, halogen, hydroxyl, methylol, carboxyl, acetyl ammonia Base, alkyl（Such as methyl, ethyl, propyl）, alkoxy（Such as methoxyl group, ethyoxyl, tert-butoxy）, alkylamino, naphthenic base, Alkenyl, alkynyl, trifluoromethyl, trifluoroacetyl group, sulfydryl, halogen, nitro, amino, azido (- N3), guanidine radicals, Cyano, tertbutyloxycarbonyl (- Boc), carbonyl (- C=O), oxo (=O) is thio (=S), sulfonyl, and aryl is miscellaneous Aryl, the substitution of one or more of heterocycle.
2. compound according to claim 1 is general formula III-X compounds represented, or chemical combination shown in general formula III-X The stereoisomer geometric isomer of object, tautomer, nitrogen oxides, raceme, hydrate, solvate, metabolite, Pharmaceutically acceptable salt or prodrug：
,
Wherein Y is O or S; T1, T2, T3, T4, T5, T6Separate is CR1, C（R1）2Or N, NR8, wherein T1, T2, T3, T4, T5, T6At most there are three can be N; V, V1, V2Separate is O, S, N or CR1Or NR8; “" indicate singly-bound or be not present;Each R1, R2, R3, R4, R8As follows：
Each R1Can be identical or different, it is each independently H, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, Carboxyl, C1-C20 alkyl, C1-C20 halogenated alkyls, C1-C20 alkoxies, C1-C20 alkylaminos, C1-C20 alkyl acyls, Hydroxyl C1-C20 alkoxies, hydroxyl C1-C20 alkylaminos, hydroxyl C1-C20 alkanoyls, C1-C20 halogenated alkoxies, C1- The halogenated alkylaminos of C20, C1-C20 ohaloalkanoyls, C1-C20 aminoalkoxies, C3-C10 naphthenic base, C3-C10 naphthenic base Oxygroup, C3-C10 cycloalkyl aminos, C3-C10 cycloalkanoyls, C2-C7 alkenyls, C2-C7 alkynyls, C5-C10 aryl, C5-C10 aryloxy group, C5-C10 aroyls, C5-C10 fragrant aminos, C5-C10 aryl C1-C5 alkoxies, C5-C10 aryl alkane Amino, C5-C12 heteroaryls, C5-C12 heteroaryloxies, C5-C12 4-hetaroylpyrazols, C5-C12 heteroaryl amino, C5-C12 are miscellaneous Aryl C1-C5 alkoxies, C5-C12 heteroaryl C1-C5 alkylaminos, C4-C12 heterocycle C1-C5 alkanoyls, C4-C12 heterocycles Alkyl, C4-C12 heterocycle oxygroups, C4-C12 heterocyclylamino groups, C4-C12 heterocyclylacyls, C4-C12 heterocycles C1-C5 Alkoxy, C4-C12 heterocycle C1-C5 alkylaminos, C4-C12 heterocycle C1-C5 alkanoyls, R6R5N-, -C(=O)NR5R6, -OC(=O)NR5R6, -OC(=O)OR5, -N(R5)C(=O)NR5R6, -N(R5)C(=O)OR6, -N(R5)C(=O)-R6, R5R6N-S(=O)t-, R5S(=O)t-, R5S(=O)tN(R6)-, R6R5N- C1-C5 alkyl, R5S(=O)t- C1-C5 alkyl, R5R6N-C (=O)-C1-C5 alkyl, R6R5N-C1-C5 alkoxies, R5S(=O)t- C1-C5 alkoxies, R5R6N-C(=O)-C1- C5 alkoxies, C5-C10 aryl-(CH2)p-G-(CH2)m, C5-C12 heteroaryls-(CH2)p-G-(CH2)m, C4-C12 heterocycles Base-(CH2)p-G-(CH2)m, or C3-C10 naphthenic base-(CH2)p-G-(CH2)m, wherein G is O, S, NR7, S(=O), S (=O)2,C(=O), -C(=O)N(R5)-, -OC(=O)N(R5)-, -OC(=O)-, -N(R5)C(=O)N(R5)-, -(R5)N-S (=O)t-, -OS(=O)t, or-OS (=O)tN(R5)-;T is l or 2;P and m is each independently 0, l, 2,3 or 4; Or wherein C5-C10 aryl-(CH2)p-G-(CH2)m, C5-C12 heteroaryls-(CH2)p-G-(CH2)m, C4-C12 heterocycles Base-(CH2)p-G-(CH2)m, or C3-C1 naphthenic base-(CH2)p-G-(CH2)mCan F, Cl be selected from by one or more, The substituent group of Br, I, alkyl, alkenyl, alkynyl, alkoxy or cyano replaces;
R2, R8It is each independently H, C1-C20 alkyl, C1-C20 halogenated alkyls, C1-C20 alkyl acyls, C1-C20 hydroxyls Base alkanoyl, C1-C20 ohaloalkanoyls, C3-C10 naphthenic base, C3-C10 cycloalkanoyls, C2-C8 alkenyls, C2-C8 Alkenyl alkanoyl, C2-C8 alkynyls, C2-C8 alkynyl alkanoyls, C6-C10 aryl, C6-C10 aroyls, C5-C12 heteroaryls Base, C5-C12 4-hetaroylpyrazols, C4-C12 heterocycle alkanoyls, C4-C12 Heterocyclylalkyls, C4-C12 heterocyclylacyls, C4- C12 heterocycle C1-C6 alkanoyls, C5-C12 condensed-bicyclic bases, C5-C12 condense miscellaneous bicyclic group ,-C (=O) NR5R6, R5R6N-S(=O)t-, R5S(=O)t-, R6R5N-C1-C6 alkyl, R5S(=O)t- C1-C6 alkyl, R5R6N-C(=O)-C1-C6 Alkyl, C6-C10 aryl-(CH2)p-G-(CH2)m, C5-C12 heteroaryls-(CH2)p-G-(CH2)m, C4-C12 heterocycles- (CH2)p-G-(CH2)m, or C3-C10 naphthenic base-(CH2)p-G-(CH2)m, wherein G is O, S, NR7, S(=O), S(= O)2,C(=O), -C(=O)N(R5)-, -OC(=O)N(R5)-, -OC(=O)-, -(R5)N-S(=O)t-, -OS(=O)t-, Or-OS (=O)tN(R5)-;T is l or 2;P and m is each independently 0, l, 2,3 or 4;Or wherein C6-C10 aryl- (CH2)p-G-(CH2)m, C5-C12 heteroaryls-(CH2)p-G-(CH2)m, C4-C12 heterocycles-(CH2)p-G-(CH2)m-, Or C3-C10 naphthenic base-(CH2)p-G-(CH2)mCan by one or more be selected from F, Cl, Br, I, cyano, alkyl, Alkenyl, alkynyl, alkoxy, aryl, heteroaryl, carbocylic radical, the substituent group substitution of heterocycle;
Each R3, R4It is each independently H, F, Cl, Br, I, C1-C20 alkyl, C1-C20 halogenated alkyls, C1-C20 alkane Base acyl group, C1-C20 hydroxyalkanoyls, C1-C20 ohaloalkanoyls, C3-C10 naphthenic base, C3-C10 cycloalkanoyls, C2-C7 alkenyls, C2-C7 alkenyl alkanoyls, C2-C7 alkynyls, C2-C7 alkynyl alkanoyls, C5-C10 aryl, C5-C10 virtues Acyl group, C5-C12 heteroaryls, C5-C12 4-hetaroylpyrazols, C4-C12 heterocycle alkanoyls, C4-C12 Heterocyclylalkyls, C4- C12 heterocyclylacyls, C4-C12 heterocycle C1-C5 alkanoyls, C5-C12 condensed-bicyclic bases, C5-C12 condense miscellaneous bicyclic group, -C(=O)NR5R6, R5R6N-S(=O)t-, R5S(=O)t-, R6R5N-C1-C5 alkyl, R5S(=O)t- C1-C5 alkyl, R5R6N-C (=O)-C1-C5 alkyl, C5-C10 aryl-(CH2)p-G-(CH2)m, C5-C12 heteroaryls-(CH2)p-G- (CH2)m, C4-C12 heterocycles-(CH2)p-G-(CH2)m, or C3-C10 naphthenic base-(CH2)p-G-(CH2)m, wherein G is O, S, NR7, S(=O), S(=O)2,C(=O), -C(=O)N(R5)-, -OC(=O)N(R5)-, -OC(=O)-, -N(R5)C (=O)N(R5)-, -(R5)N-S(=O)t-, -OS(=O)t, or-OS (=O)tN(R5)-;T is l or 2;P and m is respectively independent Ground is 0, l, 2,3 or 4;Or wherein C5-C10 aryl-(CH2)p-G-(CH2)m, C5-C12 heteroaryls-(CH2)p-G- (CH2)m, C4-C12 heterocycles-(CH2)p-G-(CH2)m, or C3-C10 naphthenic base-(CH2)p-G-(CH2)mIt can be by one It is a or multiple selected from F, Cl, Br, I, cyano, alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, carbocyclic ring Base, the substituent group substitution of heterocycle;
Wherein each R7Can be identical or different, it is each independently H, R5R6NC(=O)-, R5OC(=O)-, R5C(=O)-, R5R6NS(=O)-, R5OS(=O)-, R5S(=O)-, R5R6NS(=O)2-, R5OS(=O)2-, R5S(=O)2, C1-C3 fat Race, C1-C3 halogenated aliphatics, C1-C3 hydroxyl group aliphatics, C1-C3 amino aliphatic, C1-C3 alkoxy Cs 1-C3 fat Race, C1-C3 alkylamino C1-C3 aliphatic, C1-C3 alkylthio group C1-C3 aliphatic, C5-C10 aryl C1-C3 aliphatic, C5-C9 heteroaryl C1-C3 aliphatic, C4-C10 heterocycle C1-C3 aliphatic, C3-C10 naphthenic base C1-C3 aliphatic, C5- C10 aryloxy group C1-C3 aliphatic, C4-C10 heterocycle oxygroup C1-C3 aliphatic, C3-C10 cycloalkyl oxies C1-C3 fat Race, C5-C10 fragrant amino C1-C3 aliphatic, C4-C10 heterocyclylamino group C1-C3 aliphatic, C3-C10 cycloalkyl aminos C1- C3 aliphatic, C5-C10 aryl, C5-C10 heteroaryls, C4-C10 heterocycles or C3-C10 naphthenic base;
Wherein each R5And R6It independently is H, D, C1-C3 aliphatic, C1-C3 halogenated aliphatics, C1-C3 hydroxyl group aliphatics, C1-C3 amino aliphatic, C1-C3 alkoxy C 1-C3 aliphatic, C1-C3 alkylamino C1-C3 aliphatic, C1-C3 alkylthio groups C1-C3 aliphatic, C5-C10 aryl C1-C3 aliphatic, C5-C9 heteroaryl C1-C3 aliphatic, C4-C10 heterocycles C1-C3 Aliphatic, C3-C10 naphthenic base C1-C3 aliphatic, C5-C10 aryloxy group C1-C3 aliphatic, C4-C10 heterocycle oxygroups C1- C3 aliphatic, C3-C10 cycloalkyl oxy C1-C3 aliphatic, C5-C10 fragrant amino C1-C3 aliphatic, C4-C10 heterocycles Amino C1-C3 aliphatic, C3-C10 cycloalkyl amino C1-C3 aliphatic, C5-C10 aryl, C5-C10 heteroaryls, C4- C10 heterocycles or C3-C10 naphthenic base;Work as R5And R6It is connected on the same nitrogen-atoms, R5, R6It can be arbitrarily with nitrogen-atoms Form substituted or non-substituted 3-7 membered rings;
Above-mentioned R1, R2, R3, R4, R5, R6, R7, R8Group can appoint by deuterium, halogen, hydroxyl, methylol, carboxyl, second Acylamino-, alkyl（Such as methyl, ethyl, propyl）, alkoxy（Such as methoxyl group, ethyoxyl, tert-butoxy）, alkylamino, ring Alkyl, alkenyl, alkynyl, trifluoromethyl, trifluoroacetyl group, sulfydryl, halogen, nitro, amino, azido (- N3), Guanidine radicals, cyano, tertbutyloxycarbonyl (- Boc), carbonyl (- C=O), oxo (=O) is thio (=S), sulfonyl, virtue Base, heteroaryl, the substitution of one or more of heterocycle.
3. according to compound described in claim 1-2, wherein each R1Can be identical or different, it is each independently H, D, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, C5H11, C6H13, C8H17, trifluoromethyl, hydroxymethyl, amino methyl, methoxyl group, ethyoxyl, tert-butoxy, first Amino, ethylamino, isopropylamino, 3- hydroxyl-propyls, acetyl group, trifluoroacetyl group, Cyanoacetyl, methylamino Acetyl group, propiono, iso-propionyl, 2- hydroxypropanoyls, 2- aminopropionyls, 2- chlorine propionos, 2- bromine propionos, Valeryl, caproyl, heptanoyl group, methacrylyl, phenyl, benzoyl, p-nitrophenyl, to toluyl Base, fluoro benzoyl, p-benzoyl base, to methoxybenzoyl base, 2,4- dimethylbenzoyls are folded Nitrogen base benzoyl, benzyl, p-chlorobenzyl, vinyl, acrylic, allyl, n-butene base, isobutenyl, just Hydro carbons and its containing oxygen derivative (monoterpene or again of the multiple of pentenyl, isopentene group, isoprene or isoprene unit Hemiterpene substituent group), cyclopropyl, ring propiono, ring valeryl, cyclohexanoyl, 3- picolinoyls, naphthalene, phenethyl Imidazole radicals, pyridyl group, pyrrole radicals, oxazolyl, isoxazolyl, triazol radical, tetrazole base, furyl, thienyl, Thiazolyl, piperidyl, piperazinyl, indyl, carbazyl, benzofuranyl tetrahydrofuran base, THP trtrahydropyranyl are phonetic Pyridine base, purine bases ,-N (CH3)2,-C (C=O) NH-C1-C4 alkyl ,-OC (C=O)-NH-C1-C4 alkyl ,-OC (O= O) O-C1-C4 alkyl ,-NHC (=O) NH-C1-C4 alkyl ,-NHC (=O) O-C1-C4 alkyl ,-NHC (=O)-C1-C4 alkyl, C1-C4 alkyl-NH-S (=O)2, C1-C4 alkyl S (=O)2, C1-C4 alkyl S (=O)2NH-, phenyl-(CH2)P-G- (CH2)m, difluorophenyl-(CH2)P-G-(CH2)m, thiazolyl-(CH2)p-G-(CH2)m, pyridyl group-(CH2)p-G- (CH2)m, phenylethyl, cyclohexyl-(CH2)p-G-(CH2)m, wherein G is O, S, S (=O), S (=O)2, C(= O);P and m is each independently 0,1,2 or 3;Or wherein C5-C10 aryl-(CH2)P-G-(CH2)mIt can be by one Or it is multiple selected from F, Cl, Br, I, methyl, ethyl, propyl, acetenyl, propinyl, butynyl, methoxyl group, second The substituent group of oxygroup or cyano replaces;Or above-mentioned R1It is welcome by D, F, Cl, Br, I, hydroxyl, methylol, carboxylic Base, acetylamino, alkyl（Such as methyl, ethyl, propyl）, alkoxy（Such as methoxyl group, ethyoxyl, tert-butoxy）, alkane ammonia Base, naphthenic base, alkenyl, alkynyl, trifluoromethyl, trifluoroacetyl group, sulfydryl, halogen, nitro, amino, azido (-N3), guanidine radicals, cyano, tertbutyloxycarbonyl (- Boc), carbonyl (- C=O), oxo (=O) is thio (=S), sulphonyl Base, aryl, heteroaryl, the substitution of one or more of heterocycle;
Wherein each R2, R8Can be identical or different, it is each independently H, methyl, ethyl, propyl, isopropyl, butyl, Tertiary butyl, C5H11, C6H13, C8H17, trifluoromethyl, hydroxymethyl, amino methyl, 3- hydroxyl-propyls, acetyl group, Trifluoroacetyl group, Cyanoacetyl, methylamino acetyl group, propiono, iso-propionyl, 2- hydroxypropanoyls, 2- ammonia Base propiono, 2- chlorine propionos, 2- bromine propionos, valeryl, caproyl, heptanoyl group, methacrylyl, phenyl, Benzoyl, p-nitrophenyl, to methyl benzoyl, fluoro benzoyl, p-benzoyl base, to methoxyl group Benzoyl, 2,4- dimethylbenzoyls, azidobenzoyl, benzyl, p-chlorobenzyl, vinyl, propylene Base, allyl, n-butene base, isobutenyl, n-pentene base, isopentene group, cyclopropyl, ring propiono, ring valeryl Base, cyclohexanoyl, 3- picolinoyls, naphthalene, phenethyl imidazole radicals, pyridyl group, pyrrole radicals, oxazolyls, different evil Oxazolyl, triazol radical, tetrazole base, furyl, pyranose, thienyl, thiazolyl, piperidyl, piperazinyl, Yin Diindyl base, carbazyl, benzofuranyl tetrahydrofuran base, THP trtrahydropyranyl, pyrimidine bases, purine bases, pentose base, Hexose base ,-(C=O) NH-C1-C4 alkyl, C1-C4 alkyl-NH-S (=O)2, C1-C4 alkyl S (=O)2, phenyl- (CH2)P-G-(CH2)m, difluorophenyl-(CH2)P-G-(CH2) m, thiazolyl-(CH2)p-G-(CH2)m, pyridyl group- (CH2)p-G-(CH2)m, phenylethyl, cyclohexyl-(CH2)p-G-(CH2)m, wherein G is O, S, S (=O), S (= O)2, C(=O);P and m is each independently 0,1,2 or 3;Or wherein C5-C10 aryl-(CH2)P-G-(CH2)mIt can be with F, Cl, Br, I, methyl, ethyl, propyl, acetenyl, propinyl, butynyl, methoxy are selected from by one or more The substituent group of base, ethyoxyl or cyano replaces;Or above-mentioned R2, R8It is welcome by D, F, Cl, Br, I, hydroxyl, Hydroxyl, methylol, carboxyl, acetylamino, C1-C5 alkyl（Such as methyl, ethyl, propyl）, C1-C5 alkoxies, C1-C5 Alkylamino, trifluoromethyl, trifluoroacetyl group, sulfydryl, nitro, amino, azido (- N3), guanidine radicals, cyano, uncle Butoxy carbonyl (- Boc), carbonyl (- C=O), oxo (=O) is thio (=S), sulfonyl, one or more of phenyl Substitution;
Each R3, R4Can be identical or different, it is each independently H, D, F, Cl, Br, I, hydroxyl, amino, nitro, Cyano, methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, C5H11, C6H13, C8H17, trifluoromethyl, hydroxyl Ylmethyl, amino methyl, methoxyl group, ethyoxyl, tert-butoxy, methylamino, ethylamino, isopropylamino, 3- hydroxyls- Propyl, acetyl group, trifluoroacetyl group, Cyanoacetyl, methylamino acetyl group, propiono, iso-propionyl, 2- hydroxyls Base propiono, 2- aminopropionyls, 2- chlorine propionos, 2- bromine propionos, valeryl, caproyl, heptanoyl group, isobutyl Enoyl-, phenyl, benzoyl, p-nitrophenyl, to methyl benzoyl, fluoro benzoyl, p-aminophenyl first Acyl group, to methoxybenzoyl base, 2,4- dimethylbenzoyls, azidobenzoyl, benzyl, p-chlorobenzyl, Vinyl, acrylic, allyl, n-butene base, isobutenyl, n-pentene base, isopentene group, isoprene or different The hydro carbons and its containing oxygen derivative (monoterpene or sequiterpene substituent group) of the multiple of pentadiene unit, cyclopropyl, ring propiono, Ring valeryl, cyclohexanoyl, 3- picolinoyls, naphthalene, phenethyl imidazole radicals, pyridyl group, pyrrole radicals, oxazolyl, Isoxazolyl, triazol radical, tetrazole base, furyl, thienyl, thiazolyl, piperidyl, piperazinyl, indyl, Carbazyl, benzofuranyl tetrahydrofuran base, THP trtrahydropyranyl, pyrimidine bases, purine bases ,-N (CH3)2, -C(C= O) NH-C1-C4 alkyl ,-OC (C=O)-NH-C1-C4 alkyl ,-OC (O=O) O-C1-C4 alkyl ,-NHC (=O) NH-C1-C4 Alkyl ,-NHC (=O) O-C1-C4 alkyl ,-NHC (=O)-C1-C4 alkyl, C1-C4 alkyl-NH-S (=O)2, C1-C4 alkane Base S (=O)2, C1-C4 alkyl S (=O)2NH-, phenyl-(CH2)P-G-(CH2)m, difluorophenyl-(CH2)P-G-(CH2)m-, Thiazolyl-(CH2)p-G-(CH2)m, pyridyl group-(CH2)p-G-(CH2)m, phenylethyl, cyclohexyl-(CH2)p-G- (CH2)m, wherein G is O, S, S (=O), S (=O)2, C(=O);P and m is each independently 0,1,2 or 3;Or Person wherein C5-C10 aryl-(CH2)P-G-(CH2)mCan F, Cl, Br, I, methyl, second be selected from by one or more The substituent group of base, propyl, acetenyl, propinyl, butynyl, methoxyl group, ethyoxyl or cyano replaces;Or it is above-mentioned R3, R4It is welcome by D, F, Cl, Br, I, hydroxyl, methylol, carboxyl, acetylamino, alkyl（Such as methyl, second Base, propyl）, alkoxy（Such as methoxyl group, ethyoxyl, tert-butoxy）, alkylamino, naphthenic base, alkenyl, alkynyl, trifluoro Methyl, trifluoroacetyl group, sulfydryl, halogen, nitro, amino, azido (- N3), guanidine radicals, cyano, tertiary butyloxycarbonyl Base (- Boc), carbonyl (- C=O), oxo (=O) is thio (=S), sulfonyl, aryl, heteroaryl, in heterocycle One or more substitutions.
4. according to compound described in claim 1-3, including the tautomerism of the structure of following one or following one structure Body, racemic modification, the non-equal amount of mixture of enantiomter, geometric isomer, solvate, pharmaceutically may be used at stereoisomer The solvate of the salt of receiving or its salt, or prodrug:
。
5. claim 1-4 any one of them pharmaceutically acceptable salts are selected from：Hydrochloride, sulfate, phosphate, oxalic acid Salt, maleate, methane sulfonates, succinate, citrate, fumarate, glucuronate salt, formates, acetate, Succinate；The solvate of solvate or salt is selected from：Monohydrate, dihydrate, trihydrate, a methanol solvate, two Methanol solvate, an acetonitrile close object, diacetonitrile closes object, acetone conjunction object, two acetone close object, hemifumarate monohydrate, rich horse Hydrochlorate dihydrate, one ethanolates of fumarate;It is preferred that monohydrate, fumarate dihydrate, one ethyl alcohol of fumarate Close object.
6. a kind of pharmaceutical composition, it includes according to a kind of compound of claim 1-5 any one of them or several compounds Or the non-equal amount of mixture of its tautomer, stereoisomer, racemic modification, enantiomter, geometric isomer, solvation Any one or a few in the solvate of object, pharmaceutically acceptable salt or its salt is as active ingredient.
7. the pharmaceutical composition described in claim 6, it is characterised in that the pharmaceutical composition also includes that at least one pharmaceutically may be used Carrier, diluent or the excipient of receiving.
8. the pharmaceutical composition described in claim 7, it is characterised in that also comprising at least one, other are disease-resistant for the pharmaceutical composition Cytotoxic drug is specifically including but not limited to, virazole, rimantadine hydrochloride, amantadine hydrochloride, acyclovir, Valaciclovir, Ganciclovir, interferon, Zidovudine, arabinosy ladenosine, Ribavirin, Sebivo etc.;The pharmaceutical composition is preferably injected Agent, oral preparation, freeze drying powder injection, suspending agent etc..
9. compound or its tautomer, its stereoisomer, its racemic modification described in any one of claim 1-5, The non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, its pharmaceutically acceptable salt or its salt Pharmaceutical composition described in any one of solvate or claim 6-8 is used to prepare the purposes of antiviral drugs.
10. compound or its tautomer, its stereoisomer, its racemic modification described in any one of claim 1-5, The non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, its pharmaceutically acceptable salt or its salt Pharmaceutical composition described in any one of solvate or claim 6-8 is preparing treatment and/or is preventing by respiratory syncystial Viral (RSV), herpes simplex virus (HSV), hepatitis B (HBV), Enterovirus 71 (EV71), Coxsackie virus (Cox-B3), influenza virus (H1N1, H3N2, H5N1, H7N9), foot and mouth disease virus (FMDV), human immunodeficiency virus (HIV), the application in the drug of disease caused by SARS virus etc.;The disease selects breathing problem, pneumonia, gingivostomatitis, angle Fash, bleb and herpangina, the hand at the positions such as film conjunctivitis, encephalitis, hepatitis, genital system infection, hand, foot, oral cavity Sufficient stomatosis, immunity disease, inflammatory disease drug in application.
11. compound or its tautomer, its stereoisomer, its racemic modification described in any one of claim 1-5, The non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, its pharmaceutically acceptable salt or its salt Solvate is in anti respiratory syncytial virus (RSV), herpes simplex virus (HSV), coxsackie virus (Cox-B3), enteron aisle In the lead compound such as virus 71 (EV71), influenza virus (H1N1, H7N9), human immunodeficiency virus (HIV) Using.
12. the preparation method of compound described in claim 1：
;
Wherein A, Y, R1, R2, R3, R4, n, “" definition with any of the above-described place of the present invention to A, Y, R1, R2, R3, R4, n, “" definition;
It is characterized in that：
Step 1:With compound 1 or 2 be raw material under nitrogen or argon, with reducing agent in methanol solvate, in temperature 0- Trash ice and concentrated hydrochloric acid is added after reacting 5-30 min under 90 °C, obtains intermediate product a or b;Wherein reducing agent is selected from NaBH4、 LiAlH4、NaBH(OAc)3Deng；
Step 2:Intermediate product a or b are dehydrated under nitrogen or argon, and dewatered product occurs substitution reaction and obtains mesh Mark compound.
CN201710191188.6A 2017-03-28 2017-03-28 A kind of nitrogenous dicyclic compound and its preparation method and application Pending CN108658855A (en)

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