CN108658937A - A kind of bicyclic alkaloid compound and its preparation method and application - Google Patents

A kind of bicyclic alkaloid compound and its preparation method and application Download PDF

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CN108658937A
CN108658937A CN201710191158.5A CN201710191158A CN108658937A CN 108658937 A CN108658937 A CN 108658937A CN 201710191158 A CN201710191158 A CN 201710191158A CN 108658937 A CN108658937 A CN 108658937A
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base
alkyl
aliphatic
amino
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邵长伦
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Ocean University of China
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Ocean University of China
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Abstract

The present invention relates to a kind of bicyclic 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 anti-inflammatory, anti-fibrosis drug.

Description

A kind of bicyclic alkaloid compound and its preparation method and application
Technical field
The invention belongs to drug fields, and more particularly to a kind of bicyclic alkaloid compound, pharmaceutical composition, its system Preparation Method and its as drug especially as prepare it is anti-inflammatory and treatment, prevent tissue fibrosis drug purposes.
Background technology
Inflammation is a kind of defense reaction of the body to infection, and under normal physiological conditions, inflammation is beneficial to body. Under pathological conditions, inflammation can also cause a series of pathological changes, can cause to damage to body, such as arthritis, septicemia, group Knit organ fibrosis and atherosclerosis etc..When body is damaged, macrophage is as first of immune defence line, meeting Release a series of cellular inflammation factors, including tumor necrosis factor（Tumor necrosis factor, TNF), leucocyte Interleukin（Inter1eukin, IL), prostaglandin 2 (Prostag1andin E2, PGE2) and nitric oxide（Nitric Oxide, NO) etc., these inflammatory factors have great influence to the repair process of body.Inflammation causes parenchymatous disease cell to be sent out Raw necrosis organizes the pathologic process of extracellular matrix abnormal increase and over-deposit, less serious case to become fibrosis, and severe one causes Institutional framework is destroyed and organ sclerosis occurs.
Organ-tissue fibrosis less serious case is known as fibrosis, and severe one causes institutional framework to destroy and organ sclerosis occurs.Tissue Fibrosis not only occurs on the organs such as lung, liver, and tissue fibrosis can involve the almost all of organ of human body and system, it be by In many reasons（Such as inflammation, immune, poisonous substance, ischemic and hemodynamic responses）Cause parenchymal cell destruction, then causes The inflammation deformation of parenchyma, necrosis simultaneously activate corresponding macrophage release cytokine profiles and growth factor, these The extracellular matrix of factor activator quiescent condition（Extrace11u1ar martri, ECM) cell is generated, it is allowed to be converted into flesh Fibroblast;Myofibroblast is proliferated, and secrete cytokines, is remake for macrophage by paracrine mode. Myofibroblast can synthesize the ECM ingredients such as a large amount of collagens, while ECM degradations are reduced, to cause organ or tissue's fiber Change.
Since each organ or tissue's function, the difference of form, and each organ or tissue mainly form the difference of cell, So that Different Organs or the fibrosis of tissue in its pathogenesis existing general character, also have individual character;Cell is mainly generated with ECM For, it is hepatic stellate cells in liver, is mesangial cell in glomerulus, is renal interstitial in renal interstitial into fiber finer Born of the same parents, are lung fibroblast in lungs, are cardiac fibroblasts in heart, are Peritoneal Mesothelial Cells in peritonaeum.Therefore, exist There is also certain differences in the pathogenesis and therapy target of Different Organs or tissue fibrosis.
The drug that EP1138329A discloses a kind of known anti-fibrosis is pirfenidone or Pirfenidone, PFD, 5- methyl-1s-phenyl -2- (1- hydrogen）Pyridone.Experiment shows, in kidney fibrosis, pulmonary fibrosis zoopery and specificity In the clinical treatment of pulmonary fibrosis patient, PFD, which all has, prevents it to the effect for reversing ECM to build up.Compound of the present invention And related activity has not been reported.
Invention content
A kind of bicyclic alkaloid compound of Formulas I-II structures, tautomer, stereoisomer, racemic modification, The non-equal amount of mixture of enantiomter, the solvation of geometric isomer, solvate, pharmaceutically acceptable salt or its salt Object, it is characterised in that Formulas I and Formula II compound have the following structure：, R1, R2, R3, R4And shown in A, Y be defined as follows：
The aromatic ring or hetero-aromatic ring that A is five yuan or hexa-atomic, saturated or unsaturated carbocyclic ring or carbon heterocyclic, condensed-bicyclic or condensed miscellaneous Bicyclic, Y is O or S;N=0,1,2,3 or 4; “" indicate singly-bound or be not present;In Formulas I, A is phenyl ring, and Y is When O, R2Cannot be H;
Each R1Can 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 (R5)-, condenses miscellaneous bicyclic group-C (=O) N (R5)-, spiral shell bicyclic group, the miscellaneous bicyclic group of spiral shell, spiral shell are bicyclic Base aliphatic, the miscellaneous bicyclic group aliphatic of spiral shell, spiral shell bicyclic group oxygroup, the miscellaneous bicyclic group oxygroup of spiral shell, spiral shell bicyclic group amino, spiral shell are miscellaneous Bicyclic group amino, spiral shell bicyclic group alkoxy, the miscellaneous bicyclic group alkoxy of spiral shell, spiral shell bicyclic group alkylamino, the miscellaneous bicyclic group alkane ammonia of spiral shell Base, spiral shell bicyclic group oxygroup alkoxy, the miscellaneous bicyclic group oxygroup alkoxy of spiral shell, spiral shell bicyclic group aminoalkoxy, the miscellaneous bicyclic group of spiral shell Aminoalkoxy, spiral shell bicyclic group-C (=O)-, spiral shell bicyclic group-C (=O) O-, the miscellaneous bicyclic group-C of spiral shell (=O)-, the miscellaneous bicyclic group-of spiral shell C (=O) O-, spiral shell bicyclic group amino-C (=O)-, the miscellaneous bicyclic group amino-C of spiral shell (=O)-, spiral shell bicyclic group-C (=O) N (R5)-, spiral shell Miscellaneous bicyclic group-C (=O) N (R5)-, R6R5N-, -C(=O)NR5R6, -OC(=O)NR5R6, -OC(=O)OR5, -N(R5)C(=O) NR5R6, -N(R5)C(=O)OR6, -N(R5)C(=O)-R6, R5R6N-S(=O)t-, R5S(=O)t-, R5S(=O)tN(R6)-, R6R5N- alkyl, R5S(=O)tAlkyl, R5R6N-C (=O)-alkyl, R6R5N- alkoxies, R5S(=O)tAlkoxy, R5R6N-C (=O)-alkoxy, aryl-(CH2)p-G-(CH2)m, heteroaryl-(CH2)p-G-(CH2)m, heterocycle-(CH2)p- G-(CH2)m, or naphthenic base-(CH2)p-G-(CH2)m, wherein G is O, S, NR7, S(=O), S(=O)2,C(=O), -C (=O)N(R5)-, -OC(=O)N(R5)-, -OC(=O)-, -N(R5)C(=O)N(R5)-, -(R5)N-S(=O)t-, -OS(= O)t, or-OS (=O)tN(R5)-;T is l or 2;P and m is each independently 0, l, 2,3 or 4;Or wherein aryl- (CH2)p-G-(CH2)m, heteroaryl-(CH2)p-G-(CH2)m, heterocycle-(CH2)p-G-(CH2)m, or naphthenic base- (CH2)p-G-(CH2)mCan F, Cl, Br, I, alkyl, alkenyl, alkynyl, alkoxy or cyanogen be selected from by one or more The substituent group of base replaces;
Each R2Can be identical or different, it is 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;
Each R3And 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;
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 3-7 membered rings with nitrogen-atoms, condensed-bicyclic or Spiral shell is bicyclic;The hetero atom in heterocycle, heteroaryl, condensed miscellaneous bicyclic group, the miscellaneous bicyclic group of spiral shell involved in above-mentioned group is independent 1-5 hetero atom of the ground in N, O, S, Se;
Above-mentioned R1, R2, R3, R4, R5, R6, R7Group can appoint by deuterium, halogen, hydroxyl, methylol, carboxyl, acetyl Amino, alkyl（Such as methyl, ethyl, propyl）, alkoxy（Such as methoxyl group, ethyoxyl, tert-butoxy）, alkylamino, cycloalkanes Base, alkenyl, alkynyl, trifluoromethyl, trifluoroacetyl group, sulfydryl, halogen, nitro, amino, azido (- N3), Guanidine radicals, cyano, tertbutyloxycarbonyl (- Boc), carbonyl (- C=O), oxo (=O) is thio (=S), sulfonyl, virtue Base, heteroaryl, the substitution of one or more of heterocycle.
In other embodiments, the compound of the present invention is general formula III-X compounds represented, or general formula III- The stereoisomer geometric isomer of compound shown in X, tautomer, nitrogen oxides, raceme, hydrate, solvate, Metabolite, pharmaceutically acceptable salt or prodrug：
,
Wherein Y is O or S; T1, T2, T3, T4, T5, T6Separate is C, N or CR1Or NR8, wherein T1, T2, T3, T4, T5, T6At most there are three can be N; V, V1, V2Separate is O, S, N or CR1Or NR8;“ " indicate singly-bound or be not present;Each R1, R2, R3, R4, R8As follows：
Each R1Can be identical or different, it is 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, C1- The halogenated alkylaminos of C20, C1-C20 ohaloalkanoyls, C1-C20 aminoalkoxies, C3-C10 naphthenic base, C3-C10 naphthenic base Oxygroup, C3-C10 cycloalkyl aminos, C3-C10 cycloalkanoyls, C2-C7 alkenyls, C2-C7 alkynyls, C5-C10 aryl, C5-C10 aryloxy group, C5-C10 aroyls, C5-C10 fragrant aminos, C5-C10 aryl C1-C5 alkoxies, C5-C10 aryl alkane Amino, C5-C12 heteroaryls, C5-C12 heteroaryloxies, C5-C12 4-hetaroylpyrazols, C5-C12 heteroaryl amino, C5-C12 are miscellaneous Aryl C1-C5 alkoxies, C5-C12 heteroaryl C1-C5 alkylaminos, C4-C12 heterocycle C1-C5 alkanoyls, C4-C12 heterocycles Alkyl, C4-C12 heterocycle oxygroups, C4-C12 heterocyclylamino groups, C4-C12 heterocyclylacyls, C4-C12 heterocycles C1-C5 Alkoxy, C4-C12 heterocycle C1-C5 alkylaminos, C4-C12 heterocycle C1-C5 alkanoyls, R6R5N-, -C(=O)NR5R6, -OC(=O)NR5R6, -OC(=O)OR5, -N(R5)C(=O)NR5R6, -N(R5)C(=O)OR6, -N(R5)C(=O)-R6, R5R6N-S(=O)t-, R5S(=O)t-, R5S(=O)tN(R6)-, R6R5N- C1-C5 alkyl, R5S(=O)t- C1-C5 alkyl, R5R6N-C (=O)-C1-C5 alkyl, R6R5N- C1-C5 alkoxies, R5S(=O)t- C1-C5 alkoxies, R5R6N-C(=O)- C1-C5 alkoxies, C5-C10 aryl-(CH2)p-G-(CH2)m, C5-C12 heteroaryls-(CH2)p-G-(CH2)m-, C4-C12 Heterocycle-(CH2)p-G-(CH2)m, or C3-C10 naphthenic base-(CH2)p-G-(CH2)m, wherein G is O, S, NR7, S(= O), S(=O)2,C(=O), -C(=O)N(R5)-, -OC(=O)N(R5)-, -OC(=O)-, -N(R5)C(=O)N(R5)-, - (R5)N-S(=O)t-, -OS(=O)t, or-OS (=O)tN(R5)-;T is l or 2;P and m is each independently 0, l, 2,3 Or 4;Or wherein C5-C10 aryl-(CH2)p-G-(CH2)m, C5-C12 heteroaryls-(CH2)p-G-(CH2)m-, C4-C12 Heterocycle-(CH2)p-G-(CH2)m, or C3-C1 naphthenic base-(CH2)p-G-(CH2)mCan F be selected from by one or more, The substituent group of Cl, Br, I, alkyl, alkenyl, alkynyl, alkoxy or cyano replaces.
Wherein each R2, R8It is separate be H, C1-C20 alkyl, C1-C20 halogenated alkyls, C1-C20 alkyl acyls, C1-C20 hydroxyalkanoyls, C1-C20 ohaloalkanoyls, C3-C10 naphthenic base, C3-C10 cycloalkanoyls, C2-C7 alkene Base, C2-C7 alkenyl alkanoyls, C2-C7 alkynyls, C2-C7 alkynyl alkanoyls, C5-C10 aryl, C5-C10 aroyls, C5-C12 heteroaryls, C5-C12 4-hetaroylpyrazols, C4-C12 heterocycle alkanoyls, C4-C12 Heterocyclylalkyls, C4-C12 heterocycles Base acyl group, C4-C12 heterocycle C1-C5 alkanoyls, C5-C12 condensed-bicyclic bases, C5-C12 condense miscellaneous bicyclic group ,-C (=O) NR5R6, R5R6N-S(=O)t-, R5S(=O)t-, R6R5N-C1-C5 alkyl, R5S(=O)t- C1-C5 alkyl, R5R6N-C(= O)-C1-C5 alkyl, C5-C10 aryl-(CH2)p-G-(CH2)m, C5-C12 heteroaryls-(CH2)p-G-(CH2)m-, C4-C12 Heterocycle-(CH2)p-G-(CH2)m, or C3-C10 naphthenic base-(CH2)p-G-(CH2)m, wherein G is O, S, NR7, S(= O), S(=O)2,C(=O), -C(=O)N(R5)-, -OC(=O)N(R5)-, -OC(=O)-, -(R5)N-S(=O)t-, -OS(= O)t, or-OS (=O)tN(R5)-;T is l or 2;P and m is each independently 0, l, 2,3 or 4;Or wherein C5-C10 Aryl-(CH2)p-G-(CH2)m, C5-C12 heteroaryls-(CH2)p-G-(CH2)m, C4-C12 heterocycles-(CH2)p-G- (CH2)m, or C3-C10 naphthenic base-(CH2)p-G-(CH2)mCan by one or more be selected from F, Cl, Br, I, cyano, Alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, carbocylic radical, the substituent group substitution of heterocycle.
R3, R4Separate is H, F, Cl, Br, I, C1-C20 alkyl, C1-C20 halogenated alkyls, C1-C20 Alkyl acyl, C1-C20 hydroxyalkanoyls, C1-C20 ohaloalkanoyls, C3-C10 naphthenic base, C3-C10 cycloalkanoyls, C2-C7 alkenyls, C2-C7 alkenyl alkanoyls, C2-C7 alkynyls, C2-C7 alkynyl alkanoyls, C5-C10 aryl, C5-C10 virtues Acyl group, C5-C12 heteroaryls, C5-C12 4-hetaroylpyrazols, C4-C12 heterocycle alkanoyls, C4-C12 Heterocyclylalkyls, C4- C12 heterocyclylacyls, C4-C12 heterocycle C1-C5 alkanoyls, C5-C12 condensed-bicyclic bases, C5-C12 condense miscellaneous bicyclic group, -C(=O)NR5R6, R5R6N-S(=O)t-, R5S(=O)t-, R6R5N-C1-C5 alkyl, R5S(=O)t- C1-C5 alkyl, R5R6N-C (=O)-C1-C5 alkyl, C5-C10 aryl-(CH2)p-G-(CH2)m, C5-C12 heteroaryls-(CH2)p-G- (CH2)m, C4-C12 heterocycles-(CH2)p-G-(CH2)m, or C3-C10 naphthenic base-(CH2)p-G-(CH2)m, wherein G is O, S, NR7, S(=O), S(=O)2,C(=O), -C(=O)N(R5)-, -OC(=O)N(R5)-, -OC(=O)-, -N(R5)C (=O)N(R5)-, -(R5)N-S(=O)t-, -OS(=O)t, or-OS (=O)tN(R5)-;T is l or 2;P and m is respectively independent Ground is 0, l, 2,3 or 4;Or wherein C5-C10 aryl-(CH2)p-G-(CH2)m, C5-C12 heteroaryls-(CH2)p-G- (CH2)m, C4-C12 heterocycles-(CH2)p-G-(CH2)m, or C3-C10 naphthenic base-(CH2)p-G-(CH2)mIt can be by one It is a or multiple selected from F, Cl, Br, I, cyano, alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, carbocyclic ring Base, the substituent group substitution of heterocycle.
In some embodiments, wherein each R of compound of the present invention1Can be identical or different, it is separate to be H, D, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, butyl, Tertiary butyl, C5H11, C6H13, C8H17, trifluoromethyl, hydroxymethyl, amino methyl, methoxyl group, ethyoxyl, tertiary fourth Oxygroup, methylamino, ethylamino, isopropylamino, 3- hydroxyl-propyls, acetyl group, trifluoroacetyl group, Cyanoacetyl, Methylamino acetyl group, propiono, iso-propionyl, 2- hydroxypropanoyls, 2- aminopropionyls, 2- chlorine propionos, 2- Bromine propiono, valeryl, caproyl, heptanoyl group, methacrylyl, phenyl, benzoyl, p-nitrophenyl are right Methyl benzoyl, fluoro benzoyl, p-benzoyl base, to methoxybenzoyl base, 2,4- dimethyl benzene first Acyl group, azidobenzoyl, benzyl, p-chlorobenzyl, vinyl, acrylic, allyl, n-butene base are different The hydro carbons and its containing oxygen derivative of the multiple of cyclobutenyl, n-pentene base, isopentene group, isoprene or isoprene unit (monoterpene or sequiterpene substituent group), cyclopropyl, ring propiono, ring valeryl, cyclohexanoyl, 3- picolinoyls, naphthalene Base, phenethyl imidazole radicals, pyridyl group, pyrrole radicals, oxazolyl, isoxazolyl, triazol radical, tetrazole base, furans Base, thienyl, thiazolyl, piperidyl, piperazinyl, indyl, carbazyl, benzofuranyl tetrahydrofuran base, four Hydrogen pyranose, pyrimidine bases, purine bases ,-N (CH3)2,-C (C=O) NH-C1-C4 alkyl ,-OC (C=O)-NH-C1-C4 Alkyl ,-OC (O=O) O-C1-C4 alkyl ,-NHC (=O) NH-C1-C4 alkyl ,-NHC (=O) O-C1-C4 alkyl ,-NHC (= O)-C1-C4 alkyl, C1-C4 alkyl-NH-S (=O)2, C1-C4 alkyl S (=O)2, C1-C4 alkyl S (=O)2NH-, benzene Base-(CH2)P-G-(CH2)m, difluorophenyl-(CH2)P-G-(CH2)m, thiazolyl-(CH2)p-G-(CH2)m, pyridyl group- (CH2)p-G-(CH2)m, phenylethyl, cyclohexyl-(CH2)p-G-(CH2)m, wherein G is O, S, S (=O), S (= O)2, C(=O);P and m is each independently 0,1,2 or 3;Or wherein C5-C10 aryl-(CH2)P-G-(CH2)mIt can be with F, Cl, Br, I, methyl, ethyl, propyl, acetenyl, propinyl, butynyl, methoxy are selected from by one or more The substituent group of base, ethyoxyl or cyano replaces;Or above-mentioned R1It is welcome by D, F, Cl, Br, I, hydroxyl, hydroxyl first Base, carboxyl, acetylamino, alkyl（Such as methyl, ethyl, propyl）, alkoxy（Such as methoxyl group, ethyoxyl, tert-butoxy）, Alkylamino, naphthenic base, alkenyl, alkynyl, trifluoromethyl, trifluoroacetyl group, sulfydryl, halogen, nitro, amino are folded Nitrogen base (- N3), guanidine radicals, cyano, tertbutyloxycarbonyl (- Boc), carbonyl (- C=O), oxo (=O) is thio (=S), Sulfonyl, aryl, heteroaryl, the substitution of one or more of heterocycle.
Wherein each R2, R8Can be identical or different, it is separate be H, methyl, ethyl, propyl, isopropyl, Butyl, tertiary butyl, C5H11, C6H13, C8H17, trifluoromethyl, hydroxymethyl, amino methyl, 3- hydroxyl-propyls, second Acyl group, trifluoroacetyl group, Cyanoacetyl, methylamino acetyl group, propiono, iso-propionyl, 2- hydroxypropanoyls, 2- aminopropionyls, 2- chlorine propionos, 2- bromine propionos, valeryl, caproyl, heptanoyl group, methacrylyl, benzene Base, benzoyl, p-nitrophenyl, to methyl benzoyl, fluoro benzoyl, p-benzoyl base, to first Oxygroup benzoyl, 2,4- dimethylbenzoyls, azidobenzoyl, benzyl, p-chlorobenzyl, vinyl, Acrylic, allyl, n-butene base, isobutenyl, n-pentene base, isopentene group, cyclopropyl, ring propiono, ring Valeryl, cyclohexanoyl, 3- picolinoyls, naphthalene, phenethyl imidazole radicals, pyridyl group, pyrrole radicals, oxazolyls, Isoxazolyl, triazol radical, tetrazole base, furyl, pyranose, thienyl, thiazolyl, piperidyl, piperazinyl, Indyl, carbazyl, benzofuranyl tetrahydrofuran base, THP trtrahydropyranyl, pyrimidine bases, purine bases, pentose Base, hexose base ,-(C=O) NH-C1-C4 alkyl, C1-C4 alkyl-NH-S (=O)2, C1-C4 alkyl S (=O)2, benzene Base-(CH2)P-G-(CH2)m, difluorophenyl-(CH2)P-G-(CH2) m, thiazolyl-(CH2)p-G-(CH2)m, pyridyl group- (CH2)p-G-(CH2)m, phenylethyl, cyclohexyl-(CH2)p-G-(CH2)m, wherein G is O, S, S (=O), S (= O)2, C(=O);P and m is each independently 0,1,2 or 3;Or wherein C5-C10 aryl-(CH2)P-G-(CH2)mIt can be with F, Cl, Br, I, methyl, ethyl, propyl, acetenyl, propinyl, butynyl, methoxy are selected from by one or more The substituent group of base, ethyoxyl or cyano replaces;Or above-mentioned R2, R8It is welcome by D, F, Cl, Br, I, hydroxyl, Hydroxyl, methylol, carboxyl, acetylamino, C1-C5 alkyl（Such as methyl, ethyl, propyl）, C1-C5 alkoxies, C1-C5 Alkylamino, trifluoromethyl, trifluoroacetyl group, sulfydryl, nitro, amino, azido (- N3), guanidine radicals, cyano, uncle Butoxy carbonyl (- Boc), carbonyl (- C=O), oxo (=O) is thio (=S), sulfonyl, one or more of phenyl Substitution.
Each R3, R4Can be identical or different, separate is H, D, F, Cl, Br, I, hydroxyl, amino, nitre Base, cyano, methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, C5H11, C6H13, C8H17, trifluoromethyl, Hydroxymethyl, amino methyl, methoxyl group, ethyoxyl, tert-butoxy, methylamino, ethylamino, isopropylamino, 3- hydroxyls Base-propyl, acetyl group, trifluoroacetyl group, Cyanoacetyl, methylamino acetyl group, propiono, iso-propionyl, 2- Hydroxypropanoyl, 2- aminopropionyls, 2- chlorine propionos, 2- bromine propionos, valeryl, caproyl, heptanoyl group are different Crotonyl, phenyl, benzoyl, p-nitrophenyl, to methyl benzoyl, fluoro benzoyl, p-aminophenyl Formoxyl, to methoxybenzoyl base, 2,4- dimethylbenzoyls, azidobenzoyl, benzyl, to benzyl chloride Base, vinyl, acrylic, allyl, n-butene base, isobutenyl, n-pentene base, isopentene group, isoprene Or the hydro carbons and its containing oxygen derivative (monoterpene or sequiterpene substituent group) of the multiple of isoprene unit, cyclopropyl, ring propionyl Base, ring valeryl, cyclohexanoyl, 3- picolinoyls, naphthalene, phenethyl imidazole radicals, pyridyl group, pyrrole radicals are disliked Oxazolyl, isoxazolyl, triazol radical, tetrazole base, furyl, thienyl, thiazolyl, piperidyl, piperazinyl, Indyl, carbazyl, benzofuranyl tetrahydrofuran base, THP trtrahydropyranyl, pyrimidine bases, purine bases ,-N (CH3)2,-C (C=O) NH-C1-C4 alkyl ,-OC (C=O)-NH-C1-C4 alkyl ,-OC (O=O) O-C1-C4 alkyl ,-NHC (=O) NH-C1-C4 alkyl ,-NHC (=O) O-C1-C4 alkyl ,-NHC (=O)-C1-C4 alkyl, C1-C4 alkyl-NH-S (= O)2, C1-C4 alkyl S (=O)2, C1-C4 alkyl S (=O)2NH-, phenyl-(CH2)P-G-(CH2)m, difluorophenyl- (CH2)P-G-(CH2)m, thiazolyl-(CH2)p-G-(CH2)m, pyridyl group-(CH2)p-G-(CH2)m, phenylethyl, ring Hexyl-(CH2)p-G-(CH2)m, wherein G is O, S, S (=O), S (=O)2, C(=O);P and m are each independently 0, 1,2 or 3;Or wherein C5-C10 aryl-(CH2)P-G-(CH2)mCan F, Cl, Br, I be selected from by one or more, The substituent group of methyl, ethyl, propyl, acetenyl, propinyl, butynyl, methoxyl group, ethyoxyl or cyano replaces; Or above-mentioned R3, R4It is welcome by D, F, Cl, Br, I, hydroxyl, methylol, carboxyl, acetylamino, alkyl（Such as first Base, ethyl, propyl）, alkoxy（Such as methoxyl group, ethyoxyl, tert-butoxy）, alkylamino, naphthenic base, alkenyl, alkynyl, Trifluoromethyl, trifluoroacetyl group, sulfydryl, halogen, nitro, amino, azido (- N3), guanidine radicals, cyano, tertiary fourth Oxygen carbonyl (- Boc), carbonyl (- C=O), oxo (=O) is thio (=S), sulfonyl, aryl, heteroaryl, heterocycle One or more of base replaces.
In some embodiments, compound of the present invention have including but not limited to following one structure or with The tautomer of one of lower structure, non-equal amount of mixture, the geometrical isomerism of stereoisomer, racemic modification, enantiomter The solvate or prodrug of body, solvate, pharmaceutically acceptable salt or its salt：
。
One aspect of the present invention is related to pharmaceutical composition, including the compound of the present invention or its stereoisomer, geometrical isomerism Body, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or their prodrug Or optional pharmaceutically acceptable carrier, excipient, diluent, adjuvant, medium or combination thereof.
One aspect of the present invention is related to the method for preventing, handling, treating or mitigate patient tissue or organ fibrosis disease, Including using the pharmaceutically acceptable effective dose of the pharmaceutical composition of the compounds of this invention to be administered patient.
Another aspect of the present invention is related to the compound of the present invention and is used to prepare for preventing, handling, treat or mitigating patient The purposes of tissue or the drug of organ fibrosis disease.
Another aspect of the present invention, which is related to being used to prepare using a kind of pharmaceutical composition comprising the compound of the present invention, to be used for The purposes for preventing, handling, treating or mitigate patient tissue or the drug of organ fibrosis disease.
On the other hand, preventing or treating to move using the compounds of this invention or its pharmaceutical composition the present invention relates to a kind of The method for application of object or tissue or organ fibrosis disease, the purposes include to use the compound of the present invention or its drug Pharmaceutically acceptable effective therapeutic dose of composition is administered human body or animal.
Compound of the present invention or its pharmaceutical salts or its hydrate can effective for prevention, processing, treat or subtract Light patient tissue or organ fibrosis disease, especially can effectively treat kidney region fibrosis, glomerulosclerosis, liver fibrosis, Pulmonary fibrosis, peritoneal fibrosiss, myocardial fibrosis, fibrosis of skin, postoperative intestinal adhesion, benign prostatauxe disease, skeletal muscle Fibrosis, chorionitis, multiple sclerosis, pancreatic fibrosis, hepatic sclerosis, muscle tumor, nerve fibre onch- interstitial fibrosis, The disease of diabetic nephropathy, Alzheimer disease or vascular fibrosis.
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 Sorre11, University Science Books, Sausa1ito: 1999, and “March's Advanced Organic Chemistry,” by Michae1 B. Smith and Jerry March,John. Wi1ey&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.Alkyl more includes into one-year-old example, 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, 1,2- 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 a atom can be two rings [5.6] or [6.6] system.Suitable cyclic aliphatic group includes, but and unlimited In, naphthenic base, cycloalkenyl group and cycloalkynyl radical.The example of cyclic aliphatic group further comprises, but is not limited to, ring third Base, cyclobutyl, cyclopenta, 1- cyclopenta -1- alkenyls, 1- cyclopenta -2- alkenyls, 1- cyclopenta -3- alkenyls, hexamethylene Base, 1- cyclohexyl -1- alkenyls, 1- cyclohexyl -2- alkenyls, 1- cyclohexyl -3- alkenyls, cyclohexadienyl, suberyl, ring Octyl, cyclononyl, cyclodecyl, ring undecyl, cyclo-dodecyl, adamantyl etc..And " carbocyclic ring ", " carbon Ring group ", " naphthenic base " can be substituted or non-substituted, and wherein substituent group can be, but be not limited to, halogenated alkyl, Hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocycle Base, sulfydryl, nitro, aryloxy group, the alkoxy of hydroxyl substitution, alkyl-C (=O)-, the alkyl-C (=O)-of hydroxyl substitution, Alkyl-S (=O)-, alkyl-S (=O)2, the alkyl-S (=O)-of hydroxyl substitution, the alkyl-S (=O) of hydroxyl substitution2, carboxyl Alkoxy etc..
Term " cycloalkyl oxy " or " carbocylic radical oxygroup " include the naphthenic base optionally replaced or carbocylic radical, such as present invention It is defined, it is connected on oxygen atom, and be connected with remaining molecule by oxygen atom, such example includes, but not It is limited to cyclopropyl oxygroup, cyclopentyloxy, cyclohexyl oxygroup, the cyclopropyl oxygroup etc. of hydroxyl substitution.
Term " cycloalkyl amino " indicates that amino group is replaced by one or two group of naphthene base, wherein naphthenic base With meaning as described in the present invention, such example is including but not limited to cyclopropylamino, clopentylamino, ring Hexylamino, the cyclopropylamino of hydroxyl substitution, dicyclohexyl amino, Bicyclopropyl amino etc..
Term " cycloalkyl oxy aliphatic " indicates that aliphatic group is replaced by one or more cycloalkyl oxy groups, Wherein aliphatic group and cycloalkyl oxy group have meaning as described in the present invention, and such example includes, but not It is limited to cyclopropyl oxygroup methyl, cyclopropyl oxygroup ethyl, cyclopentyloxymethyl, cyclopentyloxy ethyl, cyclohexyl oxygen Base ethyl, halogenated cyclopropyl oxygroup ethyl etc..
Term " cycloalkyl amino aliphatic " indicates that aliphatic group is replaced by one or more cycloalkylamino groups, Wherein aliphatic group and cycloalkylamino group have meaning as described in the present invention, and such example includes, but not It is limited to Cyclopropylaminomethyl, cyclopropylamino hexyl, clopentylamino methyl, clopentylamino ethyl, cyclohexyl ammonia Base ethyl, halogenated cyclopropyl amino-ethyl etc..
Term " naphthenic base aliphatic " or " carbocylic radical aliphatic " indicate that aliphatic group can be by one or more naphthenic base Group or carbocylic radical group are replaced, wherein naphthenic base, or carbocylic radical and aliphatic group have and contain as described in the present invention Justice, such example is including but not limited to Cvclopropvlmethvl, cyclopropylethyl, Cyclopropylpropyl, cyclopentyl-methyl, Cyclohexyl-ethyl etc..
Term " heterocycle ", " heterocycle ", " heteroalicyclic " or " heterocycle " are used interchangeably here, all refer to list Ring, bicyclic, or three-ring system, one or more atoms are replaced by hetero atom individually optionally in beanstalk middle ring, and ring can be with It is fully saturated or comprising one or more degrees of unsaturation, but definitely not aromatic, is only connected to there are one tie point Other molecules get on.One or more ring hydrogen atoms are individually optionally by one or more substituent groups described in the invention Replaced.Some of embodiments are that " heterocycle " " heterocycle " " heteroalicyclic " or " heterocycle " group are the lists of 3-7 membered rings Ring（1-6 carbon atom and be N, O, P, the 1-3 hetero atom of S, in this S or P optionally by one or more oxygen atom institutes Substitution is obtained as SO, SO2, PO, PO2Group, when the ring is a three-membered ring, only one of which hetero atom), Or 7-10 members is bicyclic（4-9 carbon atom and be N, O, P, the 1-3 hetero atom of S, in this S or P optionally by one or Multiple oxygen atoms replace to obtain as SO, SO2, PO, PO2Group）.
Heterocycle can be carbon-based or heteroatom group." heterocycle " equally also includes heterocyclic group and saturation or part insatiable hunger With ring or heterocycle and close be formed by group.The example of heterocycle is including but not limited to, pyrrolidinyl, tetrahydrofuran base, Dihydrofuryl, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, Thio-morpholinyl, thioalkyls, piperazinyl, high piperazine base, azelidinyl, oxetanylmethoxy, thietanyl, Piperidyl, homopiperidinyl, glycidyl, azacycloheptyl, oxetane, thiocycloheptyl, 4- methoxyl groups-piperazine Pyridine -1- bases, 1,2,3,6- 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, 1,3- dioxymyls, pyrazolinyl, dithianyl, dithienyl group, dihydrothiophene, pyrazolidinyl imidazoles Quinoline base, imidazolidinyl, 1,2,3,4- tetrahydro isoquinolyls, 1,2,6- thiadiazine alkane 1,1- dioxy -2- bases, 4- hydroxyls Base -1,4- azepine phosphine 4- oxide -1- bases, 2- hydroxyls -1-（Piperazine -1- bases）Ethyl ketone -4- bases, 2- hydroxyls -1-（5, 6- Dihydro -1,2,4- triazines -1（4H）Base）Ethyl ketone -4- bases, 5,6- dihydros -4H- 1,2,4- oxadiazine -4- bases, 2- hydroxyls Base -1-（5,6- dihydropyridines -1（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] are phonetic Pyridine -6- bases, 4,5,6,7 1 tetrahydrochysene isoxazoles [4,3-c] pyridine -5- bases, 3HIndyl 2- oxygen -5- azabicyclos [2.2.1] heptane -5- bases, 2- oxygen -5- azabicyclos [2.2.2] octane -5- bases, quinazinyl and N- pyridyl ureas.Heterocycle The example of group further includes that two carbon atoms are replaced by oxygen atom as phonetic on 1,1- 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, C1, 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, the alkyl-S (=O) of hydroxyl substitution2-, 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, 1,2, 3- oxadiazolyls, 1,2,5- oxadiazolyls, 1,2,4- oxadiazolyls, 1,2,3- triazolyls, 1,2,3- are thio Di azoly, 1,3,4- thio biphosphole bases, 1,2,5- thio biphosphole bases, 1,3,4- thiadiazoles -2- bases, pyrazinyl, Pyrazine -2- bases, cyanuro 1,3,5, benzothiazole -2- bases, imidazo [1,5-a] pyridine -6- bases;Also include following It is bicyclic, but it is bicyclic to be not limited to these：Benzimidazolyl, benzofuranyl, benzothienyl, benzothiazolyl, Yin Diindyl base（Such as 2- indyls）, purine radicals, quinolyl（Such as 2- quinolyls, 3- quinolyls, 4- quinolyls）, and isoquinolyl （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 C1-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 C1-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, 1,2,3,4,4a, 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 1,2,3,4,4a, 5,8,8a- octahydro naphtylethyl groups, 1,2,3,4,4a, 5,8,8a- octahydro naphthalenes Methyl, 1,2,3,4,4a, 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 Be connected with molecule rest part onto oxygen atom, and by oxygen atom, such example including but not limited to 1,2, 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, and such example is including but not limited to 1,2,3,4,4a, and 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 1,2,3,4,4a, 5,8,8a- octahydro napthylmethylaminos, two（1,2,3,4,4a, 5,8,8a- octahydro naphthalene）Methylamino condenses double Ring [3.3.0] octyl methylamino, condensed-bicyclic [3.1.0] hexyl methylamino etc..
Term " condensing miscellaneous bicyclic group alkylamino " indicates that alkylamino radicals condense miscellaneous bicyclic group by one or more and replace, Wherein condense miscellaneous bicyclic group have meaning as described in the present invention, such example including but not limited to hexahydro-furans simultaneously [3,2-b] furans -2- base methylaminos, 7- azabicyclos [2.3.0] heptane -2- base methylaminos, 7- azabicyclos [2.3.0] Heptane -4- base methylaminos etc..
Term " condensed-bicyclic base alkoxy " indicates that alkoxy is replaced by one or more condensed-bicyclic base groups, Middle alkoxy and condensed-bicyclic base have a meaning as described in the present invention, such example including but not limited to 1,2, 3,4,4a, 5,8,8a- octahydro naphthylmethoxy, 1,2,3,4,4a, 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 1,2,3,4,4a, 5,8,8a- octahydro naphthalene Oxymethoxies, 1,2,3,4,4a, 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 1,2,3,4,4a, 5,8,8a- octahydro naphthyl-amino ethyoxyl, 1,2,3,4,4a, 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 that particularly ring-shaped carbon on another ring is done in a ring origin.Such as institute above Description, the bridged-ring system of a saturation（Ring B and B '）It is referred to as " condensed-bicyclic ", on the contrary what ring A and ring B was saturated at two A carbon atom is shared in member ring systems, then is referred to as " loop coil ".And at least one member ring systems include one or more hetero atoms, Wherein each member ring systems include 3-7 membered rings, that is, include 1-6 carbon atom and be N, O, P, the 1-3 hetero atom of S, This S or P optionally is replaced to obtain as SO, SO by one or more oxygen atoms2, PO, PO2, group, such example Including but not limited to 4- azaspiros [2.4] heptane -5- bases, 4- oxaspiros [2.4] heptane -5- bases, 5- azaspiros [2.4] Heptane -5- bases, 7- hydroxyl -5- azaspiros [2.4] heptane -5- bases etc..And the miscellaneous bicyclic group of spiral shell can be substitution or non-take Generation, wherein substituent group can be, but be not limited to, halogenated alkyl, oxo (=O), hydroxyl, amino, halogen, cyanogen Base, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocycle, sulfydryl, nitro, fragrant oxygen Base, the alkoxy of hydroxyl substitution, the alkyl-C (=O)-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S of hydroxyl substitution (=O)2, the alkyl-S (=O)-of hydroxyl substitution, the alkyl-S (=O) of hydroxyl substitution2, Carboxyalkoxy etc..
Term " spiral shell bicyclic group aliphatic " indicates that aliphatic group is replaced by one or more spiral shell bicyclic group groups, Middle aliphatic group and spiral shell bicyclic group group have a meaning as described in the present invention, such example including but not limited to Spiral shell [2.4] heptane ylmethyl, spiral shell [2.4] heptane base ethyl, spiral shell [2.4] heptane base propyl, spiral shell [4.4] nonane ylmethyl, Spiral shell 4.4] nonyl ethyl, 4- azaspiros [2.4] heptane -5- ylmethyls, 4- azaspiros [2.4] heptane -5- base ethyls, 4- Oxaspiro [2.4] heptane -5- base ethyls, 5- azaspiros [2.4] heptane -5- base propyl, 7- hydroxyl -5- azaspiros [2.4] heptan Alkane -5- base propyl etc..
Term " the miscellaneous bicyclic group aliphatic of spiral shell " indicates that aliphatic group is replaced by the miscellaneous bicyclic group group of one or more spiral shells, Wherein the miscellaneous bicyclic group group of aliphatic group and spiral shell has meaning as described in the present invention, and such example includes, but not It is limited to 4- azaspiros [2.4] heptane -5- ylmethyls, 4- azaspiros [2.4] heptane -5- base ethyls, 4- oxaspiros [2.4] heptan Alkane -5- base ethyls, 5- azaspiros [2.4] heptane -5- base propyl, 7- hydroxyl -5- azaspiros [2.4] heptane -5- base propyl etc..
Term " spiral shell bicyclic group oxygroup " includes that the spiral shell bicyclic group optionally replaced is connected to oxygen as defined in the present invention On atom, and it is connected with molecule rest part by oxygen atom, such example is including but not limited to spiral shell [2.4] heptan Alkane -2- oxygroups, spiral shell [2.4] heptane -3- oxygroups, spiral shell [2.4] heptane -4- oxygroups, spiral shell [4.4] nonane -2- oxygroups, spiral shell [4.4] nonane -4- oxygroups, 4- azaspiros [2.4] heptane -5- oxygroups etc..
Term " the miscellaneous bicyclic group oxygroup of spiral shell " includes the miscellaneous bicyclic group of spiral shell optionally replaced, as defined in the present invention, connection It is connected with molecule rest part onto oxygen atom, and by oxygen atom, such example is including but not limited to 4- azepines Spiral shell [2.4] heptane -5- base oxygroups, 4- oxaspiros [2.4] heptane -5- base oxygroups, 5- azaspiros [2.4] heptane -5- base oxygroups Deng.
Term " spiral shell bicyclic group amino " indicates that amino group is replaced by one or two spiral shell bicyclic group group, wherein spiral shell Bicyclic group has meaning as described in the present invention, such example including but not limited to spiral shell [2.4] heptane -2- amino, Spiral shell [2.4] heptane -3- amino, spiral shell [2.4] heptane -4- amino, spiral shell [4.4] nonane -2- amino, spiral shell [4.4] nonane -4- ammonia Base, 4- azaspiros [2.4] heptane -5- amino etc..
Term " the miscellaneous bicyclic group amino of spiral shell " indicates that amino group is replaced by the miscellaneous bicyclic group group of one or two spiral shell, The middle miscellaneous bicyclic group of spiral shell has meaning as described in the present invention, and such example is including but not limited to 4- azaspiros [2.4] heptan Alkane -5- base amino, 4- azaspiros [2.4] heptane -2- base amino, 4- oxaspiros [2.4] heptane -5- base amino, 5- azaspiros [2.4] heptane -5- bases amino etc..
Term " spiral shell bicyclic group alkoxy " indicates that alkoxy base is replaced by one or more spiral shell bicyclic groups, wherein spiral shell Bicyclic group and alkoxy base have meaning as described in the present invention, and such example is including but not limited to spiral shell [2.4] heptan Alkane -2- methoxyl groups, spiral shell [2.4] heptane -3- ethyoxyls, spiral shell [2.4] heptane -4- ethyoxyls, spiral shell [4.4] nonane -2- methoxies Base, spiral shell [4.4] nonane -4- propoxyl group, 4- azaspiros [2.4] heptane -5- methoxyl groups etc..
Term " the miscellaneous bicyclic group alkoxy of spiral shell " indicates that alkoxy base is replaced by the miscellaneous bicyclic group of one or more spiral shells, The miscellaneous bicyclic group of middle spiral shell and alkoxy base have meaning as described in the present invention, and such example is including but not limited to 4- Azaspiro [2.4] heptane -5- ylmethoxies, 4- azaspiros [2.4] heptane -2- base oxethyls, 4- oxaspiros [2.4] heptane - 5- base oxethyls, 5- azaspiros [2.4] heptane -5- base propoxyl group etc..
Term " spiral shell bicyclic group alkylamino " indicates that alkylamino radicals are replaced by one or more spiral shell bicyclic groups, wherein spiral shell Bicyclic group and alkylamino radicals have meaning as described in the present invention, and such example is including but not limited to spiral shell [2.4] heptan Alkane -2- methylaminos, spiral shell [2.4] heptane -3- ethylaminos, spiral shell [2.4] heptane -4- ethylaminos, spiral shell [4.4] nonane -2- first ammonia Base, spiral shell [4.4] third amino of nonane -4-, 4- azaspiros [2.4] heptane -5- methylaminos etc..
Term " the miscellaneous bicyclic group alkylamino of spiral shell " alkylamino radicals are replaced by the miscellaneous bicyclic group of one or more spiral shells, wherein spiral shell Miscellaneous bicyclic group and alkylamino radicals have meaning as described in the present invention, and such example is including but not limited to 4- azepines Spiral shell [2.4] heptane -5- base methylaminos, 4- azaspiros [2.4] heptane -2- base ethylaminos, 4- oxaspiros [2.4] heptane -5- bases Ethylamino, 5- azaspiros [2.4] heptane -5- third amino of base etc..
Term " spiral shell bicyclic group oxygroup alkoxy " indicates that alkoxy is replaced by one or more spiral shell bicyclic group oxygroup groups, Wherein spiral shell bicyclic group oxygroup and alkoxy base have meaning as described in the present invention, and such example includes, but and unlimited In spiral shell [2.4] heptane -2- oxygroup ethyoxyls, spiral shell [2.4] heptane -3- oxygroup propoxyl group, spiral shell [2.4] heptane -4- the third oxygen of oxygroup Base, spiral shell [4.4] nonane -2- oxygroup ethyoxyls, spiral shell [4.4] nonane -4- oxygroup propoxyl group, 4- azaspiros [2.4] heptane -5- Oxygroup propoxyl group etc..
Term " the miscellaneous bicyclic group oxygroup alkoxy of spiral shell " indicates alkoxy by the miscellaneous bicyclic group oxygroup group institute of one or more spiral shells Replace, wherein the miscellaneous bicyclic group oxygroup of spiral shell and alkoxy base include with meaning as described in the present invention, such example, But 4- azaspiros [2.4] heptane -5- base oxygroup ethyoxyls are not limited to, 4- oxaspiros [2.4] heptane -5- base oxygroup ethyoxyls, 5- azaspiros [2.4] heptane -5- base oxygroup ethyoxyls, 4- azaspiros [2.4] heptane -5- base oxygroup propoxyl group, 4- oxaspiros [2.4] heptane -5- bases oxygroup propoxyl group, 5- azaspiros [2.4] heptane -5- base oxygroup propoxyl group etc..
Term " spiral shell bicyclic group aminoalkoxy " indicates that alkoxy is replaced by one or more spiral shell bicyclic group amino, Middle alkoxy and spiral shell bicyclic group amino have meaning as described in the present invention, and such example is including but not limited to spiral shell [2.4] heptane -2- amino ethoxies, spiral shell [2.4] heptane -3- amino propoxyl group, spiral shell [2.4] heptane -4- amino ethoxies, Spiral shell [4.4] nonane -2- amino ethoxies, spiral shell [4.4] nonane -4- amino propoxyl group, 4- azaspiros [2.4] heptane -5- amino Propoxyl group etc..
Term " the miscellaneous bicyclic group aminoalkoxy of spiral shell " indicates that alkoxy is replaced by the miscellaneous bicyclic group amino of one or more spiral shells, Wherein the miscellaneous bicyclic group amino of alkoxy and spiral shell have meaning as described in the present invention, such example including but not limited to 4- azaspiros [2.4] heptane -5- base amino ethoxies, two oxygroup of 4- azaspiros [2.4] heptane -2- bases amino, 4- oxaspiros [2.4] heptane -5- bases amino ethoxy, 5- azaspiros [2.4] heptane -5- base amino propoxyl group etc..
Unless other aspects show that structural formula described in the invention includes all isomeric forms（As mapping is different Structure, diastereo-isomerism, and geometrical isomerism（Or conformational isomerism））：Such as R, S configuration containing asymmetric center, double bond (Z), (E) isomers, and (Z), (E) rotamer.Therefore, the single three-dimensional chemical isomer of the compound of the present invention Or its enantiomter, diastereoisomer, or geometric isomer（Or rotamer）Mixture belong to the present invention Range.
Term " prodrug " used in the present invention represents a compound and is converted into chemical combination shown in formula (I) in vivo Object.Such conversion is hydrolyzed by pro-drug or is influenced for precursor structure through enzymatic conversion in blood or tissue in blood. Pro-drug compounds of the present invention can be ester, and ester can have phenyl ester class as pro-drug in existing invention, Aliphatic (C1-C24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as this hair A compound in bright includes hydroxyl, can be acylated to obtain the compound of prodrug form.Other precursor medicines Object form includes phosphate, if these phosphate compounds are being obtained through the di on parent.About precursor medicine Object, which completely discusses, can refer to following documents：T. Higuchi and V.Ste11a, Pro-drugsas Nove1 De1ivery Systems, Vo1. 140f the A.C.S.Symposium Series, Edward B. Roche, ed., Bioreversib1e Carriers in Drug Design, American Pharmaceutica1 Association and Pergamon Press, 1987, J. Rautio et a1, Prodrugs: Design and C1inica1 App1ications, Nature Review Drug Discovery, 2008, 7, 255-270, and S.J. Hecker et a1, Prodrugs of Phosphates and Phosphonates, Journa1 of Medicina1 Chemistry, 2008, 51, 2328-2345.
Unless other aspects show, all tautomeric forms of the compound of the present invention be included in the scope of the present invention it It is interior.In addition, unless other aspects show, the structural formula of compound described in the invention includes one or more different originals The enriched isotope of son.
" metabolite " refers to specific compound or its salt product obtained by metabolic action in the body.One change Closing the metabolite of object can be identified that activity can pass through institute such as of the present invention by technology well-known in the art It adopts as description and is experimentally characterized.Such product can be by, by aoxidizing, being gone back to drug compound Original, hydrolysis, amidated, deamidation, esterification, degreasing, the methods of enzymatic lysis etc. obtain.Correspondingly, this hair The bright metabolite for including compound, including the compound of the present invention and mammal were come into full contact with produced by a period of time Metabolite.
The compound of the present invention can include asymmetric center or chiral centre, therefore there are different stereoisomers. All stereoisomeric forms in any ratio of the compound of the present invention, including but not limited to, diastereomer, enantiomter, resistance turn Isomers, and their mixture, such as racemic mixture constitute the part of the present invention.Many organic compounds are all Exist with optical active forms, i.e. the plane of their capable Plane of rotation polarised lights.When describing optically active compound, Prefix D, L or R, S are used for indicating the absolute configuration at molecular chiral center.Prefix D, L or (+), (-) are used for naming compound flat The symbol of plane polarized light rotation, (-) or L refer to that compound is left-handed, and it is dextrorotation that prefix (+) or D, which refer to compound,.This The chemical constitution of a little stereoisomers is identical, but their stereochemical structure is different.Specific stereoisomer can be with It is enantiomer, the mixture of isomers is commonly referred to as enantiomeric mixture.50：50 mixture of enantiomers is referred to as outer Racemic mixture or racemic modification, 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 one enol form of keto-acid and sub- one enamine of limb.Valence（Chemical valence）Tautomer packet Include the change of recombination bonding electrons.
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in fields on, such as document：S. M. Berge et a1., describe pharmaceutica11y acceptab1e sa1ts in detai1. J. Pharmaceutica1 Sciences, 66： Recorded in 1-19,1977.The salt that pharmaceutically acceptable nontoxic acid is formed is including but not limited to amino group The inorganic acid salt that reaction is formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate, and acylate such as Acetate, oxalates, maleate, tartrate, citrate, succinate, malonate, or pass through books Recorded other methods such as ion-exchange obtains these salt on document.Other pharmaceutically acceptable salts include adipic acid Salt, alginates, ascorbate, aspartate, benzene sulfonate, benzoate, bisulphate, borate, fourth Hydrochlorate, camphor hydrochlorate, camsilate, cyclopentyl propionate, digluconate, lauryl sulfate, second sulphur Hydrochlorate, formates, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, heptan Hydrochlorate, caproate, hydriodate, 2- hydroxy-ethanesulfonate salts, lactobionate, lactate, laruate, lauryl Sulfate, malate, malonate, mesylate, 2- naphthalene sulfonates, nicotinate, nitrate, oleate, palm fibre Palmitic acid hydrochlorate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, picrate, pivalate, propionate, Stearate, rhodanate, tosilate, undecylate, valerate, etc..Salt obtained by an appropriate base Including alkali metal, alkaline-earth metal, ammonium and N+(C1-C4 alkyl)4Salt.The present invention is also intended to contemplate the base of any included N The compound of group is formed by quaternary ammonium salt.Water-soluble or oil-soluble or dispersion product can be obtained by quaternization.Alkali gold Belong to or alkali salt includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further comprise it is appropriate, The amine cation that nontoxic ammonium, quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylate, sulfuric acid Compound, phosphoric acid compound, nitric acid compound, C1-C8 azochlorosulfonate acid compounds and aromatic sulphonic acid compound.
The salt of 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.
。
The present invention includes the application of the compounds of this invention and its pharmaceutically acceptable salt, anti-for producing medical product Scorching and treatment patient tissue or organ fibrosis disease, including those diseases described in the invention.The present invention includes medicine Compositions, the pharmaceutical composition include the compound and at least one pharmaceutically acceptable carrier representated by Formulas I-X, are assigned Shape agent, diluent, adjuvant, effective therapeutic dose needed for the combination of medium.
The present invention equally includes anti-inflammatory and treatment or the disease for mitigating patient tissue or organ fibrosis, or to this disease The method of disease sensitivity, this method include to be treated to patient using the therapeutically effective amount of compound representated by Formulas I-X.
Unless other aspects show, all stereoisomers of the compound of the present invention, geometric isomer mutually makes a variation Structure body, nitrogen oxides hydrates, solvate, metabolite, salt and pharmaceutically acceptable prodrug belong to the present invention Range.
Specifically, salt is pharmaceutically acceptable salt.Term " pharmaceutically acceptable " includes substance or composition must Must be suitble to chemistry or toxicologically, it is related with the other components of composition preparation and mammal for treatment.
The salt of the compound of the present invention further includes being used to prepare or purifying the intermediate of compound or Formulas I-X shown in Formulas I-X The salt of the enantiomter of shown compound separation, but it is not necessarily pharmaceutically acceptable salt.
If the compound of the present invention is alkaline, then conceivable salt can be by provided in the literature any suitable 's
Method is prepared, for example with inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid etc..Or Use organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, hydroxyl Acetic acid and salicylic acid；Pyrans saccharic acid, such as glucuronic acid and galacturonic acid；Alpha-hydroxy acid, such as citric acid and tartaric acid；Amino Acid, such as asparatate and glutamic acid；Aromatic acid, such as benzoic acid and cinnamic acid；Sulfonic acid, such as p-methyl benzenesulfonic acid, second sulphur Acid, etc..
If the compound of the present invention is acid, then conceivable salt can be prepared by suitable method, Such as, using inorganic base or organic base, such as ammonia（Primaquine, parahelium, tertiary ammonia）, alkali metal hydroxide or alkaline-earth metal hydrogen-oxygen Compound, etc..Suitable salt is including but not limited to, organic salt obtained from amino acids, such as glycine and arginine, Ammonia, such as primaquine, parahelium and tertiary ammonia, and ring-type ammonia, such as piperidines, morpholine and piperazine etc., and from sodium, calcium, potassium, magnesium, Manganese, iron, copper, zinc, aluminium and lithium obtain inorganic salts.
According on the other hand, the characteristics of pharmaceutical composition of the invention includes the compound of Formulas I-X, listed by the present invention Compound, or embodiment compound represented, and pharmaceutically acceptable carrier, adjuvant, or excipient.The present invention's The amount of compound can effectively detectably anti-inflammatory and treatment or the disease for mitigating patient tissue or organ fibrosis in composition Disease.
There are free forms for the compound of the present invention, or it is suitable, as pharmaceutically acceptable derivates.According to this Invention, pharmaceutically acceptable derivates are including but not limited to, pharmaceutically acceptable prodrug, salt, ester, esters Salt, or other any adducts or derivative that can be directly or indirectly administered according to the needs of patient, the present invention other Compound described in aspect, metabolite or his residue.
As described in the invention, the pharmaceutically acceptable composition of the present invention further includes pharmaceutically acceptable Carrier, adjuvant, or excipient, these are applied as the present invention, including any solvent, diluent, or other liquid Excipient, dispersant or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid adhesion Agent or lubricant, etc., it is suitable for distinctive target formulation.As described in following documents：In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D. B. Troy, 1ippincott Wi11iams&Wi1kins, Phi1 ade1phia, and Encyc1opedia of Pharmaceutica1 Techno1ogy, eds. J. S warbrick and J.C.Boy1an, 1988-1999, Marce1 Dekker, New York, the content of comprehensive document herein, show that different carriers can be applied to pharmaceutically connect The preparation for the composition received and their well known preparation methods.Not in addition to any conventional carrier medium and the compound of the present invention Compatible range, for example, caused by any undesirable biological effect or any other with pharmaceutically acceptable composition The interaction that component generates in harmful manner, their purposes are also the range that the present invention is considered.
The substance of pharmaceutically acceptable carrier be can be used as including but not limited to, ion-exchanger, aluminium, stearic acid Aluminium, lecithin, haemocyanin, such as human albumin, buffer substance such as phosphate, glycine, sorbic acid, sorbic acid Potassium, the partial glyceride mixtures of saturated vegetable fatty acid, water, salt or electrolyte, such as protamine sulfate, phosphoric acid hydrogen Disodium, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silicon, magnesium trisilicate, polyvinylpyrrolidone, polyacrylate, Wax, one polyoxypropylene one of polyethylene block condensate, lanolin, sugar, such as lactose, dextrose and saccharose；Starch such as corn Starch and potato starch；Cellulose and its derivative such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate；Tree Rubber powder；Malt；Gelatin；Talcum powder；Auxiliary material such as cocoa butter and suppository wax；Oil such as peanut oil, cotton seed oil, safflower oil, Sesame oil, olive oil, corn oil and soya-bean oil；Glycol compound, such as propylene glycol and polyethylene glycol；Esters such as ethyl oleate And ethyl laurate；Agar；Buffer such as magnesium hydroxide and aluminium hydroxide；Alginic acid；Pyrogen-free water；Isotonic salt；Lin Ge （Family name）Solution；Ethyl alcohol, phosphate buffer solution, and other nontoxic suitable lubricant such as Sodium Laurylsulfates and magnesium stearate, Colorant, releasing agent, coating agents, sweetener, flavoring agent and fragrance, preservative and antioxidant.
The pharmaceutical composition of the present invention can be oral medication, drug administration by injection, Aerosol inhalation, local administration, warp Rectally, nose administration, buccal administration or are administered vagina administration by implantable medicine box.Can be capsule, tablet, ball Agent, pulvis, granula and water suspension or solution.Oral medication can use following form：It is tablet, pill, capsule, dispersible Powder, particle or suspension, syrup and elixir, or be administered in a manner of external application：Ointment, gel, drug containing adhesive plaster etc., or Parenteral routes are carried out with sterile injectable solution or suspension form.The compounds of this invention parenteral or intraperitoneal can also be given Medicine.Also surfactant can properly mixed（Such as hydroxypropyl cellulose, polyvinylpyrrolidone）Water in prepare these work Property compound（As free alkali or pharmaceutically acceptable salt）Solution or suspension.It can also be in glycerine, liquid, polyethylene glycol And its prepare dispersion liquid in mixture in the oil.Under conventional storage and use condition, in these preparations containing preservative with Prevent microorganism from growing.
Medicament forms suitable for injection include：Aseptic aqueous solution or dispersion liquid and aseptic powder（It is noted for extemporaneous preparation of sterile Penetrate solution or dispersion liquid）.In all cases, these forms must be sterile and must be that fluid is arranged with being easy to syringe Go out fluid.It must be stable under conditions of manufacture and storage, and must be able to prevent microorganism（Such as bacterium and fungi）Pollution It influences.Carrier can be solvent or decentralized medium, wherein containing such as water, alcohol（Such as glycerine, propylene glycol and liquid polyethylene glycol）、 They properly mix object and vegetable oil.
Compound can be applied with local mode, without being applied with system mode.Such as usually to dilute preparation or continue The form of delivery formulations will be in compound direct injection to organ.In addition, the pharmaceutical composition containing the compounds of this invention can be with It uses in targeted drug delivery system, such as is delivered in the liposome being coated with organ specific antibody.The liposome The organ will be targeted and absorbed by the Organic selection.In addition, the composition containing the compounds of this invention can be with fast quick-release The form for putting preparation, timed release preparations or IR formulation provides.
Sucking is applied, the compound of the present invention can be aerosol, aerosol or powder type.Chemical combination of the present invention The pharmaceutical composition of object can be delivered easily in the form of aerosol spray, and the aerosol spray can be mounted in pressure In container or atomizer, suitable propellant such as dicholorodifluoromethane, Arcton 11, dichlorotetra-fluoroethane, dioxy are used Change carbon or other suitable gases.In the case of pressurized aerosol, dosage unit can be determined by valve to deliver Metered amount.Such as by taking capsule and cylindrantherae as an example, it can be prepared as containing describedization for the gelatin of inhalator or insufflator Close the mixture of powders of object and appropriate powdered substrate such as lactose or starch.
The compounds of this invention can also be prepared as rectal compositions such as enema, Gel in rectal administered, rectal foams agent, straight Intestines aerosol, suppository, gel suppository (ge1 suppository) or enema,retention (retention enema), wherein containing There is conventional suppository base such as cocoa butter or other glyceride and synthetic polymer such as polyvinylpyrrolidone, PEG. In the suppository form of composition, it is optionally first with the mixture of cocoa butter that low melt wax is such as, but not limited to fatty glyceride First it is melted.
In addition, the compounds of this invention can also be with the drug combination of other treatment fibrosis.It specifically includes, but is not limited to, Ivacaftor, roflumilast, pirfenidone, magerut, Losartan, interferon, my method-dornase, Ve1dona, Ata1uren, cortin, methotrexate, tacrolimus etc..
Pharmaceutical composition can be prepared according to the usual manner acceptable carrier of one or more physiology, wherein wrapping Include the excipient and adjuvant that can help that reactive compound is processed as to pharmaceutical preparations.Selected administration method determines appropriate Dosage form.Technology, carrier and excipient known to any can understand use appropriate according in the prior art.Contain this hair The pharmaceutical composition of bright compound can be prepared according to conventional methods, for example, by conventional mixing, dissolving, pelletize, ingot processed, It is prepared by grinding, emulsification, packing, encapsulating or pressing process.
Pharmaceutical composition will include at least one pharmaceutical acceptable carrier, diluent or excipient and free acid, free alkali or can The compound of the present invention of acceptable salt is as active constituent.In addition, pharmaceutical composition may also include other medicine or pharmacy Activating agent, carrier, adjuvant, such as preservative, stabilizer, wetting agent or emulsifier, dissolution accelerator, adjust osmotic pressure salt or Buffer.In addition, pharmaceutical composition also contains other substances for having therapeutic value.
The preparation method of composition containing compound described herein include by compound with it is one or more it is inert can Pharmaceutical excipient or carrier are prepared as solid, semisolid or liquid form together.Solid composite includes but not limited to powder, piece Agent, dispersible granule, capsule, cachet and suppository.Liquid composition includes wherein being dissolved with the solution of compound, containing Emulsion, the solution containing the liposome comprising compound disclosed herein, micelle or nano-particle for having compound.Semisolid group It includes but not limited to gelling agent, suspension and cream to close object.Composition can be aqueous agent or suspended form, be suitble to In the solid form or emulsion form that are dissolved or suspended in before use in liquid.These compositions can also contain a small amount of nontoxic Adjuvant, such as wetting agent or emulsifier, pH buffer etc..
The compound of the present invention is preferably prepared into dosage unit form to mitigate the equal of dosage and dosage by pharmaceutical formulation Even property.Term " dosage " unit type " obtains suitably treating the physical dispersion unit of required drug referred to herein as patient.However It should be appreciated that the compound of the present invention or the daily total usage of composition will be judged by attending physician according to reliable medicine range To determine.Specific effective dose level will include quilt depending on many factors for any one special patient or organism The illness for the treatment of and the seriousness of illness, the activity of particular compound, concrete composition used, the age of patient, body The discharge rate of weight, health status, gender and eating habit, administration time, administration route and particular compound used, treatment Duration, medicinal application is combined in drug combination or with specific compound, and some other pharmaceutical field is public The factor known.
The compounds of this invention can be modified by the functional group of additional suitable to improve selectivity organism characteristic.This The modification of sample is that this field is known and include to biological lacuna（Such as blood, lymphatic system, central nervous system）Infiltration, It improves Oral Availability, improve dissolubility so as to which the modification of excretion is metabolized and changed by drug administration by injection, change.It can incite somebody to action The compounds of this invention is modified by the functional group of additional suitable to improve selectivity organism characteristic.Such modification is ability Domain is known and includes to biological lacuna（Such as blood, lymphatic system, central nervous system）Infiltration, raising are oral effective Property, improve dissolubility so as to pass through drug administration by injection, change metabolism and change excretion modification.
Compound of the present invention or its pharmaceutical salts or its hydrate can be effective for anti-inflammatory and prevent, handle, control Patient tissue or organ fibrosis disease are treated or mitigated, kidney region fibrosis, glomerulosclerosis, liver especially can be effectively treated Fibrosis, pulmonary fibrosis, peritoneal fibrosiss, myocardial fibrosis, fibrosis of skin, postoperative intestinal adhesion, benign prostatauxe disease, Skeletal muscle fibre, chorionitis, multiple sclerosis, pancreatic fibrosis, hepatic sclerosis, muscle tumor, nerve fibre onch- interstitial are fine The disease of dimensionization, diabetic nephropathy, Alzheimer disease or vascular fibrosis.
General, the method that the compound of the present invention can say description through the invention is prepared, unless there are into one The explanation of step, the wherein definition of substituent group are as shown in Formulas I-X, and reaction scheme and embodiment below is for further illustrating Bright present disclosure.
Those skilled in the art will realize that：Chemical reaction described in the invention can be used for suitable prepare originally Other compounds of invention, and other methods for the preparation of the compounds of the present invention are considered as in the scope of the present invention Within.Such as can successfully it be led to by those skilled in the art according to the synthesis of the compound of those non-illustrations of the invention Method of modifying completion, such as protection interference group appropriate are crossed, by using other known reagent in addition to described in the invention , or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also public That recognizes is suitable for the preparation of other compounds of the invention.
Solvent for use of the present invention, such as anhydrous tetrahydro furan, dioxane, toluene, ether are dry by sodium metal reflux It is dry to obtain.Anhydrous methylene chloride and chloroform are dried to obtain by calcium hydride reflux.Ethyl acetate, petroleum ether, n-hexane, N, N- dimethylacetylamides and N,N-dimethylformamide are used by anhydrous sodium sulfate is dry in advance.The protons such as methanol, ethyl alcohol Property solvent is used after being dried again with anhydrous sodium sulfate after being repeatedly evaporated under reduced pressure.
Reaction is usually to cover a drying tube under positive pressure of nitrogen or argon or on anhydrous solvents below（Unless other aspects Show）, reaction bulb all by syringe squeezed into beyond the Great Wall by suitable rubber band, substrate.Glassware is by dry.
Embodiment 1：1- (the fluoro- 4- morpholino phenyls of 3-) -3- methoxyl group -4- phenylchinolines -2 (1H) -one
Step 1) 3- methoxyl group -4- phenyl-quinolins -2 (1H) -one
Under nitrogen protection, by 2- aminobenzophenones (2 mmol), methoxyacetyl chloride (3.8 mmol) and N, N- bis- Wopropyl ethyl amine (8 mmol) is dissolved in dichloromethane (5 mL), is reacted at room temperature 3 hours.Contact plate finds that raw material has reacted Finish, reaction solution is diluted with water rear ethyl acetate and extracts, and after organic phase removed under reduced pressure solvent, residue silica gel column chromatography is pure Change obtainsN-(2- benzoyloxy phenyls) -2- methoxyl acetamides.
Under nitrogen protection,N-(2- benzoyloxy phenyls) -2- methoxyl acetamides (1.0 mmol) are dissolved in tetrahydrofuran In (10 mL), t-BuOK (10 mmol) is added and reacts at room temperature 5 hours.Reaction solution is extracted with saturated ammonium chloride solution, second Acetoacetic ester extracts.After removed under reduced pressure organic phase, residue obtains 4- hydroxy-3-methoxy -4- benzene with silica gel chromatography Base -3,4- dihydroquinoline -2 (1H) -one.
In MeOH (10 mL), 10%Pd/C (0.1 mmol) and potassium carbonate (8 mmol) afterwards 50 is addedoC reacted Night.After removed under reduced pressure solvent, residue obtains 3- methoxyl group -4- phenyl-quinolins -2 (1 with silica gel chromatographyH) -one.
Step 2) 4- (the bromo- 2- fluorophenyls of 4-) morpholine
The bromo- 2- fluorobenzene of 4-（4.0 mmol) in CHC13In (40 mL), stir under nitrogen protection, BPO (0.08 mmol) and NBS (4.4 mmol) is added in the reaction solution, 5 h of heating reflux reaction, cooling.Vacuum distillation removes solvent, obtains first Walk crude product.Morpholine（0.50 mo1）Ethanol solution be added under nitrogen protection in previous step crude product, be stirred at room temperature Night.Solvent is removed under reduced pressure, crude product purifies to obtain 4- (the bromo- 2- fluorophenyls of 4-) morpholine through column chromatography.
Step 3) 1- (the fluoro- 4- morpholino phenyls of 3-) -3- methoxyl group -4- phenyl-quinolins -2 (1H) -one
Under nitrogen protection, CuI (1 mmol), Cs2CO3(20 mmol) and 2- oxocyclohexyl Ethyl formates（2 Mmol it) is added in DMSO (10 mL), 30 min is stirred at room temperature.3- methoxyl group -4- phenylchinolines -2 (1H) -one (10 ) and 4- (the bromo- 2- fluorophenyls of 4-) morpholine mmol（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), collect organic phase, decompression Solvent is boiled off, crude product purifies to obtain 1- (the fluoro- 4- morpholino phenyls of 3-) -3- methoxyl group -4- phenyl-quinolins -2 through column chromatography (1H) -one.
ESI-MS (m/z):431.17[M+H]+。
Embodiment 2：1- (the fluoro- 4- methoxy piperides -1- bases of 3-) phenyl) -3- methoxyl group -4- phenylchinolines -2 (1H) -one
Step 1）1- (the bromo- 2- fluorophenyls of 4-）- 4- methoxy piperides
The bromo- 2- fluorobenzene of 4-（4.0 mmol) in CHC13In (40 mL), stir under nitrogen protection, BPO (0.08 mmol) and NBS (4.4 mmol) is added in the reaction solution, 5 h of heating reflux reaction, cooling.Vacuum distillation removes solvent, obtains first Walk crude product.4- methoxy piperides（0.50 mo1）Ethanol solution be added under nitrogen protection in previous step crude product, room Temperature is stirred overnight.Solvent is removed under reduced pressure, crude product obtains 1- (the bromo- 2- fluorophenyls of 4- through column chromatography is pure）- 4- methoxy piperides.
Step 2) 1- (the fluoro- 4- methoxy piperides -1- bases of 3-) phenyl) -3- methoxyl group -4- phenylchinolines -2 (1H) -one
Under nitrogen protection, CuI (1 mmol), Cs2CO3(20 mmol) and 2- oxocyclohexyl Ethyl formates（2 Mmol it) is added in DMSO (10 mL), 30 min is stirred at room temperature.3- methoxyl group -4- phenylchinolines -2 (1H) -one (10 ) and 1- (the bromo- 2- fluorophenyls of 4- mmol）- 4- methoxy piperides（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), collection has Machine phase, decompression boil off solvent, and crude product purifies to obtain 1- (the fluoro- 4- methoxy piperides -1- bases of 3-) phenyl through column chromatography) -3- first Oxygroup -4- phenylchinolines -2 (1H) -one.
ESI-MS (m/z):459.20[M+H]+。
Embodiment 3.1- (the chloro- 4- of 3-（（2- morpholinyl ethyls）Amino) phenyl) -3- methoxyl group -4- phenylchinolines -2 (1H) -one
Step 1) 2- morpholinium acetonitriles
Under nitrogen protection, potassium carbonate（47 mmol) and morpholine（43 mmol) it is dissolved in acetonitrile（30 mL) in, ice bath cooling, Stirring, 2- bromoacetonitriles（43 mmol) it is added at one time in the reaction solution, 2 h of room temperature reaction, filtering are warming up to, decompression is steamed Solvent is removed, 2- morpholinium acetonitriles are obtained.
Step 2) 2- morpholine second ammonia
Under ice cooling, 4, Lithium Aluminium Hydride（84 mmol) it is added at one time dry tetrahydrofuran（35 mL) in, gained reaction Liquid stirs 20 minutes under 0 °C.2- morpholinium acetonitriles are added dropwise（28 mmol, 10 mL dry THF solution）.Drop finishes, heating To 3 h that flow back.It is cooled to room temperature rear ice bath cooling, water is slowly added into reaction system（20 mL), filtering, decompression boils off Solvent obtains 2- morpholine second ammonia.
The chloro- N- of the bromo- 2- of step 3) 4-（2- morpholinyl ethyls）Aniline
Under nitrogen protection, 2- morpholine second ammonia（6.91 mmol), 3,4- dichloro-bromobenzenes (6.91 mmol) and triethylamine（13.82 Mmol) it is dissolved in ethyl acetate（10 mL) in, it is heated to 24 h of reflux.It is cooled to room temperature, decompression boils off solvent, crude product warp Column chromatography purifies to obtain the chloro- N- of the bromo- 2- of 4-（2- morpholinyl ethyls）Aniline.
Step 4) 1- (the chloro- 4- of 3-（（2- morpholinyl ethyls）Amino) phenyl) -3- methoxyl group -4- phenylchinolines -2 (1H)- Ketone
Under nitrogen protection, CuI (1 mmol), Cs2CO3(20 mmol) and 2- oxocyclohexyl Ethyl formates（2 mmol）It is added in DMSO (10 mL), 30 min is stirred at room temperature.3- methoxyl group -4- phenylchinolines -2 (1H) -one (10 ) and the chloro- N- of the bromo- 2- of 4- mmol（2- morpholinyl ethyls）Aniline（10 mmol) DMSO (12 mL) solution, injection be added.Add Heat to 100 °C overnight.It is cooled to room temperature, filters, water is added（50 mL) and dichloromethane（50 mL × 3), it collects organic Phase, decompression boil off solvent, and crude product purifies to obtain 1- (the chloro- 4- of 3- through column chromatography（（2- morpholinyl ethyls）Amino) phenyl) -3- Methoxyl group -4- phenylchinolines -2 (1H) -one.
ESI-MS (m/z):490.18[M+H]+, 492.18[M+2+H]+。
Embodiment 4.1- (the fluoro- 4- of 3-（（4- methylpiperazine-1-yls）Methyl) phenyl) -3- methoxyl group -4- phenylchinolines -2 (1H) -one
Step 1) 1- (the bromo- 2- luorobenzyls of 4-) -4- methyl piperazines
The bromo- 2- toluene fluorides of 4-（4.0 mmol) in CC14It in (40 mL), stirs under nitrogen protection, BPO (0.08 mmol) It is added in the reaction solution with NBS (4.4 mmol), 5 h of heating reflux reaction, it is cooling.Vacuum distillation removes solvent, obtains the One step crude product.Methyl piperazine（20 mmol) ethanol solution be added under nitrogen protection in previous step crude product, room temperature It is stirred overnight.Solvent is removed under reduced pressure, crude product purifies to obtain 1- (the bromo- 2- luorobenzyls of 4-) -4- methyl piperazines through column chromatography.
Step 2) 1- (the fluoro- 4- of 3-（（4- methylpiperazine-1-yls）Methyl) phenyl) -3- methoxyl group -4- phenylchinolines -2 (1H) -one
Under nitrogen protection, CuI (1 mmol), Cs2CO3(20 mmol) and 2- oxocyclohexyl Ethyl formates（2 Mmol it) is added in DMSO (10 mL), 30 min is stirred at room temperature.3- methoxyl group -4- phenylchinolines -2 (1H) -one (10 ) and 1- (the bromo- 2- luorobenzyls of 4-) -4- methyl piperazines mmol（10 mmol) DMSO (12 mL) solution, injection be added.Add Heat to 100 °C overnight.It is cooled to room temperature, filters, water is added（50 mL) and dichloromethane（50 mL × 3), it collects organic Phase, decompression boil off solvent, and crude product purifies to obtain 1- (the fluoro- 4- of 3- through column chromatography（（4- methylpiperazine-1-yls）Methyl) phenyl)- 3- methoxyl group -4- phenylchinolines -2 (1H) -one.
ESI-MS (m/z):458.22[M+H]+。
5 1- of embodiment (4- ((diethylin) methyl) -3- fluorophenyls) -3- methoxyl group -4- phenylchinolines -2 (1H) -one
The fluoro- 4- iodobenzenes of step 1) 1- bromomethyls -2-
The fluoro- 4- iodotoluenes of 2- are added in 250 mL round-bottomed flasks（12 mmol) and be dissolved in carbon tetrachloride (120 mL), it stirs The lower addition NBS (12.6 mmol) and BPO (0.24 mmol) into solution is mixed, reaction system is heated to back under nitrogen protection 9 h of stream reaction.Reaction finishes, and is cooled to room temperature, and reaction solution decompression boils off solvent；Crude product purifies to obtain 1- bromines through column chromatography The fluoro- 4- iodobenzenes of methyl -2-.
Step 2) N- ethyls-N- (fluoro- 4 iodobenzyls of 2-）Ethamine
The fluoro- 4- iodobenzenes of 1- bromomethyls -2- are added in 100 mL two mouth flasks（6.0 mmol), under nitrogen protection, diethyl is added Amine（30 mmol) it is dissolved in ethyl alcohol（60 mL) solution, it is stirred to react at room temperature overnight.Reaction finishes, and decompression boils off solvent, remains Excess is dissolved in ethyl acetate（100 mL) in, organic layer uses water respectively（100 mL × 3) and 100 mL of saturated brine) washing. Organic layer decompression boils off solvent, obtains N- ethyls-N- (fluoro- 4 iodobenzyls of 2-）Ethamine.
Step 3) 1- (4- ((diethylin) methyl) -3- fluorophenyls) -3- methoxyl group -4- phenylchinolines -2 (1H) -one
Under nitrogen protection, by 3- methoxyl group -4- phenylchinolines -2 (1H) -one（Mmol), 5.60 N, N- dimethyl-ethylenediamine (2.24 mmol), cuprous iodide（1.12 mmol) and tripotassium phosphate（11.20 mmol) N- ethyls-N- (fluoro- 4 iodine of 2- is added Benzyl）Ethamine（5.60 mmol) it is dissolved in dioxane（50 mL) solution in, be heated under stirring 110 °C reaction 9 h, Reaction finishes, and mixture is cooled to room temperature, is poured into dichloromethane（200 mL) in, with water (200 mL × 3) and saturated brine （200 mL) washing.Organic layer decompression boils off solvent；Crude product purifies to obtain 1- (4- ((diethylin) methyl) -3- through column chromatography Fluorophenyl) -3- methoxyl group -4- phenylchinolines -2 (1H) -one.
ESI-MS (m/z):431.21[M+H]+。
Embodiment 6. 5- hydroxy-3-methoxies -1- (6- morpholinyls pyridin-3-yl) -4- phenylchinolines -2 (1H) -one
Step 1) 5- hydroxy-3-methoxy -4- phenylchinolines -2 (1H) -one
Under nitrogen protection, by 2- amino -6- hydroxy benzophenones (2 mmol), methoxyacetyl chloride (3.8 mmol) And N, N- diisopropylethylamine (8 mmol) are dissolved in dichloromethane (5 mL), are reacted at room temperature 3 hours.Contact plate finds former Material reaction finishes, and reaction solution is diluted with water rear ethyl acetate and extracts, after organic phase removed under reduced pressure solvent, residue silica gel Column chromatography purifies to obtainN-(2- benzoyl -3- hydroxy phenyls) -2- methoxyl acetamides.
Under nitrogen protection,N-(2- benzoyl -3- hydroxy phenyls) -2- methoxyl acetamides (1.0 mmol) are dissolved in In tetrahydrofuran (10 mL), t-BuOK (10 mmol) is added and reacts at room temperature 5 hours.Reaction solution saturated ammonium chloride is molten Liquid extracts, ethyl acetate extraction.After removed under reduced pressure organic phase, residue obtains 4,5- dihydroxy-with silica gel chromatography 3- methoxyl group -4- phenyl -3,4- dihydroquinoline -2 (1H) -one.
Under an atmosphere of hydrogen, by 4,5- dihydroxy -3- methoxyl group -4- phenyl -3,4- dihydroquinoline -2 (1H) -1 ketone (1 Mmol it) is dissolved in MeOH (10 mL), 10%Pd/C (0.1 mmol) and potassium carbonate (8 mmol) afterwards 50 is addedoC reacts Overnight.After removed under reduced pressure solvent, residue obtains 5- hydroxy-3-methoxy -4- phenylchinolines -2 with silica gel chromatography (1H) -one.
Step 2) 4- (5- bromopyridine -2- bases) morpholine
2- chlorine 5- bromopyridines（4.0 mmol) in CHC13It in (40 mL), stirs under nitrogen protection, BPO (0.08 mmol) It is added in the reaction solution with NBS (4.4 mmol), 5 h of heating reflux reaction, it is cooling.Vacuum distillation removes solvent, obtains the One step crude product.Morpholine（0.50 mo1）Ethanol solution be added under nitrogen protection in previous step crude product, be stirred at room temperature Overnight.Solvent is removed under reduced pressure, crude product purifies to obtain 4- (the bromo- 2- fluorophenyls of 4-) morpholine through column chromatography.
Step 3) 5- hydroxy-3-methoxies -1- (6- morpholinyls pyridin-3-yl) -4- phenylchinolines -2 (1H) -one
Under nitrogen protection, CuI (1 mmol), Cs2CO3(20 mmol) and 2- oxocyclohexyl Ethyl formates（2 Mmol it) is added in DMSO (10 mL), 30 min is stirred at room temperature.5- hydroxy-3-methoxy -4- phenylchinolines -2 (1H) -one (10 mmol) and 4- (5- bromopyridine -2- bases) morpholine（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 solvent, and crude product purifies to obtain 5- hydroxy-3-methoxies -1- (6- morpholinyls pyridin-3-yl) -4- benzene through column chromatography Base quinoline -2 (1H) -one.
ESI-MS (m/z):430.17[M+H]+。
7. 5- hydroxy-3-methoxies -1- of embodiment (5- morpholinyl pyrazine -2- bases) -4- phenylchinolines -2 (1H) -one
Step 1) 4- (5- bromo-pyrazine -2- bases) morpholine
2- chlorine 5- bromo-pyrazines（4.0 mmol) in CHC13It in (40 mL), stirs under nitrogen protection, BPO (0.08 mmol) It is added in the reaction solution with NBS (4.4 mmol), 5 h of heating reflux reaction, it is cooling.Vacuum distillation removes solvent, obtains the One step crude product.Morpholine（0.50 mo1）Ethanol solution be added under nitrogen protection in previous step crude product, be stirred at room temperature Overnight.Solvent is removed under reduced pressure, crude product purifies to obtain 4- (the bromo- 2- fluorophenyls of 4-) morpholine through column chromatography.
Step 2) 5- hydroxy-3-methoxies -1- (5- morpholinyl pyrazine -2- bases) -4- phenylchinolines -2 (1H) -one
Under nitrogen protection, CuI (1 mmol), Cs2CO3(20 mmol) and 2- oxocyclohexyl Ethyl formates（2 Mmol it) is added in DMSO (10 mL), 30 min is stirred at room temperature.5- hydroxy-3-methoxy -4- phenylchinolines -2 (1H) -one (10 mmol) and 4- (5- bromo-pyrazine -2- bases) morpholine（10 mmol) DMSO (12 mL) solution, injection be added.It is heated to 100 oC is stayed 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 5- hydroxy-3-methoxies -1- (5- morpholinyl pyrazine -2- bases) -4- benzene through column chromatography Base quinoline -2 (1H) -one.
ESI-MS (m/z):431.16[M+H]+。
8. 5- hydroxy-3-methoxies -1- of embodiment (5- morpholinyl -1,3,4- thiadiazoles -2- bases) -4- phenylchinolines - 2(1H) -one
Step 1) 4- (the bromo- 1,3,4- thiadiazoles -2- bases of 5-) morpholine
The bromo- 1,3,4- thiadiazoles of the chloro- 5- of 2-（4.0 mmol) in CHC13In (40 mL), stir under nitrogen protection, BPO (0.08 mmol) and NBS (4.4 mmol) are added in the reaction solution, 5 h of heating reflux reaction, cooling.Vacuum distillation removes Solvent obtains first step crude product.Morpholine（0.50 mol）Ethanol solution be added to previous step crude product under nitrogen protection In, it is stirred overnight at room temperature.Solvent is removed under reduced pressure, crude product purifies to obtain 4- (the bromo- 2- fluorophenyls of 4-) morpholine through column chromatography.
Step 2）5- hydroxy-3-methoxies -1- (5- morpholinyl -1,3,4- thiadiazoles -2- bases) -4- phenylchinolines -2 (1H) -one
Under nitrogen protection, CuI (1 mmol), Cs2CO3(20 mmol) and 2- oxocyclohexyl Ethyl formates（2 mmol) plus Enter into DMSO (10 ml), 30 min are stirred at room temperature.5- hydroxy-3-methoxy -4- phenylchinolines -2 (1H) -one (10 ) and 4- (the bromo- 1,3,4- thiadiazoles -2- bases of 5-) morpholine mmol（10 mmol) DMS (12 ml) solution, injection be added.Add Heat to 100 °C overnight.It is cooled to room temperature, filters, water is added（50 mL) and dichloromethane（50 mL × 3), it collects organic Phase, decompression boil off solvent, and crude product purifies to obtain 5- hydroxy-3-methoxies -1- (5- morpholinyl -1,3,4- thiophenes two through column chromatography Azoles -2- bases) -4- phenylchinolines -2 (1H) -one.
ESI-MS (m/z):431.16[M+H]+。
Embodiment 9.5- hydroxy-3-methoxies -1- (2- (4- methoxyphenyls) thiazole -5- bases) -4- phenyl -2 (1H) -one
Step 1) 2- (4- hydroxy phenyls）Thiazole
4- hydroxythiobenzamides（0.20 mol) and the bromo- 1,1- dimethoxy-ethanes of 2- (0.20 mol) in ethyl alcohol（600 ML it is stirred at room temperature in), p-methyl benzenesulfonic acid（0.20 mol) it is added into reaction solution.It is heated to 90 °C of 24 h of reaction.Reaction knot Beam postcooling to room temperature, vacuum distillation removes solvent, and water is added（200 mL), extremely with saturated sodium bicarbonate solution tune pH value 8, dichloromethane（200 mL × 3) extraction, merge organic phase, vacuum distillation is concentrated to give 2- (4- hydroxy phenyls）Thiazole.
Step 2) 2- (4- methoxyphenyls）Thiazole
2- (4- hydroxy phenyls）Thiazole（0.12 mol) and K2CO3(0.60 mol) is stirred at room temperature in acetone (1000 mL), Bromomethane（0.36 mol) it is added into reaction solution.60 °C of 11 h of reflux.It is cooled to room temperature, filters, vacuum distillation concentration filter 2- (4- methoxyphenyls are obtained after liquid）Thiazole.
Step 3) 5- bromo- 2- (4- methoxyphenyls）Thiazole
2- (4- methoxyphenyls）Thiazole（5.00 mmol) in DCM (30 mL), M gas shieldeds K is stirred at room temperature, NBS (5.50 ) and glacial acetic acid mmol（0.3 mL) it is added in reaction solution.48 °C of 3 h of reaction.It is cooled to room temperature after reaction, decompression boils off Solvent；Crude product purifies to obtain 5- bromo- 2- (4- methoxyphenyls through column chromatography）Thiazole.
Step 4) 5- hydroxy-3-methoxies -1- (2- (4- methoxyphenyls) thiazole -5- bases) -4- phenyl -2 (1H) -one
Under nitrogen protection, CuI (0.20 mmol）, Cs2CO3 (3.00 mmol) and ligand 8-hydroxyquinoline（0.20 Mmol it) is added in DMSO (2 mL), is stirred at room temperature 30 minutes.5- hydroxyls-the 3- for being dissolved in DMSO (2 mL) is added with syringe Methoxyl group -4- phenylchinolines -2 (1H) -one（2.40 mmol) and 5- bromo- 2- (4- ethoxyl phenenyls）Thiazole (2.00 mmol) Afterwards, 130 °C of 12 h of reaction are heated to.It is cooled to room temperature, filters, water（10 mL) and dichloromethane (20 mL × 3) extraction It takes, collects organic phase, evaporated under reduced pressure solvent.Crude product column chromatography purifies to obtain 5- hydroxy-3-methoxies -1- (2- (4- methoxyl groups Phenyl) thiazole -5- bases) -4- phenyl -2 (1H) -one.
ESI-MS (m/z):457.11[M+H]+。
Embodiment 10.
1- (the fluoro- 4- of 3- (1HImidazoles -1- bases) phenyl) -5- hydroxy-3-methoxy -4- phenylchinolines -2 (1H) -one
Step 1) 1- (the bromo- 2- fluorophenyls of 4-) -1HImidazoles
The bromo- 2- fluorobenzene of 4-（4.0 mmol) in CC14In (40 mL), stir under nitrogen protection, BPO (0.08 mmol) and NBS (4.4 mmol) is added in the reaction solution, 5 h of heating reflux reaction, cooling.Vacuum distillation removes solvent, obtains first Walk crude product.Imidazoles（20 mmol) ethanol solution be added under nitrogen protection in previous step crude product, be stirred at room temperature Night.Solvent is removed under reduced pressure, crude product purifies to obtain 1- (the bromo- 2- fluorophenyls of 4-) -1 through column chromatographyHImidazoles.
Step 2) 1- (the fluoro- 4- of 3- (1HImidazoles -1- bases) phenyl) -5- hydroxy-3-methoxy -4- phenylchinolines -2 (1H)- Ketone
Under nitrogen protection, CuI (1 mmol), Cs2CO3(20 mmol) and 2- oxocyclohexyl Ethyl formates（2 mmol）It is added in DMSO (10 mL), 30 min is stirred at room temperature.5- hydroxy-3-methoxy -4- phenylchinolines -2 (1H) -one (10 mmol) and 1- (the bromo- 2- fluorophenyls of 4-) -1H-Imidazoles（10 mmol) DMSO (12 mL) solution, injection be added.Add Heat to 100 °C overnight.It is cooled to room temperature, filters, water is added（50 mL) and dichloromethane（50 mL × 3), it collects organic Phase, decompression boil off solvent, and crude product purifies to obtain 1- (the fluoro- 4- of 3- (1 through column chromatographyHImidazoles -1- bases) phenyl) -5- hydroxyls -3- Methoxyl group -4- phenylchinolines -2 (1H) -one.
ESI-MS (m/z):428.13[M+H]+。
11. 3- methoxyl groups -1- (morpholinyl phenyl) -4- phenyl -1,8- naphthyridines -2 (1 of embodimentH) -one
Step 1) 3- methoxyl group -4- phenyl -1,8- naphthyridines -2 (1H) -one.
Under nitrogen protection, by (2-aminopyridine -3- bases) (phenyl) ketone (3.8 mmol) and N, N- diisopropylethylamine (8 mmol) is dissolved in dichloromethane (5 mL), is reacted at room temperature 3 hours.Contact plate finds that raw material reaction finishes, and reaction solution adds Ethyl acetate extracts after water dilution, and after organic phase removed under reduced pressure solvent, residue is obtained with silica gel chromatographyN-(3- benzene Formylpyridine -2- bases) -2- methoxyl acetamides.
Under nitrogen protection, N-(3- benzoylpyridine -2- bases) -2- methoxyl acetamides are dissolved in tetrahydrofuran (10 ML in), t-BuOK (10 mmol) is added and reacts at room temperature 5 hours.Reaction solution is extracted with saturated ammonium chloride solution, acetic acid second Ester extracts.After removed under reduced pressure organic phase, residue obtains phenyl -3 4- hydroxy-3-methoxy -4- with silica gel chromatography, 4- dihydro -1,8- benzodiazines -2 (1H)-1。
Under an atmosphere of hydrogen, by 4- hydroxy-3-methoxy -4- phenyl -3,4- dihydro -1,8- naphthyridines -2 (1H) -one (1.0 Mmol it) is dissolved in MeOH (10 mL), 10%Pd/C (0.1 mmol) and potassium carbonate (8 mmol) afterwards 50 is addedoC reacts Overnight.After removed under reduced pressure solvent, residue obtains 3- methoxyl group -4- phenyl -1,8- naphthyridines -2 with silica gel chromatography (1H) -one.
Step 2) 4- (3- bromophenyls) morpholine
Bromobenzene（4.0 mmol) in CHC13It in (40 mL), stirs under nitrogen protection, BPO (0.08 mmol) and NBS (4.4 Mmol it) is added in the reaction solution, 5 h of heating reflux reaction, it is cooling.Vacuum distillation removes solvent, obtains the first step and slightly produces Product.Morpholine（0.50 mol）Ethanol solution be added under nitrogen protection in previous step crude product, be stirred overnight at room temperature.Subtract Pressure removes solvent, and crude product purifies to obtain 4- (3- bromophenyls) morpholine through column chromatography.
Step 3) 3- methoxyl groups -1- (morpholinyl phenyl) -4- phenyl -1,8- naphthyridines -2 (1H) -one
Under nitrogen protection, CuI (1 mmol), Cs2CO3(20 mmol) and 2- oxocyclohexyl Ethyl formates（2 Mmol it) is added in DMSO (10 mL), 30 min is stirred at room temperature.3- methoxyl group -4- phenyl -1,8- naphthyridines -2 (1H) -one (10 ) and 4- (3- bromophenyls) morpholine mmol（10 mmol) DMSO (12 mL) solution, injection be added.It is heated to 100 °C of mistakes Night.It is cooled to room temperature, filters, water is added（50 mL) and dichloromethane（50 mL × 3), organic phase is collected, decompression boils off Solvent, crude product purify to obtain 3- methoxyl groups -1- (morpholinyl phenyl) -4- phenyl -1,8- naphthyridines -2 (1 through column chromatographyH)- Ketone.
ES I-MS (m/z):414.17[M+H]+。
Embodiment 12.
1- (the chloro- 4- of 3- (two own amino) phenyl) -3- methoxyl group -4- phenyl -1,8- naphthyridines -2 (1H) -one
The chloro- 4- bromanilines of step 1) N, N- dihexyl -2-
The fluoro- 4- bromobenzenes of the chloro- 1- of 2- are added in 250 mL round-bottomed flasks（0.10 mol) and it is dissolved in DMF (100 mL）In, it stirs Mix lower addition potassium carbonate（0.20 mol) and two n-hexylamines（0.10 mol), reaction system is heated to 90 °C and reacts 72 hours. Reaction finishes, and mixture is cooled to room temperature, and organic phase is concentrated into 50 mL, is poured into dichloromethane by filtering（150 mL) In, use water（150 mL × 3) and saturated salt solution（150 mL) it washs, anhydrous sodium sulfate drying, decompression boils off solvent, slightly Product purify to obtain N, the chloro- 4- bromanilines of N- dihexyls -2- through column chromatography.
Step 2) 1- (the chloro- 4- of 3- (two own amino) phenyl) -3- methoxyl group -4- phenyl -1,8- naphthyridines -2 (1H) -one
Under nitrogen protection, CuI (1 mmol), Cs2CO3(20 mmol) and 2- oxocyclohexyl Ethyl formates（2 Mmol it) is added in DMSO (10 mL), 30 min is stirred at room temperature.3- methoxyl group -4- phenyl -1,8- naphthyridines -2 (1H) -one (10 ) and the chloro- 4- bromanilines of N, N- dihexyl -2- mmol（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 solvent, and crude product purifies to obtain 1- (the chloro- 4- of 3- (two own amino) phenyl) -3- methoxyl group -4- phenyl-through column chromatography 1,8- naphthyridines -2 (1H) -one.
ESI-MS (m/z):546.28[M+H]+。
Embodiment 13.1- (the fluoro- 4- morpholino phenyls of 3-) -5- hydroxy-3-methoxy -4- phenyl -7- (thiazol-2-yl) quinoline Quinoline -2 (1H) -one
Step 1) 3- methoxyl groups -4- phenyl 5- hydroxyls -7- (thiazol-2-yl) quinoline -2 (1H) -one
Under nitrogen protection, by 2- amino -4- thiazole -6- hydroxy benzophenones (2 mmol), methoxyacetyl chloride (3.8 mmol) and N, N- diisopropylethylamine (8 mmol) are dissolved in dichloromethane (5 mL), and room temperature reaction 3 is small When.Contact plate finds that raw material reaction finishes, and reaction solution is diluted with water rear ethyl acetate and extracts, after organic phase removed under reduced pressure solvent, Residue obtains N with silica gel chromatography-(2- benzoyl -3- hydroxyls -5- (thiazol-2-yl) phenyl) -2- methoxyl group acetyl Amine.
Under nitrogen protection, N-(2- benzoyl -3- hydroxyls -5- (thiazol-2-yl) phenyl) -2- methoxyl acetamides (1.0 mmol) is dissolved in tetrahydrofuran (10 mL), and t-BuOK (10 mmol) is added and reacts at room temperature 5 hours.Reaction solution It is extracted with saturated ammonium chloride solution, ethyl acetate extraction.After removed under reduced pressure organic phase, residue is obtained with silica gel chromatography To 4,5- dihydroxy -3- methoxyl group -4- phenyl -7- (thiazol-2-yl) -3,4- dihydroquinoline -2- (1H) -one.
Under an atmosphere of hydrogen, by 4,5- dihydroxy -3- methoxyl group -4- phenyl -7- (thiazol-2-yl) -3,4- dihydro quinolines Quinoline -2- (1H) -one (1 mmol) is dissolved in MeOH (10 mL), 10%Pd/C (35 mg) and potassium carbonate (8 is added Mmol) afterwards 50oC reactions are overnight.After removed under reduced pressure solvent, residue obtains 3- methoxyl group -4- benzene with silica gel chromatography Base 5- hydroxyls -7- (thiazol-2-yl) quinoline -2 (1H) -one.
Step 2）4- (the bromo- 2- fluorophenyls of 4-) morpholine
The bromo- 2- fluorobenzene of 4-（4.0 mmol) in CHC13In (40 mL), stir under nitrogen protection, BPO (0.08 mmol) and NBS (4.4 mmol) is added in the reaction solution, 5 h of heating reflux reaction, cooling.Vacuum distillation removes solvent, obtains first Walk crude product.Morpholine（0.50 mo1）Ethanol solution be added under nitrogen protection in previous step crude product, be stirred at room temperature Night.Solvent is removed under reduced pressure, crude product purifies to obtain 4- (the bromo- 2- fluorophenyls of 4-) morpholine through column chromatography.
Step 3) 1- (the fluoro- 4- morpholino phenyls of 3-) -5- hydroxy-3-methoxy -4- phenyl -7- (thiazol-2-yl) quinoline - 2(1H) -one
Under nitrogen protection, CuI (1 mmol), Cs2CO3(20 mmol) and 2- oxocyclohexyl Ethyl formates（2 Mmol it) is added in DMSO (10 mL), 30 min is stirred at room temperature.3- methoxyl group -4- phenyl 5- hydroxyls -7- (thiazol-2-yl) Quinoline -2 (1H) -one (10 mmol) and 4- (the bromo- 2- fluorophenyls of 4-) morpholine（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 1- (the fluoro- 4- morpholino phenyls of 3-) -5- hydroxyls -3- through column chromatography Methoxyl group -4- phenyl -7- (thiazol-2-yl) quinoline -2 (1H) -one.
ESI-MS (m/z): 530.15[M+H]+。
Embodiment 14
4- (4- chlorphenyls) -6- hydroxy-3-methoxies -1- (4- morpholinyls -3- (trifluoromethyl) phenyl) -1,8- naphthyridines -2 (1H) -one
Step 1) 4- (4- chlorphenyls) -6- hydroxy-3-methoxy -1,8- naphthyridines -2 (1H) -one
Under nitrogen protection, by (2- amino -5- pyridone -3- bases) (phenyl) ketone (3.8 mmol) and N, N- bis- is different Propylethylamine (8 mmol) is dissolved in dichloromethane (5 mL), is reacted at room temperature 3 hours.Contact plate finds that raw material reaction finishes, Reaction solution is diluted with water rear ethyl acetate and extracts, and after organic phase removed under reduced pressure solvent, residue is obtained with silica gel chromatography It arrivesN-(3- (4- chlorobenzene formacyls) -5- pyridone -2- bases) -2- methoxyl acetamides.
Under nitrogen protection,N-(3- (4- chlorobenzene formacyls) -5- pyridone -2- bases) -2- methoxyl acetamides are dissolved in In tetrahydrofuran (10 mL), t-BuOK (10 mmol) is added and reacts at room temperature 5 hours.Reaction solution saturated ammonium chloride is molten Liquid extracts, ethyl acetate extraction.After removed under reduced pressure organic phase, residue obtains 4- (4- chlorobenzenes with silica gel chromatography Base) -4,6- dihydroxy -3- methoxyl group -3,4- dihydro -1,8- naphthyridines -2 (1H) -one.
Under an atmosphere of hydrogen, by 4- (4- chlorphenyls) -4,6- hydroxy-3-methoxy -3,4- dihydro -1,8- naphthyridines -2 (1H) -one (1.0 mmol) is dissolved in MeOH (10 mL), 10%Pd/C (0.1 mmol) and potassium carbonate (8 is added Mmol) afterwards 50oC reactions are overnight.After removed under reduced pressure solvent, residue obtains 4- (4- chlorphenyls)-with silica gel chromatography 6- hydroxy-3-methoxy -1,8- naphthyridines -2 (1H) -one.
Step 2) 4- (the bromo- 2- of 4-（Trifluoromethyl）Phenyl) morpholine
The bromo- 2- of 4-（Trifluoromethyl）Benzene（4.0 mmol) in CHC13It in (40 mL), stirs under nitrogen protection, BPO (0.08 Mmol it) is added in the reaction solution with NBS (4.4 mmol), 5 h of heating reflux reaction, it is cooling.Vacuum distillation removes solvent, Obtain first step crude product.Morpholine（0.50 mo1）Ethanol solution be added under nitrogen protection in previous step crude product, room Temperature is stirred overnight.Solvent is removed under reduced pressure, crude product purifies to obtain 4- (the bromo- 2- of 4- through column chromatography（Trifluoromethyl）Phenyl) morpholine.
Step 3) 4- (4- chlorphenyls) -6- hydroxy-3-methoxies -1- (4- morpholinyls -3- (trifluoromethyl) phenyl) -1,8- Naphthyridines -2 (1H) -one
Under nitrogen protection, CuI (1 mmol), Cs2CO3(20 mmol) and 2- oxocyclohexyl Ethyl formates（2 Mmol it) is added in DMSO (10 mL), 30 min is stirred at room temperature.4- (4- chlorphenyls) -6- hydroxy-3-methoxy -1,8- naphthalenes Pyridine -2 (1H) -one (10 mmol) and 4- (the bromo- 2- of 4-（Trifluoromethyl）Phenyl) morpholine（10 mmol) DMSO (12 mL) it is molten Liquid, injection are 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 solvent, and crude product purifies to obtain 4- (4- chlorphenyls) -6- hydroxyl -3- first through column chromatography Oxy-1-(4- morpholinyls-3- (trifluoromethyl) phenyl)-1,8- naphthyridines-2 (1H) -one.
ESI-MS (m/z): 532.12[M+H]+ , 534.11[M+2+H]+。
Embodiment 15
5- (chloro- 3- methoxyl groups -7- (the 1- methyl-1s of 6-HPyrroles -2- bases) -2- oxygen -4- phenylchinolines -1 (2H)-yl) -2- (two Own amino) benzonitrile
Chloro- 3- methoxyl groups -7- (the 1- methyl-1s of step 1) 6-HPyrroles -2- bases) -4- phenylchinolines -2 (1H) -one
Under nitrogen protection, by (chloro- 4 (1- methyl-1s of 2- amino -5-HPyrroles -2- bases) phenyl) (phenyl) ketone (3.8 Mmol it) is dissolved in dichloromethane (5 mL), reacts at room temperature 3 hours with N, N- diisopropylethylamine (8 mmol).Contact plate It was found that raw material reaction finishes, reaction solution is diluted with water rear ethyl acetate and extracts, after organic phase removed under reduced pressure solvent, residue It is obtained with silica gel chromatographyN(2- benzoyls -4- chloro- 5- (1- methyl-1sHPyrroles -2- bases) phenyl) -2- methoxyl group second Amide.
Under nitrogen protection,N(2- benzoyls -4- chloro- 5- (1- methyl-1sHPyrroles -2- bases) phenyl) -2- methoxyl groups Acetamide is dissolved in tetrahydrofuran (10 mL), and t-BuOK (10 mmol) is added and reacts at room temperature 5 hours.Reaction solution is used full It is extracted with ammonium chloride solution, ethyl acetate extraction.After removed under reduced pressure organic phase, residue obtains 6- with silica gel chromatography Chloro-4-hydroxyl -3- methoxyl groups -7- (1- methyl-1sHPyrroles -2- bases) -4- phenyl -3,4- dihydroquinoline -2 (1H) -one.
Under an atmosphere of hydrogen, by 6- chloro-4-hydroxyl -3- methoxyl groups -7- (1- methyl-1sHPyrroles -2- bases) -4- phenyl - 3,4- dihydroquinoline -2 (1H) -one (1.0 mmol) is dissolved in MeOH (10 mL), 10% Pd/C (0.1 mmol) is added With potassium carbonate (8 mmol) afterwards 50oC reactions are overnight.After removed under reduced pressure solvent, residue silica gel chromatography (oil Ether/ethyl acetate (v/v)=2/1) obtain chloro- 3- methoxyl groups -7- (the 1- methyl-1s of 6-HPyridine -2- bases) -4- phenyl quinazolines Quinoline -2 (1H) -one.
The bromo- 2- of step 2) 5- (two own amino) benzonitrile
The bromo- 2- fluorine benzonitriles of 5- are added in 250 ml round-bottomed flasks（0.10 mol) and it is dissolved in DMF (100 mL）In, stirring Lower addition potassium carbonate（0.20 mol) and two n-hexylamines（0.10 mol), reaction system is heated to 90 °C and reacts 72 hours.Instead It should finish, mixture is cooled to room temperature, filter, organic phase is concentrated into 50 mL, is poured into dichloromethane（150 mL) in, Use water（150 mL × 3) and saturated salt solution（150 mL) it washs, anhydrous sodium sulfate drying, decompression boils off solvent, crude product warp Column chromatography purifies to obtain the bromo- 2- of 5- (two own amino) benzonitrile.
Step 3) 5- (chloro- 3- methoxyl groups -7- (the 1- methyl-1s of 6-HPyrroles -2- bases) -2- oxygen -4- phenylchinolines -1 (2H)-yl) -2- (two own amino) benzonitrile
Under nitrogen protection, CuI (1 mmol), Cs2CO3(20 mmol) and 2- oxocyclohexyl Ethyl formates（2 Mmol it) is added in DMSO (10 mL), 30 min is stirred at room temperature.3- methoxyl group -4- phenyl -1,8- naphthyridines -2 (1H) -one (10 ) and the chloro- 4- bromanilines of N, N- dihexyl -2- mmol（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 solvent, and crude product purifies to obtain 5- (chloro- 3- methoxyl groups -7- (the 1- methyl-1s of 6- through column chromatographyHPyrroles -2- bases) -2- Oxygen -4- phenylchinolines -1 (2H)-yl) -2- (two own amino) benzonitrile.
ESI-MS (m/z): 649.32[M+H]+。
Embodiment 16.
The fluoro- 1- of 6- (the fluoro- 4- thiomorpho-linylphenyls of 3-) -3- methoxyl groups -7- (4- methylpiperazine-1-yls) -4- phenylchinolines -2 (1H) -one
Step 1) 6- fluoro- 3- methoxyl groups -7- (4- methylpiperazine-1-yls) -4- phenylchinolines -2 (1H) -one
Under nitrogen protection, by (2- amino-5-fluorines -4- (4- methylpiperazine-1-yls) phenyl) (phenyl) ketone (2 mmol), Methoxyacetyl chloride (3.8 mmol) and N, N- diisopropylethylamine (8 mmol) are dissolved in dichloromethane (5 mL), Room temperature reaction 3 hours.Contact plate finds that raw material reaction finishes, and reaction solution is diluted with water rear ethyl acetate extraction, organic phase decompression After removing solvent, residue obtains N- (the fluoro- 5- of 2- benzoyls -4- (4- methylpiperazine-1-yls) benzene with silica gel chromatography Base) -2- methoxyl acetamides.
Under nitrogen protection, N- (the fluoro- 5- of 2- benzoyls -4- (4- methylpiperazine-1-yls) phenyl) -2- methoxyl group acetyl Amine (1.0 mmol) is dissolved in tetrahydrofuran (10 mL), and t-BuOK (10 mmol) is added and reacts at room temperature 5 hours.Instead Liquid is answered to be extracted with saturated ammonium chloride solution, ethyl acetate extraction.After removed under reduced pressure organic phase, residue silica gel column chromatography is pure Change obtains 6- fluoro- 4- hydroxy-3-methoxies -7- (4- methylpiperazine-1-yls) -4- phenyl -3,4- dihydroquinoline -2 (1H) -one.
Under an atmosphere of hydrogen, by 6- fluoro- 4- hydroxy-3-methoxies -7- (4- methylpiperazine-1-yls) -4- phenyl -3,4- Dihydroquinoline -2 (1H) -one (1.0 mmol) is dissolved in MeOH (10 mL), 10%Pd/C (0.1 mmol) and carbon is added Sour potassium (8 mmol) afterwards 50oC reactions are overnight.After removed under reduced pressure solvent, it is fluoro- that residue with silica gel chromatography obtains 6- 3- methoxyl groups -7- (4- methylpiperazine-1-yls) -4- phenylchinolines -2 (1H) -one.
Step 2) 4- (the bromo- 2- fluorophenyls of 4-) thiomorpholine
The bromo- 2- fluorobenzene of 4-（4.0 mmol) in CHC13In (40 mL), stir under nitrogen protection, BPO (0.08 mmol) and NBS (4.4 mmol) is added in the reaction solution, 5 h of heating reflux reaction, cooling.Vacuum distillation removes solvent, obtains first Walk crude product.Thiomorpholine（0.50 mol）Ethanol solution be added under nitrogen protection in previous step crude product, room temperature is stirred It mixes overnight.Solvent is removed under reduced pressure, crude product purifies to obtain 4- (the bromo- 2- fluorophenyls of 4-) thiomorpholine through column chromatography.
The fluoro- 1- of step 3) 6- (the fluoro- 4- thiomorpho-linylphenyls of 3-) -3- methoxyl groups -7- (4- methylpiperazine-1-yls) -4- Phenylchinoline -2 (1H) -one
Under nitrogen protection, CuI (1 mmol), Cs2CO3(20 mmol) and 2- oxocyclohexyl Ethyl formates（2 Mmol it) is added in DMSO (10 mL), 30 min is stirred at room temperature.3- methoxyl group -4- phenylchinolines -2 (1H) -one (10 ) and 4- (the bromo- 2- fluorophenyls of 4-) morpholine mmol（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), collect organic phase, decompression Solvent is boiled off, crude product purifies to obtain the fluoro- 1- of 6- (the fluoro- 4- thiomorpho-linylphenyls of 3-) -3- methoxyl groups -7- (4- first through column chromatography Base piperazine -1- bases) -4- phenylchinolines -2 (1H) -one.
ESI-MS (m/z):563.22[M+H]+。
Embodiment 17.
3,5- dimethoxys -1- (5- phenyl -1,3,4-t thiadiazoles -2- bases) -4- (pyridin-4-yl) -1,8- naphthyridines -2 (1H)- Ketone
Step 1）3,5- dimethoxy-4 's-(pyridin-4-yl) -3,4- dihydro -1,8- naphthyridines -2 (1H) -one
Under nitrogen protection, by (- 3 base of 2- amino-4-methoxyls pyridine)（Pyridine）Ketone (5 mmol) and DIPEA (13 ML, 15 mmol) it is dissolved in DCM (10 mL), room temperature methoxyacetyl chloride (7 mmol) reacts at room temperature 3 hours afterwards.Point Plate finds that raw material reaction finishes, and reaction solution is diluted with water rear ethyl acetate and extracts, after organic phase removed under reduced pressure solvent, residual Object obtains N- (3- with silica gel chromatography（Pyridin-4-yl) acyl group -4- pyridinyl methoxy -2- bases) -2- methoxyl acetamides.
Under nitrogen protection, by N- (3-（Pyridin-4-yl) formoxyl -4- pyridinyl methoxy -2- bases) -2- methoxyl group acetyl Amine (1.0 mmol) is dissolved in THF (10 mL), and t-BuOH (10 mmol) is added and reacts at room temperature 3 hours.Reaction solution is used Saturated ammonium chloride solution extracts, ethyl acetate extraction.After removed under reduced pressure organic phase, residue is obtained with silica gel chromatography 3,4- dihydro -4- hydroxyl -3,5- dimethoxy-4 's -（Pyridin-4-yl) -1,8- naphthyridines -2 (1H) -one.
Under an atmosphere of hydrogen, by 3,4- dihydro -4- hydroxyls -3,5- dimethoxy-4 's-pyridyl group -1,8- naphthyridines -2 (1H)- Ketone (0.98 mmol) is dissolved in MeOH (10 mL), after 10%Pd/C (35 mg) and potassium carbonate (1 g) is added, 50oC reactions are overnight.After removed under reduced pressure solvent, residue obtains 3,5- dimethoxy-4 's-(pyridine -4- with silica gel chromatography Base) -3,4- dihydro -1,8- naphthyridines -2 (1H) -one.
The bromo- 5- phenyl -1,3,4- thiadiazoles of step 2) 2-
The bromo- 1,3,4- thiadiazoles of 2- chlorine 5-（4.0 mmol) in CHC13In (40 mL), stir under nitrogen protection, BPO (0.08 mmol) and NBS (4.4 mmol) are added in the reaction solution, 5 h of heating reflux reaction, cooling.Vacuum distillation removes Solvent obtains first step crude product.Benzene（0.50 mol）Ethanol solution be added to previous step crude product under nitrogen protection In, it is stirred overnight at room temperature.Solvent is removed under reduced pressure, crude product purifies to obtain the bromo- 5- phenyl -1,3,4- thiadiazoles of 2- through column chromatography.
Step 3）3,5- dimethoxys -1- (5- phenyl -1,3,4- thiadiazoles -2- bases) -4- (pyridin-4-yl) -1,8- naphthalenes Pyridine -2 (1H) -one
Under nitrogen protection, CuI (1 mmol), Cs2CO3(20 mmol) and 2- oxocyclohexyl Ethyl formates（2 mmol) It is added in DMSO (10 mL), 30 min is stirred at room temperature.5- hydroxy-3-methoxy -4- phenylchinolines -2 (1H) -one (10 ) and 4- (the bromo- 1,3,4- thiadiazoles -2- bases of 5-) morpholine mmol（10 mmol) DMSO (12 mL) solution, injection be added.Add Heat to 100 °C overnight.It is cooled to room temperature, filters, water is added（50 mL) and dichloromethane（50 mL × 3), it collects organic Phase, decompression boil off solvent, and crude product purifies to obtain 3,5- dimethoxys -1- (5- phenyl -1,3,4- thiadiazoles -2- through column chromatography Base) -4- (pyridin-4-yl) -1,8- naphthyridines -2 (1H) -one.
ESI-MS (m/z):444.11[M+H]+。
Embodiment 18.
1- (4- (isobutylamino) -3- fluorophenyls) -5- hydroxy-3-methoxy -4- phenyl -1,8- naphthyridines -2 (1H) -one
Step 1）5- hydroxy-3-methoxy -4- phenyl -3,4- dihydro -1,8- naphthyridines -2 (1H) -one
Under nitrogen protection, by (- 3 base of 2- amino-4-hydroxies pyridine)（Phenyl）Ketone (5 mmol) and DIPEA (13 ML, 15 mmol) it is dissolved in DCM (10 mL), room temperature methoxyacetyl chloride (7 mmol) reacts at room temperature 3 hours afterwards.Point Plate finds that raw material reaction finishes, and reaction solution is diluted with water rear ethyl acetate and extracts, after organic phase removed under reduced pressure solvent, residual Object obtains N- (3- benzoyl -4- pyridone -2- bases) -2- methoxyl acetamides with silica gel chromatography.
Under nitrogen protection, by N- (3- benzoyl -4- pyridone -2- bases) -2- methoxyl acetamides (1.0 Mmol it) is dissolved in THF (10 mL), t-BuOH (10 mmol) is added and reacts at room temperature 3 hours.Reaction solution saturation chlorination Ammonium salt solution extracts, ethyl acetate extraction.After removed under reduced pressure organic phase, residue obtains 4,5- bis- with silica gel chromatography Hydroxy-3-methoxy -4- phenyl -3,4- dihydro -1,8- benzodiazines -2 (1H) -one.
Under an atmosphere of hydrogen, by 4,5- dihydroxy -3- methoxyl group -4- phenyl -3,4- dihydro -1,8- benzodiazines -2 (1H) -one (0.9 mmol) is dissolved in MeOH (10 mL), after 10%Pd/C (35 mg) and potassium carbonate (1 g) is added, 50 oC reactions are overnight.After removed under reduced pressure solvent, residue obtains 5- hydroxy-3-methoxy -4- benzene with silica gel chromatography Base -3,4- dihydro -1,8- naphthyridines -2 (1H) -one.
The bromo- 2- of step 2) 4- fluoro- N, N- diisobutyl aniline
The bromo- 1,2- difluorobenzenes of 4- are added in 100 ml round-bottomed flasks（10 mmol) and be dissolved in DMSO (15 mL), it stirs Mix lower addition K2CO3(22 mmol) and di-iso-butylmanice（11 mmol), reaction system is heated to 90 °C of reactions overnight.It has reacted Finish, mixture is cooled to room temperature, adds water（50 mL), dichloromethane extraction（50 mL × 3), anhydrous sodium sulfate drying subtracts Solvent evaporated, crude product is pressed to purify to obtain the bromo- 2- of 4- fluoro- N, N- diisobutyl aniline through column chromatography.
Step 3）1- (4- (isobutylamino) -3- fluorophenyls) -5- hydroxy-3-methoxy -4- phenyl -1,8- naphthyridines -2 (1H) -one
Under nitrogen protection, CuI (1 mmol), Cs2CO3(20 mmol) and 2- oxocyclohexyl Ethyl formates（2 mmol) It is added in DMSO (10 mL), 30 min is stirred at room temperature.5- hydroxy-3-methoxy -4- phenyl -3,4- dihydro -1,8- naphthyridines - 2(1H) -one (10 mmol) and the bromo- 2- of 4- fluoro- N, N- diisobutyl aniline（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 1- (4- (isobutylamino) -3- fluorophenyls) -5- through column chromatography Hydroxy-3-methoxy -4- phenyl -1,8- naphthyridines -2 (1H) -one.
ESI-MS (m/z):490.24[M+H]+。
Embodiment 19.
1- (the fluoro- 4- of 3- (4- hydroxy piperidine -1- bases) phenyl) -5- hydroxy-3-methoxy -4- phenyl -1,8- naphthyridines -2 (1H) -one
Step 1) 1- (the bromo- 2- fluoro-phenyls of 4-）Piperidines -4- alcohol
In 1000 ml round-bottomed flasks, by 3,4- difluorobenzenes（0.10 mo1) 4- hydroxy piperidines (0.11 mo1) and three are added Ethamine（0.12 mo1) ethyl acetate（500 mL) solution.24 h are stirred at room temperature.Use water（200 mL × 4) it washs, collection has Machine phase, after being dried over anhydrous sodium sulfate, evaporated under reduced pressure solvent is dried in vacuo to obtain 1- (the bromo- 2- fluoro-phenyls of 4-）Piperidines -4- Alcohol.
Step 2）1- (the fluoro- 4- of 3- (4- hydroxy piperidine -1- bases) phenyl) -5- hydroxy-3-methoxy -4- phenyl -1,8- naphthalenes Pyridine -2 (1H) -one
Under nitrogen protection, CuI (1 mmol), Cs2CO3(20 mmol) and 2- oxocyclohexyl Ethyl formates（2 mmol) It is added in DMSO (10 mL), 30 min is stirred at room temperature.5- hydroxy-3-methoxy -4- phenyl -3,4- dihydro -1,8- naphthyridines - 2(1H) -one (10 mmol) and 1- (the bromo- 2- fluoro-phenyls of 4-）Piperidines -4- alcohol（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 1- (the fluoro- 4- of 3- (4- hydroxy piperidine -1- bases) benzene through column chromatography Base) -5- hydroxy-3-methoxy -4- phenyl -1,8- naphthyridines -2 (1H) -one.
ESI-MS (m/z):462.18[M+H]+。
Embodiment 20.
1- (the chloro- 4- of 3- ((2- morpholinyl ethyls) amino) phenyl) -5- hydroxy-3-methoxy -4- phenyl -1,8- naphthyridines -2 (1H) -one
Step 1) 2- morpholinium acetonitriles
Under nitrogen protection, potassium carbonate（47 mmol) and morpholine（43 mmol) it is dissolved in acetonitrile（30 mL) in, ice bath cooling, Stirring, 2- bromoacetonitriles（43 mmol) it is added at one time in the reaction solution, 2 h of room temperature reaction, filtering are warming up to, decompression is steamed Solvent is removed, 2- morpholinium acetonitriles are obtained.
Step 2) 2- morpholine second ammonia
Under ice cooling, 4, Lithium Aluminium Hydride（84 mmol) dry tetrahydrofuran is added in-secondary property（35 mL) in, gained reaction Liquid stirs 20 minutes under 0 °C.2- morpholinium acetonitriles are added dropwise（28 mmol, 10 mL dry THF solution）.Drop finishes, heating To 3 h that flow back.It is cooled to room temperature rear ice bath cooling, water is slowly added into reaction system（20 mL), filtering, decompression boils off Solvent obtains 2- morpholine second ammonia.
The chloro- N- of the bromo- 2- of step 3) 4-（2- morpholinyl ethyls）Aniline
Under nitrogen protection, 2- morpholines second ammonia（6.91 mmol), 3,4- dichloro-bromobenzenes (6.91 mmol) and triethylamine （13.82 mmol) it is dissolved in ethyl acetate（10 mL) in, it is heated to 24 h of reflux.It being cooled to room temperature, decompression boils off solvent, Crude product purifies to obtain the chloro- N- of the bromo- 2- of 4- through column chromatography（2- morpholinyl ethyls）Aniline.
Step 4）1- (the chloro- 4- of 3- ((2- morpholinyl ethyls) amino) phenyl) -5- hydroxy-3-methoxy -4- phenyl -1,8- Naphthyridines -2 (1H) -one
Under nitrogen protection, CuI (1 mmol), Cs2CO3(20 mmol) and 2- oxocyclohexyl Ethyl formates（2 mmol) It is added in DMSO (10 mL), 30 min is stirred at room temperature.5- hydroxy-3-methoxy -4- phenyl -3,4- dihydro -1,8- naphthyridines - 2(1H) -one (10 mmol) and the chloro- N- of the bromo- 2- of 4-（2- morpholinyl ethyls）Aniline（10 mmol) DMSO (12 mL) solution, Injection 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) organic phase, is collected, decompression boils off solvent, and crude product purifies to obtain 1- (the chloro- 4- of 3- ((2- morpholinyl ethyls) ammonia through column chromatography Base) phenyl) -5- hydroxy-3-methoxy -4- phenyl -1,8- naphthyridines -2 (1H) -one.
ESI-MS (m/z):507.17[M+H]+, 509.17[M+2+H]+。
Anti-fibrosis active testing
The method of cell experiment
Cell inoculation
The BHK-21 cells for taking exponential phase of growth, when cell growth fusion 85 95%, the digestion of routine passage method is collected thin Born of the same parents, cell count, adjustment cell density to 2 × 104A/mL is inoculated in 96 porocyte culture plates, 100μThe holes L/, At 37 °C, 5% CO2Under the conditions of be incubated.
2 cell administrations
After adherent 24 h of cell inoculation, supernatant is abandoned, changes the culture solution 100 of each compound concentration gradient containing above-mentioned preparationμ The holes L/, 3 multiple holes of each concentration group continue to cultivate 48 h after dosing.
The measurement of 3 absorbance values
After 48 h of dosing, 10 are added per holeμL (the 1/10 of nutrient solution volume) CCK-8 solution, after being incubated 2 h in incubator, Absorbance (A) value in each hole is detected at 450 nm of microplate reader.The cell inhibitory effect of each compound is calculated according to surveyed A values Rate, cell proliferation inhibition rate (inhibition ratio, IR)=(1- experimental groups (Ai) value/control group (A0) value) × 100%, data processing software calculate separately each compound 48 h IC50Value.
2 activity data of table
Note：" A " indicates that compound concentration is to indicate that compound concentration is 0.05-5.0 mM less than 0.05 mM, " B " in table, " C " indicates that compound concentration is 5-20 mM, and " D " indicates that compound concentration is 20-100 mM;
The common trait of organ fibrosis is extracellular matrix（ECM）Over-deposit, the reconstruction of organ-tissue structure, many of which Cell factor takes part in this process.It is screened by In vitro cell experiment, majority of compounds activity is better than the positive in the present invention Medicine pirfenidone;And the compound in the present invention is not present the phototoxic reaction that has of pirfenidone, safety higher, There is better potential application foreground in terms of anti-fibrosis.

Claims (10)

  1. It is tautomer, stereoisomer, racemic modification, right 1. a kind of bicyclic alkaloid compound of Formulas I-II structures The non-equal amount of mixture of isomers, the solvate of geometric isomer, solvate, pharmaceutically acceptable salt or its salt are reflected, It is characterized in that Formulas I and Formula II compound have the following structure：, R1, R2, R3, R4And shown in A, Y be defined as follows：
    The aromatic ring or hetero-aromatic ring that A is five yuan or hexa-atomic, saturated or unsaturated carbocyclic ring or carbon heterocyclic, condensed-bicyclic or condensed miscellaneous Bicyclic, Y is O or S;N=0,1,2,3 or 4; “" indicate singly-bound or be not present;In Formulas I, A is phenyl ring, and Y is When O, R2Cannot be H;
    Each R1Can 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 (R5)-, condenses miscellaneous bicyclic group-C (=O) N (R5)-, spiral shell bicyclic group, the miscellaneous bicyclic group of spiral shell, spiral shell are bicyclic Base aliphatic, the miscellaneous bicyclic group aliphatic of spiral shell, spiral shell bicyclic group oxygroup, the miscellaneous bicyclic group oxygroup of spiral shell, spiral shell bicyclic group amino, spiral shell are miscellaneous Bicyclic group amino, spiral shell bicyclic group alkoxy, the miscellaneous bicyclic group alkoxy of spiral shell, spiral shell bicyclic group alkylamino, the miscellaneous bicyclic group alkane ammonia of spiral shell Base, spiral shell bicyclic group oxygroup alkoxy, the miscellaneous bicyclic group oxygroup alkoxy of spiral shell, spiral shell bicyclic group aminoalkoxy, the miscellaneous bicyclic group of spiral shell Aminoalkoxy, spiral shell bicyclic group-C (=O)-, spiral shell bicyclic group-C (=O) O-, the miscellaneous bicyclic group-C of spiral shell (=O)-, the miscellaneous bicyclic group-of spiral shell C (=O) O-, spiral shell bicyclic group amino-C (=O)-, the miscellaneous bicyclic group amino-C of spiral shell (=O)-, spiral shell bicyclic group-C (=O) N (R5)-, spiral shell Miscellaneous bicyclic group-C (=O) N (R5)-, R6R5N-, -C(=O)NR5R6, -OC(=O)NR5R6, -OC(=O)OR5, -N(R5)C(=O) NR5R6, -N(R5)C(=O)OR6, -N(R5)C(=O)-R6, R5R6N-S(=O)t-, R5S(=O)t-, R5S(=O)tN(R6)-, R6R5N- alkyl, R5S(=O)tAlkyl, R5R6N-C (=O)-alkyl, R6R5N- alkoxies, R5S(=O)tAlkoxy, R5R6N-C (=O)-alkoxy, aryl-(CH2)p-G-(CH2)m, heteroaryl-(CH2)p-G-(CH2)m, heterocycle-(CH2)p- G-(CH2)m, or naphthenic base-(CH2)p-G-(CH2)m, wherein G is O, S, NR7, S(=O), S(=O)2,C(=O), -C (=O)N(R5)-, -OC(=O)N(R5)-, -OC(=O)-, -N(R5)C(=O)N(R5)-, -(R5)N-S(=O)t-, -OS(= O)t, or-OS (=O)tN(R5)-;T is l or 2;P and m is each independently 0, l, 2,3 or 4;Or wherein aryl- (CH2)p-G-(CH2)m, heteroaryl-(CH2)p-G-(CH2)m, heterocycle-(CH2)p-G-(CH2)m, or naphthenic base- (CH2)p-G-(CH2)mCan F, Cl, Br, I, alkyl, alkenyl, alkynyl, alkoxy or cyanogen be selected from by one or more The substituent group of base replaces;
    R2Can be identical or different, 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;
    Each R3And R4Can be identical or different, separate is hydrogen, halogen, alkyl, halogenated alkyl, alkyl acyl, hydroxyl Base alkanoyl, ohaloalkanoyl, naphthenic base, cycloalkanoyl, alkenyl, alkenyl alkanoyl, alkynyl, alkynyl alkanoyl, Aryl, aroyl, heteroaryl, 4-hetaroylpyrazol, heterocycle alkanoyl, Heterocyclylalkyl, heterocyclylacyl, heterocycle alkane Acyl group, azido alkyl, condensed-bicyclic base condense miscellaneous bicyclic group, and condensed-bicyclic base-C (=O)-condenses miscellaneous bicyclic group-C (=O)-, condensed-bicyclic base amino-C (=O)-, condensed miscellaneous bicyclic group amino-C (=O)-, spiral shell bicyclic group, the miscellaneous bicyclic group of spiral shell, Spiral shell bicyclic group aliphatic, the miscellaneous bicyclic group aliphatic of spiral shell, spiral shell bicyclic group-C (=O)-, the miscellaneous bicyclic group-C of spiral shell (=O)-, spiral shell is bicyclic Base amino-C (=O)-, the miscellaneous bicyclic group amino-C of spiral shell (=O)-,-C (=O) NR5R6, R5R6N-S(=O)t-, R5S(=O)t-, R6R5N- alkyl, R5S(=O)tAlkyl, R5R6N-C (=O)-alkyl, aryl-(CH2)p-G-(CH2)m, heteroaryl- (CH2)p-G-(CH2)m, heterocycle-(CH2)p-G-(CH2)m, or naphthenic base-(CH2)p-G-(CH2)m, wherein G is O, S, NR7, S(=O), S(=O)2,C(=O), -C(=O)N(R5)-, -OC(=O)N(R5)-, -OC(=O)-, -N(R5)C(=O) N(R5)-, -(R5)N-S(=O)t-, -OS(=O)t, or-OS (=O)tN(R5)-;T is l or 2;P and m are each independently 0, l, 2,3 or 4;Or aryl-(CH therein2)p-G-(CH2)m, heteroaryl-(CH2)p-G-(CH2)m, heterocycle- (CH2)p-G-(CH2)m, or naphthenic base-(CH2)p-G-(CH2)mCan F, Cl, Br, I, cyanogen be selected from by one or more Base, alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, carbocylic radical, the substituent group substitution of heterocycle;
    R7Can be identical or different, 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. 2. compound according to claim 1 is general formula III-X compounds represented, or chemical combination shown in general formula III-X The stereoisomer geometric isomer of object, tautomer, nitrogen oxides, raceme, hydrate, solvate, metabolite, Pharmaceutically acceptable salt or prodrug：
    ,
    Wherein Y is O or S; T1, T2, T3, T4, T5, T6Separate is C, N or CR1Or NR8, wherein T1, T2, T3, T4, T5, T6At most there are three can be N; V, V1, V2Separate is O, S, N or CR1Or NR8, “" indicate singly-bound or be not present;Each R1, R2, R3, R4, R8As follows：
    Each R1Can be identical or different, it is 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, C1- The halogenated alkylaminos of C20, C1-C20 ohaloalkanoyls, C1-C20 aminoalkoxies, C3-C10 naphthenic base, C3-C10 naphthenic base Oxygroup, C3-C10 cycloalkyl aminos, C3-C10 cycloalkanoyls, C2-C7 alkenyls, C2-C7 alkynyls, C5-C10 aryl, C5-C10 aryloxy group, C5-C10 aroyls, C5-C10 fragrant aminos, C5-C10 aryl C1-C5 alkoxies, C5-C10 aryl alkane Amino, C5-C12 heteroaryls, C5-C12 heteroaryloxies, C5-C12 4-hetaroylpyrazols, C5-C12 heteroaryl amino, C5-C12 are miscellaneous Aryl C1-C5 alkoxies, C5-C12 heteroaryl C1-C5 alkylaminos, C4-C12 heterocycle C1-C5 alkanoyls, C4-C12 heterocycles Alkyl, C4-C12 heterocycle oxygroups, C4-C12 heterocyclylamino groups, C4-C12 heterocyclylacyls, C4-C12 heterocycles C1-C5 Alkoxy, C4-C12 heterocycle C1-C5 alkylaminos, C4-C12 heterocycle C1-C5 alkanoyls, R6R5N-, -C(=O)NR5R6, -OC(=O)NR5R6, -OC(=O)OR5, -N(R5)C(=O)NR5R6, -N(R5)C(=O)OR6, -N(R5)C(=O)-R6, R5R6N-S(=O)t-, R5S(=O)t-, R5S(=O)tN(R6)-, R6R5N- C1-C5 alkyl, R5S(=O)t- C1-C5 alkyl, R5R6N-C (=O)-C1-C5 alkyl, R6R5N-C1-C5 alkoxies, R5S(=O)t- C1-C5 alkoxies, R5R6N-C(=O)-C1- C5 alkoxies, C5-C10 aryl-(CH2)p-G-(CH2)m, C5-C12 heteroaryls-(CH2)p-G-(CH2)m, C4-C12 heterocycles Base-(CH2)p-G-(CH2)m, or C3-C10 naphthenic base-(CH2)p-G-(CH2)m, wherein G is O, S, NR7, S(=O), S (=O)2,C(=O), -C(=O)N(R5)-, -OC(=O)N(R5)-, -OC(=O)-, -N(R5)C(=O)N(R5)-, -(R5)N-S (=O)t-, -OS(=O)t, or-OS (=O)tN(R5)-;T is l or 2;P and m is each independently 0, l, 2,3 or 4; Or wherein C5-C10 aryl-(CH2)p-G-(CH2)m, C5-C12 heteroaryls-(CH2)p-G-(CH2)m, C4-C12 heterocycles Base-(CH2)p-G-(CH2)m, or C3-C1 naphthenic base-(CH2)p-G-(CH2)mCan F, Cl be selected from by one or more, The substituent group of Br, I, alkyl, alkenyl, alkynyl, alkoxy or cyano replaces;
    R2, R8Separate is H, C1-C20 alkyl, C1-C20 halogenated alkyls, C1-C20 alkyl acyls, C1-C20 hydroxyls Base alkanoyl, C1-C20 ohaloalkanoyls, C3-C10 naphthenic base, C3-C10 cycloalkanoyls, C2-C8 alkenyls, C2-C8 Alkenyl alkanoyl, C2-C8 alkynyls, C2-C8 alkynyl alkanoyls, C6-C10 aryl, C6-C10 aroyls, C5-C12 heteroaryls Base, C5-C12 4-hetaroylpyrazols, C4-C12 heterocycle alkanoyls, C4-C12 Heterocyclylalkyls, C4-C12 heterocyclylacyls, C4- C12 heterocycle C1-C6 alkanoyls, C5-C12 condensed-bicyclic bases, C5-C12 condense miscellaneous bicyclic group ,-C (=O) NR5R6, R5R6N-S(=O)t-, R5S(=O)t-, R6R5N-C1-C6 alkyl, R5S(=O)t- C1-C6 alkyl, R5R6N-C(=O)-C1-C6 Alkyl, C6-C10 aryl-(CH2)p-G-(CH2)m, C5-C12 heteroaryls-(CH2)p-G-(CH2)m, C4-C12 heterocycles- (CH2)p-G-(CH2)m, or C3-C10 naphthenic base-(CH2)p-G-(CH2)m, wherein G is O, S, NR7, S(=O), S(= O)2,C(=O), -C(=O)N(R5)-, -OC(=O)N(R5)-, -OC(=O)-, -(R5)N-S(=O)t-, -OS(=O)t-, Or-OS (=O)tN(R5)-;T is l or 2;P and m is each independently 0, l, 2,3 or 4;Or wherein C6-C10 aryl- (CH2)p-G-(CH2)m, C5-C12 heteroaryls-(CH2)p-G-(CH2)m, C4-C12 heterocycles-(CH2)p-G-(CH2)m-, Or C3-C10 naphthenic base-(CH2)p-G-(CH2)mCan by one or more be selected from F, Cl, Br, I, cyano, alkyl, Alkenyl, alkynyl, alkoxy, aryl, heteroaryl, carbocylic radical, the substituent group substitution of heterocycle;
    Each R3, R4Separate is H, F, Cl, Br, I, C1-C20 alkyl, C1-C20 halogenated alkyls, C1-C20 alkane Base acyl group, C1-C20 hydroxyalkanoyls, C1-C20 ohaloalkanoyls, C3-C10 naphthenic base, C3-C10 cycloalkanoyls, C2-C7 alkenyls, C2-C7 alkenyl alkanoyls, C2-C7 alkynyls, C2-C7 alkynyl alkanoyls, C5-C10 aryl, C5-C10 virtues Acyl group, C5-C12 heteroaryls, C5-C12 4-hetaroylpyrazols, C4-C12 heterocycle alkanoyls, C4-C12 Heterocyclylalkyls, C4- C12 heterocyclylacyls, C4-C12 heterocycle C1-C5 alkanoyls, C5-C12 condensed-bicyclic bases, C5-C12 condense miscellaneous bicyclic group, -C(=O)NR5R6, R5R6N-S(=O)t-, R5S(=O)t-, R6R5N-C1-C5 alkyl, R5S(=O)t- C1-C5 alkyl, R5R6N-C (=O)-C1-C5 alkyl, C5-C10 aryl-(CH2)p-G-(CH2)m, C5-C12 heteroaryls-(CH2)p-G- (CH2)m, C4-C12 heterocycles-(CH2)p-G-(CH2)m, or C3-C10 naphthenic base-(CH2)p-G-(CH2)m, wherein G is O, S, NR7, S(=O), S(=O)2,C(=O), -C(=O)N(R5)-, -OC(=O)N(R5)-, -OC(=O)-, -N(R5)C (=O)N(R5)-, -(R5)N-S(=O)t-, -OS(=O)t, or-OS (=O)tN(R5)-;T is l or 2;P and m is respectively independent Ground is 0, l, 2,3 or 4;Or wherein C5-C10 aryl-(CH2)p-G-(CH2)m, C5-C12 heteroaryls-(CH2)p-G- (CH2)m, C4-C12 heterocycles-(CH2)p-G-(CH2)m, or C3-C10 naphthenic base-(CH2)p-G-(CH2)mIt can be by one It is a or multiple selected from F, Cl, Br, I, cyano, alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, carbocyclic ring Base, the substituent group substitution of heterocycle;
    Wherein each R7Can be identical or different, 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.
  3. 3. according to compound described in claim 1-2, wherein each R1Can 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, C6H13, C8H17, trifluoromethyl, hydroxymethyl, amino methyl, methoxyl group, ethyoxyl, tert-butoxy, first Amino, ethylamino, isopropylamino, 3- hydroxyl-propyls, acetyl group, trifluoroacetyl group, Cyanoacetyl, methylamino Acetyl group, propiono, iso-propionyl, 2- hydroxypropanoyls, 2- aminopropionyls, 2- chlorine propionos, 2- bromine propionos, Valeryl, caproyl, heptanoyl group, methacrylyl, phenyl, benzoyl, p-nitrophenyl, to toluyl Base, fluoro benzoyl, p-benzoyl base, to methoxybenzoyl base, 2,4- dimethylbenzoyls are folded Nitrogen base benzoyl, benzyl, p-chlorobenzyl, vinyl, acrylic, allyl, n-butene base, isobutenyl, just Hydro carbons and its containing oxygen derivative (monoterpene or again of the multiple of pentenyl, isopentene group, isoprene or isoprene unit Hemiterpene substituent group), cyclopropyl, ring propiono, ring valeryl, cyclohexanoyl, 3- picolinoyls, naphthalene, phenethyl Imidazole radicals, pyridyl group, pyrrole radicals, oxazolyl, isoxazolyl, triazol radical, tetrazole base, furyl, thienyl, Thiazolyl, piperidyl, piperazinyl, indyl, carbazyl, benzofuranyl tetrahydrofuran base, THP trtrahydropyranyl are phonetic Pyridine base, purine bases ,-N (CH3)2,-C (C=O) NH-C1-C4 alkyl ,-OC (C=O)-NH-C1-C4 alkyl ,-OC (O= O) O-C1-C4 alkyl ,-NHC (=O) NH-C1-C4 alkyl ,-NHC (=O) O-C1-C4 alkyl ,-NHC (=O)-C1-C4 alkyl, C1-C4 alkyl-NH-S (=O)2, C1-C4 alkyl S (=O)2, C1-C4 alkyl S (=O)2NH-, phenyl-(CH2)P-G- (CH2)m, difluorophenyl-(CH2)P-G-(CH2)m, thiazolyl-(CH2)p-G-(CH2)m, pyridyl group-(CH2)p-G- (CH2)m, phenylethyl, cyclohexyl-(CH2)p-G-(CH2)m, wherein G is O, S, S (=O), S (=O)2, C(= O);P and m is each independently 0,1,2 or 3;Or wherein C5-C10 aryl-(CH2)P-G-(CH2)mIt can be by one Or it is multiple selected from F, Cl, Br, I, methyl, ethyl, propyl, acetenyl, propinyl, butynyl, methoxyl group, second The substituent group of oxygroup or cyano replaces;Or above-mentioned R1It is welcome by D, F, Cl, Br, I, hydroxyl, methylol, carboxylic Base, acetylamino, alkyl（Such as methyl, ethyl, propyl）, alkoxy（Such as methoxyl group, ethyoxyl, tert-butoxy）, alkane ammonia Base, naphthenic base, alkenyl, alkynyl, trifluoromethyl, trifluoroacetyl group, sulfydryl, halogen, nitro, amino, azido (-N3), guanidine radicals, cyano, tertbutyloxycarbonyl (- Boc), carbonyl (- C=O), oxo (=O) is thio (=S), sulphonyl Base, aryl, heteroaryl, the substitution of one or more of heterocycle;
    Wherein each R2, R8Can be identical or different, it is separate be H, methyl, ethyl, propyl, isopropyl, butyl, Tertiary butyl, C5H11, C6H13, C8H17, trifluoromethyl, hydroxymethyl, amino methyl, 3- hydroxyl-propyls, acetyl group, Trifluoroacetyl group, Cyanoacetyl, methylamino acetyl group, propiono, iso-propionyl, 2- hydroxypropanoyls, 2- ammonia Base propiono, 2- chlorine propionos, 2- bromine propionos, valeryl, caproyl, heptanoyl group, methacrylyl, phenyl, Benzoyl, p-nitrophenyl, to methyl benzoyl, fluoro benzoyl, p-benzoyl base, to methoxyl group Benzoyl, 2,4- dimethylbenzoyls, azidobenzoyl, benzyl, p-chlorobenzyl, vinyl, propylene Base, allyl, n-butene base, isobutenyl, n-pentene base, isopentene group, cyclopropyl, ring propiono, ring valeryl Base, cyclohexanoyl, 3- picolinoyls, naphthalene, phenethyl imidazole radicals, pyridyl group, pyrrole radicals, oxazolyls, different evil Oxazolyl, triazol radical, tetrazole base, furyl, pyranose, thienyl, thiazolyl, piperidyl, piperazinyl, Yin Diindyl base, carbazyl, benzofuranyl tetrahydrofuran base, THP trtrahydropyranyl, pyrimidine bases, purine bases, pentose base, Hexose base ,-(C=O) NH-C1-C4 alkyl, C1-C4 alkyl-NH-S (=O)2, C1-C4 alkyl S (=O)2, phenyl- (CH2)P-G-(CH2)m, difluorophenyl-(CH2)P-G-(CH2) m, thiazolyl-(CH2)p-G-(CH2)m, pyridyl group- (CH2)p-G-(CH2)m, phenylethyl, cyclohexyl-(CH2)p-G-(CH2)m, wherein G is O, S, S (=O), S (= O)2, C(=O);P and m is each independently 0,1,2 or 3;Or wherein C5-C10 aryl-(CH2)P-G-(CH2)mIt can be with F, Cl, Br, I, methyl, ethyl, propyl, acetenyl, propinyl, butynyl, methoxy are selected from by one or more The substituent group of base, ethyoxyl or cyano replaces;Or above-mentioned R2, R8It is welcome by D, F, Cl, Br, I, hydroxyl, Hydroxyl, methylol, carboxyl, acetylamino, C1-C5 alkyl（Such as methyl, ethyl, propyl）, C1-C5 alkoxies, C1-C5 Alkylamino, trifluoromethyl, trifluoroacetyl group, sulfydryl, nitro, amino, azido (- N3), guanidine radicals, cyano, uncle Butoxy carbonyl (- Boc), carbonyl (- C=O), oxo (=O) is thio (=S), sulfonyl, one or more of phenyl Substitution;
    Each R3, R4Can be identical or different, it is separate be H, D, F, Cl, Br, I, hydroxyl, amino, nitro, Cyano, methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, C5H11, C6H13, C8H17, trifluoromethyl, hydroxyl Ylmethyl, amino methyl, methoxyl group, ethyoxyl, tert-butoxy, methylamino, ethylamino, isopropylamino, 3- hydroxyls- Propyl, acetyl group, trifluoroacetyl group, Cyanoacetyl, methylamino acetyl group, propiono, iso-propionyl, 2- hydroxyls Base propiono, 2- aminopropionyls, 2- chlorine propionos, 2- bromine propionos, valeryl, caproyl, heptanoyl group, isobutyl Enoyl-, phenyl, benzoyl, p-nitrophenyl, to methyl benzoyl, fluoro benzoyl, p-aminophenyl first Acyl group, to methoxybenzoyl base, 2,4- dimethylbenzoyls, azidobenzoyl, benzyl, p-chlorobenzyl, Vinyl, acrylic, allyl, n-butene base, isobutenyl, n-pentene base, isopentene group, isoprene or different The hydro carbons and its containing oxygen derivative (monoterpene or sequiterpene substituent group) of the multiple of pentadiene unit, cyclopropyl, ring propiono, Ring valeryl, cyclohexanoyl, 3- picolinoyls, naphthalene, phenethyl imidazole radicals, pyridyl group, pyrrole radicals, oxazolyl, Isoxazolyl, triazol radical, tetrazole base, furyl, thienyl, thiazolyl, piperidyl, piperazinyl, indyl, Carbazyl, benzofuranyl tetrahydrofuran base, THP trtrahydropyranyl, pyrimidine bases, purine bases ,-N (CH3)2, -C(C= O) NH-C1-C4 alkyl ,-OC (C=O)-NH-C1-C4 alkyl ,-OC (O=O) O-C1-C4 alkyl ,-NHC (=O) NH-C1-C4 Alkyl ,-NHC (=O) O-C1-C4 alkyl ,-NHC (=O)-C1-C4 alkyl, C1-C4 alkyl-NH-S (=O)2, C1-C4 alkane Base S (=O)2, C1-C4 alkyl S (=O)2NH-, phenyl-(CH2)P-G-(CH2)m, difluorophenyl-(CH2)P-G-(CH2)m-, Thiazolyl-(CH2)p-G-(CH2)m, pyridyl group-(CH2)p-G-(CH2)m, phenylethyl, cyclohexyl-(CH2)p-G- (CH2)m, wherein G is O, S, S (=O), S (=O)2, C(=O);P and m is each independently 0,1,2 or 3;Or Person wherein C5-C10 aryl-(CH2)P-G-(CH2)mCan F, Cl, Br, I, methyl, second be selected from by one or more The substituent group of base, propyl, acetenyl, propinyl, butynyl, methoxyl group, ethyoxyl or cyano replaces;Or it is above-mentioned R3, R4It is welcome by D, F, Cl, Br, I, hydroxyl, methylol, carboxyl, acetylamino, alkyl（Such as methyl, second Base, propyl）, alkoxy（Such as methoxyl group, ethyoxyl, tert-butoxy）, alkylamino, naphthenic base, alkenyl, alkynyl, trifluoro Methyl, trifluoroacetyl group, sulfydryl, halogen, nitro, amino, azido (- N3), guanidine radicals, cyano, tertiary butyloxycarbonyl Base (- Boc), carbonyl (- C=O), oxo (=O) is thio (=S), sulfonyl, aryl, heteroaryl, in heterocycle One or more substitutions.
  4. 4. according to compound described in claim 1-3, including but not limited to the mutual of one of following structure or following one structure Non- equal amount of mixture, geometric isomer, solvate, the medicine of tautomeric, stereoisomer, racemic modification, enantiomter The solvate or prodrug of acceptable salt or its salt on：
    。
  5. 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. 6. a kind of pharmaceutical composition, it includes according to a kind of compound of claim 1-5 any one of them or several compounds Or the non-equal amount of mixture of its tautomer, stereoisomer, racemic modification, enantiomter, geometric isomer, solvation Any one or a few in the solvate of object, pharmaceutically acceptable salt or its salt is as active ingredient.
  7. 7. the pharmaceutical composition described in claim 6, it is characterised in that the pharmaceutical composition also includes that at least one pharmaceutically may be used Carrier, diluent or the excipient of receiving;It is further characterized in that the pharmaceutical composition also includes other at least one anti-fibrosis Drug, be specifically including but not limited to roflumilast, pirfenidone, magerut, Losartan, interferon, my method-dornase, Cortin, methotrexate, tacrolimus etc.;Pharmaceutical composition optimizing injection, oral preparation, freeze drying powder injection, the suspension Agent etc..
  8. 8. compound or its tautomer, its stereoisomer, its racemic modification described in any one of claim 1-5, The non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, its pharmaceutically acceptable salt or its salt Pharmaceutical composition described in any one of solvate or claim 6-7 is used to prepare for anti-inflammatory and prevention, processing, treatment Or mitigate the purposes of patient tissue or the drug of organ fibrosis disease.
  9. 9. compound or its tautomer, its stereoisomer, its racemic modification described in any one of claim 1-5, The non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, its pharmaceutically acceptable salt or its salt Drug complexes described in any one of solvate or claim 6-7 can effective for it is anti-inflammatory and prevent, processing, treatment or Mitigate patient tissue or organ fibrosis disease, especially can effectively treat chronic pneumonia, pulmonary fibrosis, ephritis, renal interstitial fibre Dimensionization, glomerulosclerosis, liver fibrosis, peritoneal fibrosiss, myocarditis, myocardial fibrosis, fibrosis of skin, postoperative intestinal adhesion, Benign prostatauxe disease, skeletal muscle fibre, chorionitis, multiple sclerosis, pancreatic fibrosis, hepatic sclerosis, muscle tumor, god Disease through fiber onch- interstitial fibrosis, diabetic nephropathy, Alzheimer disease or vascular fibrosis.
  10. 10. the preparation method of compound described in claim 1：
    ;
    Wherein A, Y, R1, R2, R3, R4, n, “" definition with any of the above-described place of the present invention to A, Y, R1, R2, R3, R4, n, “" definition;
    It is characterized in that：
    Step 1:With compound 1 or 2 be raw material under nitrogen or argon, with reducing agent in methanol solvate, in temperature 0- Trash ice and concentrated hydrochloric acid is added after reacting 5-30 min under 90 °C, obtains intermediate product a or b;Wherein reducing agent is selected from NaBH4、 LiAlH4、NaBH(OAc)3Deng；
    Step 2:Intermediate product a or b are dehydrated under nitrogen or argon, and dewatered product occurs substitution reaction and obtains mesh Mark compound.
CN201710191158.5A 2017-03-28 2017-03-28 A kind of bicyclic alkaloid compound and its preparation method and application Pending CN108658937A (en)

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US11541059B2 (en) 2014-03-19 2023-01-03 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
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