CN108658975A - A kind of nitrogenous compound and preparation method thereof and application as marine antifoulant - Google Patents

A kind of nitrogenous compound and preparation method thereof and application as marine antifoulant Download PDF

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Publication number
CN108658975A
CN108658975A CN201710191283.6A CN201710191283A CN108658975A CN 108658975 A CN108658975 A CN 108658975A CN 201710191283 A CN201710191283 A CN 201710191283A CN 108658975 A CN108658975 A CN 108658975A
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group
base
alkyl
aliphatic
amino
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邵长伦
牟晓凤
魏美燕
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Ocean University of China
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Ocean University of China
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    • C—CHEMISTRY; METALLURGY
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    • 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
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
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    • A—HUMAN NECESSITIES
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    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
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    • A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
    • A01N43/78—1,3-Thiazoles; Hydrogenated 1,3-thiazoles
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    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/84—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms six-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,4
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/88—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms six-membered rings with three ring hetero atoms
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    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
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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
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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
    • C07D401/04—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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    • C07D401/14—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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    • C07D405/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D5/00—Coating compositions, e.g. paints, varnishes or lacquers, characterised by their physical nature or the effects produced; Filling pastes
    • C09D5/16—Antifouling paints; Underwater paints
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Abstract

A kind of nitrogenous compound and preparation method thereof and application as marine antifoulant, 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 compounds and its pharmaceutical composition as drug, especially as the purposes of marine biofouling prevention coating material.

Description

A kind of nitrogenous compound and preparation method thereof and application as marine antifoulant
Technical field
The invention belongs to biological fields, and more particularly to a kind of nitrogenous compound and its pharmaceutical composition and nitrogen Close the application of object and its pharmaceutical composition in preparing marine biofouling prevention coating material.
Background technology
Marine biofouling is that subduction is set in ocean for organic molecule, microorganism, animal, plant and their by-product Apply the harmfulness accumulation on surface.This harmfulness accumulation frequently occurs in the surface for the ocean subduction facility that do not protect, including The ship of sea-freight and tourism, naval's warship, heat exchanger, sea sensor and aquaculture base etc..Biodeterioration draws Huge economic loss is played, only by taking USN's warship as an example, economic loss in this respect is in 18 to 26 hundred million U.S.s every year Between member, and USN's warship quantity only accounts for the 0.5% of global ships quantity, therefore marine biofouling is extremely serious Natural hazard.Barnacle is that representativeness very universal in fouling organism known today is biological because of its very strong Adhering capacity.From After the whole world in 2008 eliminate the use of poisonous anti-fouling agent organotin, finding safe and efficient marine antifoulant becomes in the world It is badly in need of the project solved.（J.A. Callow, M.E. Callow,Nat. Commun. 2011, 2, 244–253; C.M. Kirschner, A.B. Brennan, Annu. Rev. Mater. Res. 2012, 42, 1–19;M. Schultz, J. Bendick, E. Holm, W. Hertel, Biofouling 2011, 27, 87–98; P.-Y. Qian, Y. Xu, N. Fusetani, Biofouling 2010, 26, 223–234.）.
WO2014044615, which discloses compound as follows, has insecticidal activity.
Chinese patent 2014102548186, which discloses compound as follows, has antifouling activity.
The fouling resistance that Chinese patent 201510917619.3 and 201510918196.7 individually discloses compound as follows is lived Property.
Chinese patent 201410254857.6, which discloses compound as follows, has anti-fouling activity.
For the present invention on the basis of the above patent, research nitrogenous compound and the like is in terms of preparing marine antifoulant Using, in the prior art, though disclosed compound has certain similarity with the compounds of this invention, shown in the present invention Compound and the prior art have a significant difference, the anti-biofouling of the new derivative of nitrogenous compound is lived in the present invention Property be greatly improved, not only anti-fouling activity have broad spectrum activity, and toxicity reduce, effect toxicity ratio is much stronger than U.S. High-efficiency low-toxicity anti-fouling agent standard as defined in naval of state.
Invention content
A kind of nitrogenous compound of Formulas I and Formula II structure, 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 compound has the following structure：, wherein A, B are each From being independently five yuan or hexa-atomic aromatic ring, hetero-aromatic ring, carbocyclic ring or carbon heterocyclic;N=1,2,3, or 4; k = 1, 2, 3,4 or 5; “" indicate singly-bound or be not present, R1, R2, R3, R4Shown in being defined as follows：
Each R1, R4Can be identical or different, separate is 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 (R6)-, condenses miscellaneous bicyclic group-C (=O) N (R6)-, 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;
R2Can be identical or different, it is separate be 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;
R3Can be identical or different, separate is 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 (R6)-, condenses miscellaneous bicyclic group-C (=O) N (R6)-, 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 separate is 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;
R7Can be identical or different, separate is 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 is independently 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 3-8 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 some embodiments, the compounds of this invention is general formula III and IV compounds represented, or general formula III and IV The stereoisomer geometric isomer of shown compound, tautomer, nitrogen oxides, raceme, hydrate, solvate, Metabolite, pharmaceutically acceptable salt or prodrug：
,
Wherein T1, T2, T3, T4, separate is N or CR1, and at most there are three can be N; V1, V2, V3, V4, V5Separate is N or CR4, and as many as there are three can be N; “" indicate singly-bound or be not present, each R1, R2, R3, R4As follows：
Each R1, R4Can be identical or different, separate is H, F, Cl, Br, I, hydroxyl, amino, nitro, cyanogen Base, carboxyl, C1-C20 alkyl, C1-C20 halogenated alkyls, C1-C20 alkoxies, C1-C20 alkylaminos, C1-C20 alkyl Acyl group, hydroxyl C1-C20 alkoxies, hydroxyl C1-C20 alkylaminos, hydroxyl C1-C20 alkanoyls, C1-C20 halogenated alkoxies, The halogenated alkylaminos of C1-C20, C1-C20 ohaloalkanoyls, C1-C20 aminoalkoxies, C3-C10 naphthenic base, C3-C10 rings Alkyl oxy, C3-C10 cycloalkyl aminos, C3-C10 cycloalkanoyls, C2-C8 alkenyls, C2-C8 alkynyls, C6-C10 virtues Base, C6-C10 aryloxy group, C6-C10 aroyls, C6-C10 fragrant aminos, C6-C10 aryl C1-C6 alkoxies, C6-C10 virtues Base alkylamino, C5-C12 heteroaryls, C5-C12 heteroaryloxies, C5-C12 4-hetaroylpyrazols, C5-C12 heteroaryl amino, C5- C12 heteroaryl C1-C6 alkoxies, C5-C12 heteroaryl C1-C6 alkylaminos, C4-C12 heterocycle C1-C6 alkanoyls, C4- C12 Heterocyclylalkyls, C4-C12 heterocycle oxygroups, C4-C12 heterocyclylamino groups, C4-C12 heterocyclylacyls, C4-C12 heterocycles Base C1-C6 alkoxies, C4-C12 heterocycle C1-C6 alkylaminos, C4-C12 heterocycle C1-C6 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-C6 alkyl, R5S(=O)t- C1-C6 alkane Base, R5R6N-C (=O)-C1-C6 alkyl, R6R5N-C1-C6 alkoxies, R5S(=O)t- C1-C6 alkoxies, R5R6N-C(=O)- C1-C6 alkoxies, C6-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(R6)-, -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 C6-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;
R2Separate is H, C1-C20 alkyl, C1-C20 halogenated alkyls, C1-C20 alkyl acyls, C1-C20 hydroxyl alkane Acyl group, C1-C20 ohaloalkanoyls, C3-C10 naphthenic base, C3-C10 cycloalkanoyls, C2-C8 alkenyls, C2-C8 alkenyls Alkanoyl, C2-C8 alkynyls, C2-C8 alkynyl alkanoyls, C6-C10 aryl, C6-C10 aroyls, C5-C12 heteroaryls, 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;
R3It is separate be 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, the halogenated alkylaminos of C1-C20, C1- C20 ohaloalkanoyls, C1-C20 aminoalkoxies, C3-C10 naphthenic base, C3-C10 cycloalkyl oxies, C3-C10 naphthenic base Amino, C3-C10 cycloalkanoyls, C2-C8 alkenyls, C2-C8 alkynyls, C6-C10 aryl, C6-C10 aryloxy group, C6- C10 aroyls, C6-C10 fragrant aminos, C6-C10 aryl C1-C6 alkoxies, C6-C10 aryl alkane aminos, C5-C12 heteroaryls Base, C5-C12 heteroaryloxies, C5-C12 4-hetaroylpyrazols, C5-C12 heteroaryl amino, C5-C12 heteroaryl C1-C6 alkoxies, C5-C12 heteroaryl C1-C6 alkylaminos, C4-C12 heterocycle C1-C6 alkanoyls, C4-C12 Heterocyclylalkyls, C4-C12 heterocycles Base oxygroup, C4-C12 heterocyclylamino groups, C4-C12 heterocyclylacyls, C4-C12 heterocycle C1-C6 alkoxies, C4-C12 are miscellaneous Ring group C1-C6 alkylaminos, C4-C12 heterocycle C1-C6 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-C6 alkyl, R5S(=O)t- C1-C6 alkyl, R5R6N-C (=O)-C1-C6 alkane Base, R6R5N-C1-C6 alkoxies, R5S(=O)t- C1-C6 alkoxies, R5R6N-C (=O)-C1-C6 alkoxies, C6-C10 virtues Base-(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(R6)-, -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 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-C1 naphthenic base-(CH2)p-G-(CH2)mCan by one or more be selected from F, Cl, Br, I, alkyl, The substituent group of alkenyl, alkynyl, alkoxy or cyano replaces;
Wherein each R7Can be identical or different, separate is 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, C6-C10 aryl C1-C3 aliphatic, C5-C9 heteroaryl C1-C3 aliphatic, C4-C10 heterocycle C1-C3 aliphatic, C3-C10 naphthenic base C1-C3 aliphatic, C6- C10 aryloxy group C1-C3 aliphatic, C4-C10 heterocycle oxygroup C1-C3 aliphatic, C3-C10 cycloalkyl oxies C1-C3 fat Race, C6-C10 fragrant amino C1-C3 aliphatic, C4-C10 heterocyclylamino group C1-C3 aliphatic, C3-C10 cycloalkyl aminos C1- C3 aliphatic, C6-C10 aryl, C5-C10 heteroaryls, C4-C10 heterocycles or C3-C10 naphthenic base;
Wherein each R5And R6It is independently 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, C6-C10 aryl C1-C3 aliphatic, C5-C9 heteroaryl C1-C3 aliphatic, C4-C10 heterocycles C1-C3 Aliphatic, C3-C10 naphthenic base C1-C3 aliphatic, C6-C10 aryloxy group C1-C3 aliphatic, C4-C10 heterocycle oxygroups C1- C3 aliphatic, C3-C10 cycloalkyl oxy C1-C3 aliphatic, C6-C10 fragrant amino C1-C3 aliphatic, C4-C10 heterocycles Amino C1-C3 aliphatic, C3-C10 cycloalkyl amino C1-C3 aliphatic, C6-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 3-8 membered rings;
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 some embodiments, each R of compound in the present invention1, R4Can be identical or different, separate is H, D, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, butyl, tertiary fourth Base, C5H11, C6H13, C8H17, trifluoromethyl, hydroxymethyl, amino methyl, methoxyl group, ethyoxyl, tert-butoxy, Methylamino, ethylamino, isopropylamino, 3- hydroxyl-propyls, acetyl group, trifluoroacetyl group, Cyanoacetyl, methyl ammonia Base acetyl group, propiono, iso-propionyl, 2- hydroxypropanoyls, 2- aminopropionyls, 2- chlorine propionos, 2- bromine propionyl Base, valeryl, caproyl, heptanoyl group, methacrylyl, phenyl, benzoyl, p-nitrophenyl, to methylbenzene Formoxyl, fluoro benzoyl, p-benzoyl base, to methoxybenzoyl base, 2,4- dimethylbenzoyls, Between azidobenzoyl, benzyl, p-chlorobenzyl, vinyl, acrylic, allyl, n-butene base, isobutenyl, The multiple of n-pentene base, isopentene group, isoprene or isoprene unit hydro carbons and its containing oxygen derivative (monoterpene or Sequiterpene substituent group), cyclopropyl, ring propiono, ring valeryl, cyclohexanoyl, 3- picolinoyls, naphthalene, benzene second Base imidazole radicals, pyridyl group, pyrrole radicals, oxazolyl, isoxazolyl, triazol radical, tetrazole base, furyl, thiophene Base, 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 alkane Base, 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 C6-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 R1, R4It is welcome by D, F, Cl, Br, I, hydroxyl, methylol, Carboxyl, acetylamino, alkyl（Such as methyl, ethyl, propyl）, alkoxy（Such as methoxyl group, ethyoxyl, tert-butoxy）, alkane Amino, naphthenic base, alkenyl, alkynyl, trifluoromethyl, trifluoroacetyl group, sulfydryl, halogen, nitro, amino, nitrine 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;
In further embodiments, each R in the compounds of this invention2For 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 C6-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 R2It is welcome by D, F, Cl, Br, I, hydroxyl, hydroxyl Base, methylol, carboxyl, acetylamino, C1-C6 alkyl（Such as methyl, ethyl, propyl）, C1-C6 alkoxies, C1-C6 alkane Amino, trifluoromethyl, trifluoroacetyl group, sulfydryl, nitro, amino, azido (- N3), guanidine radicals, cyano, tertiary fourth Oxygen carbonyl (- Boc), carbonyl (- C=O), oxo (=O), thio (=S), sulfonyl, one or more of phenyl takes Generation
In some embodiments, R in the compounds of this invention3Separate is H, D, F, Cl, Br, I, hydroxyl, ammonia Base, nitro, cyano, methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, C5H11, C6H13, C8H17, three Methyl fluoride, hydroxymethyl, amino methyl, methoxyl group, ethyoxyl, tert-butoxy, methylamino, ethylamino, isopropyl ammonia Base, 3- hydroxyl-propyls, acetyl group, trifluoroacetyl group, Cyanoacetyl, methylamino acetyl group, propiono, isopropyl Acyl group, 2- hydroxypropanoyls, 2- aminopropionyls, 2- chlorine propionos, 2- bromine propionos, valeryl, caproyl, heptan Acyl group, methacrylyl, phenyl, benzoyl, p-nitrophenyl, to methyl benzoyl, fluoro benzoyl, P-benzoyl base, to methoxybenzoyl base, 2,4- dimethylbenzoyls, azidobenzoyl, benzyl, P-chlorobenzyl, vinyl, acrylic, allyl, n-butene base, isobutenyl, n-pentene base, isopentene group are different The hydro carbons and its containing oxygen derivative (monoterpene or sequiterpene substituent group) of pentadiene or the multiple of isoprene unit, cyclopropyl, Ring propiono, ring valeryl, cyclohexanoyl, 3- picolinoyls, naphthalene, phenethyl imidazole radicals, pyridyl group, pyrroles Base, oxazolyl, isoxazolyl, triazol radical, tetrazole base, furyl, thienyl, thiazolyl, piperidyl, piperazine Piperazine base, 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 C6-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 R3It is welcome by D, F, Cl, Br, I, hydroxyl, methylol, carboxyl, acetylamino, alkyl（As methyl, Ethyl, propyl）, alkoxy（Such as methoxyl group, ethyoxyl, tert-butoxy）, alkylamino, naphthenic base, alkenyl, alkynyl, three Methyl fluoride, 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 substitution.
In further embodiments, the compounds of this invention is including but not limited to one of following structure or following one knot The tautomer of structure, stereoisomer, racemic modification, the non-equal amount of mixture of enantiomter, geometric isomer, solvation The solvate of object, pharmaceutically acceptable salt or its salt, or prodrug:
。
One aspect of the present invention is related to a kind of composition, including the compound of the present invention, or its stereoisomer, geometry Isomers, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or Combination thereof.
One aspect of the present invention is related to a kind of anti-fouling agent on protection submerged structure surface.
It is a kind of to inhibit marine organisms to the attachment on submerged structure surface and/or the anti-fouling agent being stained, contain Formulas I-IVization Object or its pharmaceutically acceptable salt are closed as active ingredient.
Some embodiments are, the marine organisms of the present invention for causing submerged structure surface to be stained are to be stained microorganism, attached One kind in microalgae biology, macro, barnacle class biology, coil pipe insects biology, shellfish biology and ectoproctous polyzoa biology Or it is several, specifically include pseudomonas aeruginosa, yellowish-brown pseudomonad, Vibrio anguillarum, enterobacter cloacae, barnacle, lime worm, coil pipe Worm, ascidian, bryozoan, oyster, mussel etc..
Some embodiments are, anti-fouling agent of the present invention be used to prevent marine organisms to the attachment on submerged structure surface and/ Or the method being stained includes：Anti-fouling agent of the present invention is coated on the submerged structure surface.
Some of embodiments are application of the compound of the present invention in preparing marine antifoulant, especially Prepare the application in terms of the bioantifoulings agent such as anti-barnacle, lime worm, coil pipe worm, ascidian, bryozoan, oyster, mussel.
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 There is the positioning of negation " just " or " E ∥ Z ", 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, while have 9 or 10 The bicyclic carbocyclic ring of atom can be two rings [5.6] or [6.6] system.Suitable cyclic aliphatic group including but not limited to, Naphthenic base, cycloalkenyl group and cycloalkynyl radical.The example of cyclic aliphatic group further comprises, but is not limited to, cyclopropyl, ring Butyl, cyclopenta, 1- cyclopenta -1- alkenyls, 1- cyclopenta -2- alkenyls, 1- cyclopenta -3- alkenyls, cyclohexyl, 1- rings Hexyl -1- alkenyls, 1- cyclohexyl -2- alkenyls, 1- cyclohexyl -3- alkenyls, cyclohexadienyl, suberyl, cyclooctyl, ring Nonyl, cyclodecyl, ring undecyl, cyclo-dodecyl, adamantyl etc..And " carbocyclic ring ", " carbocylic radical ", " 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, mercapto Base, 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, the alkyl-S (=O) of hydroxyl substitution2, carboxyl alcoxyl Base 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, Thio-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, 3H- indyl 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, and two carbon atoms are replaced by oxygen atom as phonetic on 1- dioxidothiomorpholinyls, and 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- are thio Di azoly, l, 3,4- thio biphosphole bases, l, 2,5- thio biphosphole bases, 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,（1,2,3,4,4a, 5,8,8a- octahydro naphthalene）Methylamino, condensed-bicyclic [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.
Unless other aspects show, all tautomeric forms of the compound of the present invention are included in the model of the present invention Within enclosing.In addition, unless other aspects show, the structural formula of compound described in the invention includes one or more different Atom enriched isotope.
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（+）、（-）For naming chemical combination object plane The symbol of polarised light rotation,（-）Or it is left-handed, prefix that L, which refers to compound,（+）Or it is dextrorotation that D, which refers to compound,.These The chemical constitution of stereoisomer is identical, but their stereochemical structure is different.Specifically stereoisomer can be The mixture of enantiomer, isomers is commonly referred to as enantiomeric mixture.50：50 mixture of enantiomers is referred to as outer disappear Mixture or racemic modification are revolved, this may lead to do not have stereoselectivity or stereoselectivity in chemical reaction process.Term " racemic mixture " and " racemic modification " refers to the mixture of equimolar two enantiomters, lacks 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 keto-enol and imine-enamine.Valence（Chemical valence）Tautomer includes Recombinate the change of 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 in J. Pharmaceutical Sciences, 66:1-19,1977. recorded.The salt that pharmaceutically acceptable nontoxic acid is formed is including but not limited to ammonia Base group, which reacts the inorganic acid salt to be formed, a hydrochloride, hydrobromate, phosphate, sulfate, perchlorate, and organic Hydrochlorate, such as acetate, oxalates, maleate, tartrate, citrate, succinate, malonate, or These salt are obtained by other methods described in the books or literature such as ion-exchange.Other pharmaceutically acceptable salt packets It includes:Adipate, alginates, ascorbate, aspartate, benzene sulfonate, benzoate, bisulphate, Borate, butyrate, camphor hydrochlorate, camsilate, cyclopentyl propionate, digluconate, dodecyl sulphur Hydrochlorate, esilate, formates, fumarate, gluceptate, glycerophosphate, gluconate, half Sulfate, enanthate, caproate, hydriodate, 2- hydroxy-ethanesulfonate salts, lactobionate, lactate, lauric acid Salt, lauryl sulfate, malate, malonate, mesylate, 2- naphthalene sulfonates, nicotinate, nitrate, Oleate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, picrate, pivalic acid Salt, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..By appropriate The obtained salt of alkali include alkali metal, alkaline-earth metal, ammonium and N+(C1-C4 alkyl)4Salt.The present invention is also intended to contemplate any The compound of the group of included N is formed by quaternary ammonium salt.Water-soluble or oil-soluble or dispersion product can be turned by quaternary ammonium With obtaining.Alkali or alkaline earth metal salt includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt is further Including appropriate, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylic Compound, hydrosulphate, phosphoric acid compound, nitric acid compound, C1-C8 azochlorosulfonate acid compounds and aromatic sulphonic acid compound.
The salt of part of compounds of the present invention can be illustrated with following particular compound salt, but not limit 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.
" solvate " of the compound of the present invention or " solvate " of the compound of the present invention salt can be as follows Illustrate, but does not limit the present invention.
。
Unless other aspects show, all stereoisomers of the compound of the present invention, geometric isomer mutually makes a variation Structure body, nitrogen oxides, hydrate, solvate, metabolite, salt and pharmaceutically acceptable prodrug belong to this hair Bright range.
The salt of the compound of the present invention further includes the intermediate or Formulas I-for being used to prepare or purifying compound shown in Formulas I-IV The salt of the enantiomter of the separation of compound shown in IV, 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-IV, listed by the present invention The compound gone out, or embodiment compound represented or its pharmaceutically acceptable salt.Compound in the composition of the present invention Amount can effectively inhibit the attachment of barnacle, bryozoan, periphtic algae.
Embodiment 1：3- methoxyl group -1- pentyls -4-（2- pyridyl groups）- 1,5- naphthyridines -2 (1H) -one
Step 1) under nitrogen protection, by 3-（4-aminopyridine）- 2- pyridinyl methanones (2 mmol), methoxyacetyl chloride (3.7 mmol) and N, N- diisopropylethylamine (7 mmol) are dissolved in dichloromethane (5 mL), are reacted at room temperature 3 hours. Contact plate finds that raw material reaction finishes, and reaction solution is diluted with water rear ethyl acetate and extracts, residual after organic phase removed under reduced pressure solvent Object is stayed to obtain 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 -1,5- naphthyridines -2 (1H) -one.
Step 3）Under an atmosphere of hydrogen, 4- hydroxy-3-methoxies -4- (2- pyridines) -3,4- dihydro -1,5- naphthyridines -2 (1H) -one is dissolved in MeOH (10 mL), 10%Pd/C (0.1 mmol) and potassium carbonate (7 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）- 1,5- naphthalenes Pyridine -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 is stirred at room temperature.3- methoxyl groups -4（2- pyridyl groups）- 1,5- naphthyridines -2 (1H) -one (10 mmol) and bromo pentane（10 mmol）DMSO (12 mL) solution, injection be added.It is heated to l00 °C of mistake 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）- 1,5- naphthyridines -2 (1H) -one.
ESI-MS (m/z):324.24[M+H]+。
Embodiment 2：1- pentamethylene base -3- methoxyl groups -4-（4- methoxyphenyls）- 6- propiono -1,5- naphthyridines -2 (1H)- Ketone
Step 1) under nitrogen protection, by 1- (4- amino -5- (4- methoxybenzoyls base)-pyridine -2- propyl -1- ketone (2 mmol), methoxyacetyl chloride (3.7 mmol) and N, N- diisopropylethylamine (7 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）- 6- propiono -3,4- dihydro -1,5- naphthyridines -2 (1H) -one.
Step 3）Under an atmosphere of hydrogen, 4- hydroxy-3-methoxies -4-（4- methoxyphenyls）- 6- propionos -3,4- two Hydrogen -1,5- naphthyridines -2 (1H) -one is dissolved in MeOH (10 mL), 10%Pd/C (0.1 mmol) and potassium carbonate (7 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）- 6- propiono -1,5- 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 is stirred at room temperature.3- methoxyl groups -4-（4- methoxyphenyls）- 6- third Acyl group -1,5- 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）, receive 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）- 6- propiono -1,5- naphthyridines -2 (1H) -one.
ESI-MS (m/z):406.47 [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 is 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]+。
Embodiment 4.1- benzyl -3- ethyoxyls -4-（3- hydroxy phenyls) quinoline -2 (1H) -one
Step 1）3- ethyoxyls -4-（3- hydroxy phenyls）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 is stirred at room temperature.33- ethyoxyls -4-（3- hydroxy phenyls）Quinoline -2 (1H) -one (10 mmol) and benzyl bromine（10 mmol) DMSO (12 mL) solution, injection be 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）, organic phase is collected, decompression boils off molten Agent, crude product purify to obtain 1- benzyl -3- ethyoxyls -4- through column chromatography（3- hydroxy phenyls）Quinoline -2 (1H) -one.
ESI-MS (m/z):362.14[M+H]+。
5. 1- of embodiment (3- (N, N- dimethylamino) propyl) -3- methoxyl group -4- phenyl -1,5- naphthyridines -2 (1H) -one
Step 1）3- methoxyl group -4- phenyl -1,5- naphthyridines -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 is stirred at room temperature.3- methoxyl group -4- phenyl -1,5- 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 cooled to room temperature, filters, water is added（50 mL）And dichloromethane（50 mL×3）, organic phase is collected, decompression boils off molten Agent, crude product purify to obtain 1- (3- (N, N- dimethylamino) propyl) -3- methoxyl group -4- phenyl -1,5- naphthyridines -2 through column chromatography (1H) -one.
ESI-MS (m/z):337.42[M+H]+。
6. 3- benzyloxies -1- (2- furans) -5- methyl 4-phenyls quinoline -2 (1 of embodimentH) -one
Step 1) 3- benzyloxy -4- phenyl -5- Methyl-quinolines -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- benzyloxy -4- phenyl -5- Methyl-quinolines -2 (1H) -one (10 mmol) and bromo pentane（10 mmol）DMSO (12 mL) solution, injection be 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）, organic phase is collected, decompression is steamed Solvent, crude product is gone to purify to obtain 3- benzyloxies -1- (2- furans) -5- methyl 4-phenyls quinoline -2 (1 through column chromatographyH) -one.
ESI-MS (m/z):407.16[M+H]+。
7 field sea upper hanging plate testing method of embodiment
The experiment of field sea upper hanging plate is using traditional fouling resistance biology field sea upper hanging plate test method (referring to national standard GB/T 5370-2007) test the antifouling activity of compound.
Negative control group：Paint is the paint for not adding any anti-fouling agent, is referred to as priming paint;
Positive controls：The anti-fouling paint of 211TM containing Sea-Nine (w/w30%);
Experimental group：Anti-fouling paint containing the compounds of this invention (w/w 30%).
The PVC board for being coated with paint is bundled in acrylic fibers rope on the buoyant raft of brace, it is made to be immersed in shallow sea.Periodically see Marine fouling organism attachment kind adhesion amount and breeding degree on hanging plate are examined, photographs to record and is stained situation, while paying attention to comparing Experimental group, negative control group and positive controls, result evaluation anti-fouling paint antifouling property according to the observation.In this experiment, Sea area field hanging plate starts from marine organism growth vigorous April, and experiment hanging plate respectively prepares 3 pieces, the extension of same test series Plate is fixed on the extra large depth of same leaching on same frame, and each concentration is arranged 3 experiments and repeats.
The antifouling experimental result of compound
After hanging plate 2 months, be attached on negative control plate a large amount of fouling organism barnacle, lime worm, ascidian, seaweed and The fouling organisms such as oyster（The area percentage that fouling organism accounts for the monoblock space of a whole page is more than 50%）, and only have on experimental group plate a small amount of Sea grass and several barnacles, illustrate the compounds of this invention to neritic area it is main be stained microorganism, microalgae biology, macro, Barnacle class biology, coil pipe insects biology, shellfish biology and ectoproctous polyzoa biology have good antifouling activity, especially to dirt Damage microorganism, barnacle, lime worm, coil pipe worm, ascidian, bryozoan, oyster, mussel etc..

Claims (10)

1. the nitrogenous compound of a kind of Formulas I and Formula II structure, 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 compound has the following structure：, wherein A, B are respectively It is independently five yuan or hexa-atomic aromatic ring, hetero-aromatic ring, carbocyclic ring or carbon heterocyclic;N=1,2,3 or 4; k = 1, 2, 3, 4 Or 5; “" indicate singly-bound or be not present, R1, R2, R3, R4Shown in being defined as follows：
Each R1, R4Can be identical or different, separate is 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;
R2Can be identical or different, separate is 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;
R3Can be identical or different, it is separate be hydrogen, halogen, hydroxyl, amino, nitro, cyano, carboxyl, alkyl, Halogenated alkyl, alkoxy, alkylamino, alkyl acyl, hydroxy alkoxy base, Hydroxyalkylamino, hydroxyalkanoyl are halogenated Alkoxy, halogenated alkylamino, ohaloalkanoyl, aminoalkoxy, naphthenic base, cycloalkyl oxy, cycloalkyl amino, 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 are miscellaneous Aryl, heteroaryloxy, 4-hetaroylpyrazol, heteroaryl amino, heteroarylalkoxy, heteroarylalkylamino, heterocycle alkanoyl, Heterocyclylalkyl, heterocycle oxygroup, heterocyclylamino group, heterocyclylacyl, heterocyclylalkoxy, heterocycle alkylamino are miscellaneous Ring group 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 group Amino, condensed-bicyclic base alkoxy condense miscellaneous bicyclic group alkoxy, and condensed-bicyclic base alkylamino condenses miscellaneous bicyclic group alkane Amino, condensed-bicyclic base oxygroup alkoxy condense miscellaneous bicyclic group oxygroup alkoxy, and condensed-bicyclic base aminoalkoxy is thick Close miscellaneous bicyclic group aminoalkoxy, 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, it is thick Close bicyclic group-C (=O) N (R6)-, condenses miscellaneous bicyclic group-C (=O) N (R6)-, 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 oxygroup, the miscellaneous bicyclic group oxygroup of spiral shell, spiral shell bicyclic group amino, spiral shell are miscellaneous double Ring group amino, spiral shell bicyclic group alkoxy, the miscellaneous bicyclic group alkoxy of spiral shell, spiral shell bicyclic group alkylamino, the miscellaneous bicyclic group alkylamino of spiral shell, Spiral shell bicyclic group oxygroup alkoxy, the miscellaneous bicyclic group oxygroup alkoxy of spiral shell, spiral shell bicyclic group aminoalkoxy, the miscellaneous bicyclic group amino of spiral shell Alkoxy, 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-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 (R5)-, spiral shell is 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;
R7Can be identical or different, separate is 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 is independently 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 and IV compounds represented, or shown in general formula III and IV The stereoisomer geometric isomer of compound, tautomer, nitrogen oxides, raceme, hydrate, solvate, metabolism Product, pharmaceutically acceptable salt or prodrug：
,
Wherein T1, T2, T3, T4Separate is N or CR1, and at most there are three can be N; V1, V2, V3, V4, V5 Separate is N or CR4, and as many as there are three can be N; “" indicate singly-bound or be not present, each R1, R2, R3, R4As follows：
Each R1, R4Can be identical or different, separate is H, F, Cl, Br, I, hydroxyl, amino, nitro, cyanogen Base, carboxyl, C1-C20 alkyl, C1-C20 halogenated alkyls, C1-C20 alkoxies, C1-C20 alkylaminos, C1-C20 alkyl Acyl group, hydroxyl C1-C20 alkoxies, hydroxyl C1-C20 alkylaminos, hydroxyl C1-C20 alkanoyls, C1-C20 halogenated alkoxies, The halogenated alkylaminos of C1-C20, C1-C20 ohaloalkanoyls, C1-C20 aminoalkoxies, C3-C10 naphthenic base, C3-C10 rings Alkyl oxy, C3-C10 cycloalkyl aminos, C3-C10 cycloalkanoyls, C2-C7 alkenyls, C2-C7 alkynyls, C5-C10 virtues Base, C5-C10 aryloxy group, C5-C10 aroyls, C5-C10 fragrant aminos, C5-C10 aryl C1-C5 alkoxies, C5-C10 virtues Base alkylamino, C5-C12 heteroaryls, C5-C12 heteroaryloxies, C5-C12 4-hetaroylpyrazols, C5-C12 heteroaryl amino, C5- C12 heteroaryl C1-C5 alkoxies, C5-C12 heteroaryl C1-C5 alkylaminos, C4-C12 heterocycle C1-C5 alkanoyls, C4- C12 Heterocyclylalkyls, C4-C12 heterocycle oxygroups, C4-C12 heterocyclylamino groups, C4-C12 heterocyclylacyls, C4-C12 heterocycles Base C1-C5 alkoxies, 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 alkane Base, 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;
R2Separate is H, C1-C20 alkyl, C1-C20 halogenated alkyls, C1-C20 alkyl acyls, C1-C20 hydroxyl alkane Acyl group, C1-C20 ohaloalkanoyls, C3-C10 naphthenic base, C3-C10 cycloalkanoyls, C2-C8 alkenyls, C2-C8 alkenyls Alkanoyl, C2-C8 alkynyls, C2-C8 alkynyl alkanoyls, C6-C10 aryl, C6-C10 aroyls, C5-C12 heteroaryls, 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;
R3It is separate be 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, the halogenated alkylaminos of C1-C20, C1- C20 ohaloalkanoyls, C1-C20 aminoalkoxies, C3-C10 naphthenic base, C3-C10 cycloalkyl oxies, C3-C10 naphthenic base Amino, C3-C10 cycloalkanoyls, C2-C8 alkenyls, C2-C8 alkynyls, C6-C10 aryl, C6-C10 aryloxy group, C6- C10 aroyls, C6-C10 fragrant aminos, C6-C10 aryl C1-C6 alkoxies, C6-C10 aryl alkane aminos, C5-C12 heteroaryls Base, C5-C12 heteroaryloxies, C5-C12 4-hetaroylpyrazols, C5-C12 heteroaryl amino, C5-C12 heteroaryl C1-C6 alkoxies, C5-C12 heteroaryl C1-C6 alkylaminos, C4-C12 heterocycle C1-C6 alkanoyls, C4-C12 Heterocyclylalkyls, C4-C12 heterocycles Base oxygroup, C4-C12 heterocyclylamino groups, C4-C12 heterocyclylacyls, C4-C12 heterocycle C1-C6 alkoxies, C4-C12 are miscellaneous Ring group C1-C6 alkylaminos, C4-C12 heterocycle C1-C6 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-C6 alkyl, R5S(=O)t- C1-C6 alkyl, R5R6N-C (=O)-C1-C6 alkane Base, R6R5N-C1-C6 alkoxies, R5S(=O)t- C1-C6 alkoxies, R5R6N-C (=O)-C1-C6 alkoxies, C6-C10 virtues Base-(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(R6)-, -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 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-C1 naphthenic base-(CH2)p-G-(CH2)mCan by one or more be selected from F, Cl, Br, I, alkyl, The substituent group of alkenyl, alkynyl, alkoxy or cyano replaces;
Wherein R7Can be identical or different, separate is 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 is independently 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, 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.
3. according to compound described in claim 1-2, wherein each R1, R4Can be identical or different, it is separate be H, D, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, C5H11, C5H13, C7H16, 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 Pentenyl, isopentene 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, tetrahydrochysene pyrrole It mutters base, pyrimidine bases, purine bases ,-N (CH3)2,-C (C=O) NH-C1-C4 alkyl ,-OC (C=O)-NH-C1-C4 alkane Base ,-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 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 R1, R4It is welcome by D, F, Cl, Br, I, hydroxyl, Methylol, carboxyl, acetylamino, alkyl（Such as methyl, ethyl, propyl）, alkoxy（Such as methoxyl group, ethyoxyl, tertiary fourth oxygen Base）, alkylamino, naphthenic base, alkenyl, alkynyl, trifluoromethyl, trifluoroacetyl group, sulfydryl, halogen, nitro, ammonia Base, azido (- 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;
According to compound described in claim 1-2, wherein each R2Can be identical or different, separate is H, methyl, second Base, propyl, isopropyl, butyl, tertiary butyl, C5H11, C6H13, C8H17, trifluoromethyl, hydroxymethyl, amino first Base, 3- hydroxyl-propyls, acetyl group, trifluoroacetyl group, Cyanoacetyl, methylamino acetyl group, propiono, isopropyl Acyl group, 2- hydroxypropanoyls, 2- aminopropionyls, 2- chlorine propionos, 2- bromine propionos, valeryl, caproyl, heptan Acyl group, methacrylyl, phenyl, benzoyl, p-nitrophenyl, to methyl benzoyl, fluoro benzoyl, P-benzoyl base, to methoxybenzoyl base, 2,4- dimethylbenzoyls, azidobenzoyl, benzyl, P-chlorobenzyl, vinyl, acrylic, allyl, n-butene base, isobutenyl, n-pentene base, isopentene group, ring Propyl, 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, 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)mCan by one or more be selected from F, Cl, Br, I, methyl, ethyl, propyl, acetenyl, The substituent group of propinyl, butynyl, methoxyl group, ethyoxyl or cyano replaces;Or above-mentioned R2It 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 alkylaminos, trifluoromethyl, trifluoroacetyl group, sulfydryl, nitro, amino, azido (- N3), guanidine radicals, cyano, tertbutyloxycarbonyl (- Boc), carbonyl (- C=O), oxo (=O) is thio (=S), sulfonyl, One or more of phenyl replaces;
According to compound, R described in claim 1-23Can be identical or different, it is separate be H, 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, methylamino, ethylamino, Isopropylamino, 3- hydroxyl-propyls, acetyl group, trifluoroacetyl group, Cyanoacetyl, methylamino acetyl group, propionyl Base, iso-propionyl, 2- hydroxypropanoyls, 2- aminopropionyls, 2- chlorine propionos, 2- bromine propionos, valeryl, oneself Acyl group, heptanoyl group, methacrylyl, phenyl, benzoyl, p-nitrophenyl, to methyl benzoyl, fluorobenzene Formoxyl, p-benzoyl base, to methoxybenzoyl base, 2,4- dimethylbenzoyls, azidobenzoyl Base, benzyl, p-chlorobenzyl, vinyl, acrylic, allyl, n-butene base, isobutenyl, n-pentene base are different Pentenyl, cyclopropyl, ring propiono, ring valeryl, cyclohexanoyl, 3- picolinoyls, naphthalene, phenethyl imidazoles Base, pyridyl group, pyrrole radicals, oxazolyls, isoxazolyl, triazol radical, tetrazole base, furyl, thienyl, thiophene Oxazolyl, piperidyl, piperazinyl, indyl, carbazyl, benzofuranyl tetrahydrofuran base, THP trtrahydropyranyl, pyrimidine 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 C6-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 R3It is welcome by D, F, Cl, Br, I, hydroxyl, hydroxyl, hydroxyl first Base, carboxyl, acetylamino, C1-C6 alkyl（Such as methyl, ethyl, propyl）, C1-C6 alkoxies, C1-C6 alkylaminos, three Methyl fluoride, trifluoroacetyl group, sulfydryl, nitro, amino, azido（-N3）, guanidine radicals, cyano, tertbutyloxycarbonyl（- Boc）, carbonyl（-C=O）, oxo（=O）, thio（=S）, sulfonyl, the substitution of one or more of phenyl.
4. compound according to claim 1, including but not limited to the change of one of following structure or following one structure 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:
。
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 inhibit marine organisms to the attachment on submerged structure surface and/or the anti-fouling agent being stained, it is characterised in that it contains Compound or its pharmaceutically acceptable salt described in claim 1-4 is as active ingredient.
7. the anti-fouling agent described in claim 6, wherein the marine organisms are to be stained microorganism, attachment microalgae biology, large size One or more of algae, barnacle class biology, coil pipe insects biology, shellfish biology and ectoproctous polyzoa biology, specifically include It is pseudomonas aeruginosa, yellowish-brown pseudomonad, Vibrio anguillarum, enterobacter cloacae, barnacle, lime worm, coil pipe worm, ascidian, bryozoan, male Oyster, mussel etc..
8. anti-fouling agent described in claim 6-7 is for preventing marine organisms to the attachment on submerged structure surface and/or the side being stained Method, including：In the anti-fouling agent described in the coating claim 6-7 of the submerged structure surface.
9. application of the compound in preparing marine antifoulant described in claim 1-5, especially prepare fouling resistance microorganism, Application in terms of the bioantifoulings agent such as barnacle, lime worm, coil pipe worm, ascidian, bryozoan, oyster, mussel.
10. the preparation method of compound of formula I described in claim 1 is:
;
Wherein A, B, R1, R2, R3, R4, the same any of the above-described place of the present invention of definition of n, k are to A, B, R1, R2, R3, R4, the definition of n, k;It is characterized in that it is characterized in that:
Step 1:Using substituted aryl ketone derivatives and carboxylic acid halides as raw material, acylation reaction occurs under nitrogen or argon, Obtain intermediate product 1;Acylation reaction condition is this field normal condition:In organic solvent, under alkali and acylating reagent effect Reaction, wherein acylating reagent is preferred, wherein X is halogen, preferably chlorine, bromine, iodine; R3Definition with this hair Bright any of the above-described place is to R3Definition;Alkali preferred alkali metal carbonate (preferably potassium carbonate, sodium carbonate, cesium carbonate), alkali metal Alcoholates (preferably sodium methoxide, sodium ethoxide, potassium tert-butoxide etc.), triethylamine, pyridine, sodium acetate, quinoline, imidazoles, two Methylaniline, DMAP, 2,6- lutidines etc., the above-mentioned preferred dichloromethane of organic solvent, acetonitrile, benzene, toluene, Tetrahydrofuran, ether, DMF, dioxane react at 20-90 °C of temperature;
Step 2:Amide intermediate product 1 under nitrogen or argon, occurs Aldol condensation reactions and generates intermediate product 2; Aldol condensation reaction conditions are this field popular response condition:In organic solvent, react in the presence of alkali;Alkali is preferred Alkali carbonate (preferably potassium carbonate, sodium carbonate, cesium carbonate), alkali alcoholate (preferably sodium methoxide, sodium ethoxide, uncle Butanol potassium etc.), triethylamine, pyridine, sodium acetate, quinoline, imidazoles, dimethylaniline, DMAP, 2,6- lutidines Deng, the above-mentioned preferred dichloromethane of organic solvent, acetonitrile, benzene, toluene, tetrahydrofuran, ether, DMF, dioxane, It is reacted at 20-90 °C of temperature;
Step 3:After under nitrogen or argon dehydration occurs for intermediate product 2, hydrocarbonylation or acylation reaction obtain chemical combination Object I;Alkylation reaction condition is this field popular response condition:In organic solvent, reacted under alkali, the effect of hydrocarbonylation reagent, The wherein preferred R of hydrocarbonylation reagent2X, wherein X are halogen, preferably chlorine, bromine, iodine; R2Definition with any of the above-described place pair of the present invention R2Definition;Alkali preferred alkali metal carbonate (preferably potassium carbonate, sodium carbonate, cesium carbonate), alkali metal hydroxide is (preferably LiOH, NaOH, KOH), alkali metal hydride (preferably NaH, LiH, KH), alkali alcoholate (preferably sodium methoxide, Sodium ethoxide, potassium tert-butoxide etc.);Acylation reaction condition is also this field normal condition:In organic solvent, in alkali and acylated examination The lower reaction of agent effect, the wherein preferred R of acylating reagent2X (acyl chlorides) or R2OR2(acid anhydrides), wherein X are halogen, preferred chlorine, Bromine, iodine; R2Definition with any of the above-described place of the present invention to R2Definition;Alkali preferred alkali metal carbonate (preferably potassium carbonate, Sodium carbonate, cesium carbonate), alkali alcoholate (preferably sodium methoxide, sodium ethoxide, potassium tert-butoxide etc.), triethylamine, pyridine, Sodium acetate, quinoline, imidazoles, dimethylaniline, DMAP, 2,6- lutidines etc., the above-mentioned preferred dichloro of organic solvent Methane, acetonitrile, benzene, toluene, tetrahydrofuran, ether, DMF, dioxane react at 20-90 °C of temperature.
CN201710191283.6A 2017-03-28 2017-03-28 A kind of nitrogenous compound and preparation method thereof and application as marine antifoulant Pending CN108658975A (en)

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