CN110218206A - Bisindole maleimide derivative and its preparation method and application - Google Patents
Bisindole maleimide derivative and its preparation method and application Download PDFInfo
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Abstract
A kind of bisindole maleimide derivative and its preparation method and application is provided.The bisindole maleimide derivative is following compound of formula I, Formula II compound or their pharmaceutically acceptable salts or prodrug, it is with good oncotherapy effect, especially to the curative effect of some drug-resistant tumors, the accurate treatment to these drug-resistant tumors can be realized.
Description
Technical field:
The present invention relates to bisindole maleimide derivatives and its preparation method and application.
Background technique:
Tumour is the common disease and frequently-occurring disease that the world today endangers human life and health.According to WHO Report: complete
The existing tumor patient in the world about 76,000,000, because cancer mortality is up to the 12% of the total death toll of 6,000,000, Zhan, and its disease incidence is every
Year's harvest ascendant trend (Tang Jun, Fu great Xu target small molecule original new drug modern biomedical progress .2010,10 (20):
3997).Cancer annual new cases in China's are about 1,600,000, existing number of patients 2,000,000, and annual death is in continuous up to 1,300,000
The trend of rising.In recent years, although the treatment for tumours such as leukaemia, malignant lymphomas achieves certain progress, tumour is suffered from
The life span of person is obviously prolonged, but does not obtain promising result yet to the treatment of the strongest solid tumor of mortality.
Because mutation etc. causes tumour cell to lose sensitivity to the preferable drug of originally curative effect, drug resistance is generated, also to innovation
The research of drug brings new challenge.
Bisindole maleimide derivative is received significant attention because of its structure diversity and good bioactivity.Zhu Wei
It is bright etc. to disclose a kind of indole carbazole with protein kinase C (PKC) inhibitory activity and with antitumor action and double indoles horses
Come acid imide alkaloid (Zhu Weiming, Xu Zhihong, Zhang Yapeng, king's Qe, Liu Peipei indole carbazole and bisindole maleimide
Preparation method and application Chinese invention patent ZL201010167113.2.2012 25 days 04 month).
The new eutherapeutic antitumor bisindole maleimide derivative of exploitation still has great significance.
Summary of the invention:
The present inventor is dedicated to developing drug effect preferably antitumor bisindole maleimide derivative.In addition, this hair
Bright people's discovery, bisindole maleimide derivative have important prospect in terms for the treatment of drug-resistant tumor.
For this purpose, the present inventor provides a kind of formula A compound, its pharmaceutically acceptable salt or prodrug:
Wherein,
Dotted line indicates no chemical bond or is singly-bound;
R1And R2It is each independently selected from :-H;Alkyl, the alkyl optionally by amino, cyano, hydroxyl, carboxyl, alkoxy,
Alicyclic heterocyclic base, aryl, heteroaryl ,-COA replace;Alkenyl, the alkenyl optionally by amino, cyano, hydroxyl, carboxyl, alkoxy,
Alicyclic heterocyclic base, aryl, heteroaryl ,-COA replace;The hydroxyl hydrogen of monosaccharide groups, the monosaccharide groups is optionally replaced by alkyl;Wherein A is selected
From hydrogen ,-NR13R14, aryl, fragrant amino, the alkyl optionally replaced by hydroxyl, halogen, the alcoxyl optionally replaced by hydroxyl, halogen
Base;
Alternatively, R1And R2Composition-(CH together2)m1-O-(CH2)m2, H therein is optionally by-(CH2)0~8-NR13R14Replace,
m1And m2It is each independently 1~6 integer;
Alternatively, R1And R2Following group is constituted together:
Wherein, R9、R10It independently is-H or alkyl;Alternatively, R9With R10Composition-C (=O)-together;
R8It is selected from :-H;Hydroxyl;Alkyl, the alkyl are optionally replaced by alkoxy;Alkenyl;Alkynyl;Aryl, the aryl
Optionally replaced by amino, hydroxyl, halogen, alkoxy, alkyl, halogenated alkyl;Alicyclic heterocyclic base, the alicyclic heterocyclic base is optionally by ammonia
Base, hydroxyl, halogen, alkoxy, alkyl, halogenated alkyl replace;Heteroaryl, the heteroaryl optionally by amino, hydroxyl, halogen,
Alkoxy, alkyl, halogenated alkyl replace;- C (=Y1)-Y2;- S (=O)2-Y3;
Y1It is selected from :=O;=S;=NH;
Y2It is selected from: alkyl;Alkoxy;Azanol base;-NR13R14;Aryl, the aryl is optionally by amino, hydroxyl, halogen, alkane
Oxygroup, alkyl, halogenated alkyl replace;Heteroaryl, the heteroaryl is optionally by amino, hydroxyl, halogen, alkoxy, alkyl, halogenated
Alkyl replaces;Alicyclic heterocyclic base, the alicyclic heterocyclic base are optionally taken by amino, hydroxyl, halogen, alkoxy, alkyl, halogenated alkyl
Generation;The alkyl-substituted alicyclic heterocyclic base that alicyclic heterocyclic base replaces, the alicyclic heterocyclic base is optionally by amino, hydroxyl, halogen, alcoxyl
Base, alkyl, halogenated alkyl replace;Alkylamino, the alkylamino are replaced by least one of oxygen, hydroxyl, heteroaryl, aryl, institute
Heteroaryl, aryl is stated optionally to be replaced by amino, hydroxyl, halogen, alkoxy, alkyl, halogenated alkyl;
Y3For the aryl optionally replaced by halogen, halogenated alkyl;
R3Selected from-H;Hydroxyl;Halogen;-NR13R14;(C=O) NR11R12;(C=O) R15;- O (C=O) R16;-NR17-(C
=O) R18;-NR19-(COO)R20;-NR21-(SO2)R22;- O (C=O) NR23R24;-SR25;(S=O) R26;-(SO2)R27;-
(SO2)NR32R33;Alkyl, the alkyl is optionally by hydroxyl, cyano, carboxyl, monosaccharide groups, alkoxy, aryl, heteroaryl, alicyclic heterocyclic
Base ,-NH-CO- alkylidene (NH2)(A1)、-NR13R14Replace, the aryl, heteroaryl, alicyclic heterocyclic base optionally by amino, hydroxyl,
Halogen, alkyl, halogenated alkyl replace;Alkenyl, the alkenyl optionally by hydroxyl, cyano, carboxyl, monosaccharide groups, alkoxy, aryl,
Heteroaryl, alicyclic heterocyclic base ,-NH-CO- alkylidene (NH2)(A1)、-NR13R14Replace;Alkynyl, the alkynyl is optionally by hydroxyl, cyanogen
Base, carboxyl, monosaccharide groups, alkoxy, aryl, heteroaryl, alicyclic heterocyclic base ,-NH-CO- alkylidene (NH2)(A1)、-NR13R14Replace;
A1Selected from-H, optionally the alkyl being substituted by heteroaryl;
R4With R5Composition=O and/or R together6With R7Composition=O together;
Work as R4With R5Or R6With R7Do not constitute=O when, be each independently selected from-H;Hydroxyl;-NR13R14;(C=O) R15;-
NR17(C=O) R18;-SR25;Aryl, the aryl optionally by be selected from halogen, hydroxyl, cyano, nitro, carboxyl, azido ,-
NR13R14,-S (O)0-2R34Replace;Heteroaryl, the heteroaryl are optionally selected from halogen, hydroxyl, cyano, nitro, carboxyl, nitrine
Base ,-NR13R14,-S (O)0-2R34Replace;Alkoxy, the alkoxy optionally by be selected from halogen, hydroxyl, cyano, nitro, carboxyl,
Azido ,-NR13R14,-S (O)0-2R34Replace;Aryloxy group, the aryloxy group optionally by be selected from halogen, hydroxyl, cyano, nitro,
Carboxyl, azido ,-NR13R14,-S (O)0-2R34Replace;
G1~G8It is each independently selected from-H;Halogen;Hydroxyl;Cyano;Nitro;Carboxyl;-NR13R14;(C=O)
NR11R12;(C=O) R15;- O (C=O) R16;-NR17(C=O) R18;-NR19-(COO)R20;-NR21-(SO2)R22;- O (C=
O)NR23R24;-SR25;(S=O) R26;-(SO2)R27;- CH=NOR28;- CH=NR29;- CH=NNR30R31;-(SO2)
NR32R33;Alkyl, the alkyl are optionally selected from halogen, hydroxyl, cyano, nitro, carboxyl, azido ,-NR13R14,-S (O)0- 2R34Replace;Alkenyl, the alkenyl are optionally selected from halogen, hydroxyl, cyano, nitro, carboxyl, azido ,-NR13R14,-S
(O)0-2R34Replace;Alkynyl, the alkynyl are optionally selected from halogen, hydroxyl, cyano, nitro, carboxyl, azido ,-NR13R14,-S
(O)0-2R34Replace;Aryl, the aryl are optionally selected from halogen, hydroxyl, cyano, nitro, carboxyl, azido ,-NR13R14,-S
(O)0-2R34Replace;Heteroaryl, the heteroaryl optionally by be selected from halogen, hydroxyl, cyano, nitro, carboxyl, azido ,-
NR13R14,-S (O)0-2R34Replace;Alkoxy, the alkoxy are optionally selected from halogen, hydroxyl, cyano, nitro, carboxyl, nitrine
Base ,-NR13R14,-S (O)0-2R34Replace;Aryloxy group, the aryloxy group optionally by be selected from halogen, hydroxyl, cyano, nitro, carboxyl,
Azido ,-NR13R14,-S (O)0-2R34Replace;
R13、R14It is each independently selected from-H;Amino;The hydroxyl hydrogen of monosaccharide groups, the monosaccharide groups is optionally replaced by alkyl;
Alkyl, the alkyl are optionally selected from halogen, hydroxyl, cyano, nitro, carboxyl, azido ,-NR13R14,-S (O)0-2R34Replace;
Aryl, the aryl are optionally replaced by amino, hydroxyl, halogen, alkyl, the alkyl optionally by be selected from halogen, hydroxyl, cyano,
Nitro, carboxyl, azido ,-NR13R14,-S (O)0-2R34Replace;Alicyclic heterocyclic base, the alicyclic heterocyclic base optionally by amino, hydroxyl,
Halogen, alkyl replace, and the alkyl is optionally selected from halogen, hydroxyl, cyano, nitro, carboxyl, azido ,-NR13R14,-S
(O)0-2R34Replace;
R11、R12、R15、R16、R17、R18、R19、R20、R21、R22、R23、R24、R25、R26、R27、R28、R29、R30、R31、R32、
R33、R34It is each independently selected from :-H;Alkyl;Aryl;
The alicyclic heterocyclic base and heteroaryl contain 1-4 hetero atom each independently, and the hetero atom is selected from N, O, S.
Optionally, in above-mentioned formula A compound, its pharmaceutically acceptable salt or prodrug: the alkyl and halogenated alkyl, alkane
Alkyl in oxygroup, alkylamino is C1~C20Alkyl, or be C1~C18Alkyl, or be C1~C6Alkyl, or be C1~C4
Alkyl;The alkenyl is C2~C20Alkenyl, or be C2~C18Alkenyl, or be C2~C6Alkenyl, or be C2~C4Alkenyl;
The alkynyl is C2~C20Alkynyl, or be C2~C18Alkynyl, or be C2~C6Alkynyl, or be C2~C4Alkynyl;The rouge
Heterocycle is 4~14 unit monocycles or polycyclic alicyclic heterocyclic base, and hetero atom number is that hetero atom number is 1~2 on 1~3 or ring on ring;
Aryl in the aryl and aryloxy group is C6~C14Monocycle or polyaromatic;The heteroaryl is 5~14 unit monocycles or polycyclic
Heteroaryl, hetero atom number is that hetero atom number is 1~2 on 1~3 or ring on ring.
Optionally, in above-mentioned formula A compound, its pharmaceutically acceptable salt or prodrug:
R1And R2It is each independently selected from :-H;C1~C6Alkyl, the C1~C6Alkyl optionally by amino, cyano, hydroxyl,
Carboxyl, C1~C6Alkoxy, 5 or 6 yuan of alicyclic heterocyclic bases, C6~C10Aryl, 5~10 unit's heteroaryls ,-COA replace;C2~C6Alkenyl,
The C2~C6Alkenyl is optionally by amino, cyano, hydroxyl, carboxyl, C1~C6Alkoxy, 5 or 6 yuan of alicyclic heterocyclic bases, C6~C10Virtue
Base, 5~10 unit's heteroaryls ,-COA replace;Monosaccharide groups, the hydroxyl hydrogen of the monosaccharide groups is optionally by C1~C6Alkyl replaces;Wherein A
Selected from hydrogen ,-NR13R14, C6~C10Aryl, C6~C10Fragrant amino, the C optionally replaced by hydroxyl, halogen1~C6Alkyl, optionally quilt
The C that hydroxyl, halogen replace1~C6Alkoxy;
Alternatively, R1And R2Following group is constituted together:
Wherein, R9、R10It independently is-H or C1~C6Alkyl;Alternatively, R9With R10Composition-C (=O)-together;
R8It is selected from :-H;Hydroxyl;C1~C18Alkyl, the C1~C18Alkyl is optionally by C1~C6Alkoxy replaces;C2~C18
Alkenyl;C2~C18Alkynyl;C6~C10Aryl, the C6~C10Aryl is optionally by amino, hydroxyl, halogen, C1~C6Alkoxy, C1
~C6Alkyl, C1~C6Halogenated alkyl replaces;5 or 6 yuan of alicyclic heterocyclic bases, the alicyclic heterocyclic base is optionally by amino, hydroxyl, halogen, C1
~C6Alkoxy, C1~C6Alkyl, C1~C6Halogenated alkyl replaces;5~10 unit's heteroaryls, the heteroaryl is optionally by amino, hydroxyl
Base, halogen, C1~C6Alkoxy, C1~C6Alkyl, C1~C6Halogenated alkyl replaces;- C (=Y1)-Y2;- S (=O)2-Y3;
Y1It is selected from :=O;=S;=NH;
Y2It is selected from: C1~C18Alkyl;C1~C18Alkoxy;Azanol base;-NR13R14;C6~C10Aryl, the C6~C10Virtue
Base is optionally by amino, hydroxyl, halogen, C1~C6Alkoxy, C1~C6Alkyl, C1~C6Halogenated alkyl replaces;5~10 yuan of heteroaryls
Base, the heteroaryl is optionally by amino, hydroxyl, halogen, C1~C6Alkoxy, C1~C6Alkyl, C1~C6Halogenated alkyl replaces;5
Or 6 yuan of alicyclic heterocyclic bases, the alicyclic heterocyclic base is optionally by amino, hydroxyl, halogen, C1~C6Alkoxy, C1~C6Alkyl, C1~C6
Halogenated alkyl replaces;The C that 5 or 6 yuan of alicyclic heterocyclic bases replace1~C6Alkyl-substituted 5 or 6 yuan of alicyclic heterocyclic bases, the alicyclic heterocyclic base
Optionally by amino, hydroxyl, halogen, C1~C6Alkoxy, C1~C6Alkyl, C1~C6Halogenated alkyl replaces;C1~C6Alkylamino,
The C1~C6Alkylamino is by oxygen, hydroxyl, 5~10 unit's heteroaryls, C6~C10At least one of aryl replaces, and described 5~10 yuan miscellaneous
Aryl, C6~C10Aryl is optionally by amino, hydroxyl, halogen, C1~C6Alkoxy, C1~C6Alkyl, C1~C6Halogenated alkyl replaces;
Y3For optionally by halogen, halogenated C1~C6Alkyl-substituted C6~C10Aryl;
R3Selected from-H;Hydroxyl;Halogen;-NR13R14;(C=O) NR11R12;(C=O) R15;- O (C=O) R16;-NR17-(C
=O) R18;-NR19-(COO)R20;-NR21-(SO2)R22;- O (C=O) NR23R24;-SR25;(S=O) R26;-(SO2)R27;-
(SO2)NR32R33;C1~C6Alkyl, the C1~C6Alkyl is optionally by hydroxyl, cyano, carboxyl, monosaccharide groups, C1~C6Alkoxy, C6
~C10Aryl, 5~10 unit's heteroaryls, 5 or 6 yuan of alicyclic heterocyclic bases ,-NH-CO-C1~C6Alkylidene (NH2)(A1)、-NR13R14It takes
Generation, the C6~C10Aryl, 5~10 unit's heteroaryls, 5 or 6 yuan of alicyclic heterocyclic bases are optionally by amino, hydroxyl, halogen, C1~C6Alkyl,
C1~C6Halogenated alkyl replaces;C2~C6Alkenyl, the C2~C6Alkenyl is optionally by hydroxyl, cyano, carboxyl, monosaccharide groups, C1~C6Alkane
Oxygroup, C6~C10Aryl, 5~10 unit's heteroaryls, 5 or 6 yuan of alicyclic heterocyclic bases ,-NH-CO-C1~C6Alkylidene (NH2)(A1)、-
NR13R14Replace;C2~C6Alkynyl, the C2~C6Alkynyl is optionally by hydroxyl, cyano, carboxyl, monosaccharide groups, C1~C6Alkoxy, C6
~C10Aryl, 5~10 unit's heteroaryls, 5 or 6 yuan of alicyclic heterocyclic bases ,-NH-CO-C1~C6Alkylidene (NH2)(A1)、-NR13R14It takes
Generation;
A1The C replaced selected from-H, optionally by 5~10 unit's heteroaryls1~C6Alkyl;
R4With R5Composition=O and/or R together6With R7Composition=O together;
Work as R4With R5Or R6With R7Do not constitute=O when, be each independently selected from-H;Hydroxyl;-NR13R14;(C=O) R15;-
NR17(C=O) R18;-SR25;C6~C10Aryl, the C6~C10Aryl is optionally selected from halogen, hydroxyl, cyano, nitro, carboxylic
Base, azido ,-NR13R14,-S (O)0-2R34Replace;5~10 unit's heteroaryls, the heteroaryl optionally by be selected from halogen, hydroxyl,
Cyano, nitro, carboxyl, azido ,-NR13R14,-S (O)0-2R34Replace;C1~C6Alkoxy, the C1~C6Alkoxy is optional
It is selected from halogen, hydroxyl, cyano, nitro, carboxyl, azido ,-NR13R14,-S (O)0-2R34Replace;C6~C10Aryloxy group, it is described
C6~C10Aryloxy group is optionally selected from halogen, hydroxyl, cyano, nitro, carboxyl, azido ,-NR13R14,-S (O)0-2R34Replace;
G1~G8It is each independently selected from-H;Halogen;Hydroxyl;Cyano;Nitro;Carboxyl;-NR13R14;(C=O)
NR11R12;(C=O) R15;- O (C=O) R16;-NR17(C=O) R18;-NR19-(COO)R20;-NR21-(SO2)R22;- O (C=
O)NR23R24;-SR25;(S=O) R26;-(SO2)R27;- CH=NOR28;- CH=NR29;- CH=NNR30R31;-(SO2)
NR32R33;C1~C6Alkyl, the C1~C6Alkyl optionally by be selected from halogen, hydroxyl, cyano, nitro, carboxyl, azido ,-
NR13R14,-S (O)0-2R34Replace;C2~C6Alkenyl, the C2~C6Alkenyl is optionally selected from halogen, hydroxyl, cyano, nitro, carboxylic
Base, azido ,-NR13R14,-S (O)0-2R34Replace;C2~C6Alkynyl, the C2~C6Alkynyl optionally by be selected from halogen, hydroxyl,
Cyano, nitro, carboxyl, azido ,-NR13R14,-S (O)0-2R34Replace;C6~C10Aryl, the C6~C10Aryl is optionally selected
From halogen, hydroxyl, cyano, nitro, carboxyl, azido ,-NR13R14,-S (O)0-2R34Replace;5~10 unit's heteroaryls, it is described miscellaneous
Aryl is optionally selected from halogen, hydroxyl, cyano, nitro, carboxyl, azido ,-NR13R14,-S (O)0-2R34Replace;C1~C6Alcoxyl
Base, the C1~C6Alkoxy is optionally selected from halogen, hydroxyl, cyano, nitro, carboxyl, azido ,-NR13R14,-S (O)0-2R34
Replace;C6~C10Aryloxy group, the C6~C10Aryloxy group optionally by be selected from halogen, hydroxyl, cyano, nitro, carboxyl, azido ,-
NR13R14,-S (O)0-2R34Replace;
R13、R14It is each independently selected from-H;Amino;Monosaccharide groups, the hydroxyl hydrogen of the monosaccharide groups is optionally by C1~C6Alkyl
Replace;C1~C6Alkyl, the C1~C6Alkyl optionally by be selected from halogen, hydroxyl, cyano, nitro, carboxyl, azido ,-
NR13R14,-S (O)0-2R34Replace;C6~C10Aryl, the C6~C10Aryl is optionally by amino, hydroxyl, halogen, C1~C6Alkyl
Replace, the C1~C6Alkyl is optionally selected from halogen, hydroxyl, cyano, nitro, carboxyl, azido ,-NR13R14,-S (O)0-2R34
Replace;5 or 6 yuan of alicyclic heterocyclic bases, the alicyclic heterocyclic base is optionally by amino, hydroxyl, halogen, C1~C6Alkyl replaces, the C1~C6
Alkyl is optionally selected from halogen, hydroxyl, cyano, nitro, carboxyl, azido ,-NR13R14,-S (O)0-2R34Replace;
R11、R12、R15、R16、R17、R18、R19、R20、R21、R22、R23、R24、R25、R26、R27、R28、R29、R30、R31、R32、
R33、R34It is each independently selected from :-H;C1~C6Alkyl;C6~C10Aryl;
The alicyclic heterocyclic base and heteroaryl contain 1-4 hetero atom each independently, and the hetero atom is selected from N, O, S.
Optionally, above-mentioned formula A compound, its pharmaceutically acceptable salt or prodrug are as follows: following compound of formula I, Formula II
Object or their pharmaceutically acceptable salts or prodrug are closed,
Wherein, in Formulas I,
Dotted line indicates no chemical bond or is singly-bound;
G1~G8It is each independently selected from-H;Halogen;C1~C6Alkyl;C2~C6Alkenyl;C2~C6Alkynyl;
R3Selected from-H;-NR13R14;C1~C6Alkyl, the C1~C6Alkyl optionally by hydroxyl, cyano, carboxyl, monosaccharide groups,
C1~C6Alkoxy, C6~C10Aryl, 5~10 unit's heteroaryls, 5 or 6 yuan of alicyclic heterocyclic bases ,-NH-CO-C1~C6Alkylidene (NH2)
(A1)、-NR13R14Replace, 5 or 6 yuan of alicyclic heterocyclic bases, 5~10 unit's heteroaryls, C6~C10Aryl is optionally by amino, hydroxyl, halogen
Element, C1~C6Alkyl, C1~C6Halogenated alkyl replaces;
Wherein A1It is selected from :-H;C1~C6Alkyl, the C1~C6Alkyl is optionally replaced by 5~10 unit's heteroaryls, described 5~
10 unit's heteroaryls are optionally by amino, hydroxyl, halogen, C1~C6Alkyl, C1~C6Halogenated alkyl replaces;R13、R14It selects each independently
From :-H;C1~C6Alkyl;
R1And R2It is each independently selected from :-H;C1~C6Alkyl, the C1~C6Alkyl optionally by cyano, hydroxyl, carboxyl,
C6~C10Aryl, 5~10 unit's heteroaryls replace, the C6~C10Aryl, 5~10 unit's heteroaryls are optionally by amino, hydroxyl, halogen
Element, C1~C6Alkyl, C1~C6Halogenated alkyl replaces;
In Formula II,
G1~G8It is each independently selected from-H;Halogen;
R3Selected from-H;C1~C6Alkyl, the C1~C6Alkyl is optionally by hydroxyl, cyano, carboxyl, monosaccharide groups, C1~C6Alkane
Oxygroup, C6~C10Aryl, 5~10 unit's heteroaryls, 5 or 6 yuan of alicyclic heterocyclic bases ,-NH-CO-C1~C6Alkylidene (NH2)(A1)、-
NR13R14Replace, 5 or 6 yuan of alicyclic heterocyclic bases, 5~10 unit's heteroaryls, C6~C10Aryl is optionally by amino, hydroxyl, halogen, C1
~C6Alkyl, C1~C6Halogenated alkyl replaces;
Wherein A1It is selected from :-H;C1~C6Alkyl, the C1~C6Alkyl is optionally replaced by 5~10 unit's heteroaryls, described 5~
10 unit's heteroaryls are optionally by amino, hydroxyl, halogen, C1~C6Alkyl, C1~C6Halogenated alkyl replaces;R13、R14It selects each independently
From :-H;C1~C6Alkyl;
R4With R5Composition=O and/or R together6With R7Composition=O together;
Work as R4With R5Or R6With R7Do not constitute=O when, be each independently selected from-H or-OR35, R35For-H or C1~C6Alkane
Base;
R9、R10It independently is-H or C1~C6Alkyl;R8Selected from-C (=Y1)-Y2,-S (=O)2-Y3;
Wherein, Y1Selected from=O;=S;=NH;
Y2Selected from azanol base;C6~C10Aryl, the C6~C10Aryl is optionally by amino, hydroxyl, halogen, C1~C6Alcoxyl
Base, C1~C6Alkyl, C1~C6Halogenated alkyl replaces;5~10 unit's heteroaryls, 5~10 unit's heteroaryl is optionally by amino, hydroxyl
Base, halogen, C1~C6Alkoxy, C1~C6Alkyl, C1~C6Halogenated alkyl replaces;5 or 6 yuan of alicyclic heterocyclic bases, 5 or 6 yuan of rouge
Heterocycle is optionally by amino, hydroxyl, halogen, C1~C6Alkoxy, C1~C6Alkyl, C1~C6Halogenated alkyl replaces;5 or 6 yuan of rouge
The C that heterocycle replaces1~C6Alkyl-substituted 5 or 6 yuan of alicyclic heterocyclic bases, 5 or 6 yuan of alicyclic heterocyclic bases are optionally by amino, hydroxyl
Base, halogen, C1~C6Alkoxy, C1~C6Alkyl, C1~C6Halogenated alkyl replaces;C1~C6Alkylamino, the C1~C6Alkylamino
By oxygen, hydroxyl, 5~10 unit's heteroaryls, C6~C10At least one of aryl replaces, 5~10 unit's heteroaryl, C6~C10Aryl
Optionally by amino, hydroxyl, halogen, C1~C6Alkoxy, C1~C6Alkyl, C1~C6Halogenated alkyl replaces;
Y3For optionally by halogen, halogenated C1~C6Alkyl-substituted C6~C10Aryl;
Alternatively, R9With R10Composition-C (=O)-together, R8Selected from-H;C1~C18Alkyl;C1~C6The C that alkoxy replaces1~
C18Alkyl.
In above-mentioned formula A compound, its pharmaceutically acceptable salt or prodrug:
Optionally, in Formulas I,
Dotted line indicates no chemical bond or is singly-bound;
G1~G8Definition in compound of formula I as claimed in claim 4;
R3Selected from-H;-NR13R14;C1~C6Alkyl, the C1~C6Alkyl optionally by hydroxyl, cyano, carboxyl, monosaccharide groups,
C1~C6Alkoxy, morpholinyl, piperidyl, piperazinyl, pyridyl group, phenyl or-NH-CO-C1~C6Alkylidene (NH2)(A1)、-
NR13R14Replace, the morpholinyl, piperidyl, piperazinyl, pyridyl group, phenyl are optionally by amino, hydroxyl, halogen, C1~C6Alkane
Base, C1~C6Halogenated alkyl replaces;
Wherein A1It is selected from :-H;C1~C6Alkyl, the C1~C6Alkyl is optionally replaced by imidazole radicals, indyl, the imidazoles
Base, indyl are optionally by amino, hydroxyl, halogen, C1~C6Alkyl, C1~C6Halogenated alkyl replaces;R13、R14It selects each independently
From :-H;C1~C6Alkyl;
R1And R2It is each independently selected from-H;C1~C6Alkyl, the C1~C6Alkyl is optionally by cyano, hydroxyl, carboxyl, benzene
Base, naphthalene, pyridyl group replace, and the phenyl, naphthalene, pyridyl group are optionally by amino, hydroxyl, halogen, C1~C6Alkyl, C1~C6
Halogenated alkyl replaces;
Optionally, in Formula II,
G1~G8Definition in Formula II compound as claimed in claim 4;
R3Selected from-H;C1~C6Alkyl, the C1~C6Alkyl is optionally by amino, hydroxyl, phenyl, morpholinyl, piperidyl, piperazine
Piperazine base replaces, and the phenyl, morpholinyl, piperidyl, piperazinyl are optionally by amino, hydroxyl, halogen, C1~C6Alkyl, C1~C6Halogen
Substituted alkyl replaces;
R4With R5Composition=O and/or R together6With R7Composition=O together;
Work as R4With R5Or R6With R7Do not constitute=O when, be each independently selected from-H or-OH;
R9、R10For methyl;
R8Selected from-C (=Y1)-Y2;- S (=O)2-Y3;
Wherein, Y1Selected from=O;=S;=NH;
Y2It is selected from: azanol base;Phenyl, the phenyl is optionally by amino, hydroxyl, halogen, C1~C6Alkoxy, C1~C6Alkane
Base, C1~C6Halogenated alkyl replaces;Imidazole radicals;Piperazinyl, the piperazinyl are optionally replaced by morpholinyl;Alkylamino, the alkane ammonia
Base is replaced by least one of oxygen, hydroxyl, indyl, phenyl;
Y3For optionally by halogen, C1~C6The phenyl that halogenated alkyl replaces;
Alternatively, R9With R10Composition-C (=O)-together, R8Selected from-H;C1~C18Alkyl;C1~C6The C that alkoxy replaces1~
C18Alkyl.
In above-mentioned formula A compound, its pharmaceutically acceptable salt or prodrug:
Optionally, in Formulas I,
Dotted line indicates no chemical bond or is singly-bound;
G1~G8Definition in compound of formula I as claimed in claim 4;
R3It is selected from: C1~C6Alkyl, the C1~C6Alkyl by morpholinyl, piperidyl, piperazinyl, pyridyl group, phenyl or-
NH-CO-C1~C6Alkylidene (NH2)(A1) at least one of replace, the morpholinyl, piperidyl, piperazinyl, pyridyl group, phenyl
Optionally by amino, hydroxyl, halogen, C1~C6Alkyl, C1~C6Halogenated alkyl replaces;C2~C6Alkyl, the C2~C6Alkyl is by hydroxyl
Base replaces;C3~C6Alkyl, the C3~C6Alkyl is by-NR13R14Replace;
Wherein A1It is selected from :-H;C1~C6Alkyl, the C1~C6Alkyl is optionally replaced by imidazole radicals, indyl, the imidazoles
Base, indyl are optionally by amino, hydroxyl, halogen, C1~C6Alkyl, C1~C6Halogenated alkyl replaces;R13、R14It selects each independently
From :-H;C1~C6Alkyl;
R1And R2It is each independently selected from C1~C6Alkyl, the C1~C6Alkyl by phenyl, naphthalene, pyridyl group at least
A kind of substitution;
Optionally,
In Formulas I,
Dotted line indicates no chemical bond or is singly-bound;
G1~G8It is each independently selected from-H, halogen, allyl, isopentene group;
R3Selected from-H;-Me;-(CH2)1~6OH;-(CH2)0~6NH2;-(CH2)1~4NMe2;-(CH2)1~4CN;-(CH2)1~ 4CO2H;-(CH2)1~4C6H5OH;-(CH2)1~4C6H5OMe;-(CH2)1~4C6H5NH2;-(CH2)1~4M;Morpholine ethyl;Piperidines second
Base;Piperazine ethyl;Methyl piperazine ethyl;Pyridine ethyl;Halophenethyl;-(CH2)1~6-NH-CO-CH(NH2)(A1);Wherein,
A1、R13、R14As claimed in claim 4, M is monosaccharide groups;
Alternatively, the R3Selected from morpholine ethyl;Piperidinoethyl;Piperazine ethyl;Methyl piperazine ethyl;Pyridine ethyl;Amino
Benzyl;Aminophenethyl;Hydroxyphenylmethyl;Halophenethyl;-(CH2)1~6-NH-CO-CH(NH2)(A1);-(CH2)2~ 4OH;-(CH2)3~6NH2;-(CH2)1~4NMe2;Wherein, A1Selected from-H;Imidazolmethyl;Indole methyl;
Alternatively, the R3Selected from 2- (4- morpholinyl) ethyl;2- (piperidin-1-yl) ethyl;2- (piperazine -1- base) ethyl;
2- (4- methylpiperazine-1-yl) ethyl;2- (pyridine -2- base) ethyl;P-aminophenyl methyl;P-aminophenyl ethyl;Para hydroxybenzene
Methyl;2- (the chloro- 6- fluorophenyl of 2-) ethyl;-(CH2)1~6-NH-CO-CH(NH2)(A1);-(CH2)2~4OH;-(CH2)3~6NH2;-
(CH2)1~4NMe2;Wherein, A1Selected from-H;(imidazol-4 yl) methyl;(indol-3-yl) methyl;
R1And R2It is each independently selected from-H;-Et;-(CH2)1~4CN;-(CH2)1~4CO2H;-(CH2)1~4OH;Phenethyl;
Naphthylethyl;Pyridine ethyl;
Alternatively, the R1And R2It is each independently selected from phenethyl;Naphthylethyl;Pyridine ethyl;
Optionally, in Formula II,
G1~G8It is each independently selected from-H;Halogen;
R3For-H;
R4With R5Composition=O and/or R together6With R7Composition=O together;
Work as R4With R5Or R6With R7Do not constitute=O when, be each independently selected from-H or-OR35, R35For-H or C1~C6Alkane
Base;
R9、R10It is methyl;
R8Selected from-C (=Y1)-Y2;- S (=O)2-Y3;
Wherein, Y1Selected from=O;=S;=NH;
Y2It is selected from: azanol base;Phenyl, the phenyl is optionally by halogen, C1~C6Halogenated alkyl replaces;Imidazole radicals;Oxo Yin
Diindyl base ethylamino;Oxo phenylethylamino;(morpholine ethyl) piperazinyl;(halogenophenyl) methylamino;(halogenophenyl) ethylamino;
(halomethylphenyl) ethylamino;Phenyl methylamino;(methoxyphenyl) methylamino;Hydroxy propyl amido;4- (bis- (the 2- chloroethenes of N, N-
Base) amino) phenyl propyl;
Alternatively, Y2It is selected from: azanol base;Phenyl;Halogenophenyl;The phenyl that trifluoromethyl replaces;2- oxygen subunit -2- (1H- Yin
Diindyl -3- base) -1- ethylamino;Imidazoles -1- base;2- oxygen subunit -2- phenyl -1- ethylamino;4- (2 (morpholine -1- base) ethyl) piperazine
Piperazine -1- base;(2,6- difluorophenyl) methylamino;(the chloro- 4- fluorophenyl of 3-) methylamino;2- (the chloro- 6- fluorophenyl of 2-) -1- second ammonia
Base;2- (4- trifluoromethyl) -1- ethylamino;Phenylmethyl amino;(4- methoxyphenyl) methylamino;(S) -2- hydroxyl -
The third amino of 1-;4- (bis- (2- chloroethyl) amino of N, N-) phenyl propyl;
Y3For optionally by halogen, C1~C6The phenyl that halogenated alkyl replaces;
Alternatively, Y3Selected from halogenophenyl;The phenyl that trifluoromethyl replaces;
Alternatively,
R9With R10Composition-C (=O)-together;
R8Selected from-H;C1~C18Alkyl;C1~C6The C that alkoxy replaces1~C18Alkyl;Alternatively, R8For methyl.
Optionally, above-mentioned formula A compound, its pharmaceutically acceptable salt or prodrug are selected from following compounds, its pharmacy
Upper acceptable salt or prodrug:
Optionally, in above-mentioned formula A compound, its pharmaceutically acceptable salt or prodrug, the pharmaceutically acceptable salt
Salt including organic or inorganic acid;Optionally, the pharmaceutically acceptable salt is selected from the formula A compound and following acidification is closed
The salt that object is formed: hydrochloric acid;Sulfuric acid;Phosphoric acid;Formic acid;Acetic acid;Propionic acid;Lactic acid;Citric acid;Tartaric acid;Succinic acid;Fumaric acid;Horse
Come sour;Tussol;Malic acid;Camphorsulfonic acid;
Optionally, the pharmaceutically acceptable prodrug includes the phosphate prodrugs or carbamic acid of the formula A compound
Ester prodrugs.
The present invention also provides a kind of methods for preparing above-mentioned formula A compound, its pharmaceutically acceptable salt or prodrug, special
Sign is: the preparation step including -1 compound of Formulas I, I-2 compound, I-3 compound, II-1 compound or II-2 compound
Suddenly,
In -1 compound of Formulas I, G1~G8、R1、R2As described above, the preparation step of -1 compound of Formulas I includes:
1) preparation step of formula a3 compound is selected from following methods (1) or method (2),
Method (1): formula a3 compound is made by Perkin condensation reaction in formula a1 compound and formula a2 compound;
Method (2): formula a2 compound, formula a6 compound and formula a7 compound are reacted by Grignard, and and iodine
Ethane, which reacts, is made formula a8 compound, then by formula a8 compound by hydrolyzing under alkaline condition, is then acidified and formula a3ization is made
Close object;
With the preparation step of 2) -1 compound of Formulas I,
- 1 compound of Formulas I is made by reacting by formula a3 compound;
In -2 compound of Formulas I, G1~G8、R1、R2、R3As described above, still R3It is not H, -2 compound of Formulas I
Preparation step includes: that -2 compound of Formulas I is made by -1 compound of Formulas I;
G in -3 compound of Formulas I1~G8、R1、R2、R3As described above, the preparation step of -3 compound of Formulas I includes:
1): -1 compound of Formulas I is reacted into the formula of being made by cyclization or dichloro dicyanoquinone (DDQ) oxidative cyclization
A5 compound, then -3 compound of Formulas I is made by formula a5 compound, wherein R in -3 compound of Formulas I3For H;
Either 2): -2 compound of Formulas I is anti-by illumination cyclization or dichloro dicyanoquinone (DDQ) oxidative cyclization
- 3 compound of Formulas I should be made, wherein R in -3 compound of Formulas I3It is not H;
Wherein, work as R1、R2Optionally blocking group to be used to be protected when reactive group;
In -1 compound of Formula II, R9、R10For-H or alkyl;G1~G8、R3、R4、R5、R6、R7、R8As described above, described
The preparation step of -1 compound of Formula II includes: II-1-A class compound, II-1-B class compound, II-1-C class compound, II-1-
The preparation step of D class compound or II-1-E class compound,
The II-1-A class compound is such as undefined -1 compound of Formula II: R in -1 compound of Formula II8For-C (=Y1)-
Y2, Y1Selected from=O or=S;Y2For aryl, the aryl is optionally taken by amino, hydroxyl, halogen, alkoxy, alkyl, halogenated alkyl
Generation;
The II-1-A class compound producing step includes: to be tried by formula b1 compound and aryl formyl reagent or arylsulfonyl
Agent is made by acylation reaction, the substituent group and Y on aryl in the aryl formyl reagent or arylsulfonyl reagent2On aryl
Substituent group it is identical;In the formula b1 compound, G1~G8、R3、R4、R5、R6、R7、R9、R10Such as institute in II-1-A class compound
It states;
The II-1-B class compound is such as undefined -1 compound of Formula II: R in -1 compound of Formula II8For-C (=Y1)-
Y2, Y1Selected from=O or=S;Y2For imidazole radicals;The II-1-B class compound producing step include: by formula b1 compound and 1,
1 '-thio-carbonyldiimidazole or triphosgene react to obtain formula b2 compound with imidazoles;Wherein Y in the formula b2 compound1For
=O or=S;
The II-1-C class compound is such as undefined -1 compound of Formula II: R in -1 compound of Formula II8For-C (=Y1)-
Y2, Y1Selected from=O or=S;Y2Selected from azanol base;-NR13R14;The alkyl-substituted alicyclic heterocyclic base that alicyclic heterocyclic base replaces, it is described
Alicyclic heterocyclic base is optionally replaced by amino, hydroxyl, halogen, alkoxy, alkyl, halogenated alkyl;Alkylamino, the alkylamino quilt
At least one of oxygen, hydroxyl, heteroaryl, aryl replace, the heteroaryl, aryl optionally by amino, hydroxyl, halogen, alkoxy,
Alkyl, halogenated alkyl replace;Wherein, R13、R14As described above;The preparation step of the II-1-C class compound includes: formula b2ization
Object and iodomethane reaction production b3 compound are closed, formula b3 compound is reacted with compound R to be made;Wherein, the compound R choosing
The alkyl-substituted alicyclic heterocyclic replaced from alicyclic heterocyclic base, the alicyclic heterocyclic base and alicyclic heterocyclic are optionally by amino, hydroxyl, halogen
Element, alkoxy, alkyl, halogenated alkyl replace;Alkane ammonia, the alkane ammonia are replaced by least one of oxygen, hydroxyl, heteroaryl, aryl,
The heteroaryl, aryl are optionally replaced by amino, hydroxyl, halogen, alkoxy, alkyl, halogenated alkyl;
The II-1-D class compound is such as undefined -1 compound of Formula II: R in -1 compound of Formula II8For-C (=
NH)-NHOH;The preparation step of the II-1-D class compound includes: that formula b4 compound, formula b4 chemical combination is made by formula b1 compound
Object is reacted with hydroxylamine hydrochloride to be made;
The II-1-E class compound is such as undefined -1 compound of Formula II: R in -1 compound of Formula II8For-C (=Y1)-
Y2, Y1For=O, Y2For 4- (bis- (2- chloroethyl) amino of N, N-) phenyl propyl;The preparation step packet of the II-1-E class compound
Include: formula b1 compound is reacted with Chlorambucil to be made;
In -2 compound of Formula II, R9With R10Composition-C (=O)-together;G1~G8、R3、R4、R5、R6、R7、R8Such as right
It is required that described in any one of 1-8;The preparation step of -2 compound of Formula II includes: that formula c1 compound is reacted with formula c2 compound
Formula c3 compound is made, then formula c4 compound is made by reacting, then formula c5 compound is made by reacting, then pass through reaction system
Formula c6 compound is obtained, then formula c7 compound is made by reacting, then formula c8 compound is made by reaction, then be made by reaction
Formula c9 compound, then -2 compound of Formula II is made by reacting;
R3To be protected when reactive group optionally with blocking group;
Optionally, the Perkin condensation reaction is in oxalyl chloride, triethylamine (Et3N), carried out in the presence of methylene chloride
's;
Optionally, the ammonolysis reaction is in hmds gastral cavity (HMDS), n,N-Dimethylformamide and methanol
In the presence of carry out;
Optionally, use acetone for solvent in the illumination cyclization, using elemental iodine as catalyst, in high-pressure mercury
Light shines lower progress;
Optionally, dichloro dicyanoquinone (DDQ) oxidative cyclization reaction be under the catalysis of p-methyl benzenesulfonic acid,
Oxidative cyclization occurs with DDQ in benzene solvent to react;
Optionally, the formula a6 compound is made by dibromo-maleimide and iodomethane reaction;
Optionally, the formula a8 compound is obtained after the acidification such as hydrochloric acid by hydrolyzing in the alkaline solutions such as KOH or NaOH
To formula a3 compound;
Optionally, work as R1、R2Or R3When for reactive group, the blocking group is selected from (Boc)2O;
Optionally, R in the II-1-A class compound3For-H;R6With R7Composition=O together;R8For methyl, the II-1-
The preparation step of A class compound includes: 1. acylation reaction, and staurosporine is dissolved in methylene chloride, triethylamine is added, with halogeno-benzene
Acylation reaction occurs for formylation reagent;2. halogenating reaction, by step 1. products therefrom in methyl alcohol with N-halosuccinimides room
Temperature is lower to occur halogenating reaction;3. oxidation reaction, by step, 2. products therefrom is obtained containing R with oxidizing4、R5Be independently selected from-
H;-OH;Or R4With R5Composition=O compound together;The acylation reaction, halogenating reaction, oxidation reaction by optional sequence into
Row;Optionally, the oxidation reaction is carried out using following reagents: O2, DMSO, t-BuOK and optional NaOH;
Optionally, the R in the II-1-B class compound, in formula b2 compound3For-H;R4、R5It is independently selected from-H;R6With R7
Composition=O together;R8For methyl;The preparation of the II-1-B class compound carries out by the following method: method 1.: by cross spore
Then triethylamine is added in methylene chloride in alkali soluble, and 1, the reaction of 1 '-thio-carbonyldiimidazole is made;Or method is 2.: by cross
Then spore alkali soluble is added diisopropylethylamine and triphosgene reaction, reacting coarse product is dissolved in tetrahydrofuran, is added in tetrahydrofuran
Enter diisopropylethylamine, imidazoles and dimethylamino naphthyridine is made;
Optionally, R in the II-1-C class compound3For-H;R4、R5It is-H;R6With R7Composition=O together;R8For first
Base;The preparation step of the II-1-C class compound include: by formula b2 compound in acetonitrile solvent with iodomethane at salt, it is rear molten
In methylene chloride, triethylamine is added and compound R carries out substituted in reaction imidazole salts and is made;
Optionally, R in the II-1-D class compound3For-H;R4、R5It is-H;R6With R7Composition=O together;R8For first
Base;The preparation method of described classification (4) compound is the following steps are included: Fradcarbazole C reacts obtained with hydroxylamine hydrochloride;
Optionally, R in the II-1-E class compound3For-H, R4、R5It is-H;R6With R7Composition=O together;R8For first
Base;The preparation step of the II-1-E class compound includes: that staurosporine reacts obtained with Chlorambucil;
Optionally, in -2 compound of Formula II, R3For-H;R4With R5Composition=O together;R6With R7Composition=O together;R8
For methyl;The preparation step of -2 compound of Formula II includes: 1. using glucose as raw material, process is full acetylated, 1- bromos,
1,2-, at alkene reaction, deacetylation, the TIPS protection of 6- hydroxyls, 3,4- building oxazole cyclic ketones, methylates, oxymercuration boron
Hydrogenation sodium reduction obtains saccharide donor in 1- introducing hydroxyls;2. 3- dibromo-maleimide is raw material with 2, protected by BOM
Shield react one molecule indoles of introducing with indoles Grignard Reagent, then the nitrogen hydrogen of indoles is protected with Boc, later again with indoles grignard
Reagent reacts to obtain parent nucleus;3. utilizing Mitsunobu reaction to carry out sugar the step 1. saccharide donor and the step 2. parent nucleus
Glycosidation forms first glycosidic bond, and the isomers of glycosidic bond is separated by silica gel column chromatography, then carries out Boc and TIPS and protects
The removing of base is protected, high voltage mercury lamp radiation carries out cyclization, then 6- hydroxyls replaced with iodine, and 5,6- de- iodine are at double bond, then in iodine
Catalysis is lower to form second glycosidic bond, takes off iodine with tetrabutyl stannane, 20% hydroxide palladium carbon removing BOM is made;
Optionally, in -2 compound of Formula II, R3For-H;R8For methyl;R4With R5Composition=O together, R6、R7Be-
H;Alternatively, R4、R5It is-H, R6With R7Composition=O together;The preparation step of -2 compound of Formula II includes: by the R3For-
H, R4With R5Composition=O together, R6With R7Composition=O together, R8For methyl -2 compound of Formula II by sodium borohydride reduction and
The reduction of zinc powder acetic acid is made;
Optionally, -2 compound of Formula II, which is used, carries out glycosidic bond and oxazole cyclic ketones structure with D-Glucose or L- glucose
The preparation of the different isomers of type.
In the present invention, above compound 1~81,158~166 and its important intermediate 24c, 26c, 43c, 46c, 49c,
The indoles and heteroauxin that 52c and 58c can replace from indoles or halogen are prepared through following chemical synthesis process:
In above-mentioned formula A-I, formula A-II, G1~G8It is each independently-H ,-F ,-Cl ,-Br, allyl or isopentene group;X
For-H ,-Me ,-NH2, 2- (4- morpholinyl -) ethyl, 2- (piperidin-1-yl) ethyl ,-(CH2)nNH2、-(CH2)nNMe2、-(CH2)nCN、-(CH2)nCO2H、-(CH2)nOY、-(CH2)nC6H5R3(Y is-H, glucosyl group or amino acidic group, n=1~4, R3=-
OH,-OMe);R1,R2Representative-H ,-Et ,-(CH2)mCN、-(CH2)mCO2H、-(CH2)mOH (m=1~4) ,-CH2Ph。
The indoles and dibromo-maleimide that compound 82~101 can be replaced by halogen are through following chemical synthesis process system
It is standby and obtain:
In above-mentioned formula A-III, G5~G8It is each independently-H ,-F ,-Cl or-Br;X is-H ,-Me or-CH2OH, R1,R2
It is each independently-H ,-Et or-CH2OH。
Compound 102~129 and its intermediate product 102f and 116c can be from indoles and dibromo-maleimide through following
Chemical synthesis process is prepared:
In above-mentioned formula A-IV, G5~G8It is-H;X representative-H,-Me, 2- (piperazine -1- base) ethyl, (the chloro- 6- of 2- is fluoro- by 2-
Benzene -1- base) ethyl, 2- (4- morpholinyl) ethyl, 2- (piperidin-1-yl) ethyl, 2- (4- methylpiperazine-1-yl) ethyl, -
(CH2)nOH、-(CH2)nNH2, (n=1,2);R1For phenylethyl or 2- (naphthalene -1- base) ethyl.
Compound 130~157 can be tried by staurosporine (staurosporine) and the reagent of benzoyl containing halogen and benzene sulfonyl
Agent is prepared through following chemical synthesis process:
In above-mentioned formula A-V and A-VI, R1For-H ,-F ,-Cl ,-Br ,-I or-CF3;R2、R3It is each independently=O ,-H
Or-OH;X is-H or-Br.
Compound 167~184 can be by staurosporine and thiocarbonyldiimidazole or triphosgene, imidazoles, iodomethane and amine
Compound preparation;Or it is prepared by staurosporine and Chlorambucil through following chemical synthesis process:
In above-mentioned formula A-VII, R4Representative=O ,=S or=NH, R5Represent 2- oxygen subunit -2- (1H- indol-3-yl) -1- second
Amino, imidazoles -1- base, azanol base, 2- oxygen subunit -2- phenyl -1- ethylamino, 4- (2- (4- morpholinyl) ethyl) piperazine -1- base,
(2,6- difluorophenyl) methylamino, (the chloro- 4- fluorophenyl of 3-) methylamino, 2- (the chloro- 6- fluorophenyl of 2-) -1- ethylamino, 2- (3- tri-
Trifluoromethylphenyl) -1- ethylamino, phenylmethyl amino, (4- methoxyphenyl) methylamino, the third amino of (S) -2- hydroxyl -1-, 4-
(bis- (2- chloroethyl) aminophenyls of N, N-) propyl.
Compound in formula A-VIII is 185~196, and wherein compound 185~187 can be by D-Glucose and dibromo Malaysia
Acid imide is prepared through following chemical synthesis process, and in formula A-VIII, 188~190 can be by compound 26b in the same way
It is made;191~195 can substitute D-Glucose by L- glucose is made in the same way.
In above-mentioned formula A-VIII, R1a、R1bIt is each independently-H or-OH or R1a、R1bIt is formed together=O, R2a、R2b
It is each independently-H or-OH or R2a、R2bIt is formed together=O, R3For-H,-Me, 2- (piperazine -1- base) ethyl, 2- (2-
Chloro- 6- fluorophenyl) ethyl, 2- (4- morpholinyl) ethyl, 2- (piperidin-1-yl) ethyl, 2- (4- methylpiperazine-1-yl) ethyl ,-
(CH2)nOH or-(CH2)nNH2, (n=1 or 2);R3Represent H ,-(CH2)nCH3(n=0~17) or-(CH2)nOY, (n=1,2, Y
=Me, Et).
The present invention also provides a kind of antineoplastic pharmaceutical compositions, including above-mentioned formula A compound, its pharmaceutically acceptable salt
Or at least one of prodrug and pharmaceutically acceptable auxiliary material;Optionally, the anti-tumor drug is overriding resistance tumour medicine;
Optionally, the anti-tumor drug is anti-leukemia medicine, anti-breast cancer medicines, anti-lung-cancer medicament or medicines resistant to liver cancer;It is optional
Ground, the anti-tumor drug are anti-mutability leukemia medicament or anti-mutability lung-cancer medicament;Optionally, the anti-tumor drug
For anti-acute promyelocytic leukemic drug, anti-chronic myelogenous leukemia drug, anti-T lymphocyte leukemia medicament, anti-FLT3-
Acute double phenotype (B, monokaryon) the myelocytic leukemia drugs of people of ITD mutation, adriamycin drug-resistant leukemia drug, the leaching of anti-mammary gland
Lubricant nature conduit cancer drug, Antilung gland cancer medicine, anti-K-ras saltant type adenocarcinoma of lung drug or anti-Gefitinib or Erlotinib
Acquired EGFR-T790M/L858R is mutated adenocarcinoma of lung drug.
Optionally, the anti-tumor drug is acute promyelocytic leukemic HL-60 inhibitor, chronic myelogenous leukemia K562
Inhibitor, T lymphocyte leukaemia Jurkat inhibitor, acute double phenotype (the B, monokaryon) myelocytes of people of FLT3-ITD mutation are white
Blood disease MV-4-11 inhibitor, leukemia K 562/A02 inhibitor of Adriamycin resistant, infiltration ductal carcinomas of breast MCF-7 inhibit
Agent, adenocarcinoma of lung A549 inhibitor, Gefitinib or the acquired EGFR-T790M/L858R adenocarcinoma of lung medicament-resistant mutation strain of Erlotinib
H1975 inhibitor or hepatocellular carcinoma H22 inhibitor.
Formula A compound, its pharmaceutically acceptable salt or prodrug or antineoplastic pharmaceutical compositions can pass through mouth
Clothes administration and drug administration by injection are also suitble to other administration modes, such as percutaneous dosing.Antineoplastic pharmaceutical compositions of the invention can
Think the dosage forms such as tablet, capsule, pulvis, particle, pastille, suppository, oral solution or sterile parenteral suspension.It further include various
The injections form such as injection, freeze dried powder of capacity.The drug of above-mentioned dosage form can be prepared according to the conventional method of pharmaceutical field.
In antineoplastic pharmaceutical compositions of the present invention, auxiliary material used includes the auxiliary material of this field routine, such as diluent, filler, viscous
Mixture, wetting agent, sorbefacient, surfactant, absorption carrier, lubricant etc..
Formula A compound, its pharmaceutically acceptable salt or prodrug are alternatively arranged as inhibiting the low molecule of cell Proliferation
Bioprobe is used for life science, and when as probe application, formula A compound, its pharmaceutically acceptable salt or prodrug can
It is dissolved in methanol, water or aqueous methanol, also dissolves in the aqueous solution of dimethyl sulfoxide and be applied.
The present invention also provides above-mentioned formula A compound, its pharmaceutically acceptable salt or prodrugs in the preparation of antitumor drugs
Purposes, optionally, the anti-tumor drug be overriding resistance tumour medicine;Optionally, the anti-tumor drug is anti-leukocythemia
Drug, anti-breast cancer medicines, anti-lung-cancer medicament or medicines resistant to liver cancer;Optionally, the anti-tumor drug is the white blood of anti-mutability
Medicine or anti-mutability lung-cancer medicament;Optionally, the anti-tumor drug be anti-acute promyelocytic leukemic drug, resist it is chronic
Myelogenous leukemia drug, anti-T lymphocyte leukemia medicament, acute double phenotype (the B, monokaryon) marrows of people of anti-FLT3-ITD mutation are thin
Born of the same parents' leukemia medicament, adriamycin drug-resistant leukemia drug, anti-infiltration ductal carcinomas of breast drug, Antilung gland cancer medicine, anti-K-
Ras saltant type adenocarcinoma of lung drug or the acquired EGFR-T790M/L858R of anti-Gefitinib or Erlotinib are mutated adenocarcinoma of lung
Drug.
The present invention also provides above-mentioned formula A compound, its pharmaceutically acceptable salt or prodrug it is antitumor in purposes, it is optional
Ground, the tumour are drug-resistant tumor;Optionally, the tumour is leukaemia, breast cancer, lung cancer or liver cancer;Optionally, described swollen
Tumor is mutability leukaemia or mutability lung cancer;Optionally, the tumour is that acute promyelocytic leukemia, chronic Myelogenous are white
Acute double phenotype (the B, monokaryon) myelocytic leukemias of blood disease, T lymphocyte leukaemia, FLT3-ITD mutant human, adriamycin are resistance to
The leukaemia of medicine, infiltration ductal carcinomas of breast, adenocarcinoma of lung, K-ras saltant type adenocarcinoma of lung, Gefitinib or Erlotinib are acquired
EGFR-T790M/L858R is mutated adenocarcinoma of lung or liver cancer.
Formula A compound have it is one or more kinds of following the utility model has the advantages that
Human leukemia cell's inhibitory activity: stronger people's acute promyelocytic leukemic HL-60 inhibitory activity;Stronger people is slow
Property myelogenous leukemia K562 inhibitory activity;Stronger human T lymphocyte's leukaemia Jurkat inhibitory activity;
People's mutability leukaemia cell's inhibitory activity: acute double phenotype (the B, monokaryon) marrows of people of stronger FLT3-ITD mutation
Chronic myeloid leukemia MV-4-11 inhibitory activity can be used for the accurate treatment of such leukaemic;
People's drug-resistant leukemia cell inhibitory activity: the leukemia K 562 of stronger Adriamycin resistant/A02 inhibitory activity, it can
Accurate treatment for such drug-resistant leukemia patient;
Human breast cancer cell inhibitory activity: stronger infiltration ductal carcinoma of breast MCF-7 inhibitory activity;
Human lung cancer inhibitory activity: stronger human lung adenocarcinoma A549 inhibitory activity;
People's drug resistance lung adenocarcinoma cell inhibitory activity: stronger Gefitinib or the acquired EGFR-T790M/ of Erlotinib
The inhibitory activity of L858R adenocarcinoma of lung medicament-resistant mutation strain H1975, can be used for the accurate treatment of such patients with lung cancer;
Human liver cancer cell inhibitory activity: stronger human liver cancer cell HepG2 inhibitory activity;
Selectivity with higher;
With lower toxicity.
Specific embodiment:
The present invention is illustrated by the following examples, but the scope of the present invention is not limited to these embodiments.
The preparation of [embodiment 1] compound 1~196
The preparation of compound 1
I) 1- ethyl -3-indolyl acetic acid (1a) preparation
Argon gas protection under, in 250mL there-necked flask be added 4g sodium hydride (mass fraction 60%, be scattered in paraffin),
80mL tetrahydrofuran is added the indole-3-acetic acid (3.5g, 20mmol) of 30mL tetrahydrofuran dissolution, stirs in 0 DEG C of stirring suspension
After mixing half an hour, the iodoethane (5mL, 60mmol) of 30mL tetrahydrofuran dissolution is added dropwise, is slowly increased to room temperature, after reaction overnight,
Be down at 0 DEG C, be added dropwise 10 drop methanol, then plus suitable quantity of water to bright yellow solution, ethyl acetate extraction, after water layer enriching hydrochloric acid again
Extraction merges organic layer, and uses anhydrous Na2SO4It is dry, evaporated in vacuo, after by silica gel column chromatography separation, petroleum ether: acetic acid second
Ester=8:1 (v/v) elutes to obtain product (1a) 3.87g, yield 95.4%.1H NMR(600MHz,CDCl3) δ 7.59 (d, 1H, J=
8.2Hz, Ar-H), 7.30 (d, 1H, J=8.2Hz, Ar-H), 7.20 (dt, 1H, J=8.2Hz, 0.9Hz, Ar-H), 7.10 (dt,
1H, J=8.2Hz, 1.0Hz, Ar-H), 7.07 (s, 1H, Ar-H), 4.10 (q, 2H, J=7.3Hz, CH3-CH 2-),3.77(s,
2H,-CH 2-CO2), H 1.41 (t, 3H, J=7.3Hz ,-CH2-CH 3).13C NMR(150MHz,CDCl3)δ178.6,135.9,
127.6,126.1,121.7,119.2,119.0,109.4,106.0,40.8,31.1,15.4.ESI-MS m/z 202.1[M-
H]–.
Ii) the preparation of 1- cyanogen methyl indol (1b)
Under argon gas protection, 180mg sodium hydride (mass fraction 60%, be dispersed in paraffin) is added in 100mL there-necked flask
The indoles (351mg, 3.0mmol) of 10mL acetonitrile dissolution is added dropwise, is stirred to react in -5 DEG C of stirring suspensions with 30mL acetonitrile
The 2- bromoacetonitrile (300 μ L, 4.5mmol) of 10mL acetonitrile dissolution is slowly added dropwise in 30min, is slowly increased to room temperature, after reaction for 24 hours,
Saturation NH is added4Cl aqueous solution terminates reaction, and ethyl acetate extracts (100mL × 3 time), merges organic layer, and use anhydrous Na2SO4
Dry, evaporated in vacuo, silica gel column chromatography separation, petroleum ether: ethyl acetate=15:1 (v/v) elutes to obtain colorless oil as product (1b)
299mg, yield 64%.1H NMR(600MHz,CDCl3) δ 7.64 (d, 1H, J=8.2Hz, Ar-H), 7.33-7.28 (m, 2H,
), Ar-H 7.19 (d, 1H, J=6.9Hz, Ar-H), 7.02 (d, 1H, J=3.2Hz, Ar-H), 6.58 (d, 1H, J=3.2Hz,
Ar-H),4.87(s,2H,-CH 2-CN).13C NMR(150MHz,CDCl3)δ135.6,128.9,127.1,122.8,121.5,
120.8,114.4,108.7,104.1,34.1.ESI-MS m/z 157.1[M+H]+.
Iii) the preparation of 2- (1- ethyl -3- indoles) -3- (1- cyanogen methyl -3- indoles) maleic anhydride (1c)
Compound 1a (299mg, 1.92mmol) is used into 25mL CH2Cl25mL CH is added dropwise in dissolution at -5 DEG C2Cl2Dissolution
Oxalyl chloride (366mg, 2.88mmol), drop finishes, in -5 DEG C of reaction 2h, after add oxalyl chloride 0.5mL, the reaction was continued 2.5h, liter
To room temperature, vacuum drains solvent and obtains yellow crystals.With 30mL CH2Cl2It re-dissolves, is added drop-wise to 15mL CH2Cl2The change of dissolution
It closes in object 1b (390mg, 1.92mmol) and triethylamine (388mg, 3.84mmol), through silica gel column chromatography separation, petroleum ether: acetic acid
Ethyl ester=3:1 (v/v) elutes to obtain red powder (1c) 270mg, yield 36%.1H NMR(600MHz,DMSO-d6)δ7.97(s,
1H, Ar-H), 7.95 (s, 1H, Ar-H), 7.64 (d, 1H, J=8.2Hz, Ar-H), 7.54 (d, 1H, J=8.2Hz, Ar-H),
7.22 (t, 1H, J=7.3Hz, Ar-H), 7.12 (t, 1H, J=7.8Hz, Ar-H), 6.90 (d, 1H, J=7.7Hz, Ar-H),
6.87 (d, 1H, J=7.8Hz, Ar-H), 6.85 (t, 1H, J=7.7Hz, Ar-H), 6.77 (t, 1H, J=7.8Hz, Ar-H),
5.67(s,2H,-CH 2- CN), 4.28 (q, 2H, J=7.3Hz ,-CH 2-CH3), 1.33 (t, 3H, J=7.3Hz ,-CH2-CH 3)
.13C NMR(150MHz,DMSO-d6)δ166.2,166.1,135.7,135.6,133.2,132.5,129.9,126.1,
125.5,125.3,123.1,122.3,121.7,121.6,120.9,120.3,116.0,110.6,110.4,106.0,
104.0,40.9,34.1,15.2.ESI-MS m/z 396.2[M+H]+.
Iv) the preparation of 2- (1- ethyl -3- indoles) -3- (1- cyanogen methyl -3- indoles) maleimide (1)
In single port bottle, with 4mL DMF dissolved compound 1c (126mg, 0.32mmol), by HMDS under being stirred after sealing
It after (6.7mL, 32mmol) and MeOH (0.64mL, 16mmol) mixing, is injected into single port bottle, reaction solution becomes light from red
Yellow dregs fade to clarified solution as reaction carries out, and color gradient is orange red.After reaction overnight, 25mL cold water is poured into
In, ethyl acetate extracts (50mL × 3 time), merges organic layer, and use anhydrous Na2SO4It is dry, evaporated in vacuo.Silica gel column chromatography point
Orange red powder (1) 118mg, yield 94% are eluted to obtain from, chloroform.1H NMR(600MHz,DMSO-d6)δ11.00(s,1H,
), imide-NH 7.87 (s, 1H, Ar-H), 7.82 (s, 1H, Ar-H), 7.57 (d, 1H, J=8.2Hz, Ar-H), 7.48 (d, 1H,
J=8.2Hz, Ar-H), 7.15 (t, 1H, J=8.3Hz, Ar-H), 7.05 (t, 1H, J=7.4Hz, Ar-H), 6.83 (d, 1H, J
=8.3Hz, Ar-H), 6.80 (d, 1H, J=8.2Hz, Ar-H), 6.75 (t, 1H, J=7.8Hz, Ar-H), 6.68 (t, 1H, J=
7.8Hz,Ar-H),5.64(s,2H,N-CH 2- CN), 4.26 (q, 2H, J=7.3Hz ,-CH 2-CH3), 1.32 (t, 3H, J=
7.3Hz,-CH2-CH 3).13C NMR(150MHz,DMSO-d6)δ172.7,172.6,135.5,135.4,131.8,131.4,
129.1,126.0,125.8,122.6,121.8,121.5,121.2,121.0,120.4,119.6,116.1,110.1,
110.0,106.8,104.6,40.7,34.0,15.2.ESI-MS m/z 395.2[M+H]+.
The preparation of compound 2
I) preparation of 1- cyanoethyl indoles (2b)
According to the preparation method of compound 1b, (360mg, 9.0mmol are dispersed in paraffin sodium hydride, mass fraction
60%), indoles (702mg, 6.0mmol) and 3- bromo propionitrile (744 μ L, 9.0mmol) are raw material preparation, through silica gel column chromatography point
From, petroleum ether: ethyl acetate=15:1 (v/v) elutes to obtain colorless oil as product (2b) 949mg, yield 94%.1H NMR
(600MHz,CDCl3) δ 7.65 (d, 1H, J=7.8Hz, Ar-H), 7.30 (d, 1H, J=7.8Hz, Ar-H), 7.25 (t, 1H, J
=7.8Hz, Ar-H), 7.15 (t, 1H, J=6.8Hz, Ar-H), 7.13 (d, 1H, J=3.2Hz, Ar-H), 6.55 (d, 1H, J=
3.2, Ar-H), 4.42 (t, 2H, J=6.9Hz, N-CH 2-CH2), CN 2.78 (t, 2H, J=J=6.9Hz, NCH2-CH2 -CN)
.13C NMR(150MHz,CDCl3)δ135.4,129.1,127.5,122.3,121.6,120.2,117.4,108.7,103.0,
42.2,19.2.
Ii) the preparation of 2- (1- ethyl -3- indoles) -3- (1- cyanoethyl -3- indoles) maleic anhydride (2c)
According to the preparation method of compound 1c, by compound 2b (988mg, 5.81mmol), oxalyl chloride (1107mg,
8.72mmol), 1a (1180mg, 5.81mmol) and triethylamine (1176mg, 11.64mmol) preparation, separated through silica gel column chromatography,
Petroleum ether: ethyl acetate=2:1 (v/v) elutes to obtain red powder (2c) 530mg, yield 23%.1H NMR(600MHz,CDCl3)
δ 7.84 (s, 1H, Ar-H), 7.66 (s, 1H, Ar-H), 7.35 (d, 1H, J=8.3Hz, Ar-H), 7.34 (d, 1H, J=8.3Hz,
), Ar-H 7.22 (dt, 1H, J=7.3Hz, 1.0Hz, Ar-H), 7.16 (dt, 1H, J=7.5Hz, 1.4Hz, Ar-H), 7.11 (d,
1H, J=7.8Hz, Ar-H), 6.90 (dt, 1H, J=7.8Hz, 1.0Hz, Ar-H), 6.89 (d, 1H, J=8.2Hz, Ar-H),
6.82 (dt, 1H, J=7.3Hz, 1.0Hz, Ar-H), 4.47 (t, 2H, J=6.9Hz, N-CH 2-CH2- CN), 4.23 (q, 2H, J=
7.3Hz,-CH 2-CH3), 2.85 (t, 2H, J=6.9Hz ,-NCH2-CH 2- CN), 1.51 (t, 3H, J=7.3Hz ,-CH2-CH 3)
.13C NMR(150MHz,CDCl3)δ166.7,166.6,136.2,135.5,132.8,131.5,129.6,126.2,126.0,
125.6,123.4,122.9,122.8,122.5,121.3,120.8,116.5,110.0,109.1,106.7,105.0,42.4,
41.7,19.0,15.1.ESI-MS m/z 410.2[M+H]+.
Iii) the preparation of 2- (1- ethyl -3- indoles) -3- (1- cyanoethyl -3- indoles) maleimide (2d)
According to the preparation method of compound 1, by compound 2c (230mg, 0.56mmol), HMDS (12mL, 57mmol) and
MeOH (1.2mL, 28.5mmol) preparation elutes to obtain orange red powder (2d) 219mg, yield through silica gel column chromatography separation, chloroform
95%.1H NMR(600MHz,CDCl3)δ7.75(s,1H,Ar-H),7.58(s,1H,Ar-H),7.51(s,1H,-NH),7.31
(d, 1H, J=8.2Hz, Ar-H), 7.29 (d, 1H, J=8.2Hz, Ar-H), 7.16 (t, 1H, J=7.3Hz, Ar-H), 7.11
(t, 1H, J=8.2Hz, Ar-H), 7.09 (d, 1H, J=8.2Hz, Ar-H), 6.88 (d, 1H, J=8.2Hz, Ar-H), 6.85
(t, 1H, J=7.4Hz, Ar-H), 6.77 (t, 1H, J=7.3Hz, Ar-H), 4.45 (t, 2H, J=6.9Hz, N-CH 2-CH2CN),
4.20 (q, 2H, J=7.3Hz ,-CH 2-CH3), 2.80 (t, 2H, J=6.9Hz ,-NCH2-CH 2- CN), 1.48 (t, 3H, J=
7.3Hz,-CH2CH 3).13C NMR(150MHz,CDCl3)δ171.8,171.7,136.0,135.4,131.7,130.6,129.5,
126.6,126.3,125.9,123.0,122.7,122.3,122.2,120.8,120.2,116.7,109.6,108.8,
107.3,105.4,42.3,41.5,18.9,15.2.ESIMS:m/z 407.1[M–H]–.
Iv) the preparation of N- methylol -2- (1- ethyl -3- indoles) -3- (1- cyanoethyl -3- indoles) maleimide (2)
Compound 2d (16.2mg, 39.7 μm of ol) and NaHCO are added in 15mL reaction flask3(6.7mg, 79.4 μm of ol),
Be added formalin (3mL, mass fraction 37%), 85 DEG C be stirred to react 10 hours after pour into cold water.Ethyl acetate extraction, is closed
And organic layer, and use anhydrous Na2SO4It is dry, evaporated in vacuo, silica gel column chromatography separation, petroleum ether: ethyl acetate=3:1 (v/v)
Elute to obtain red powder (2) 17.1mg, yield 98%.1H NMR(600MHz,DMSO-d6)δ7.93(s,1H,Ar-H),7.85
(s, 1H, Ar-H), 7.59 (d, 1H, J=8.2Hz, Ar-H), 7.47 (d, 1H, J=8.3Hz, Ar-H), 7.06 (dt, 1H, J=
7.8Hz, 0.9Hz, Ar-H), 7.04 (dt, 1H, J=7.3Hz, 1.0Hz, Ar-H), 6.83 (d, 1H, J=8.3Hz, Ar-H),
6.78 (d, 1H, J=8.3Hz, Ar-H), 6.69 (dt, 1H, J=7.3Hz, 1.0Hz, Ar-H), 6.68 (dt, 1H, J=7.8Hz,
0.9Hz, Ar-H), 6.31 (t, 1H, J=7.0Hz ,-OH), 4.98 (d, 2H, J=6.9Hz, N-CH 2-OH),4.59(t,2H,J
=6.4Hz, N-CH 2-CH2), CN 4.26 (q, 2H, J=7.3Hz, CH 2-CH3), 3.03 (t, 2H, J=6.4Hz, N-CH2-CH 2-
), CN 1.34 (t, 3H, J=7.3Hz ,-CH2CH 3).13C NMR(150MHz,DMSO-d6)δ171.5,171.4,136.2,
136.1,132.3,132.2,128.4,126.7,126.5,126.4,122.6,122.3,121.9,121.7,120.5,
120.3,119.0,110.9,110.7,106.2,105.3,60.8,42.0,41.3,19.1,15.8.ESI-MS m/z 439.2
[M+H]+.
The preparation of compound 3
I) preparation of 1- cyanogen propyl indole (3b)
According to the preparation method of compound 1b, by indoles (1170mg, 10mmol), NaH (600mg, 15mmol, quality point
Number 60%, is dispersed in paraffin) and 4- bromobutyronitrile (1.6mL, 15mmol) preparation, silica gel column chromatography separation, petroleum ether: acetic acid
Ethyl ester=20:1 (v/v) elutes to obtain colorless oil as product (3b) 1042mg, yield 57%.1H NMR(600MHz,CDCl3)δ7.70
(d, 1H, J=7.7Hz, Ar-H), 7.38 (d, 1H, J=8.3Hz, Ar-H), 7.29 (t, 1H, J=7.7Hz, Ar-H), 7.19
(t, 1H, J=7.4Hz, Ar-H), 7.12 (d, 1H, J=3.3Hz, Ar-H), 6.58 (d, 1H, J=3.3Hz, Ar-H), 4.28
(t, 2H, J=6.6Hz, N-CH2 -(CH2)2), CN 2.19 (t, 2H, J=5.5Hz, N (CH2)2-CH2 -CN),2.16-2.14(m,
2H,-NCH2-CH2 -CH2CN)。13C NMR(150MHz,CDCl3)δ135.9,128.9,127.8,122.1,121.4,119.9,
119.0,109.3,102.2,44.5,26.1,14.7.ESI-MS m/z 185.1[M+H]+.ii) 2- (1- ethyl -3- indoles) -
The preparation of 3- (1- cyanogen propyl -3- indoles) maleic anhydride (3c)
According to the preparation method of compound 1c, by 3b (407mg, 2.21mmol), oxalyl chloride (421mg, 3.32mmol), change
Object 1a (449mg, 2.21mmol) and triethylamine (447mg, 4.42mmol) preparation are closed, silica gel column chromatography separation, chloroform elute
Red powder (3c) 415mg, yield 45%.1H NMR(600MHz,DMSO-d6)δ7.89(s,1H,Ar-H),7.88(s,1H,
), Ar-H 7.57 (d, 1H, J=8.8Hz, Ar-H), 7.54 (d, 1H, J=8.2Hz, Ar-H), 7.14 (t, 1H, J=8.2Hz,
), Ar-H 7.12 (t, 1H, J=7.7Hz, Ar-H), 6.94 (d, 1H, J=8.3Hz, Ar-H), 6.91 (d, 1H, J=8.3Hz,
), Ar-H 6.80 (t, 1H, J=7.1Hz, Ar-H), 6.79 (t, 1H, J=7.1Hz, Ar-H), 4.33 (t, 2H, J=7.1Hz, N-
CH 2-(CH2)2), CN 4.26 (q, 2H, J=7.1Hz ,-CH 2-CH3), 2.44 (t, 2H, J=7.4Hz, N (CH2)2-CH 2-CN),
2.06-2.04(m,2H,-NCH2-CH 2-CH2), CN 1.32 (t, 3H, J=7.1Hz ,-CH2-CH 3)。13C NMR(150MHz,
DMSO-d6)δ166.9×2,136.6,136.3,133.6,133.5,128.8,127.8,125.8,125.7,122.9,
122.8,122.3,122.2,120.8,120.7,120.4,111.1,111.0,105.2,104.7,55.5,40.4,26.1,
15.7,14.3.ESI-MS m/z424.2[M+H]+.
III) 2- (1- ethyl -3- indoles) -3- (1- cyanogen propyl -3- indoles) maleimide (3) preparation
According to the preparation method of compound 1, by 3c (205mg, 0.49mmol), HMDS (10.2mL, 48.5mmol) and
MeOH (0.97mL, 24.3mmol) preparation, silica gel column chromatography separation, chloroform elute to obtain orange red powder (3) 203mg, yield
98%.1H NMR(600MHz,DMSO-d6)δ10.94(s,1H,imide-NH),7.78(s,1H,Ar-H),7.74(s,1H,Ar-
), H 7.50 (d, 1H, J=8.3Hz, Ar-H), 7.47 (d, 1H, J=8.3Hz, Ar-H), 7.07 (dt, 1H, J=7.1Hz,
1.1Hz, Ar-H), 7.05 (dt, 1H, J=7.1Hz, 1.1Hz, Ar-H), 6.86 (d, 1H, J=7.7Hz, Ar-H), 6.85 (d,
1H, J=7.7Hz, Ar-H), 6.71 (t, 1H, J=7.7Hz, Ar-H), 6.69 (t, 1H, J=7.1Hz, Ar-H), 4.29 (t,
2H, J=6.6Hz, N-CH 2-(CH2)2), CN 4.24 (q, 2H, J=7.2Hz ,-CH 2-CH3), 2.40 (t, 2H, J=7.1Hz, N
(CH2)2-CH 2-CN),2.05-2.03(m,2H,NCH2-CH 2-CH2), CN 1.32 (t, 3H, J=7.2Hz ,-CH2-CH 3).13C
NMR(150MHz,DMSO-d6)δ173.4×2,136.4,136.1,132.4,132.2,128.5,127.6,126.3,126.2,
122.4,122.3,122.0,121.9,120.5,120.3,120.0,110.7,110.6,105.9,105.3,45.0,41.2,
26.2,15.8,14.3.HR-ESIMS m/z 421.1645[M–H]–(calcd.for C26H21N4O2,421.1665).
The preparation of compound 4
According to the preparation method of compound 2, by compound 3 (6.3mg, 13.9 μm of ol), NaHCO3(2.3mg,27.9μ
Mol it) is prepared with formalin (3mL, mass fraction 37%), silica gel column chromatography separation, petroleum ether: ethyl acetate=3:1 (v/v)
Elute to obtain red powder N- methylol -2- (1- ethyl -3- indoles) -3- (1- cyanogen propyl -3- indoles) maleimide (4)
6.8mg, yield 99%.1H NMR(600MHz,CDCl3)δ7.74(s,1H,Ar-H),7.50(s,1H,Ar-H),7.33(d,1H,
J=5.5Hz, Ar-H), 7.32 (d, 1H, J=5.5Hz, Ar-H), 7.17-7.15 (m, 2H, Ar-H), 7.11 (t, 1H, J=
7.3Hz, Ar-H), 6.88 (d, 2H, J=7.3Hz, Ar-H), 6.74 (t, 1H, J=7.3Hz, Ar-H), 5.25 (d, 2H, J=
7.8Hz,N-CH 2- OH), 4.27 (t, 2H, J=6.4Hz, N-CH 2-(CH2)2), CN 4.20 (q, 2H, J=7.3Hz, N-CH 2-
CH3), 3.15 (brs, 1H ,-OH), 2.17 (t, 2H, J=5.9Hz, N (CH2)2-CH 2-CN),2.13-2.11(m,2H,NCH2-
CH 2-CH2), CN 1.48 (t, 3H, J=7.3Hz ,-CH2-CH 3).13C NMR(150MHz,CDCl3)δ171.8,171.7,
136.2,136.1,131.7,131.2,128.5,126.4,126.3,125.9,122.9,122.8,122.4,122.3,
120.7,120.2,118.6,109.9,109.3,106.7,105.5,61.9,44.8,41.6,25.9,15.3,14.6.ESI-
MS m/z 475.1[M+Na]+.
The preparation of compound 5
I) preparation of 1- cyanogen indole-butyl (5b)
According to the preparation method of compound 1b, by indoles (585mg, 5mmol), NaH (300mg, 7.5mmol, mass fraction
60%, be dispersed in paraffin) and 5- bromo valeronitrile (880 μ L, 7.5mmol) preparation, silica gel column chromatography separation, petroleum ether: acetic acid
Ethyl ester=10:1 (v/v) elutes to obtain colorless oil as product (5b) 627mg, yield 83%.1H NMR(600MHz,DMSO-d6)δ
7.68 (d, 1H, J=8.0Hz, Ar-H), 7.35 (d, 1H, J=8.4Hz, Ar-H), 7.26 (t, 1H, J=7.7Hz, Ar-H),
7.16 (t, 1H, J=7.3Hz, Ar-H), 7.12 (d, 1H, J=2.7Hz, Ar-H), 6.58 (d, 1H, J=2.7Hz, Ar-H),
4.17 (t, 2H, J=6.8Hz, N-CH 2-(CH2)3), CN 2.26 (t, 2H, J=7.3Hz, N (CH2)3-CH 2-CN),1.98-1.93
(m,2H,NCH2-CH 2-(CH2)2CN),1.61-1.54(m,2H,N(CH2)2-CH 2-CH2CN).13C NMR(150MHz,DMSO-
d6)δ136.0,128.8,127.7,121.8,121.3,119.6,119.4,109.3,101.7,45.5,29.4,23.0,
17.0.
Ii) the preparation of 2- (1- ethyl -3- indoles) -3- (1- cyanogen butyl -3- indoles) maleic anhydride (5c)
According to the preparation method of compound 1c, by 5b (627mg, 3.17mmol), oxalyl chloride (604mg, 4.76mmol), change
Close object 1a (644mg, 3.17mmol) and triethylamine (640mg, 6.34mmol) preparation, silica gel column chromatography separation, petroleum ether: acetic acid
Ethyl ester=2:1 (v/v) elution, obtains red powder (5c) 712mg, yield 51%.1H NMR(600MHz,DMSO-d6)δ7.91(s,
1H, Ar-H), 7.90 (s, 1H, Ar-H), 7.56 (d, 1H, J=8.3Hz, Ar-H), 7.53 (d, 1H, J=8.3Hz, Ar-H),
7.11 (dt, 1H, J=7.5Hz, 1.0Hz, Ar-H), 7.10 (dt, 1H, J=7.8Hz, 0.9Hz, Ar-H), 6.88 (d, 1H, J=
8.3Hz, Ar-H), 6.86 (d, 1H, J=8.7Hz, Ar-H), 6.76 (dt, 1H, J=7.8Hz, 1.0Hz, Ar-H), 6.75 (dt,
1H, J=7.4Hz, 0.9Hz, Ar-H), 4.30 (t, 2H, J=6.9Hz, N-CH 2-(CH2)3CN), 4.28 (q, 2H, J=7.3Hz,
N-CH 2-CH3), 2.51 (t, 2H, J=7.3Hz, N (CH2)3-CH 2-CN),1.84-1.81(m,2H,NCH2-CH 2-(CH2)2CN),
1.50-1.48(m,2H,N(CH2)2-CH 2-CH2), CN 1.34 (t, 3H, J=7.3Hz ,-CH2-CH 3).13C NMR(150MHz,
DMSO-d6)δ166.9×2,136.5,136.3,133.7,133.3,128.5,127.9,125.9×2,122.8,122.7,
122.1×2,121.0,120.7,120.6,111.2,111.1,104.9,104.8,45.7,41.5,29.3,22.7,16.4,
15.7.ESI-MS m/z 438.1[M+H]+.
III) 2- (1- ethyl -3- indoles) -3- (1- cyanogen butyl -3- indoles) maleimide (5) preparation
With the preparation method of compound 1, by 5c (616mg, 1.14mmol), HMDS (12mL, 57mmol) and MeOH
(1.14mL, 28.5mmol) preparation, silica gel column chromatography separation, chloroform elute to obtain orange red powder (5) 585mg, yield 95%.1H
NMR(600MHz,DMSO-d6)δ10.92(s,1H,imide-NH),7.80(s,1H,Ar-H),7.77(s,1H,Ar-H),7.50
(d, 1H, J=8.2Hz, Ar-H), 7.47 (d, 1H, J=8.2Hz, Ar-H), 7.04 (dt, 1H, J=7.4Hz, 0.9Hz, Ar-
), H 7.03 (dt, 1H, J=7.8Hz, 1.0Hz, Ar-H), 6.81 (d, 1H, J=8.2Hz, Ar-H), 6.79 (d, 1H, J=
7.8Hz, Ar-H), 6.67 (dt, 1H, J=7.4Hz, 0.9Hz, Ar-H), 6.65 (dt, 1H, J=7.8Hz, 1.0Hz, Ar-H),
4.28 (t, 2H, J=6.8Hz, N-CH 2-(CH2)3), CN 4.26 (q, 2H, J=7.3Hz, N-CH 2-CH3), 2.52 (t, 2H, J=
7.3Hz,N(CH2)3-CH 2-CN),1.82-1.79(m,2H,NCH2-CH 2-(CH2)2CN),1.50-1.47(m,2H,N(CH2)2-
CH 2-CH2), CN 1.34 (t, 3H, J=7.3Hz ,-CH2CH 3).13C NMR(150MHz,DMSO-d6)δ173.4×2,136.3,
136.0,132.4,132.0,128.8,128.2×2,127.7,126.4,122.3,122.2 121.8,121.0×2,
120.0,110.8,110.7,105.6,105.4,45.5,41.3,29.3,22.7,16.4,15.8.ESI-MS m/z 437.1
[M+H]+.
The preparation of compound 6
According to the preparation method of compound 2, by compound 5 (6.7mg, 14.4 μm of ol), NaHCO3(2.4mg,28.8μ
Mol it) is prepared with formalin (3mL, mass fraction 37%), through silica gel column chromatography separation, petroleum ether: ethyl acetate=5:2 (v/
V) red powder N- methylol -2- (1- ethyl -3- indoles) -3- (1- cyanogen butyl -3- indoles) maleimide (6) is eluted to obtain
6.9mg, yield 96%.1H NMR(600MHz,CDCl3)δ7.70(s,1H,Ar-H),7.55(s,1H,Ar-H),7.32(d,1H,
J=8.2Hz, Ar-H), 7.27 (d, 1H, J=8.3Hz, Ar-H), 7.13 (dt, 1H, J=7.8Hz, 1.0Hz, Ar-H), 7.11
(dt, 1H, J=7.8Hz, 1.0Hz, Ar-H), 7.06 (d, 1H, J=7.8Hz, Ar-H), 6.91 (d, 1H, J=7.8Hz, Ar-
), H 6.81 (d, 1H, J=7.8Hz, Ar-H), 6.74 (d, 1H, J=7.8Hz, Ar-H), 5.25 (d, 2H, J=7.8Hz, N-
CH 2- OH), 4.19 (q, 2H, J=7.3Hz, N-CH 2-CH3), 4.15 (t, 2H, J=6.4Hz, N-CH 2-(CH2)3CN),3.34
(t, 1H, J=7.8Hz ,-OH), 2.27 (t, 2H, J=6.8Hz, N (CH2)3-CH 2-CN),1.90-1.94(m,2H,NCH2-CH 2-
(CH2)2CN),1.57-1.51(m,2H,N(CH2)2-CH 2-CH2), CN 1.47 (t, 3H, J=7.3Hz ,-CH2-CH 3).13C NMR
(150MHz,CDCl3)δ171.9×2,136.1×2,131.5×2,127.9,126.7,126.3,126.0,122.7,
122.6,122.5,122.3,120.5,120.2,119.2,109.7,109.5,106.2,105.6,61.8,45.8,41.6,
29.0,22.8,17.0,15.2.ESI-MS m/z489.1[M+Na]+.
The preparation of compound 7
I) 1- cyanogen methyl -3-indolyl acetic acid (7a) preparation
Under argon gas protection, in 100mL there-necked flask, (1028mg, 25.7mmol, mass fraction 60%, are dispersed in plus hydrogenated sodium
In paraffin) in 40mL DMF, in -5 DEG C of stirring suspensions, be added 10mL DMF dissolution 3-indolyl acetic acid (900mg,
5.14mmol), after stirring 30min, the bromoacetonitrile (1.03mL, 15.4mmol) of 10mL DMF dissolution is added dropwise, is slowly increased to room temperature,
After reaction overnight, be down to 0 DEG C hereinafter, be added dropwise 10mL methanol, then plus suitable quantity of water to bright yellow solution, with 30mL ether extraction remove
Deparaffnize oil, water layer are acidified to faintly acid with 6N hydrochloric acid, and ethyl acetate extracts (100mL × 3 time), combined ethyl acetate layer, nothing
Water Na2SO4Dry, evaporated in vacuo elutes to obtain white crystal (7a) by the separation of Sephadex LH-20 gel column chromatography, methanol
314mg, yield 29%.1H NMR(600MHz,DMSO-d6)δ12.33(s,1H,-CO2 H), 7.58 (d, 1H, J=8.3Hz, Ar-
), H 7.56 (d, 1H, J=8.2Hz, Ar-H), 7.36 (s, 1H, Ar-H), 7.26 (dt, 1H, J=7.8Hz, 1.0Hz, Ar-H),
7.13 (dt, 1H, J=7.4Hz, 0.9Hz, Ar-H), 5.52 (s, 2H ,-CH2 -CN),3.69(s,2H,-CH2 -CO2H).13C NMR
(150MHz,DMSO-d6)δ173.4,136.3,128.7,127.6,122.8,120.4,119.9,117.2,110.3,110.2,
34.2,31.1.
Ii) prepared by (the 1- cyanogen methyl -3- indoles) maleic anhydride (7b) of 2,3- bis-
According to the preparation method of compound 1c, by compound 1b (226mg, 1.45mmol), oxalyl chloride (274mg,
2.18mmol), compound 7a (310mg, 1.45mmol) and triethylamine (293mg, 2.9mmol) are raw material preparation, through silicagel column
Chromatographic isolation, petroleum ether: ethyl acetate=3:1 (v/v) elutes to obtain red powder (7b) 235mg, yield 40%.1H NMR
(600MHz,DMSO-d6) δ 8.05 (s, 2H, Ar-H), 7.64 (d, 2H, J=8.3Hz, Ar-H), 7.22 (dt, 2H, J=
7.6Hz, 1.2Hz, Ar-H), 6.89 (d, 2H, J=7.9Hz, Ar-H), 6.84 (dt, 2H, J=7.9Hz, 0.8Hz, Ar-H),
5.69(s,4H,-CH2 -CN).13C NMR(150MHz,DMSO-d6)δ166.0×2,135.6×2,132.9×2,128.6×
2,125.5×2,123.2×2,121.6×2,121.1×2,115.9×2,110.4×2,105.8×2,34.2×2.ESI-
MS m/z 407.2[M+H]+.
Iii) the preparation of 2,3- bis- (1- cyanogen methyl -3- indoles) maleimide (7)
According to the preparation method of compound 1, by compound 7b (200mg, 0.49mmol), HMDS (4.1mL, 19.6mmol)
It is prepared with MeOH (0.39mL, 9.8mmol), through silica gel column chromatography separation, petroleum ether: ethyl acetate=2:1 (v/v) elutes orange
Red powder (7) 183mg, yield 92%.1H NMR(600MHz,DMSO-d6)δ11.10(s,1H,imide-NH),7.94(s,
2H, Ar-H), 7.58 (d, 2H, J=8.3Hz, Ar-H), 7.15 (dt, 2H, J=7.4Hz, 1.1Hz, Ar-H), 6.82 (d, 2H, J
=8.0Hz, Ar-H), 6.75 (dt, 2H, J=7.0Hz, 0.8Hz, Ar-H), 5.65 (s, 4H ,-CH2 -CN).13C NMR
(150MHz,DMSO-d6)δ172.4×2,135.5×2,131.8×2,127.8×2,126.1×2,122.7×2,121.3
×2,120.6×2,116.1×2,110.1×2,106.5×2,34.1×2.ESI-MS m/z406.1[M+H]+.
The preparation of compound 8
I) 1- cyanogen propyl -3-indolyl acetic acid (8a) preparation
According to the preparation method of compound 7a, heteroauxin (1.4g, 8mmol), NaH (1.6g, 40mmol, mass fraction
60%, be dispersed in paraffin) and bromine butyronitrile (2.4mL, 24mmol) be made for raw material, through silica gel column chromatography separation, petroleum ether: second
Acetoacetic ester=3:1 (v/v) elutes to obtain white crystal (8a) 541mg, yield 30%.1H NMR(600MHz,DMSO-d6)δ7.54
(d, 1H, J=7.3Hz, Ar-H), 7.42 (d, 1H, J=7.7Hz, Ar-H), 7.22 (s, 1H, Ar-H), 7.12 (t, 1H, J=
7.3Hz, Ar-H), 7.00 (1H, t, J=7.3Hz, Ar-H), 4.17 (t, 2H, J=6.9Hz, N-CH2 -(CH2)2CN),3.53
(s,2H,-CH2 -CO2), H 2.43 (t, 2H, J=6.9Hz, N (CH2)2-CH2 -CN),2.03-2.01(2H,m,NCH2-CH2 -
CH2CN).13C NMR(150MHz,DMSO-d6)δ175.0,136.3,128.6,127.2,121.6,120.7,119.9,
119.0,110.4,109.8,44.5,33.2,26.4,14.4.ESI-MS m/z 241.1[M–H]–.
Ii) the preparation of 2,3- bis- (1- cyanogen propyl -3- indoles) maleic anhydride (8b)
According to the preparation method of compound 1c, compound 3b (452mg, 2.46mmol), oxalyl chloride (469mg,
3.69mmol), compound 8a (595mg, 2.46mmol) and triethylamine (497mg, 4.92mmol) are made for raw material, through silicagel column
Chromatographic isolation, petroleum ether: ethyl acetate=1:1 (v/v) elutes to obtain red powder (8b) 500mg, yield 44%1H NMR
(600MHz,DMSO-d6) δ 7.88 (s, 2H, Ar-H), 7.57 (d, 2H, J=8.4Hz, Ar-H), 7.14 (dt, 2H, J=
7.8Hz, 0.9Hz, Ar-H), 6.95 (d, 2H, J=8.4Hz, Ar-H), 6.81 (dt, 2H, J=7.8Hz, 0.9Hz, Ar-H),
4.30 (t, 4H, J=6.9Hz, N-CH2 -(CH2)2), CN 2.42 (t, 4H, J=7.3Hz, N (CH2)2-CH2 -CN),2.05-2.02
(m,4H,NCH2-CH2 -CH2CN).13C NMR(150MHz,DMSO-d6)δ166.8×2,136.6×2,133.7×2,128.5
×2,125.7×2,123.0×2,122.2×2,120.8×2,120.4×2,111.1×2,105.1×2,45.3×2,
26.1×2,14.3×2.ESI-MS m/z 463.2[M+H]+.
Iii) the preparation of 2,3- bis- (1- cyanogen propyl -3- indoles) maleimide (8)
According to the preparation method of compound 1, by compound 8b (375mg, 0.81mmol), HMDS (6.8mL, 32.5mmol)
It is prepared with MeOH (0.66mL, 16.2mmol), through silica gel column chromatography separation, petroleum ether: ethyl acetate=2:1 (v/v) elutes
Orange red powder (8) 341mg, yield 91%.1H NMR(600MHz,DMSO-d6)δ10.98(s,1H,imide-NH),7.76
(s, 2H, Ar-H), 7.50 (d, 2H, J=8.2Hz, Ar-H), 7.08 (dt, 2H, J=7.8Hz, 0.9Hz, Ar-H), 6.90 (d,
2H, J=8.2Hz, Ar-H), 6.73 (dt, 2H, J=7.4Hz, 0.9Hz, Ar-H), 4.28 (t, 4H, J=6.9Hz, N-CH2 -
(CH2)2), CN 2.38 (4H, t, J=7.3Hz, N (CH2)2-CH2 -CN),2.04-2.02(m,4H,NCH2-CH2 -CH2CN).13C
NMR(150MHz,DMSO-d6)δ173.3×2,136.4×2,132.5×2,128.2×2,126.2×2,122.5×2,
121.9×2,120.5×2,120.2×2,110.7×2,105.8×2,45.0×2,26.1×2,14.3×2.HR-ESIMS
m/z 460.1769[M–H]–(calcd.for C28H22N5O2,460.1774).
The preparation of compound 9
I) preparation of 1- cyanogen indole-butyl -3- acetic acid (9a)
According to the preparation method of compound 7a, heteroauxin (1.4g, 8mmol), NaH (1.6g, 40mmol, 60% dispersion
In paraffin) and bromine valeronitrile (2mL, 16mmol) for raw material be made, through silica gel column chromatography separation, petroleum ether: ethyl acetate=3:1
(v/v) white crystal (9a) 1.69g, yield 83% are eluted to obtain.1H NMR(600MHz,DMSO-d6)δ12.30(s,1H,-
CO2 H), 7.59 (d, 1H, J=7.8Hz, Ar-H), 7.45 (d, 1H, J=8.2Hz, Ar-H), 7.27 (s, 1H, Ar-H), 7.18
(dt, 1H, J=7.8Hz, 0.9Hz, Ar-H), 7.08 (dt, 1H, J=7.8Hz, 0.9Hz, Ar-H), 4.13 (t, 2H, J=
6.9Hz,N-CH 2-(CH2)3CN),3.72(s,2H,-CH2 -CO2), H 2.44 (t, 2H, J=6.9Hz, N (CH2)3-CH2 -CN),
1.81-1.79(m,2H,NCH2-CH 2-(CH2)2CN),1.51-1.48(m,2H,N(CH2)2-CH2 -CH2CN).13C NMR
(150MHz,DMSO-d6)δ173.7,136.4,128.2,127.7,121.8,121.0,119.6,119.2,110.2,107.9,
45.1,31.4,29.6,22.8,16.3.ESI-MS m/z 255.1[M–H]–.
Ii) the preparation of 2,3- bis- (1- cyanogen butyl -3- indoles) maleic anhydride (9b)
According to the preparation method of compound 1c, compound 5b (1140mg, 5.76mmol), oxalyl chloride (1097mg,
8.64mmol), compound 9a (1470mg, 5.76mmol) and triethylamine (1163mg, 11.5mmol) are raw material preparation, through silica gel
Pillar layer separation, petroleum ether: ethyl acetate=2:1 (v/v) elutes to obtain product red powder (9b) 900mg, yield 32%.1H
NMR(600MHz,DMSO-d6) δ 7.93 (s, 2H, Ar-H), 7.55 (d, 2H, J=8.3Hz, Ar-H), 7.09 (t, 2H, J=
7.3Hz, Ar-H), 6.83 (d, 2H, J=8.3Hz, Ar-H), 6.73 (2H, t, J=7.4Hz, Ar-H), 4.32 (t, 4H, J=
6.9Hz,N-CH 2-(CH2)3), CN 2.52 (t, 4H, J=7.3Hz, N (CH2)3-CH2 -CN),1.85-1.83(m,4H,NCH2-
CH 2-(CH2)2CN),1.51-1.48(m,4H,N(CH2)2-CH2 -CH2CN).13C NMR(150MHz,DMSO-d6)δ166.9×
2,136.4×2,133.6×2,128.3×2,126.0×2,122.8×2,121.9×2,121.0×2,120.6×2,
111.2×2,104.9×2,45.7×2,29.3×2,22.7×2,16.4×2.ESI-MS m/z 491.2[M+H]+.
Iii) the preparation of 2,3- bis- (1- cyanogen butyl -3- indoles) maleimide (9)
According to the preparation method of compound 1, by compound 9b (470mg, 0.96mmol), HMDS (8.1mL, 38.4mmol)
It is raw material preparation with MeOH (0.77mL, 19.2mmol), through silica gel column chromatography separation, petroleum ether: ethyl acetate=3:2 (v/v)
Elute to obtain orange red powder (9) 426mg, yield 90%.1H NMR(600MHz,DMSO-d6)δ10.93(s,1H,imide-NH),
7.80 (s, 2H, Ar-H), 7.48 (d, 2H, J=8.2Hz, Ar-H), 7.02 (dt, 2H, J=7.8Hz, 1.0Hz, Ar-H), 6.77
(d, 2H, J=8.2Hz, Ar-H), 6.63 (dt, 2H, J=7.4Hz, 0.9Hz, Ar-H), 4.29 (t, 4H, J=6.9Hz, N-
CH 2-(CH2)3), CN 2.51 (t, 4H, J=7.3Hz, N (CH2)3-CH2 -CN),1.83-1.81(m,4H,NCH2-CH 2-(CH2)2CN),1.50-1.48(m,4H,N(CH2)2-CH2 -CH2CN).13C NMR(150MHz,DMSO-d6)δ173.4×2,136.3×
2,132.4×2,128.0×2,126.5×2,122.3×2,121.6×2,121.0×2,120.0×2,110.8×2,
105.6×2,45.5×2,29.3×2,22.7×2,16.3×2.ESI-MS m/z 488.2[M–H]–.
The preparation of compound 10
Compound 1 (50mg, 0.127mmol) is used into 10mL acetic acid in 25mL single port bottle: concentrated hydrochloric acid=3:1 (v/v)
Mixed liquor dissolves, and after 120 DEG C of reflux 30min, is down to room temperature, adds water and ethyl acetate to extract, organic layer is evaporated, silica gel column chromatography
Separation, dichloromethane eluent obtain red solid 2- (1- ethyl -3- indoles) -3- (1- carboxymethyl -3- indoles) maleimide
(10) 50mg, yield 95%.1H NMR(600MHz,DMSO-d6)δ10.97(brs,1H,imide-NH),7.88(s,1H,Ar-
), H 7.66 (s, 1H, Ar-H), 7.45 (d, 1H, J=8.2Hz, Ar-H), 7.32 (d, 1H, J=8.2Hz, Ar-H), 7.04 (t,
1H, J=7.1Hz, Ar-H), 7.02 (d, 1H, J=8.2Hz, Ar-H), 6.97 (t, 1H, J=8.2Hz, Ar-H), 6.72 (t,
1H, J=7.1Hz, Ar-H), 6.60 (d, 1H, J=7.7Hz, Ar-H), 6.58 (t, 1H, J=7.7Hz, Ar-H), 4.86 (s,
2H,-CH2 -CO2), H 4.21 (q, 2H, J=7.2Hz ,-CH2 -CH3), 1.27 (t, 3H, J=7.2Hz ,-CH2-CH3 ).13C NMR
(150MHz,DMSO-d6)δ173.6,173.5,172.2,137.2,135.9,134.2,131.7,128.1,127.2,126.9,
126.0,122.2,122.1,122.0,121.7,120.1,119.9,111.0,110.5,105.6,105.2,49.9,41.1,
15.8.ESI-MSm/z 412.0[M–H]–.
The preparation of compound 11
In 50mL two-mouth bottle, with 10mL DMF suspension NaH, (68mg, 1.7mmol, mass fraction 60%, are dispersed in paraffin
In), it is added the compound 1 (200mg, 0.56mmol) of 10mL DMF dissolution under -5 DEG C of stirring conditions, after low-temp reaction 30min,
Bromoacetonitrile (114 μ L, 1.7mmol), low-temp reaction 30min is slowly added dropwise.Saturation NH is added dropwise4Cl solution terminates reaction, acetic acid
Ethyl ester extraction, organic layer concentration, gel column chromatography separation, methanol elute to obtain red solid powder N- cyanogen methyl -2- (1- ethyl -
3- indoles) -3- (1- cyanogen methyl -3- indoles) maleimide (11) 161mg, yield 66%.1H NMR(600MHz,DMSO-d6)
δ 7.93 (s, 1H, Ar-H), 7.89 (s, 1H, Ar-H), 7.60 (d, 1H, J=8.2Hz, Ar-H), 7.50 (d, 1H, J=8.2Hz,
), Ar-H 7.18 (t, 1H, J=7.1Hz, Ar-H), 7.08 (t, 1H, J=7.2Hz, Ar-H), 6.86 (d, 1H, J=8.2Hz,
), Ar-H 6.85 (d, 1H, J=8.3Hz, Ar-H), 6.79 (t, 1H, J=7.1Hz, Ar-H), 6.72 (t, 1H, J=7.7Hz,
Ar-H),5.66(s,2H,N-CH2 -CN),4.75(s,2H,N-CH2 - CN), 4.27 (q, 2H, J=7.1Hz ,-CH2 -CH3),
1.33 (t, 3H, J=7.1Hz ,-CH2-CH3 ).13C NMR(150MHz,DMSO-d6)δ170.3,170.2,136.2×2,
133.0,132.3,129.5,126.4,126.3,125.9,123.4,122.6,122.1,121.9,121.2,120.5,
116.7,116.3,110.9,110.8,107.1,105.1,41.4,34.7,26.4,15.7.ESI-MS m/z 434.1[M+H]+.
The preparation of compound 12
It is raw material preparation, silica gel column chromatography with compound 11 (50mg, 0.12mmol) according to the preparation method of compound 10
Separation, methylene chloride: methanol=5:1 (v/v) elutes to obtain red solid N- carboxymethyl -2- (1- ethyl -3- indoles) -3- (1- carboxylic
Methyl -3- indoles) maleimide (12) 48mg, yield 85%.1H NMR(600MHz,DMSO-d6)δ7.93(s,1H,Ar-
), H 7.80 (s, 1H, Ar-H), 7.47 (d, 1H, J=8.3Hz, Ar-H), 7.38 (d, 1H, J=8.2Hz, Ar-H), 7.05 (t,
1H, J=7.7Hz, Ar-H), 7.02 (t, 1H, J=7.1Hz, Ar-H), 6.96 (d, 1H, J=7.7Hz, Ar-H), 6.72 (t,
1H, J=7.7Hz, Ar-H), 6.70 (d, 1H, J=8.2Hz, Ar-H), 6.65 (t, 1H, J=7.1Hz, Ar-H), 5.13 (s,
2H,N-CH2 -CO2H),4.29(s,2H,-CH2 -CO2), H 4.25 (q, 2H, J=7.1Hz ,-CH2 -CH3), 1.32 (t, 3H, J=
7.1Hz,-CH2-CH 3).13C NMR(150MHz,DMSO-d6)δ171.6,171.5,170.5,170.0,137.2,136.0,
134.0,132.2,127.6,126.9,126.6,126.1,122.5,122.4,122.1,121.7,120.4,120.3,
110.9,110.7,105.8,105.4,48.1,41.3,39.9,15.7.ESI-MS m/z 470.0[M–H]–.
The preparation of compound 13
I) preparation of 1,2,3,4,6-D- glucopyranose pentaacetate (13a)
In 100mL single port bottle, add glucose (2g, 11.1mmol), anhydrous sodium acetate (2.5g, 30.5mmol), acetic acid
Acid anhydride 12.5mL, 110 DEG C of reflux while hot pour into reaction solution in about 100g trash ice, a large amount of white solids of stirring generation, after ice-out
It filters, filter cake is recrystallized with dehydrated alcohol, obtains white powder (13a) 4.1g, yield 95%.ESI-MS m/z 391.1[M+H]+.
Ii) the preparation of tetra- acetyl-D- glucopyranose (13b) of 2,3,4,6-O-
In N2Under protection, in 50mL two-mouth bottle, 13a (525mg, 1.35mmol) is dissolved with the anhydrous THF of 10mL, at -5 DEG C
It is added dropwise benzylamine (0.22mL, 2.02mmol), is slowly increased to room temperature, overnight, TLC detects fully reacting, evaporated in vacuo, silica gel for reaction
Pillar layer separation, petroleum ether: ethyl acetate=3:1 (v/v) elutes to obtain white solid (13b) 441mg, yield 94%.ESI-MS
m/z 349.2[M+H]+.iii) the preparation of tetra- acetyl-D- glucopyranose trichloroacetic acid imines ester (13c) of 2,3,4,6-O-
In two-mouth bottle, N2Under protection, with 5mL CH2Cl2It dissolves 13b (390mg, 1.12mmol), trichlorine is added dropwise at -5 DEG C
The DBU of catalytic amount is added dropwise in acetonitrile (1.35mL, 13.45mmol), and reaction solution becomes light yellow from yellowish, after reacting 30min,
Evaporated in vacuo, silica gel column chromatography separation, petroleum ether: ethyl acetate=4:1 (v/v) elutes to obtain Off-white solid (13c) 381mg,
Yield 70%.ESI-MS m/z 492.0[M+H]+.
Iv) O-2- (1- ethyl -3- indoles) -3- (1- cyanoethyl -3- indoles) maleimide -2,3,4,6-O- tetrem
Acyl-α-D- glucopyranose glucosides (13d)
It is added to after compound 13c (10mg, 22.8 μm of ol) and compound 4 (7.5mg, 16.5 μm of ol) are drained with air pump
In 15mL two-mouth bottle, 3h is taken out in drier.Molecular sieve crushes after being dried with Muffle furnace, and powder burns 30min, gas with alcohol blast burner
After pumping is cold plus about 200mg is into reaction flask, and the dry CH of 5mL is added2Cl2, air pump changes N2Three times, it is down at -20 DEG C and reacts
2 μ L BF are added dropwise in 20min3·Et2O becomes purple from red immediately, then replys red, is warmed to room temperature reaction 10h, has reacted
Entirely.- 5 DEG C are down to, 10mg NaHCO is added3Reaction is terminated, is filtered, solvent evaporated, gel column chromatography separation, methylene chloride: methanol
=1:1 (v/v) elutes to obtain red solid (13d) 16.7mg, yield 95%.1H NMR(600MHz,CDCl3)δ7.79(s,1H,
), Ar-H 7.61 (s, 1H, Ar-H), 7.31 (d, 1H, J=8.2Hz, Ar-H), 7.30 (d, 1H, J=8.2Hz, Ar-H), 7.17
(t, 1H, J=8.3Hz, Ar-H), 7.11 (t, 1H, J=8.2Hz, Ar-H), 7.08 (d, 1H, J=8.2Hz, Ar-H), 6.86
(d, 1H, J=7.3Hz, Ar-H), 6.85 (t, 1H, J=7.3Hz, Ar-H), 6.77 (t, 1H, J=7.3Hz, Ar-H), 5.36/
5.28 (d, 2H, J=11.5Hz, N-CH2 - O), 5.19 (t, 1H, J=10.0Hz, Glc-C3-H), 5.10 (t, 1H, J=
10.0Hz, Glc-C2-H), 5.00 (t, 1H, J=10.0Hz, Glc-C4-H), 4.86 (d, 1H, J=8.2Hz, Glc-C1-H),
4.46 (t, 2H, J=7.3Hz, N-CH2 -CH2), CN 4.21 (q, 2H, J=7.3Hz, N-CH2 -CH3),4.18/4.03(dd,2H,
J=12.4Hz, 2.8Hz, Glc-C6-H2 ), 3.70 (dt, 1H, J=10.1Hz, 3.7Hz, Glc-C5-H), 2.82 (t, 2H, J=
7.3Hz,NCH2-CH2 -CN),1.94(s,12H,4-COCH3 ), 1.49 (t, 3H, J=7.3Hz ,-CH2-CH3 ).13C NMR
(150MHz,CDCl3)δ171.4,171.3,170.8,170.4,169.5,169.4,136.2,135.5,131.9,130.9,
129.0,126.5,125.9,125.8,123.2,122.8,122.5,122.4,121.0,120.5,116.8,109.8,
109.0,107.3,105.5,100.0,73.0,72.1,71.2,68.1,66.2,61.6,42.4,41.6,20.8,20.7,
20.6,20.6,19.0,15.3.ESI-MS m/z 791.4[M+Na]+.
V) O-2- (1- ethyl -3- indoles) -3- (1- cyanoethyl -3- indoles) maleimide-α-D- glucopyranose sugar
The preparation of glycosides (13)
In single port bottle, by sample 13d 1mL CH2Cl2Dissolution adds 4mL anhydrous methanol, and 0 DEG C of stirring is lower to be added dropwise NaOMe/
MeOH is warmed to room temperature reaction 30min, TLC detection without starting material left until pH 9~10, at 0 DEG C plus saturation NH4Cl solution terminates
Reaction.Ethyl acetate extraction, is evaporated, and gel column chromatography separation, methanol elute to obtain red solid (13) 13mg, yield 100%.1H
NMR(600MHz,DMSO-d6) δ 7.94 (s, 1H, Ar-H), 7.87 (s, 1H, Ar-H), 7.60 (d, 1H, J=8.2Hz, Ar-H),
7.48 (d, 1H, J=8.2Hz, Ar-H), 7.06 (t, 1H, J=7.8Hz, Ar-H), 7.04 (t, 1H, J=7.3Hz, Ar-H),
6.82 (d, 1H, J=7.8Hz, Ar-H), 6.78 (d, 1H, J=8.3Hz, Ar-H), 6.68 (t, 2H, J=7.8Hz, Ar-H),
5.20/5.14 (d, 2H, J=11.0Hz, N-CH2 - O), 5.10 (d, 1H, J=5.5Hz, Glc-C1-H), 4.99 (d, 1H, J=
3.7Hz,Glc-C2-OH), 4.92 (d, 1H, J=3.7Hz, Glc-C3-OH), 4.60 (t, 2H, J=6.7Hz, N-CH2 -
CH2), CN 4.47 (t, 1H, J=6.0Hz, Glc-C6-OH), 4.41 (d, 1H, J=8.2Hz, Glc-C4-OH),4.27(q,2H,
J=7.3Hz, N-CH2 -CH3),3.62(m,1H,Glc-C2-H),3.48(m,1H,Glc-C3-H),3.11(m,2H,Glc-C6-H2 ), 3.09 (m, 1H, Glc-C4-H), 3.04 (t, 2H, J=6.7Hz, NCH2-CH2 -CN),2.95(m,1H,Glc-C5-H),
1.34 (t, 3H, J=7.3Hz, N-CH2-CH3 ).13C NMR(150MHz,DMSO-d6)δ171.5,171.4,136.1,136.0,
132.5,132.4,128.4,126.7,126.4,126.3,122.6,122.4,122.0,121.8,120.5,120.4,
119.0,110.9,110.7,106.2,105.3,103.0,77.6,77.3,73.8,70.2,66.2,61.4,41.9,41.3,
19.1,15.8.HR-ESIMS m/z 623.2139[M+Na]+(C33H35N4O8Na,623.2118).
The preparation of compound 14
1c (20mg, 50.6 μm of ol) 2mL DMF to be dissolved, 0.5mL ethylenediamine is added with stirring, room temperature reaction is stayed overnight,
Suitable quantity of water, ethyl acetate extraction is added, organic layer is evaporated, and silica gel column chromatography separation, methylene chloride: methanol=10:1 (v/v) is washed
Take off to obtain orange red powder N- (2- aminoethyl) -2- (1- ethyl -3- indoles) -3- (1- cyanogen methyl -3- indoles) maleimide
(14) 22mg, yield 99%.1H NMR(600MHz,DMSO-d6)δ7.89(s,1H,Ar-H),7.84(s,1H,Ar-H),7.60
(d, 1H, J=8.2Hz, Ar-H), 7.49 (d, 1H, J=8.2Hz, Ar-H), 7.17 (t, 1H, J=7.8Hz, Ar-H), 7.07
(t, 1H, J=7.4Hz, Ar-H), 6.88 (d, 1H, J=7.8Hz, Ar-H), 6.86 (d, 1H, J=7.6Hz, Ar-H), 6.78
(t, 1H, J=7.4Hz, Ar-H), 6.71 (t, 1H, J=7.6Hz, Ar-H), 5.67 (s, 2H ,-CH2 -CN),4.26(q,2H,J
=7.3Hz, N-CH2 -CH3), 3.71 (t, 2H, J=6.2Hz, N-CH2 -CH2-NH2), 2.94 (t, 2H, J=6.2Hz, N-CH2-
CH2 -NH2), 1.32 (t, 3H, J=7.3Hz, N-CH2-CH3 ).13C NMR(150MHz,DMSO-d6)δ171.9×2,136.0,
135.9,132.4,132.0,129.0,126.4,126.2,125.7,123.1,122.4,122.1,121.9,121.0,
120.2,116.7,110.7,110.6,107.3,105.2,41.2,40.0,39.0,34.6,15.7.ESI-MS m/z 438.1
[M+H]+.
The preparation of compound 15
It is raw material preparation, silicagel column color with compound 2c (60mg, 146.7 μm of ol) according to the preparation method of compound 14
Spectrum separation, methylene chloride: methanol=10:1 (v/v) elutes to obtain red crystals N- (2- aminoethyl) -2- (1- ethyl -3- indoles) -
3- (1- cyanoethyl -3- indoles) maleimide (15) 74.5mg, yield 100%.1H NMR(600MHz,DMSO-d6)δ7.89
(s, 1H, Ar-H), 7.82 (s, 1H, Ar-H), 7.60 (d, 1H, J=8.3Hz, Ar-H), 7.48 (d, 1H, J=8.3Hz, Ar-
), H 7.07 (t, 1H, J=7.8Hz, Ar-H), 7.05 (t, 1H, J=7.3Hz, Ar-H), 6.87 (d, 1H, J=8.0Hz, Ar-
), H 6.83 (d, 1H, J=8.0Hz, Ar-H), 6.70 (t, 1H, J=7.3Hz, Ar-H), 6.69 (t, 1H, J=7.8Hz, Ar-
), H 4.59 (t, 2H, J=6.4Hz-CH2 -CH2- CN), 4.27 (q, 2H, J=7.2Hz, N-CH2 -CH3), 3.76 (t, 2H, J=
6.1Hz,N-CH2 -CH2-NH2), 3.03 (t, 2H, J=6.1Hz, N-CH2-CH2 -NH2), 3.00 (t, 2H, J=6.4Hz ,-CH2 -
), CN 1.33 (t, 3H, J=7.2Hz, N-CH2-CH3 ).13C NMR(150MHz,DMSO-d6)δ171.4,171.3,135.5,
135.4,131.5,131.4,127.7,126.4,125.9,125.8,121.9,121.7,121.5,121.2,119.7,
119.6,118.3,110.2,110.0,105.7,104.9,41.3,40.6,38.5,37.4,18.4,15.1.ESI-MS m/z
452.3[M+H]+.
The preparation of compound 16
Compound 15 (20mg, 0.044mmol) is dissolved in 4N hydrochloric acid/ethyl acetate solution, 6h is stirred at room temperature, is evaporated
Solvent, after being freeze-dried 5h, dehydrated alcohol/petroleum ether (v/v, 5:1) recrystallizes to obtain peony crystal N- (2- aminoethyl) -2-
(1- ethyl -3- indoles) -3- (1- cyanoethyl -3- indoles) maleimide hydrochloride (16) 17mg, yield 79.2%.1H NMR
(600MHz,DMSO-d6)δ8.15(brs,3H,-NH3 +),7.92(s,1H,Ar-H),7.85(s,1H,Ar-H),7.65(d,1H,
J=8.0Hz, Ar-H), 7.52 (d, 1H, J=8.0Hz, Ar-H), 7.07 (t, 1H, J=7.8Hz, Ar-H), 7.15 (t, 1H, J
=7.6Hz, Ar-H), 6.89 (d, 1H, J=8.0Hz, Ar-H), 6.81 (d, 1H, J=8.0Hz, Ar-H), 6.72 (t, 1H, J=
7.3Hz, Ar-H), 6.70 (t, 1H, J=7.8Hz, Ar-H), 4.58 (t, 2H, J=6.4HzN-CH2 -CH2CN),4.27(q,2H,
J=7.2Hz, N-CH2 -CH3), 3.96 (t, 2H, J=6.2Hz, N-CH2 -CH2-NH3 +), 3.73 (t, 2H, J=6.2Hz, N-
CH2-CH2 -NH3 +), 3.01 (t, 2H, J=6.4Hz, NCH2-CH2 - CN), 1.32 (t, 3H, J=7.2Hz, N-CH2-CH3 ).13C
NMR(150MHz,DMSO-d6)δ171.4,171.2,135.6,135.4,131.5,131.3,127.7,127.4,125.9,
125.8,121.9,121.6,121.5,121.2,119.7,119.5,118.3,110.2,110.1,105.7,104.7,45.3,
42.6,38.5,37.4,18.4,15.1.ESI-MS m/z 452.2[M–Cl]+.
The preparation of compound 17
It is raw material preparation, silicon with compound 3c (24mg, 56.7 μm of ol) and ethylenediamine according to the preparation method of compound 14
Rubber column gel column chromatographic isolation, methylene chloride: methanol=10:1 (v/v) elutes to obtain dark red solid N- (2- aminoethyl) -2- (1- ethyl -
3- indoles) -3- (1- cyanogen propyl -3- indoles) maleimide (17) 26mg, yield 98%.1H NMR(600MHz,DMSO-d6)δ
7.79 (s, 1H, Ar-H), 7.76 (s, 1H, Ar-H), 7.53 (d, 1H, J=8.3Hz, Ar-H), 7.50 (d, 1H, J=8.3Hz,
), Ar-H 7.09 (t, 1H, J=8.5Hz, Ar-H), 7.07 (t, 1H, J=8.5Hz, Ar-H), 6.90 (t, 2H, J=7.9Hz,
), Ar-H 6.75 (d, 1H, J=7.4Hz, Ar-H), 6.72 (d, 1H, J=7.4Hz, Ar-H), 4.31 (t, 2H, J=6.7Hz, N-
CH2 -(CH2)2), CN 4.25 (q, 2H, J=7.2Hz, N-CH2 -CH3), 3.76 (t, 2H, J=5.7Hz, N-CH2 -CH2-NH2),
3.01 (t, 2H, J=5.7Hz, NCH2-CH2 -NH2), 2.41 (t, 2H, J=7.2Hz, N (CH2)2-CH2 -CN),2.02(m,2H,
NCH2-CH2 -CH2), CN 1.31 (t, 3H, J=7.2Hz, N-CH2-CH3 ).13C NMR(150MHz,DMSO-d6)δ171.5×2,
135.9,135.6,131.9,131.8,127.4,126.4,125.6×2,122.0,121.8,121.6×2,120.0,
119.8,119.6,110.3,110.2,105.4,104.9,44.5,40.7,38.5,37.2,25.6,15.2,13.7.HR-
ESIMS m/z 466.2266[M+H]+(calcd.for C28H28N5O2,466.2243).
The preparation of compound 18
It is raw material preparation, silica gel column chromatography with compound 4c (24mg, 54.9 μm of ol) according to the preparation method of compound 14
Separation, methylene chloride: methanol=10:1 (v/v) elutes to obtain red solid N- (2- aminoethyl) -2- (1- ethyl -3- indoles) -3-
(1- cyanogen butyl -3- indoles) maleimide (18) 30mg, yield 100%.1H NMR(600MHz,DMSO-d6)δ7.82(s,
1H, Ar-H), 7.80 (s, 1H, Ar-H), 7.51 (d, 1H, J=8.4Hz, Ar-H), 7.47 (d, 1H, J=8.4Hz, Ar-H),
7.05 (t, 1H, J=7.5Hz, Ar-H), 7.04 (t, 1H, J=7.4Hz, Ar-H), 6.83 (d, 1H, J=8.5Hz, Ar-H),
6.82 (d, 1H, J=8.7Hz, Ar-H), 6.68 (t, 1H, J=7.5Hz, Ar-H), 6.66 (t, 1H, J=7.4Hz, Ar-H),
4.30 (t, 2H, J=6.8Hz, N-CH2 -(CH2)3), CN 4.26 (q, 2H, J=7.2Hz, N-CH2 -CH3), 3.60 (t, 2H, J=
6.4Hz,N-CH2 -CH2-NH2), 2.82 (t, 2H, J=6.4Hz, N-CH2-CH2 -NH2), 2.51 (t, 2H, J=7.2Hz, N
(CH2)3-CH2 -CN),1.82(m,2H,NCH2-CH2 -(CH2)2CN),1.46(m,2H,N(CH2)2-CH2 -CH2CN),1.33(t,
3H, J=7.2Hz, N-CH2-CH3 ).13C NMR(150MHz,DMSO-d6)δ172.2×2,136.2,136.0,132.4,
132.0,127.9,127.3,126.8,126.3,122.3,122.2,121.8,121.0,120.0,119.9,114.3,
110.7,110.6,105.6,105.4,45.4,41.2,40.8,40.0,29.2,22.6,16.3,15.7.ESI-MS m/z
480.2[M+H]+.
The preparation of compound 19
I) preparation of N- tertiary butyl oxycarbonyl glycine (19a)
In 15mL single port bottle, with 4mL 10%Na2CO3Aqueous dissolution glycine (1.0g, 13mmol) drips at -5 DEG C
It is subject to the Boc acid anhydrides (2.84g, 13mmol) of 2mL acetonitrile dissolution, drop, which finishes, to be warmed to room temperature, and is stirred overnight, is filtered, filtrate is with petroleum
Ether extraction discards petroleum ether layer, and water layer is adjusted to acidity with hydrochloric acid, and ethyl ester extracts, dry, evaporated in vacuo, silica gel column chromatography separation,
Methylene chloride: methanol=30:1 (v/v) elutes to obtain white needle-like crystals (19a) 0.8g, yield 35%.ESI-MS m/z 389.3
[2M+K]+.
Ii) N- (N- tertiary butyl oxycarbonyl glycyl ethyl) -2- (1- ethyl -3- indoles) -3- (1- cyanogen methyl -3- indoles)
The preparation of maleimide (19b)
In 25mL two-mouth bottle, with 2mL CH2Cl2Dissolved compound 19a (26mg, 0.15mmol), compound 14 (50mg,
0.11mmol) with DMAP (4mg, 0.03mmol), 0.5mL CH is added2Cl2The DCC (35mg, 0.17mmol) of dissolution, room temperature is anti-
It should stay overnight, TLC detects fully reacting, filters, and filtrate is evaporated, silica gel column chromatography separation, petroleum ether: ethyl acetate=1:3 (v/v)
Elute to obtain Orange red solid (19b) 47mg, yield 69%.1H NMR(600MHz,DMSO-d6) δ 8.05 (t, 1H, J=5.5Hz ,-
NH), 7.87 (s, 1H, Ar-H), 7.86 (s, 1H, Ar-H), 7.59 (d, 1H, J=8.2Hz, Ar-H), 7.50 (d, 1H, J=
8.2Hz, Ar-H), 7.17 (dt, 1H, J=7.2Hz, 1.1Hz, Ar-H), 7.07 (dt, 1H, J=7.2Hz, 1.1Hz, Ar-H),
6.90 (t, 1H, J=5.9Hz ,-NH), 6.86 (d, 1H, J=8.2Hz, Ar-H), 6.85 (d, 1H, J=8.2Hz, Ar-H),
6.79 (t, 1H, J=7.7Hz, Ar-H), 6.70 (t, 1H, J=7.7Hz, Ar-H), 5.64 (s, 2H ,-CH2 -CN),4.27(q,
2H, J=7.1Hz, N-CH2 -CH3), 3.65 (t, 2H, J=6.1Hz, N-CH2 -CH2-NH),3.51(m,2H,N-CH2-CH2 -
NH), 3.35 (' q'like, J=5.5Hz, 6.1Hz ,-CO-CH2 -NH-),1.35(s,9H,-C(CH3)3 ), 1.33 (t, 3H, J=
7.1Hz,N-CH2-CH3 ).13C NMR(150MHz,DMSO-d6)δ171.9,171.8,171.0,169.0,136.1×2,
132.5,132.0,129.1,126.6,126.3,125.6,123.3,122.5,122.2,121.9,121.1,120.3,
116.7,110.8,110.6,107.5,105.3,78.6,60.4,41.3,38.1,37.8,34.6,28.7,15.8.ESI-MS
m/z 495.3[M+H]+.
Iii) N- glycyl ethyl -2- (1- ethyl -3- indoles) -3- (1- cyanogen methyl -3- indoles) maleimide (19)
Preparation
With 8mL toluene dissolved compound 19b (30mg, 0.05mmol), appropriate 100~200 mesh silica gel, N is added2Under protection
110 DEG C of condensate return 3.5h, are cooled to room temperature, and decompression column filters, and organic layer is evaporated, silica gel column chromatography separation, methylene chloride:
Methanol=50:1 (v/v) elutes to obtain red solid (19) 23.5mg, yield 95%.1H NMR(600MHz,DMSO-d6)δ7.87
(s, 1H, Ar-H), 7.82 (s, 1H, Ar-H), 7.59 (d, 1H, J=8.3Hz, Ar-H), 7.49 (d, 1H, J=8.3Hz, Ar-
), H 7.17 (dt, 1H, J=7.7Hz, 1.1Hz, Ar-H), 7.07 (dt, 1H, J=7.7Hz, 1.1Hz, Ar-H), 6.86 (d, 1H,
J=7.7Hz, Ar-H), 6.84 (d, 1H, J=7.1Hz, Ar-H), 6.79 (t, 1H, J=7.7Hz, Ar-H), 6.71 (t, 1H, J
=7.7Hz, Ar-H), 5.65 (s, 2H ,-CH2 - CN), 4.25 (q, 2H, J=7.1Hz, N-CH2 -CH3), 3.66 (t, 2H, J=
5.5Hz,N-CH2 -CH2NH),3.50-3.60(brs.2H,-NH2), 3.49 (t, 2H, J=5.5Hz, NCH2-CH2 -NH),3.23
(s,2H,-CO-CH2 -NH2),3.15(s,1H,NCH2-CH2-NH), 1.31 (t, 3H, J=7.1Hz, N-CH2-CH3 ).13C NMR
(150MHz,DMSO-d6)δ171.9×2,170.7,136.1×2,132.5,132.0,129.1,126.5,126.3,125.7,
123.3,122.5,122.2,122.0,121.1,120.3,116.7,110.8,110.7,107.4,105.3,63.2,43.1,
38.1,37.8,34.6,15.8.ESI-MS m/z 495.3[M+H]+.
The preparation of compound 20
I) N- tertiary butyl oxycarbonyl-l-Alanine (20a) preparation
It is that raw material obtains white needle-like crystals with l-Alanine (1.3g, 15mmol) according to the preparation method of compound 19a
(20a) 0.66g, yield 23%.ESI-MS m/z 212.2[M+Na]+.)
Ii) N- (N- tertiary butyl oxycarbonyl-L- alanyl ethyl) -2- (1- ethyl -3- indoles) -3- (1- cyanogen methyl -3- Yin
Diindyl) maleimide (20b) preparation
According to the preparation method of compound 19b, with compound 20a (30mg, 0.16mmol), compound 14 (50mg,
0.11mmol), DMAP (4mg, 0.03mmol) and DCC (35mg, 0.17mmol) is that raw material obtains Orange red solid (20b) 45mg,
Yield 65%.1HNMR(600MHz,DMSO-d6) δ 8.05 (t, 1H, J=5.5Hz ,-NH), 7.85 (s, 1H, Ar-H), 7.82 (s,
1H, Ar-H), 7.58 (d, 1H, J=8.2Hz, Ar-H), 7.48 (d, 1H, J=8.2Hz, Ar-H), 7.16 (dt, 1H, J=
7.1Hz, 1.1Hz, Ar-H), 7.06 (dt, 1H, J=7.1Hz, 1.1Hz, Ar-H), 6.85 (d, 2H, J=7.7Hz, Ar-H),
6.77 (t, 1H, J=7.2Hz, Ar-H), 6.70 (t, 1H, J=7.7Hz, Ar-H), 5.64 (s, 2H ,-CH2 -CN),4.24(q,
2H, J=7.1Hz, N-CH2 -CH3), 3.87 (q, 1H, J=8.3Hz, CH3-CH-NH-),3.62(m,2H,N-CH2 -CH2NH),
3.47 (m, 1H, J=6.1Hz, NCH2-CH2 - NH-), 3.26 (m, 1H, J=6.1Hz, NCH2-CH2 -NH-),1.32(s,9H,-C
(CH3)3), 1.30 (t, 3H, J=7.1Hz, N-CH2-CH3 ), 1.13 (d, 3H, J=6.6Hz ,-NH-CH-CH3 ).13C NMR
(150MHz,DMSO-d6)δ171.9,171.8,171.0,169.0,136.1×2,132.5,132.0,129.1,126.6,
126.3,125.6,123.3,122.5,122.2,121.9,121.1,120.3,116.7,110.8,110.6,107.5,
105.3,78.6,60.4,41.3,38.1,37.8,34.6,28.7,15.8.ESI-MS m/z 1219.2[2M+H]+.
Iii) N- (L- alanyl ethyl) -2- (1- ethyl -3- indoles) -3- (1- cyanogen methyl -3- indoles) maleimide
(20) preparation
It is that product (20) are made in raw material with compound 20b (30mg, 0.049mmol) according to the preparation method of compound 19
23.4mg, yield 94%.1H NMR(600MHz,DMSO-d6) δ 8.41 (t, 1H, J=5.5Hz ,-NH), 7.84 (s, 1H, Ar-
), H 7.67 (s, 1H, Ar-H), 7.46 (d, 1H, J=8.3Hz, Ar-H), 7.33 (d, 1H, J=8.3Hz, Ar-H), 7.06 (t,
2H, J=7.1Hz, Ar-H), 7.03 (d, 1H, J=8.3Hz, Ar-H), 6.74 (t, 1H, J=7.1Hz, Ar-H), 6.65 (dd,
2H, J=7.1Hz, 8.3Hz, Ar-H), 4.90 (s, 2H ,-CH2 - CN), 4.21 (q, 2H, J=7.1Hz, N-CH2 -CH3),3.66
(m,2H,N-CH2 -CH2NH),3.49(m,2H,NCH2-CH2 - NH-), 3.53 (m, 1H, J=6.6Hz ,-CO-CH-NH2),1.28
(t, 3H, J=7.1Hz ,-NCH2-CH3 ), 1.18 (d, 3H, J=7.1Hz, H2NCH-CH3 ).13C NMR(150MHz,DMSO-d6)
δ173.4,172.1,169.4,137.1,136.0,134.1,131.9,127.2×2,126.7,126.0,122.4,122.3×
2,122.2,121.9,120.2×2,110.8,110.6,105.6×2,49.7,49.1,41.2,38.0,37.4,19.7,
15.7.ESI-MS m/z 509.2[M+H]+.
The preparation of compound 21
I) preparation of N, N- di-t-butyl oxygen carbonyl-L-Histidine (21a)
It is that raw material obtains white needle-like crystals (21a) with histidine (1.0g, 7mmol) according to the preparation method of compound 18a
0.92g, yield 37%.ESI-MS m/z 356.4[M+H]+.
Ii) N- (N, N- di-t-butyl oxygen carbonyl-L- histidyl- ethyl) -2- (1- ethyl -3- indoles) -3- (1- cyanogen methyl -
3- indoles) maleimide (21b) preparation
According to the preparation method of compound 18b, with compound 21a (80.9mg, 0.16mmol), compound 14 (50mg,
0.11mmol), DMAP (4.2mg, 0.03mmol) and DCC (35mg, 0.17mmol) is that raw material obtains product (21b) 35mg, yield
45%.ESI-MSm/z 775.5[M+H]+.
Iii) N- (L- histidyl- ethyl) -2- (1- ethyl -3- indoles) -3- (1- cyanogen methyl -3- indoles) maleimide
(21) preparation
It is that raw material obtains product (21) with compound 21b (30mg, 0.039mmol) according to the preparation method of compound 18
20.2mg, yield 90%.1H NMR(600MHz,DMSO-d6)δ7.85(s,1H,Ar-H),7.80(s,1H,Ar-H),7.58(d,
1H, J=8.2Hz, Ar-H), 7.54 (s, 1H, imidazole-H), 7.48 (d, 1H, J=8.2Hz, Ar-H), 7.16 (t, 1H, J
=7.1Hz, Ar-H), 7.05 (t, 1H, J=7.1Hz, Ar-H), 6.84 (d, 2H, J=8.2Hz, Ar-H), 6.77 (t, 1H, J=
6.6Hz, Ar-H), 6.76 (s, 1H, imidazole-H), 6.68 (t, 1H, J=7.7Hz, Ar-H), 5.63 (s, 2H ,-CH2 -
), CN 4.23 (q, 2H, J=7.1Hz, N-CH2 -CH3),3.65(m,2H,N-CH2 -CH2-NH),3.59(m,1H,NCH2-CH2 -
), NH- 3.53 (m, 1H, J=4.4Hz ,-CO-CH-NH2),3.4(m,2H,imidazole-CH2 -CHNH2),1.29(t,3H,J
=7.1Hz, NCH2-CH3 ).13C NMR(150MHz,DMSO-d6)δ173.6,172.0,171.9,136.1,135.4,135.3,
132.7,132.5,131.9,129.2,126.6,126.3,123.3,122.5,122.2,122.0,121.1,120.3,
116.7,110.8,110.7,107.5,105.3,70.3,60.4,55.4,42.3,38.2,34.6,29.5,22.6,
15.7.ESI-MS m/z575.3[M+H]+.
The preparation of compound 22
I) N- tertiary butyl oxycarbonyl-L-Trp (22a) preparation
It is that raw material obtains white needle-like crystals (22a) with tryptophan (1.0g, 5mmol) according to the preparation method of compound 18a
1.3g, yield 63%.ESI-MS m/z 305.3[M+H]+.
Ii) N- (N- tertiary butyl oxycarbonyl-L- tryptophanyl ethyl) -2- (1- ethyl -3- indoles) -3- (1- cyanogen methyl -3- Yin
Diindyl) maleimide (22b) preparation
According to the preparation method of compound 18b, with compound 22a (72mg, 0.17mmol), compound 13 (50mg,
0.11mmol), DMAP (4.2mg, 0.03mmol) and DCC (35mg, 0.17mmol) is that raw material obtains compound (22b) 80mg, is received
Rate 89%.ESI-MSm/z 724.2[M+H]+,746.2[M+Na]+.
Iii) N- (L- tryptophanyl ethyl) -2- (1- ethyl -3- indoles) -3- (1- cyanogen methyl -3- indoles) maleimide
(22) preparation
It is that raw material obtains product (22) with compound 22b (30mg, 0.041mmol) according to the preparation method of compound 18
23.2mg, yield 90%.1H NMR(600MHz,DMSO-d6) δ 10.81 (brs, 1H ,-NH), 8.22 (t, 1H, J=6.1Hz ,-
), NH 7.86 (s, 1H, Ar-H), 7.81 (s, 1H, Ar-H), 7.58 (d, 1H, J=8.3Hz, Ar-H), 7.46 (dd, 2H, J=
8.2Hz, 7.7Hz, Ar-H), 7.32 (d, 2H, J=8.2Hz, Ar-H), 7.16 (t, 1H, J=8.8Hz, Ar-H), 7.04-7.02
(m, 2H, Ar-H), 6.88-6.86 (m, 3H, Ar-H), 6.74 (t, 1H, J=7.7Hz, Ar-H), 6.67 (t, 1H, J=7.2Hz,
Ar-H),5.61(s,2H,-CH2 - CN), 4.21 (q, 2H, J=7.1Hz, N-CH2 -CH3),3.67(m,2H,-N-CH2 -CH2-
NH),3.43(m,2H,-CH-CH2 - indole), 3.1 (d, 2H, J=3.8Hz ,-CH-CH2 -indole),2.68–2.65(m,
2H,NCH2-CH2 - NH-), 1.26 (t, 3H, J=7.1Hz, NCH2-CH3 ).13C NMR(150MHz,DMSO-d6)δ175.2,
172.0,171.9,136.8,136.6,136.1,132.4,132.0,129.2,127.9,126.6,126.3,125.7,
124.1,123.2,122.4,122.2,122.0,121.4,121.1,120.3,119.0,118.7,116.7,111.8,
111.1,110.8,110.6,107.5,105.3,60.3,55.8,41.3,38.2,34.6,31.3,15.7.ESI-MS m/z
624.4[M+H]+.
The preparation of compound 23
According to the preparation method of compound 16, with compound N-(2- aminoethyl) -2- (1- ethyl -3- indoles) -3- (3- Yin
Diindyl) maleimide (930mg, 2.34mmol) be raw material obtain its hydrochloride 23 (893mg, yield 88%).1H NMR
(500MHz,DMSO-d6)δ11.84(s,1H,indole-NH),8.19(brs,3H,-NH3 +), 7.77 (d, 1H, J=2.5Hz,
), Ar-H 7.70 (s, 1H, Ar-H), 7.48 (d, 1H, J=8.2Hz, Ar-H), 7.39 (d, 1H, J=8.1Hz, Ar-H), 7.05
(t, 1H, J=7.6Hz, Ar-H), 6.99 (dd, 2H, J=7.1Hz, 5.0Hz, Ar-H), 6.74 (t, 1H, J=8.7Hz, Ar-
), H 6.73 (t, 1H, J=7.9Hz, Ar-H), 6.63 (t, 1H, J=7.5Hz, Ar-H), 4.25 (q, 2H, J=7.2Hz ,-
NCH2 -CH3), 3.84 (t, 2H, J=5.7Hz, N-CH 2-CH2NH3 +), 3.10 (t, 2H, J=5.7Hz, NCH2-CH2 -NH3 +),
1.29 (t, 3H, J=7.2Hz ,-CH2-CH3 ).13C NMR(125MHz,DMSO-d6)δ172.2,172.1,136.5,135.9,
131.8,129.8,127.6,126.9,126.4,125.4,122.2,122.1,121.9,121.5,120.0,119.8,
112.3,110.5,106.0,105.5,41.1,40.2,39.4,15.7.HR-ESIMS m/z 399.1826[M–Cl]+
(calcd.for C24H23N4O2, 399.1815) and the preparation of compound 24
I) preparation of 1- benzylindole (24a)
In 100mL there-necked flask, NaH (300mg, 7.5mmol, mass fraction 60%, be scattered in paraffin) is used into 30mL
DMF suspends, and the indoles (585mg, 5mmol) of 10mL DMF dissolution is slowly added dropwise at -5 DEG C, is warmed to room temperature reaction 30min and drops again
To -5 DEG C.It is added dropwise cylite (0.89mL, 7.5mmol), is added dropwise, 30min is stirred to react at -5 DEG C, fully reacting is added
10mL methanol adds 100mL saturated ammonium chloride solution, CH afterwards2Cl2It extracts (100mL × 3), merges organic layer, anhydrous sodium sulfate is dry
Dry, evaporated in vacuo, silica gel column chromatography separation, petroleum ether: ethyl acetate=100:1 (v/v) elutes to obtain Off-white solid (24a)
1.02g, yield 99%.1H NMR(600MHz,CDCl3) δ 7.76 (d, 1H, J=7.7Hz, Ar-H), 7.38-7.33 (m, 4H,
), Ar-H 7.27 (dt, 1H, J=6.8Hz, 0.9Hz, Ar-H), 7.22 (dt, 1H, J=6.9Hz, 0.9Hz, Ar-H), 7.20 (t,
1H, J=3.2Hz, Ar-H), 7.18 (d, 2H, J=6.8Hz, Ar-H), 6.65 (dd, 1H, J=3.2Hz, 0.9Hz, Ar-H),
5.37(s,2H,Ph-CH2-).13C NMR(150MHz,CDCl3)δ137.7,136.5,128.9,128.9,128.4,127.8,
127.0,126.9,121.9,121.2,119.7×2,109.9,101.9,50.2.ESI-MS m/z 208.2[M+H]+.
Ii) the preparation of 2- (1- ethyl -3- indoles) -3- (1- benzyl -3- indoles) maleic anhydride (24b)
According to the preparation method of compound 1c, with compound 24a (356mg, 1.72mmol), oxalyl chloride (328mg,
2.58mmol), compound 1a (349mg, 1.72mmol) and Et3N (347mg, 3.44mmol) is that raw material obtains red solid (24b)
299mg, yield 39%.1H NMR(600MHz,DMSO-d6)δ8.02(s,1H,Ar-H),7.94(s.1H,Ar-H),7.53(d,
1H, J=7.3Hz, Ar-H), 7.44 (d, 1H, J=7.8Hz, Ar-H), 7.33 (t, 2H, J=6.4Hz, Ar-H), 7.27 (t,
1H, J=6.8Hz, Ar-H), 7.20 (d, 2H, J=5.9Hz, Ar-H), 7.11 (t, 1H, J=7.3Hz, Ar-H), 7.05 (t,
1H, J=6.8Hz, Ar-H), 6.91 (d, 1H, J=7.3Hz, Ar-H), 6.88 (d, 1H, J=7.3Hz, Ar-H), 6.75 (t,
1H, J=7.3Hz, Ar-H), 6.73 (t, 1H, J=7.3Hz, Ar-H), 5.52 (s, 2H, Ph-CH2), 4.29 (q, 2H, J=
6.8Hz,-CH2 -CH3), 1.34 (t, 3H, J=6.8Hz ,-CH2-CH3 ).13C NMR(150MHz,DMSO-d6)δ167.0,
166.9,137.9,136.6,136.3,133.9,133.3,129.2×2,128.8,128.1,127.8,127.6×2,
126.2,125.9,122.9,122.8,122.2,122.0,120.8,120.7,111.5,111.1,105.3,104.7,50.0,
40.5,15.7.ESI-MS m/z447.2[M+H]+.
Iii) the preparation of 2- (1- ethyl -3- indoles) -3- (1- benzyl -3- indoles) maleimide (24c)
According to the preparation method of compound 1, by compound 24b (260mg, 0.58mmol), HMDS (2.44mL,
11.7mmol) and MeOH (0.23mL, 5.8mmol) is prepared into red powder solid (24c) 248mg, yield 96%.1H NMR
(600MHz,DMSO-d6)δ10.95(s,1H,imide-NH),7.90(s,1H,Ar-H),7.83(s,1H,Ar-H),7.46(d,
1H, J=8.2Hz, Ar-H), 7.36 (d, 1H, J=8.2Hz, Ar-H), 7.32 (t, 2H, J=7.6Hz, Ar-H), 7.26 (t,
1H, J=7.3Hz, Ar-H), 7.17 (d, 2H, J=7.3Hz, Ar-H), 7.04 (t, 1H, J=7.8Hz, Ar-H), 6.97 (t,
1H, J=7.3Hz, Ar-H), 6.84 (d, 1H, J=8.2Hz, Ar-H), 6.82 (d, 1H, J=7.7Hz, Ar-H), 6.65 (t,
1H, J=7.8Hz, Ar-H), 6.64 (t, 1H, J=7.4Hz, Ar-H), 5.49 (s, 2H, Ph-CH2), 4.26 (q, 2H, J=
7.3Hz,-CH2 -CH3), 1.34 (t, 3H, J=7.3Hz ,-CH2-CH3 ).13C NMR(150MHz,DMSO-d6)δ173.4×2,
138.2,136.4,136.0,132.8,132.0,129.1×2,128.5,128.0,127.5,127.4×2,126.7,
126.4,122.4,122.2,121.8,121.7,120.2,120.1,111.1,110.7,106.0,105.4,49.9,41.3,
15.8.ESI-MS m/z446.2[M+H]+.
Iv) the preparation of 2- (1- ethyl -3- indoles) -3- (3- indoles) maleimide (24d)
Compound 24c (100mg, 0.225mmol) is dissolved with DMSO (0.85mL), under stirring condition, the t- of 1M is added dropwise
BuOK/THF solution (8.4mL, 8.4mmol), is added dropwise, O is passed through into reaction solution2About 30min adds saturated ammonium chloride solution
Reaction is terminated, ethyl acetate extracts (100mL × 3 time), is associated with organic layer, and use anhydrous Na2SO4It is dry, evaporated in vacuo.Silicon
Rubber column gel column chromatographic isolation, methylene chloride: ethyl acetate=6:1 (v/v) elutes to obtain red powder (24d) 70.5mg, yield 89%.1H
NMR(600MHz,DMSO-d6)δ11.66(s,1H,indole-NH),10.90(s,1H,imido-NH),7.76(s,1H,Ar-
), H 7.72 (s, 1H, Ar-H), 7.46 (d, 1H, J=8.2Hz, Ar-H), 7.37 (d, 1H, J=8.1Hz, Ar-H), 7.04 (t,
1H, J=7.6Hz, Ar-H), 6.98 (t, 1H, J=7.5Hz, Ar-H), 6.90 (d, 1H, J=8.0Hz, Ar-H), 6.74 (d,
1H, J=8.1Hz, Ar-H), 6.69 (t, 1H, J=7.5Hz, Ar-H), 6.62 (t, 1H, J=7.5Hz, Ar-H), 4.24 (q,
2H, J=7.2Hz ,-CH2 -CH3), 1.31 (t, 3H, J=7.2Hz ,-CH2-CH3 ).13C NMR(150MHz,DMSO-d6)δ
173.6,173.5,136.6,136.0,131.9,129.8,128.4,127.7,126.6,125.7,122.2,122.1,
121.9,121.6,120.1,119.9,112.3,110.6,106.1,105.5,41.2,15.8.ESI-MS m/z 356.1[M+
H]+.
V) preparation of 2- (1- ethylindole) -3- (3- indoles) maleic anhydride (24e)
In 50mL single port bottle, with the KOH aqueous solution suspended compound 24d (50mg, 0.14mmol) of 20mL 10%, 110
It flows back at DEG C and is cooled to room temperature after 40min, the acidification of 2N hydrochloric acid is added dropwise, ethyl acetate extraction is associated with organic layer, and with anhydrous sulphur
Sour sodium is dry, vacuum concentration, and silica gel column chromatography separation, dichloromethane eluent obtain red solid (24e) 43mg, yield 86%.1H
NMR(600MHz,DMSO-d6) δ 11.96 (s, 1H, indole-NH), 7.89 (d, 1H, J=2.8Hz, Ar-H), 7.83 (s, 1H,
), Ar-H 7.52 (d, 1H, J=8.3Hz, Ar-H), 7.44 (d, 1H, J=8.3Hz, Ar-H), 7.10 (t, 1H, J=7.4Hz,
), Ar-H 7.05 (t, 1H, J=7.7Hz, Ar-H), 6.98 (d, 1H, J=7.7Hz, Ar-H), 6.78 (t, 1H, J=7.6Hz,
), Ar-H 6.77 (d, 1H, J=7.6Hz, Ar-H), 6.70 (t, 1H, J=7.1Hz, Ar-H), 4.25 (q, 2H, J=7.3Hz ,-
CH2 -CH3), 1.30 (t, 3H, J=7.3Hz ,-CH2-CH3 ).13C NMR(150MHz,DMSO-d6)δ167.1,167.0,
136.8,136.2,133.1,131.3,128.7,127.9,126.1,125.2,122.7×2,122.2,121.9,120.7,
120.5,112.8,111.0,105.5,104.8,41.4,15.7.ESI-MS m/z 357.1[M+H]+.
Vi) N- (N, N- dimethylaminoethyl) -2- (1- ethyl -3- indoles) -3- (3- indoles) maleimide (24)
Preparation
With 30mL toluene dissolved compound 24d (55mg, 0.154mmol), N, N- dimethyl-ethylenediamine (84.4 μ L,
0.772mmol) and catalytic amount Et3N, after toluene dissolution, under nitrogen protection, 110 DEG C of condensate return 17h, solvent evaporated adds
Compression leg chromatographic isolation, methylene chloride: methanol=10:1 (v/v) elutes to obtain red solid (24) 52mg, yield 79%.1H NMR
(600MHz,DMSO-d6) δ 11.73 (s, 1H, indole-NH), 7.80 (d, 1H, J=2.7Hz, Ar-H), 7.77 (s, 1H, Ar-
), H 7.47 (d, 1H, J=8.3Hz, Ar-H), 7.39 (d, 1H, J=8.1Hz, Ar-H), 7.05 (t, 1H, J=7.7Hz, Ar-
), H 6.99 (t, 1H, J=7.6Hz, Ar-H), 6.89 (d, 1H, J=7.9Hz), 6.74 (d, 1H, J=8.1Hz, Ar-H),
6.70 (d, 1H, J=7.4Hz, Ar-H), 6.62 (d, 1H, J=7.8Hz, Ar-H), 4.24 (q, 2H, J=7.2Hz ,-CH2 -
CH3), 3.66 (t, 2H, J=6.4Hz, N-CH2 -CH2N(CH3)2), 2.49 (t, J=6.4Hz, 2H, NCH2-CH2 -N(CH3)2),
2.18(s,6H,-N(CH3)2), 1.31 (t, 3H, J=7.2Hz ,-CH2-CH3 ).13C NMR(150MHz,DMSO-d6)δ172.1
×2,136.6,136.0,132.1,130.0,127.4,126.8,126.5,125.6,122.3,122.2,121.9,121.6,
120.2,120.0,112.4,110.7,106.1,105.5,57.3,45.7×2,41.3,36.3,15.8.HR-ESIMS m/z
427.2140[M+H]+(calcd.for C26H27N4O2,427.2134).
The preparation of compound 25
It is that raw material obtains its hydrochloride: N- with compound 24 (50mg, 0.117mmol) according to the preparation method of compound 16
(N, N- dimethylaminoethyl) -2- (1- ethyl -3- indoles) -3- (3- indoles) maleimide hydrochloride (25) (48mg, yield
90%).1H NMR(500MHz,DMSO-d6)δ11.94(s,1H,indole-NH),10.61(brs,1H,(CH3)2NH +),7.77
(d, 1H, J=2.4Hz, Ar-H), 7.69 (s, 1H, Ar-H), 7.47 (d, 1H, J=8.2Hz, Ar-H), 7.40 (d, 1H, J=
8.1Hz, Ar-H), 7.05 (t, 1H, J=7.6Hz, Ar-H), 6.99 (d, 1H, J=7.8Hz, Ar-H), 6.98 (t, 1H, J=
7.8Hz, Ar-H), 6.76 (d, 1H, J=8.0Hz, Ar-H), 6.72 (t, 1H, J=7.5Hz, Ar-H), 6.62 (t, 1H, J=
7.5Hz, Ar-H), 4.23 (q, 2H, J=7.0Hz ,-CH2 -CH3), 3.93 (t, 2H, J=5.7Hz, N-CH 2-CH2(CH3)2NH+), 3.36 (t, 2H, J=6.0Hz, NCH2-CH2 -(CH3)2NH+),2.84(s,6H,(CH3)2 NH+), 1.28 (t, 3H, J=
7.1Hz,-CH2-CH3 ).13C NMR(125MHz,DMSO-d6)δ171.9×2,136.5,135.9,131.8,129.9,128.0,
127.1,126.4,125.3,122.2,122.1×2,121.7,120.0,119.8,112.4,110.9,105.9,105.5,
54.8,42.6×2,41.1,33.9,15.7.HR-ESIMS m/z 427.2141[M–Cl]+(calcd.for C26H26N4O2,
426.2056).
The preparation of compound 26
I) preparation of 1- benzyl -6- bromo indole (26a)
According to the synthetic method of compound 24a, with 6- bromo indole (980mg, 5mmol), NaH (300mg, 7.5mmol, matter
Measure score 60%, be dispersed in paraffin) and cylite (1283mg, 7.5mmol) be raw material prepare, silica gel column chromatography separate, stone
Oily ether: ethyl acetate=60:1 (v/v) elutes white powdery solids (26a) 1.14g, yield 80%.1H NMR(600MHz,
CDCl3) δ 7.54 (d, 1H, J=8.8Hz, Ar-H), 7.47 (s, 1H, Ar-H), 7.35-7.31 (m, 3H, Ar-H), 7.25 (dd,
1H, J=8.8Hz, 1.9Hz, Ar-H), 7.10-7.12 (m, 3H, Ar-H), 6.56 (d, 1H, J=3.8Hz, Ar-H), 5.27 (s,
2H,Ph-CH2 -).13C NMR(150MHz,CDCl3)δ137.3,137.1,129.0×2,127.9,127.7,126.8×2,
123.0,122.3,115.5,112.8,102.1,50.2.ESI-MS m/z286.0/288.0[M+H]+.
Ii) the preparation of 2- (1- ethyl -3- indoles) -3- (the bromo- 3- indoles of 1- benzyl -6-) maleic anhydride (26b)
According to the preparation method of compound 24b, with compound 24a (1100mg, 3.86mmol), (COCl)2(500μL,
5.79mmol), compound 1c (783mg, 3.86mmol) and Et3N (1070 μ L, 7.72mmol) is raw material preparation, and methanol is tied again
It is brilliant to obtain red powder (26b) 652mg, yield 32.2%.1H NMR(600MHz,DMSO-d6)δ8.02(s,1H,Ar-H),7.99
(s, 1H, Ar-H), 7.73 (s, 1H, Ar-H), 7.54 (d, 1H, J=8.2Hz, Ar-H), 7.35 (t, 2H, J=7.7Hz, Ar-
), H 7.29 (t, 1H, J=6.6Hz, Ar-H), 7.19 (d, 2H, J=7.1Hz, Ar-H), 7.12 (t, 1H, J=7.7Hz, Ar-
), H 6.90 (d, 1H, J=8.2Hz, Ar-H), 6.88 (d, 1H, J=7.7Hz, Ar-H), 6.76 (d, 1H, J=7.7Hz, Ar-
), H 6.71 (t, 1H, J=7.7Hz, Ar-H), 5.53 (s, 2H, Ph-CH2), 4.32 (q, 2H, J=7.2Hz ,-CH2 -CH3),
1.37 (t, 3H, J=7.2Hz ,-CH2-CH3 ).13C NMR(150MHz,DMSO-d6)δ166.9,166.8,137.6,137.3,
136.3,134.4,133.6,130.0,129.2×2,128.2,127.5×2,126.8,125.7,125.4,123.6,
123.5,122.9,122.0,120.8,115.8,114.3,111.2,105.5,104.5,50.0,41.6,15.8.ESI-MS
m/z 525.1/527.1[M+H]+.
Iii) prepared by 2- (1- ethyl -3- indoles) -3- (the bromo- 3- indoles of 1- benzyl -6-) maleimide (26c)
According to the preparation method of compound 24c, with compound 26b (600mg, 1.14mmol), HMDS (12mL,
57.3mmol) and MeOH (1.2mL, 28.7mmol) is raw material preparation, is obtained through silica gel column chromatography separation, dichloromethane eluent red
Pulverulent solids (26c) 218mg, yield 95%.1H NMR(600MHz,DMSO-d6)δ10.99(s,1H,imide-NH),7.90
(s, 1H, Ar-H), 7.89 (s, 1H, Ar-H), 7.65 (s, 1H, Ar-H), 7.48 (d, 1H, J=8.3Hz, Ar-H), 7.34 (t,
2H, J=7.7Hz, Ar-H), 7.28 (t, 1H, J=7.1Hz, Ar-H), 7.17 (d, 2H, J=7.1Hz, Ar-H), 7.05 (t,
1H, J=7.7Hz, Ar-H), 6.82 (d, 1H, J=8.8Hz, Ar-H), 6.79 (d, 1H, J=7.1Hz, Ar-H), 6.72 (d,
1H, J=8.3Hz, Ar-H), 6.63 (t, 1H, J=7.1Hz, Ar-H), 5.51 (s, 2H, Ph-CH2), 4.29 (q, 2H, J=
7.1Hz,-CH2 -CH3), 1.37 (t, 3H, J=7.1Hz ,-CH2-CH3 ).13C NMR(150MHz,DMSO-d6)δ173.3,
173.1,137.9,137.2,136.1,133.4,132.3,129.3,129.2×2,128.1,127.4,127.4,126.5,
126.2,125.9,123.3,123.0,122.3,121.7,120.2,115.3,113.9,110.8,106.3,105.1,49.8,
41.3,15.8.ESI-MSm/z 524.1/526.1[M+H]+.
Iv) the preparation of 2- (1- ethyl -3- indoles) -3- (the bromo- 3- indoles of 6-) maleimide (26d)
According to the preparation method of compound 24d, with compound 26c (538mg, 1.03mmol), DMSO (1.7mL), 1M
T-BuOK/THF solution (16.8mL, 16.8mmol) and O2For raw material preparation.Silica gel column chromatography separation, petroleum ether: ethyl acetate
=3:1 (v/v) elutes to obtain red powder (26d) 366mg, yield 82%.1H NMR(600MHz,DMSO-d6)δ7.81(s,1H,
), Ar-H 7.76 (d, 1H, J=2.8Hz, Ar-H), 7.57 (s, 1H, Ar-H), 7.46 (d, 1H, J=8.3Hz, Ar-H), 7.04
(dt, 1H, J=8.2Hz, 1.1Hz, Ar-H), 6.78 (d, 1H, J=8.0Hz, Ar-H), 6.75 (dd, 1H, J=8.6Hz,
1.8Hz, Ar-H), 6.71 (d, 1H, J=8.8Hz, Ar-H), 6.69 (dt, 1H, J=7.3Hz, 0.9Hz, Ar-H), 4.26 (q,
2H, J=7.1Hz ,-CH2 -CH3), 1.34 (t, 3H, J=7.1Hz ,-CH2-CH3 ).13C NMR(150MHz,DMSO-d6)δ
173.4×2,137.4,136.0,132.2,130.6,128.6,127.4,126.4,125.0,123.1,122.6,122.3,
121.7,120.2,115.0,114.9,110.7,106.3,105.3,41.3,15.8.ESI-MS m/z434.0/436.0[M+
H]+,HR-ESIMS m/z 434.0506[M+H]+(calcd.for C22H17N3O2Br,434.0504).
V) preparation of 2- (1- ethyl -3- indoles) -3- (the bromo- 3- indoles of 6-) maleic anhydride (26e)
According to the preparation method of compound 24e, it is raw material preparation by compound 26d (80mg, 0.185mmol), obtains orange red
Color solid (26e) 60mg, yield 75%.1H NMR(600MHz,DMSO-d6)δ11.99(s,1H,indole-NH),7.88(d,
1H, J=2.7Hz, Ar-H), 7.84 (s, 1H, Ar-H), 7.62 (s, 1H, Ar-H), 7.49 (d, 1H, J=8.0Hz, Ar-H),
7.08 (t, 1H, J=7.6Hz, Ar-H), 6.80 (t, 2H, J=7.1Hz, Ar-H), 6.73 (t, 2H, J=7.5Hz, Ar-H),
4.26 (q, 2H, J=8.2Hz ,-CH2 -CH3), 1.32 (t, 3H, J=7.2Hz ,-CH2-CH3 ).13C NMR(150MHz,DMSO-
d6)δ166.8×2,137.4,136.1,133.2,131.7,128.9,127.5,125.8,124.4,123.2,123.0,
122.7,121.9,120.7,115.7,115.2,111.0,105.5,104.5,41.4,15.8.ESI-MSm/z 435.0/
437.0[M+H]+.
Vi) N- (N, N- dimethylaminoethyl) -2- (1- ethyl -3- indoles) -3- (the bromo- 3- indoles of 6-) maleimide
(26) preparation
According to the preparation method of compound 24, with compound 26e (50mg, 0.115mmol), N, N- dimethyl-ethylenediamine
(81 μ L, 0.575mmol) and catalytic amount Et3N is raw material preparation, obtains red solid (26) 46.4mg, yield 80%.1H NMR
(500MHz,DMSO-d6)δ11.79(s,1H,indole-NH),7.84(s,1H,Ar-H),7.77(s,1H,Ar-H),7.56
(d, 1H, J=1.4Hz, Ar-H), 7.47 (d, 1H, J=8.2Hz, Ar-H), 7.03 (t, 1H, J=7.6Hz, Ar-H), 6.74
(d, 2H, J=8.5Hz, Ar-H), 6.69 (d, 1H, J=6.5Hz, Ar-H), 6.68 (t, 1H, J=62Hz, Ar-H), 4.26 (q,
2H, J=7.2Hz ,-CH2 -CH3), 3.64 (t, 2H, J=6.4Hz ,-NCH2 CH2-N(CH3)2), 2.46 (t, 2H, J=6.5Hz ,-
NCH2CH2 -N(CH3)2),2.16(s,6H,-N(CH3)2), 1.33 (t, 3H, J=7.2Hz ,-CH2-CH3 ).13C NMR
(125MHz,DMSO-d6)δ171.8×2,137.3,136.0,132.2,130.5,127.6,126.3,126.2,124.8,
122.9,122.6,122.3,121.6,120.1,114.9,114.8,110.7,106.2,105.1,57.2,45.6,41.2,
36.2,15.7.HR-ESIMS m/z 505.1250[M+H]+(calcd.for C26H26N4O2Br,505.1239).
The preparation of compound 27
It is that raw material obtains its hydrochloride: N- with compound 26 (100mg, 0.198mmol) according to the preparation method of compound 16
(N, N- dimethylaminoethyl) -2- (1- ethyl -3- indoles) -3- (the bromo- 3- indoles of 6-) maleimide hydrochloride (27)
(91mg, yield 85%).1H NMR(500MHz,DMSO-d6)δ12.08(s,1H,indole-NH),10.63(brs,1H,-
(CH3)2NH +), 7.79 (s, 1H, Ar-H), 7.74 (s, 1H, Ar-H), 7.60 (s, 1H, Ar-H), 7.48 (d, 1H, J=8.2Hz,
), Ar-H 7.05 (t, 1H, J=7.5Hz, Ar-H), 6.84 (d, 1H, J=8.0Hz, Ar-H), 6.76 (d, 1H, J=7.2Hz,
), Ar-H 6.74 (s, 1H, Ar-H), 6.70 (d, 1H, J=7.4Hz, Ar-H), 4.26 (q, 2H, J=6.9Hz ,-CH2 -CH3),
3.92 (t, 2H, J=4.9Hz, N-CH 2-CH2N(CH3)2H+), 3.04 (t, 2H, J=4.9Hz, NCH2-CH2 -N(CH3)2H+),
2.83(s,6H,-(CH3)2 NH+), 1.32 (t, 3, J=6.9Hz ,-CH2-CH3 ).13C NMR(125MHz,DMSO-d6)δ171.8,
171.6,137.4,136.0,132.1,130.5,128.0,126.9,126.1,124.7,123.1,122.5,122.3,
121.8,120.1,115.0,114.8,110.7,106.2,105.2,54.8,45.6,42.6×2,41.2,33.5,
15.7.HR-ESIMS m/z 505.1246[M–Cl]+(calcd.for C26H27N4O2Br,505.1250).
The preparation of compound 28
According to the preparation method of compound 14, it is made with compound 26e (49mg, 0.114mmol) and ethylenediamine for raw material
Red solid N- (2- aminoethyl) -2- (1- ethyl -3- indoles) -3- (the bromo- 3- indoles of 6-) maleimide (28) 49mg, yield
90%.1H NMR(500MHz,DMSO-d6)δ7.81(s,1H,Ar-H),7.76(s,1H,Ar-H),7.56(s,1H,Ar-H),
7.46 (d, 1H, J=8.3Hz, Ar-H), 7.03 (t, 1H, J=7.6Hz, Ar-H), 6.77 (d, 1H, J=8.0Hz, Ar-H),
6.74 (dd, 1H, J=8.6Hz, 1.4Hz, Ar-H), 6.70 (d, 1H, J=8.6Hz, Ar-H), 6.67 (t, 1H, J=7.5Hz,
), Ar-H 4.25 (q, 2H, J=7.2Hz ,-CH2 -CH3), 3.56 (t, 2H, J=6.5Hz, N-CH2 -CH2NH2),2.77(t,2H,J
=6.5Hz, NCH2-CH2 -NH2), 1.32 (t, 3H, J=7.2Hz ,-CH2-CH3 ).13CNMR(125MHz,DMSO-d6)δ172.1
×2,137.3,135.9,132.0,130.4,127.7,126.4,126.2,124.8,123.0,122.5,122.2,121.6,
120.1,114.9,114.8,110.7,106.3,105.2,41.3,41.2,40.6,15.7.HR-ESIMS m/z 477.0934
[M+H]+(calcd.for C24H22N4O2Br,477.0926).
The preparation of compound 29
It is that raw material obtains its hydrochloride: N- with compound 28 (200mg, 0.42mmol) according to the preparation method of compound 16
(2- aminoethyl) -2- (1- ethyl -3- indoles) -3- (the bromo- 3- indoles of 6-) maleimide hydrochloride (29) 172mg, yield
80%.1H NMR(500MHz,DMSO-d6)δ12.03(s,1H,indole-NH),8.20(brs,3H,-NH3 +),7.80(s,
1H, Ar-H), 7.75 (s, 1H, Ar-H), 7.60 (s, 1H, Ar-H), 7.48 (d, 1H, J=8.1Hz, Ar-H), 7.05 (t, 1H, J
=7.4Hz, Ar-H), 6.83 (d, 1H, J=7.9Hz, Ar-H), 6.76 (d, 1H, J=8.5Hz, Ar-H), 6.73 (d, 1H, J=
8.8Hz, Ar-H), 6.72 (t, 1H, J=7.8Hz, Ar-H), 4.26 (q, 2H, J=6.9Hz ,-CH2 -CH3),3.83(t,2H,J
=6.4Hz, N-CH2 -CH2NH3 +), 3.08 (t, 2H, J=6.5Hz, NCH2-CH2 -NH3 +), 1.32 (t, 3H, J=6.9Hz ,-
CH2-CH3 ).13C NMR(125MHz,DMSO-d6)δ171.9,171.8,137.4,136.9,132.0,130.5,127.9,
126.8,126.1,124.7,123.1,122.5,122.3,121.8,120.1,115.0,114.8,110.7,106.2,
105.2,41.2,38.1,36.1,15.7.HR-ESIMS m/z 477.0932[M–Cl]+(calcd.for C24H22N4O2Br,
477.0934).
The preparation of compound 30,31,32
At 0 DEG C, NaH (13.5mg, 0.563mmol, mass fraction 60%, be scattered in paraffin) is suspended with DMF, is added dropwise
DMF dissolution compound 24d (40mg, 0.113mmol), with DMF suspension NaH (338mg, 14.1mmol, mass fraction 60%,
It is scattered in paraffin), it is added dropwise chloroethanol (38 μ L, 0.563mmol), low-temp reaction 20min is conducted into conduit to chemical combination
In the suspension of object 24d, after reacting 20min, it is warmed to room temperature, condensate return 4.5h.- 5 DEG C are cooled to, MeOH is added dropwise, is added
Appropriate saturated ammonium chloride solution, ethyl acetate extraction are associated with organic layer, and, solvent evaporated in vacuo dry with anhydrous sodium sulfate,
Pressurize pillar layer separation, methylene chloride: methanol=100:1 (v/v) elutes to obtain red solid N- (2- ethoxy) -2- (1- ethyl -
3- indoles) -3- (3- indoles) maleimide (30), 2- (1- ethyl -3- indoles) -3- (1- (2- ethoxy) -3- indoles) horse
Come acid imide (31) and N- (2- ethoxy) -2- (1- ethyl -3- indoles) -3- (1- (2- ethoxy) -3- indoles) maleimide
Amine (32) is respectively 23mg, 5mg and 4mg, and yield is respectively 51%, 11% and 8%.
Compound 30:1H NMR(600MHz,DMSO-d6) δ 11.67 (s, 1H, indole-NH), 7.78 (d, 1H, J=
2.1Hz, Ar-H), 7.73 (s, 1H, Ar-H), 7.45 (d, 1H, J=8.2Hz, Ar-H), 7.37 (d, 1H, J=8.1Hz, Ar-
), H 7.03 (t, 1H, J=7.6Hz, Ar-H), 6.97 (t, 1H, J=7.6Hz, Ar-H), 6.91 (d, 1H, J=8.0Hz, Ar-
), H 6.73 (d, 1H, J=8.0Hz, Ar-H), 6.68 (t, 1H, J=7.5Hz, Ar-H), 6.61 (t, 1H, J=7.6Hz, Ar-
), H 4.89 (t, 1H, J=5.5Hz, imide-NCH2CH2OH), 4.22 (q, 2H, J=7.2Hz ,-CH2 -CH3),3.62-3.59
(m,4H,imide-N(CH2)2), 1.29 (t, 3H, J=7.2Hz ,-CH2-CH3 ).13C NMR(150MHz,DMSO-d6)δ
172.1×2,136.5,135.9,131.8,129.7,127.5,126.8,126.4,125.5,122.1×2,121.8,
121.5,120.0,119.8,112.2,110.5,106.0,105.5,58.7,41.1,40.9,15.6.HR-ESIMS m/z
400.1666[M+H]+(calcd.for C24H22N3O3,400.1661).
Compound 31:1H NMR(600MHz,DMSO-d6)δ10.92(s,1H,imide-NH),7.82(s,1H,Ar-H),
7.70 (s, 1H, Ar-H), 7.48 (d, 1H, J=8.2Hz, Ar-H), 7.46 (d, 1H, J=8.2Hz, Ar-H), 7.05 (t, 1H, J
=7.6Hz, Ar-H), 7.02 (t, 1H, J=7.1Hz, Ar-H), 6.92 (d, 1H, J=8.0Hz, Ar-H), 6.72 (d, 1H, J=
7.3Hz, Ar-H), 6.71 (t, 1H, J=6.9Hz, Ar-H), 6.64 (t, 1H, J=7.7Hz, Ar-H), 4.95 (t, 1H, J=
5.2Hz,indole-NCH2CH2OH), 4.26 (t, 2H, J=5.6Hz, indole-NCH2 CH2), 4.23 (q, 2H, J=
7.2Hz,-CH2 -CH3)3.71-3.69(m,2H,indole-NCH2CH2 ), 1.30 (t, 3H, J=7.2Hz ,-CH2-CH3 ).13C
NMR(150MHz,DMSO-d6)δ173.5×2,136.7,136.0,133.4,131.9,128.0,127.5,126.9,126.1,
122.2,122.1,122.0,121.9,120.1,120.0,111.0,110.6,105.5,105.2,60.6,49.1,41.2,
15.8.HR-ESIMS m/z 400.1668[M+H]+(calcd.for C24H22N3O3,400.1661).
Compound 32:1H NMR(500MHz,DMSO-d6)δ7.84(s,1H,Ar-H),7.72(s,1H,Ar-H),7.48
(d, 1H, J=7.8Hz, Ar-H), 7.46 (d, 1H, J=7.8Hz, Ar-H), 7.05 (t, 1H, J=7.2Hz, Ar-H), 7.02
(t, 1H, J=7.4Hz, Ar-H), 6.93 (d, 1H, J=8.0Hz, Ar-H), 6.73 (d, 1H, J=7.8Hz, Ar-H), 6.71
(t, 1H, J=7.5Hz, Ar-H), 6.65 (t, 1H, J=7.3Hz, Ar-H), 4.93 (t, 1H, J=4.7Hz, indole-
NCH2CH2OH), 4.88 (t, 1H, J=4.8Hz, imide-NCH2CH2OH), 4.26 (t, 2H, J=5.3Hz, indole-
NCH2 CH2), 4.22 (q, 2H, J=7.1Hz ,-CH2 -CH3), 3.70 (t, 2H, J=5.3Hz, indole-NCH2CH2 -),
3.65-3.57(m,4H,imide-N(CH2)2), 1.29 (t, 3H, J=7.1Hz ,-CH2-CH3 ).13C NMR(125MHz,
DMSO-d6)δ172.0×2,136.6,135.9,133.3,131.8,127.1,126.7,126.4,125.9,122.1,122.0
×2,121.8,120.0,119.9,110.9,110.5,105.9,105.2,60.5,58.6,49.0,41.1,40.9,
15.6.HR-ESIMS m/z 444.1934(calcd.for C26H26N3O4,444.1923[M+H]+).
The preparation of compound 33
According to the preparation method of compound 24, with 4- methoxybenzylamine (185 μ L, 1.4mmol) and compound 24e (50mg,
0.14mmol) N- (4- methoxy-benzyl) -2- (1- ethyl -3- indoles) -3- (3- indoles) maleimide (33) is obtained for raw material
48mg, yield 72%.1H NMR(600MHz,DMSO-d6) δ 11.75 (s, 1H, indole-NH), 7.82 (d, 1H, J=2.7Hz,
), Ar-H 7.77 (s, 1H, Ar-H), 7.45 (d, 1H, J=8.3Hz, Ar-H), 7.39 (d, 1H, J=8.1Hz, Ar-H), 7.29
(d, 2H, J=8.7Hz, Ar-H), 7.04 (t, 1H, J=7.6Hz, Ar-H), 6.98 (t, 1H, J=7.6Hz, Ar-H), 6.90
(d, 2H, J=6.7Hz, Ar-H), 6.89 (d, 1H, J=2.1Hz, Ar-H), 6.74 (d, 1H, J=8.1Hz, Ar-H), 6.69
(t, 1H, J=7.5Hz, Ar-H), 6.62 (t, 1H, J=7.5Hz, Ar-H), 4.68 (s, 2H ,-CH2 ), 4.24 (q, 2H, J=
7.2Hz,-CH2 -CH3),3.70(s,3H,-OCH3), 1.29 (t, 3H, J=7.2Hz ,-CH2-CH3 ).13CNMR(150MHz,
DMSO-d6)δ172.0,171.9,159.1,136.6,136.0,132.2,130.1,129.9,129.6×2,127.5,
127.3,126.9,126.5,125.6,122.3×2,121.9,121.6,120.2,112.0,114.5,112.4,110.7,
106.1,105.5,55.6,41.2,41.1,15.7.ESI-MS m/z 498.2[M+Na]+.
The preparation of compound 34
According to the preparation method of compound 2, with compound 33 (60mg, 0.126mmol) and NaHCO3(42mg,
0.5mmol) and HCHO (3mL, mass fraction 37%) solution is raw material preparation, and gel column chromatography separation, methanol elute dark red
Color solid N- (4- methoxy-benzyl) -2- (1- ethyl -3- indoles) -3- (1- methylol -3- indoles) maleimide (34)
51mg, yield 78%.1H NMR(600MHz,DMSO-d6)δ7.99(s,1H,Ar-H),7.74(s,1H,Ar-H),7.55(d,
1H, J=8.3Hz, Ar-H), 7.47 (d, 1H, J=8.2Hz, Ar-H), 7.39 (t, 1H, J=8.1Hz, Ar-H), 7.29 (d,
2H, J=8.8Hz, Ar-H), 7.05 (m, 2H, Ar-H), 6.99 (d, 1H, J=8.1Hz, Ar-H), 6.91 (d, 2H, J=
8.8Hz, Ar-H), 6.72 (d, 1H, J=7.2Hz, Ar-H), 6.69 (t, 1H, J=8.1Hz ,-CH2OH), 6.63 (d, 1H, J=
7.0Hz, Ar-H), 5.60 (d, 2H, J=7.2Hz ,-CH2 OH),4.70(s,2H,-CH2), 4.23 (q, 2H, J=7.2Hz ,-
CH2 -CH3),3.71(s,3H,-OCH3), 1.30 (t, 3H, J=7.2Hz ,-CH2-CH3 ).13C NMR(150MHz,DMSO-d6)δ
171.9,171.8,159.2,136.1,136.0,132.6×2,132.2,129.8,129.6,127.4,126.9,126.8,
126.4,122.4×2,121.9,121.8,120.5,120.3,114.6,111.4,110.7,105.9,105.5,100.0,
69.7,60.3,41.7,41.3,15.7.ESI-MS m/z 528.1[M+Na]+.
The preparation of compound 35
According to the preparation method of compound 24, with 4- hydroxy benzylamine (86mg, 0.7mmol) and compound 24e (50mg,
0.14mmol) it is raw material, N- (4- hydroxybenzyl) -2- (1- ethyl -3- indoles) -3- (3- indoles) maleimide (35) is made
35mg, yield 60%.1H NMR(600MHz,DMSO-d6)δ11.72(s,1H,indole-NH),9.26(s,1H,Ar-OH),
7.80 (d, 1H, J=2.3Hz, Ar-H), 7.77 (s, 1H, Ar-H), 7.45 (d, 1H, J=8.3Hz, Ar-H), 7.38 (d, 1H, J
=8.1Hz, Ar-H), 7.17 (d, 1H, J=8.5Hz, Ar-H), 7.11 (d, 2H, J=8.3Hz, Ar-H), 7.03 (t, 1H, J=
7.4Hz, Ar-H), 6.97 (d, 1H, J=7.5Hz, Ar-H), 6.89 (d, 1H, J=8.0Hz, Ar-H), 6.71 (d, 2H, J=
8.4Hz, Ar-H), 6.68 (d, 1H, J=7.4Hz, Ar-H), 6.61 (t, 1H, J=7.4Hz, Ar-H), 4.64 (s, 2H ,-
NCH2), Ar 4.22 (q, 2H, J=7.2Hz ,-CH2 -CH3), 1.30 (t, 3H, J=7.2Hz ,-CH2-CH3 ).13CNMR
(150MHz,DMSO-d6)δ172.0×2,156.7,136.6,136.0,134.1,132.1,132.0,130.1,129.9,
129.7,129.2,128.1,127.9,127.5,126.9,126.5,125.6,115.8×2,115.5×2,112.4,
110.7,106.1,105.5,56.6,41.2,15.7.ESI-MS m/z 462.3[M+H]+.
The preparation of compound 36
According to the preparation method of compound 2, with compound 35 (59mg, 0.128mmol) and NaHCO3(53.7mg,
0.64mmol) it is raw material, dark red solid N- (4- hydroxybenzyl) -2- (1- ethyl -3- indoles) -3- (1- methylol -3- is made
Indoles) maleimide (36) 50mg, yield 80%.1H NMR(600MHz,DMSO-d6)δ9.44(s,1H,Ar-OH),8.00
(s, 1H, Ar-H), 7.75 (s, 1H, Ar-H), 7.56 (d, 1H, J=8.3Hz, Ar-H), 7.47 (d, 1H, J=8.3Hz, Ar-
), H 7.19 (d, 2H, J=8.5Hz, Ar-H), 7.05 (m, 2H, Ar-H), 7.00 (d, 1H, J=8.1Hz, Ar-H), 6.74 (d,
2H, J=8.6Hz, Ar-H), 6.72 (d, 1H, J=7.4Hz, Ar-H), 6.69 (t, 1H, J=7.4Hz ,-CH2OH),6.63(d,
1H, J=3.3Hz, Ar-H), 5.61 (d, 2H, J=7.4Hz ,-CH2 OH),4.65(s,2H,-NCH2), Ar 4.03 (q, 2H, J=
7.1Hz,-CH2 -CH3), 1.17 (t, 3H, J=7.1Hz ,-CH2-CH3 ).13C NMR(150MHz,DMSO-d6)δ171.9×2,
157.3,136.1,136.0,132.7,132.6,132.2,129.7,128.1,127.3,126.8×2,126.4,122.4×
2,121.9,121.8,120.5,120.3,115.8,111.4,110.7,105.9,105.5,100.0,69.7,60.3,41.3,
15.7.ESI-MSm/z 514.1[M+Na]+.
The preparation of compound 37
According to the preparation method of compound 24, with 4- (2- aminoethyl) morpholine (771 μ L, 0.59mmol) and compound 24e
(50mg, 0.14mmol) is raw material, and N- (2- (4- morpholine) ethyl) -2- (1- ethyl -3- indoles) -3- (3- indoles) Malaysia is made
Acid imide (37) 41mg, yield 61%.1H NMR(500MHz,DMSO-d6)δ11.68(s,1H,indole-NH),7.78(s,
1H, Ar-H), 7.73 (s, 1H, Ar-H), 7.46 (d, 1H, J=8.3Hz, Ar-H), 7.37 (d, 1H, J=8.1Hz, Ar-H),
7.04 (t, 1H, J=7.6Hz, Ar-H), 6.98 (t, 1H, J=7.5Hz, Ar-H), 6.90 (d, 1H, J=8.0Hz, Ar-H),
6.71 (d, 1H, J=8.3Hz, Ar-H), 6.70 (t, 1H, J=7.5Hz, Ar-H), 6.62 (t, 1H, J=7.5Hz, Ar-H),
4.23 (q, 2H, J=7.2Hz ,-CH2 -CH3), 3.68 (t, 2H, J=6.4Hz, imide-NCH2 CH2), 3.53 (t, 4H, J=
4.4Hz,morpholine-N(CH2-CH 2)2), O 2.53 (t, 2H, J=6.4Hz, imide-NCH2CH2 ), 2.44 (t, 4H, J=
4.4Hz,morpholine-N(CH 2-CH2)2), O 1.30 (t, 3H, J=7.2Hz ,-CH2-CH3 ).13C NMR(125MHz,
DMSO-d6)δ172.0×2,136.5,135.9,131.9,129.8,127.4,126.8,126.4,125.4,122.2,
122.1,121.7,121.4,120.0,119.8,112.3,110.5,106.0,105.3,66.7×2,56.3,53.6×2,
41.1,35.2,15.6.HR-ESIMS m/z 469.2247[M+H]+(calcd.for C28H29N4O3,469.2240[M+H]+).
The preparation of compound 38
According to the preparation method of compound 2, with compound 37 (33mg, 0.071mmol) and NaHCO3(30mg,
0.35mmol) it is raw material, dark red solid N- (2- (4- morpholine) ethyl) -2- (1- ethyl -3- indoles) -3- (1- hydroxyl first is made
Base -3- indoles) maleimide (38) 29mg, yield 82%.1H NMR(500MHz,DMSO-d6)δ7.96(s,1H,Ar-H),
7.70 (s, 1H, Ar-H), 7.55 (d, 1H, J=8.2Hz, Ar-H), 7.47 (d, 1H, J=8.2Hz, Ar-H), 7.05 (t, 1H, J
=8.1Hz, Ar-H), 7.02 (t, 1H, J=8.4Hz, Ar-H), 6.73 (t, 1H, J=7.5Hz, Ar-H), 6.67 (t, 1H, J=
7.3Hz, Ar-H), 6.62 (d, 1H, J=8.5Hz, Ar-H), 6.60 (d, 1H, J=8.0Hz, Ar-H), 5.59 (d, 2H, J=
7.3Hz,indole-CH2 - OH), 4.22 (q, 2H, J=7.2Hz ,-CH2 -CH3), 3.72 (t, 2H, J=6.4Hz, imide-
NCH2 CH2), 3.56 (t, 4H, J=4.5Hz, morpholine-N (CH2-CH 2)2), O 2.57 (t, 2H, J=6.4Hz, imide-
NCH2CH2 ), 2.47 (t, 4H, J=4.5Hz, morpholine-N (CH 2-CH2)2), O 1.29 (t, 3H, J=7.2Hz ,-CH2-
CH3 ).13C NMR(125MHz,DMSO-d6)δ171.9×2,136.0,135.9,132.4,131.9,127.3,126.9,
126.6,126.2,122.3,122.2,121.8,121.6,120.3,120.1,111.9,110.6,105.7,105.4,69.5,
66.6×2,56.3,53.5×2,41.1,35.3,15.6.HR-ESIMS m/z 499.2352[M+H]+(calcd.for
C29H31N4O4,499.2345).
The preparation of compound 39
According to the preparation method of compound 24, with 2- (2- aminoethyl) pyridine (50 μ L, 0.421mmol) and compound 24e
(30mg, 0.084mmol) is raw material, and N- (2- (2- pyridine) ethyl) -2- (1- ethyl -3- indoles) -3- (3- indoles) horse is made
Come acid imide (39) 25mg, yield 64%.1H NMR(600MHz,DMSO-d6)δ11.71(s,1H,indole-NH),8.48(d,
1H, J=4.7Hz, Ar-H), 7.75 (d, 1H, J=2.7Hz, Ar-H), 7.73-7.70 (m, 2H, Ar-H), 7.48 (d, 1H, J=
8.2Hz, Ar-H), 7.38 (d, 1H, J=8.1Hz, Ar-H), 7.31 (d, 1H, J=7.7Hz, Ar-H), 7.23 (dd, 1H, J=
7.4,4.9Hz, Ar-H), 7.05 (t, 1H, J=7.6Hz, Ar-H), 6.99 (t, 1H, J=7.5Hz, Ar-H), 6.88 (d, 1H, J
=8.1Hz, Ar-H), 6.71 (t, 2H, J=8.0Hz, Ar-H), 6.64 (d, 1H, J=7.7Hz, Ar-H), 4.24 (q, 2H, J=
7.2Hz,-CH2 -CH3), 3.93 (t, 2H, J=7.1Hz, imide-NCH2 CH2), 3.09 (t, 2H, J=7.1Hz, imide-
NCH2CH2 ), 1.30 (t, 3H, J=7.2Hz ,-CH2-CH3 ).13C NMR(150MHz,DMSO-d6)δ172.0,171.9,
158.9,149.7,137.2,136.6,136.0,132.0,129.9,127.6,126.9,126.5,125.6,123.8,
122.3,122.2,121.9,121.6,120.1,119.9,112.4,110.7,106.0,105.5,100.0,41.2,38.2,
36.7,15.8.HR-ESIMS m/z 461.1981[M+H]+(calcd.for C29H25N4O2,461.1978).
The preparation of compound 40
It is that its hydrochloride is made in raw material with compound 39 (200mg, 0.435mmol) according to the preparation method of compound 16:
N- (2- (2- pyridine) ethyl) -2- (1- ethyl -3- indoles) -3- (3- indoles) maleimide hydrochloride (40) 173mg, yield
80%.1H NMR(500MHz,DMSO-d6)δ11.88(s,1H,indole-NH),10.60(brs,1H,-pryidine-H+),
8.82 (s, 1H, Ar-H), 8.45 (t, 1H, J=7.2Hz, Ar-H), 7.99 (d, 1H, J=6.4Hz, Ar-H), 7.87 (t, 1H, J
=7.0Hz, Ar-H), 7.68 (d, 1H, J=7.1Hz, Ar-H), 7.61 (d, 1H, J=7.6Hz, Ar-H), 7.45 (d, 1H, J=
7.7Hz, Ar-H), 7.37 (d, 1H, J=7.4Hz, Ar-H), 7.04 (t, 1H, J=6.8Hz, Ar-H), 6.97 (t, 1H, J=
7.1Hz, Ar-H), 6.87 (d, 1H, J=7.5Hz, Ar-H), 6.70 (t, 1H, J=6.6Hz, Ar-H), 6.65 (d, 1H, J=
7.1Hz, Ar-H), 6.61 (d, 1H, J=6.6Hz, Ar-H), 4.20 (q, 2H, J=7.1Hz ,-CH2-CH3),4.02(t,2H,J
=7.1Hz, imide-NCH2 CH2), 3.39 (t, 2H, J=7.1Hz, imide-NCH2CH2 ), 1.26 (t, 3H, J=
7.1Hz,-CH2-CH3 ).13C NMR(125MHz,DMSO-d6)δ171.7×2,155.0,145.7,142.4,136.5,135.9,
131.8,129.9,127.9,127.6,126.7,126.3,125.4,125.9,122.2,122.1,121.9,121.6,
120.0,119.8,112.3,110.6,105.8,105.3,45.7,41.1,37.6,15.6.HR-ESIMS m/z 461.1989
[M-Cl]+(calcd.for C29H25N4O2,461.1978).
The preparation of compound 41
With 10mL THF dissolved compound 24e (52mg, 0.146mmol), it is added dropwise hydrazine hydrate (73 μ L, 1.46mmol).Instead
Liquid is answered to be heated to 45 DEG C of reaction 15min, solvent evaporated in vacuo adds water and ethyl acetate to extract, and organic layer is evaporated, silica gel column chromatography
Separation, methylene chloride: methanol=100:1 (v/v) elutes to obtain red solid N- amino -2- (- 3 indoles of 1- ethyl) -3- (3- Yin
Diindyl) maleimide (41) 45mg, yield 83.3%.1H NMR(600MHz,DMSO-d6) δ 11.71 (d, 1H, J=2.2Hz,
), indole-NH 7.81 (d, 1H, J=2.2Hz, Ar-H), 7.73 (s, 1H, Ar-H), 7.46 (d, 1H, J=8.3Hz, Ar-H),
7.40 (d, 1H, J=8.3Hz, Ar-H), 7.05 (t, 1H, J=7.1Hz, Ar-H), 6.99 (t, 1H, J=7.1Hz, Ar-H),
6.93 (d, 1H, J=7.7Hz, Ar-H), 6.74 (d, 1H, J=8.2Hz, Ar-H), 6.71 (t, 1H, J=7.7Hz, Ar-H),
6.63 (t, 1H, J=7.7Hz, Ar-H), 4.85 (s, 2H ,-NH2), 4.22 (q, 2H, J=7.7Hz ,-CH2 -CH3),1.30(t,
3H, J=7.7Hz ,-CH2-CH3 ).13C NMR(150MHz,DMSO-d6)δ171.5,171.4,136.6,136.0,131.9,
129.9,126.6,126.1,125.6,125.4,122.3,122.2,121.9,121.5,120.1,119.9,112.4,
110.7,106.2,105.6,41.2,15.8.HR-ESIMS m/z 371.1511[M+H]+(calcd.for C22H19N4O2,
371.1508).
The preparation of compound 42
In 10mL single port bottle, with HCHO (4mL, mass fraction 37%) suspended compound 24d (22mg, 0.05mmol),
Room temperature reaction is overnight.TLC is detected to end of reaction, is poured into ice water (30mL), and ethyl acetate extracts (2 × 50mL), saturation food
Salt water (2 × 50mL) merges organic phase, and anhydrous sodium sulfate is dry, and vacuum revolving removes solvent, with silica gel column chromatography separation, two
Chloromethanes: methanol=80:1 (v/v) elutes to obtain red solid N- methylol -2- (1- ethyl -3- indoles) -3- (3- indoles) Malaysia
Acid imide (42) 12mg, yield 60%.1H NMR(500MHz,DMSO-d6)δ11.71(s,1H,indole-NH),7.81(d,
1H, J=2.7Hz, Ar-H), 7.76 (s, 1H, Ar-H), 7.48 (d, 1H, J=8.2Hz, Ar-H), 7.39 (d, 1H, J=
8.1Hz, Ar-H), 7.06 (t, 1H, J=7.0Hz, Ar-H), 6.99 (t, 1H, J=7.4Hz, Ar-H), 6.92 (d, 1H, J=
8.0Hz, Ar-H), 6.73 (dd, 2H, J=7.7Hz, 4.6Hz, Ar-H), 6.64 (d, 1H, J=7.4Hz, Ar-H), 6.30 (t,
1H, J=7.0Hz ,-CH2-OH), 4.97 (d, 2H, J=7.0Hz ,-CH2 - OH), 4.25 (q, 2H, J=7.2Hz ,-CH2 -CH3),
1.32 (t, 3H, J=7.2Hz ,-CH2-CH3 ).13C NMR(125MHz,DMSO-d6)δ171.7×2,136.6,136.1,
132.1,130.1,128.0,127.3,126.6,125.6,122.3×2,121.9,121.5,120.2,120.0,112.4,
110.7,106.0,105.4,60.8,41.6,15.7.HR-ESIMS m/z 386.1490[M+H]+(calcd.for
C23H20N3O3,386.1499[M+H]+).
The preparation of compound 43
I) preparation of 1- benzyl -6- fluoro indole (43a)
According to the synthetic method of compound 24a, with 6- fluoro indole (675mg, 5mmol), NaH (300mg, 7.5mmol, matter
Measure score 60%, be scattered in paraffin) and cylite (1283mg, 7.5mmol) obtain white crystalline powder (43a) for raw material
1.01g, yield 90%.1HNMR(600MHz,CDCl3) δ 7.53 (dd, 1H, J=8.7Hz, 5.5Hz, Ar-H), 7.29-7.24
(m, 3H, Ar-H), 7.06-7.09 (m, 3H, Ar-H), 6.92 (dd, 1H, J=9.6Hz, 2.3Hz, Ar-H), 6.86 (dt, 1H, J
=9.6Hz, 2.3Hz, Ar-H), 6.51 (d, 1H, J=3.2Hz, Ar-H), 5.21 (s, 2H ,-CH2-Ph).13C NMR
(150MHz,CDCl3)δ159.9(d,1JCF=240Hz), 137.2,136.5 (d,3JCF=12Hz), 129.0,128.9 × 2,
127.9,126.9×2,125.3,121.7(d,3JCF=10Hz), 108.5 (d,2JCF=25Hz), 102.0,96.3 (d,2JCF=
26Hz),50.4.ESI-MS m/z 225.1[M+H]+.
Ii) the preparation of 2- (1- ethyl -3- indoles) -3- (the fluoro- 3- indoles of 1- benzyl -6-) maleic anhydride (43b)
According to the synthetic method of compound 24b, with compound 43a (600mg, 2.67mmol), (COCl)2(345μL,
4.00mmol), compound 1a (541mg, 2.67mmol) and Et3N (738 μ L, 5.33mmol) is raw material, and red solid is made
(43b) 400mg, yield 32%.1H NMR(600MHz,DMSO-d6)δ8.00(s,1H,Ar-H),7.99(s,1H,Ar-H),
7.53 (d, 1H, J=8.3Hz, Ar-H), 7.36 (dd, 1H, J=8.7Hz, 2.3Hz, Ar-H), 7.34 (t, 2H, J=7.3Hz,
), Ar-H 7.28 (t, 1H, J=7.3Hz, Ar-H), 7.22 (d, 2H, J=7.3Hz, Ar-H), 7.11 (t, 1H, J=6.9Hz,
), Ar-H 6.89 (dd, 1H, J=8.7Hz, 5.5Hz, Ar-H), 6.78 (d, 1H, J=7.8Hz, Ar-H), 6.69 (t, 1H, J=
7.8Hz, Ar-H), 6.63 (dt, 1H, J=9.2Hz, 2.3Hz, Ar-H), 5.49 (s, 2H ,-CH2- Ph), 4.32 (q, 2H, J=
7.3Hz,-CH2 -CH3), 1.36 (t, 3H, J=7.3Hz ,-CH2-CH3 ).13C NMR(150MHz,DMSO-d6)δ166.9,
166.8,155.9(d,1JCF=235Hz), 137.6,136.6 (d,3JCF=12Hz), 136.3,134.3,133.5,129.6,
129.2×2,128.2,127.6×2,127.1,125.8,123.1(d,3JCF=13Hz), 123.0,122.8,122.1,
120.7,111.2,109.2(d,2JCF=23Hz), 105.5,104.6,98.0 (d,2JCF=26Hz), 50.0,41.5,
15.8.ESI-MS m/z 465.2[M+H]+.
Iii) the preparation of 2- (1- ethyl -3- indoles) -3- (the fluoro- 3- indoles of 1- benzyl -6-) maleimide (43c)
According to the preparation method of compound 24c, with compound 43b (317mg, 0.68mmol), HMDS (7.2mL,
34.3mmol) and MeOH (0.68mL, 17.2mmol) is raw material, and red powder solid (43c) 287mg, yield 91% is made.1H
NMR(600MHz,DMSO-d6)δ11.00(s,1H,imide-NH),7.89(s,1H,Ar-H),7.88(s,1H,Ar-H),7.46
(d, 1H, J=8.3Hz, Ar-H), 7.33 (t, 2H, J=7.3Hz, Ar-H), 7.28 (dd, 1H, J=8.7Hz, 2.3Hz, Ar-
), H 7.27 (t, 1H, J=7.8Hz, Ar-H), 7.19 (d, 2H, J=7.3Hz, Ar-H), 7.04 (t, 1H, J=8.2Hz, Ar-
), H 6.83 (dd, 1H, J=8.7Hz, 5.5Hz, Ar-H), 6.76 (d, 1H, J=8.2Hz, Ar-H), 6.63 (t, 1H, J=
7.8Hz, Ar-H), 6.53 (dt, 1H, J=9.2Hz, 2.3Hz, Ar-H), 5.47 (s, 2H ,-CH2- Ph), 4.26 (q, 2H, J=
7.3Hz,-CH2 -CH3), 1.34 (t, 3H, J=7.3Hz ,-CH2-CH3 ).13C NMR(150MHz,DMSO-d6)δ173.3×2,
159.4(d,1JCF=235Hz), 137.9,136.5 (d,3JCF=12Hz), 136.0,133.2,132.2,129.2,129.0 ×
2,128.1,127.5×2,126.8,126.3,123.5,122.7(d,3JCF=11Hz), 122.3,121.8,120.1,
110.8,108.6(d,2JCF=24Hz), 106.3,105.2,97.6 (d,2JCF=26Hz), 49.9,41.3,15.8.ESI-MS
m/z 464.2[M+H]+.
Iv) the preparation of 2- (1- ethyl -3- indoles) -3- (the fluoro- 3- indoles of 6-) maleimide (43)
According to the preparation method of compound 24d, with compound 43c (247mg, 0.53mmol), DMSO (0.85mL), 1M
T-BuOK/THF solution (8.4mL, 8.4mmol) and O2It is prepared for raw material, silica gel column chromatography separation, petroleum ether: ethyl acetate=
3:1 (v/v) elutes to obtain red powder solid (43) 118mg, yield 60%.1H NMR(500MHz,DMSO-d6)δ11.69(s,
1H,indole-NH),10.92(s,1H,imide-NH),7.76(s,1H,Ar-H),7.72(s,1H,Ar-H),7.45(d,1H,
J=8.2Hz, Ar-H), 7.14 (d, 1H, J=8.6Hz, Ar-H), 7.04 (t, 1H, J=7.9Hz, Ar-H), 6.81 (d, 1H, J
=8.1Hz, Ar-H), 6.71 (dd, 1H, J=8.5Hz, 5.9Hz, Ar-H), 6.67 (d, 1H, J=7.3Hz, Ar-H), 6.47
(t, 1H, J=8.6Hz, Ar-H), 4.24 (q, 2H, J=7.1Hz ,-CH2 -CH3), 1.32 (t, 3H, J=7.1Hz ,-CH2-
CH3 ).13C NMR(125MHz,DMSO-d6)δ173.4×2,159.3(d,1JCF=235Hz), 136.5 (d,3JCF=12Hz),
136.0,132.1,130.4,128.2,127.7,126.4,122.6,122.4(d,3JCF=11Hz), 122.3,121.8,
120.1,110.7,108.2(d,2JCF=24Hz), 106.2,105.3,98.4 (d,2JCF=27Hz), 41.3,15.8.HR-
ESIMS m/z 374.1314[M+H]+(calcd.for C22H17N3O2F,374.1305).
The preparation of compound 44
According to the synthetic method of compound 42, by compound 43 (20mg, 0.05mmol) and HCHO (5mL, mass fraction
37%) it synthesizes, with silica gel column chromatography separation, methylene chloride: methanol=70:1 (v/v) elutes to obtain red solid N- methylol -2-
(1- ethyl -3- indoles) -3- (the fluoro- 3- indoles of 6-) maleimide (44) 12mg, yield 60%.1H NMR(500MHz,
DMSO-d6) δ 11.74 (s, 1H, indole-NH), 7.81 (s, 1H, Ar-H), 7.79 (d, 1H, J=2.7Hz, Ar-H), 7.49
(d, 1H, J=8.3Hz, Ar-H), 7.17 (dd, 1H, J=8.7Hz, 2.3Hz, Ar-H), 7.06 (s, 1H, Ar-H), 6.84 (d,
1H, J=8.0Hz, Ar-H), 6.73-6.69 (m, 2H, Ar-H), 6.50 (td, J=8.4Hz, 2.4Hz, 1H, Ar-H), 6.30
(t, 1H, J=7.0Hz ,-CH2-OH), 4.97 (d, 2H, J=7.0Hz ,-CH2 - OH), 4.27 (q, 2H, J=7.2Hz ,-CH2 -
CH3), 1.34 (t, 3H, J=7.2Hz ,-CH2-CH3 ).13C NMR(125MHz,DMSO-d6)δ171.6,171.5,159.4(d,1JCF=235Hz), 136.62 (d,3JCF=12Hz), 136.1,132.2 × 2,130.6,128.2,127.9,127.3,126.4,
122.5(d,3JCF=11Hz), 121.8,120.3,110.8,108.3 (d,2JCF=25Hz), 106.1,105.2,98.5 (d,2JCF=27Hz), 60.8,41.3,15.6.HR-ESIMS m/z 404.1393 [M+H]+(calcd.for C23H19N3O3F,
404.1405).
The preparation of compound 45
According to the preparation method of compound 2, with compound 43 (30mg, 0.08mmol), formalin (3mL, mass fraction
And NaHCO 37%)3(13.5mg, 0.16mmol) is raw material preparation, silica gel column chromatography separation, petroleum ether: ethyl acetate=2:1
(v/v) red solid N- methylol -2- (1- ethyl -3- indoles) -3- (the fluoro- 3- indoles of 1- methylol -6-) Malaysia acyl is eluted to obtain
Imines (45) 35mg, yield 99%.1H NMR(600MHz,DMSO-d6)δ7.95(s,1H,Ar-H),7.78(s,1H,Ar-H),
7.48 (d, 1H, J=8.3Hz, Ar-H), 7.41 (dd, 1H, J=9.0Hz, 1.5Hz, Ar-H), 7.06 (t, 1H, J=7.7Hz,
), Ar-H 6.91 (d, 1H, J=8.1Hz, Ar-H), 6.73 (t, 1H, J=7.9Hz, Ar-H), 6.61 (dd, J=8.8Hz,
5.4Hz, Ar-H), 6.51 (dd, 1H, J=8.8Hz, 2.0Hz), 5.57 (s, 2H ,-CH2 -OH),4.95(s,2H,-CH2 -OH),
4.25 (q, 2H, J=7.3Hz ,-CH2 -CH3), 1.31 (t, 3H, J=7.3Hz ,-CH2-CH3 ).13C NMR(150MHz,DMSO-
d6)δ171.5×2,159.4(d,1JCF=235Hz), 136.2 (d,3JCF=12Hz), 136.1,133.0,132.2,128.3,
126.7,126.6,123.2,122.6(d,3JCF=11Hz), 122.5,121.8,120.4,110.8,108.8 (d,2JCF=
25Hz),106.0,105.3,98.0(d,2JCF=26Hz), 69.8,60.8,41.3,15.8.HR-ESIMS m/z 456.1342
[M+Na]+(calcd.for C24H20N3O4FNa,456.1336).
The preparation of compound 46
I) preparation of 1- benzyl -6- chloro-indole (46a)
According to the synthetic method of compound 24a, with 6- chloro-indole (303mg, 2mmol), NaH (120mg, 3mmol, quality
Score 60%, is scattered in paraffin) and cylite (513mg, 3mmol) be raw material preparation, silica gel column chromatography separation, petroleum ether:
Ethyl acetate=60:1 (v/v) elutes to obtain white powdery solids (46a) 483mg, yield 100%.1H NMR(600MHz,
CDCl3) δ 7.55 (d, 1H, J=8.22Hz, Ar-H), 7.26-7.33 (m, 4H, Ar-H), 7.12 (d, 1H, J=3.2Hz, Ar-
), H 7.09 (d, 2H, J=7.7Hz, Ar-H), 7.08 (d, 1H, J=1.8Hz, Ar-H), 6.53 (dd, 1H, J=3.4Hz,
0.9Hz,Ar-H),5.28(s,2H,Ph-CH2-).13C NMR(150MHz,CDCl3)δ137.1,136.8,129.1,129.0,
127.9,127.8,127.3,126.8×2,121.9,120.4,109.8,102.0×2,50.2.ESI-MS m/z 242.1/
244.1[M+H]+.
Ii) the preparation of 2- (1- ethyl -3- indoles) -3- (the chloro- 3- indoles of 1- benzyl -6-) maleic anhydride (46b)
According to the synthetic method of compound 24b, with compound 46a (419mg, 1.73mmol), (COCl)2(446μL,
5.20mmol), compound 1a (352mg, 1.73mmol) and Et3N (480 μ L, 3.47mmol) is raw material preparation, recrystallizing methanol
Obtain red powder (46b) 278mg, yield 33.4%.1H NMR(600MHz,DMSO-d6)δ8.01(s,2H,Ar-H),7.59(s,
1H, Ar-H), 7.54 (d, 1H, J=8.2Hz, Ar-H), 7.34 (t, 2H, J=7.8Hz, Ar-H), 7.29 (t, 1H, J=
7.3Hz, Ar-H), 7.19 (d, 2H, J=7.8Hz, Ar-H), 7.11 (t, 1H, J=7.7Hz, Ar-H), 6.92 (d, 1H, J=
8.7Hz, Ar-H), 6.77 (d, 1H, J=8.7Hz, Ar-H), 6.75 (d, 1H, J=7.3Hz, Ar-H), 6.69 (t, 1H, J=
7.3Hz,Ar-H),5.53(s,2H,Ph-CH2), 4.32 (q, 2H, J=7.3Hz ,-CH2 -CH3), 1.37 (t, 3H, J=
7.3Hz,-CH2-CH3 ).13C NMR(150MHz,DMSO-d6)δ166.9,166.8,137.6,136.9,136.3,134.5,
133.6,129.9,129.3×2,128.2,127.7,127.5×2,126.8,125.7,125.2,123.2,122.9,
122.0,121.0,120.8,111.4,111.2,105.5,104.5,50.0,41.5,15.8.ESI-MS m/z 481.2/
483.2[M+H]+.
Iii) the preparation of 2- (1- ethyl -3- indoles) -3- (the chloro- 3- indoles of 1- benzyl -6-) maleimide (46c)
According to the preparation method according to compound 24c, with compound 46b (240mg, 0.5mmol), HMDS (4.2mL,
20mmol) and MeOH (0.4mL, 10mmol) is raw material preparation, obtains red powder through silica gel column chromatography separation, dichloromethane eluent
Shape solid (46c) 218mg, yield 91%.1H NMR(600MHz,DMSO-d6)δ11.00(s,1H,imide-NH),7.91(s,
1H, Ar-H), 7.90 (s, 1H, Ar-H), 7.51 (d, 1H, J=1.9Hz, Ar-H), 7.47 (d, 1H, J=8.2Hz, Ar-H),
7.34 (t, 2H, J=7.4Hz, Ar-H), 7.28 (t, 1H, J=7.3Hz, Ar-H), 7.17 (d, 2H, J=7.3Hz, Ar-H),
7.05 (t, 1H, J=7.7Hz, Ar-H), 6.84 (d, 1H, J=8.2Hz, Ar-H), 6.72 (d, 1H, J=7.8Hz, Ar-H),
6.67 (dd, 1H, J=8.7Hz, 1.9Hz, Ar-H), 6.62 (t, 1H, J=7.3Hz, Ar-H), 5.50 (s, 2H, Ph-CH2-),
4.28 (q, 2H, J=7.3Hz ,-CH2 -CH3), 1.36 (t, 3H, J=7.3Hz ,-CH2-CH3 ).13CNMR(150MHz,DMSO-
d6)δ173.3×2,137.9,136.8,136.1,133.5,132.3,129.3,129.2×2,128.1,127.4×2,
127.2,126.5,126.2,125.6,122.9,122.3,121.7,120.5,120.2,111.0,110.8,106.3,
105.1,49.8,41.3,15.8.ESI-MS m/z 480.1/482.2[M+H]+.
Iv) the preparation of 2- (1- ethyl -3- indoles) -3- (the chloro- 3- indoles of 6-) maleimide (46)
According to the preparation method of compound 23d, with compound 46c (160mg, 0.33mmol), DMSO (0.85mL), 1M
T-BuOK/THF solution (8.4mL, 8.4mmol) and O2It is prepared for raw material, silica gel column chromatography separation, petroleum ether: ethyl acetate=
3:1 (v/v) elutes to obtain red powder (46) 128mg, yield 99%.1H NMR(500MHz,DMSO-d6)δ11.75(s,1H,
), indole-NH 10.94 (s, 1H, imide-NH), 7.79 (s, 1H, Ar-H), 7.76 (s, 1H, Ar-H), 7.45 (d, 1H, J=
8.3Hz, Ar-H), 7.41 (s, 1H, Ar-H), 7.02 (t, 1H, J=7.6Hz, Ar-H), 6.77 (d, 1H, J=7.7Hz, Ar-
), H 6.73 (d, 1H, J=8.2Hz, Ar-H), 6.66 (t, 1H, J=7.5Hz, Ar-H), 6.61 (dd, 1H, J=8.5Hz,
1.1Hz, Ar-H), 4.24 (q, 2H, J=7.2Hz ,-CH2 -CH3), 1.32 (t, 3H, J=7.2Hz ,-CH2-CH3 ).13C NMR
(125MHz,DMSO-d6)δ173.3×2,136.8,135.9,132.0,130.5,128.4,127.2,126.6,126.2,
124.6,122.5,122.2,121.6,120.0,119.9,111.8,110.6,106.1,105.1,41.1,15.7.HR-
ESIMS m/z390.1014[M+H]+(calcd.for C22H17N3O2Cl,390.1009).
The preparation of compound 47
According to the synthetic method of compound 42, by compound 46 (19mg, 0.05mmol) and HCHO (5mL, mass fraction
37%) it synthesizes, with silica gel column chromatography separation, methylene chloride: methanol=80:1 (v/v) elutes to obtain red solid N- methylol -2-
(1- ethyl -3- indoles) -3- (the chloro- 3- indoles of 6-) maleimide (47) 10mg, yield 50%.1H NMR(500MHz,
DMSO-d6) δ 11.78 (s, 1H, indole-NH), 7.83 (s, 1H, Ar-H), 7.79 (s, 1H, Ar-H), 7.48 (d, 1H, J=
8.3Hz, Ar-H), 7.42 (d, 1H, J=1.3Hz, Ar-H), 7.04 (t, 1H, J=7.5Hz, Ar-H), 6.77 (d, 1H, J=
8.0Hz, Ar-H), 6.71 (d, 1H, J=8.6Hz, Ar-H), 6.68 (t, 1H, J=7.5Hz, Ar-H), 6.62 (dd, 1H, J=
8.6Hz, 1.5Hz, Ar-H), 6.30 (t, 1H, J=6.9Hz, imide-CH2-OH), 4.94 (d, 2H, J=6.9Hz, imide-
CH2 - OH), 4.28 (q, 2H, J=7.2Hz ,-CH2 -CH3), 1.33 (t, 3H, J=7.2Hz ,-CH2-CH3 ).13C NMR
(125MHz,DMSO-d6)δ171.5×2,137.0,136.1,132.3,130.9,128.2,127.0,126.9,126.4,
124.6,122.6,122.4,121.7,120.3,120.2,112.1,110.9,106.2,105.2,60.8,41.3,
15.8.HR-ESIMS m/z 420.1107[M+H]+(calcd.for C23H19N3O3Cl,420.1109).
The preparation of compound 48
According to the preparation method of compound 2, with compound 46 (14mg, 36.0 μm of ol), formalin (3mL, mass fraction
And NaHCO 37%)3(7mg, 0.083mmol) is raw material preparation, silica gel column chromatography separation, petroleum ether: ethyl acetate=3:1 (v/
V) red solid N- methylol -2- (1- ethyl -3- indoles) -3- (the chloro- 3- indoles of 1- methylol -6-) maleimide is eluted to obtain
(48) 16mg, yield 99%.1H NMR(600MHz,DMSO-d6)δ7.99(s,1H,Ar-H),7.83(s,1H,Ar-H),7.69
(d, 1H, J=1.8Hz, Ar-H), 7.50 (d, 1H, J=8.2Hz, Ar-H), 7.06 (t, 1H, J=7.8Hz, Ar-H), 6.89
(d, 1H, J=8.2Hz, Ar-H), 6.75 (t, 1H, J=7.3Hz ,-CH2-OH), 6.72 (t, 1H, J=7.7Hz, Ar-H),
6.66 (dd, 1H, J=8.2Hz, 1.8Hz, Ar-H), 6.62 (d, 1H, J=8.2Hz, Ar-H), 6.35 (t, 1H, J=6.8Hz ,-
CH2-OH), 5.61 (d, 2H, J=7.3Hz ,-N-CH2 - OH), 4.97 (d, 2H, J=6.8Hz ,-N-CH2 -OH),4.28(q,2H,
J=6.8Hz ,-CH2 -CH3), 1.32 (t, 3H, J=6.8Hz ,-CH2-CH3 ).13C NMR(150MHz,DMSO-d6)δ171.4×
2,136.5,136.0,133.3,132.4,128.6,127.2,126.6,126.3,125.4,122.7,122.5,121.7,
120.6,120.4,111.5,110.9,105.9,105.2,69.8,60.9,41.3,15.8.HR-ESIMS m/z 472.1046
[M+Na]+(calcd.for C24H20N3O4ClNa,472.1040).
The preparation of compound 49
I) preparation of 1- benzyl -4- bromo indole (49a)
According to the preparation method of compound 24a, with compound 4- bromo indole (700mg, 3.59mmol), NaH (129mg,
5.38mmol, mass fraction 60%, is scattered in paraffin) and cylite (0.64mL, 5.38mmol) be raw material preparation, silicagel column
Chromatographic isolation, petroleum ether: ethyl acetate=100:1 (v/v) elutes to obtain white crystal (49a) 0.88g, yield 86%.1H NMR
(600MHz,DMSO-d6) δ 7.64 (d, 1H, J=3.3Hz, Ar-H), 7.49 (d, 1H, J=8.3Hz, Ar-H), 7.29-7.27
(m, 2H, Ar-H), 7.25-7.23 (m, 2H, Ar-H), 7.19-7.18 (m, 2H, Ar-H), 7.03 (t, 1H, J=7.7Hz, Ar-
), H 6.45 (d, 1H, J=2.8Hz, Ar-H), 5.43 (s, 2H, Ph-CH2-).13C NMR(150MHz,DMSO-d6)δ138.4,
136.7,130.9,129.2,129.1,128.0,127.6,127.4,123.0×2,122.4,114.2,110.5,101.4,
50.0.ESI-MS m/z 286.0/288.0[M+H]+.
Ii) the preparation of 2- (1- ethyl -3- indoles) -3- (the bromo- 3- indoles of 1- benzyl -4-) maleic anhydride (49b)
According to the preparation method of compound 24b, with compound 49a (400mg, 1.4mmol), (COCl)2(214μL,
2.25mmol), compound 1a (548mg, 2.7mmol) and Et3N (626 μ L, 4.5mmol) is raw material preparation, silica gel column chromatography point
From, petroleum ether: ethyl acetate=7:1 (v/v) elutes to obtain red powder (49b) 220mg, yield 30.0%.1H NMR
(600MHz,pyridine-d5) δ 8.37 (s, 1H, Ar-H), 7.63 (s, 1H, Ar-H), 7.41 (d, 1H, J=3.8Hz, Ar-
), H 7.42 (m, 3H, Ar-H), 7.24-7,22 (m, 4H, Ar-H), 7.06-7.04 (m, 4H, Ar-H), 6.77 (t, 1H, J=
7.2Hz, Ar-H), 5.3 (d, 1H, J=15.9Hz, Ph-CH2 ), 5.24 (d, 1H, J=15.9Hz, Ph-CH2-),4.05(q,
2H, J=8.2Hz ,-CH2 -CH3), 1.37 (t, 3H, J=8.2Hz ,-CH2-CH3 ).13C NMR(150MHz,pyridine–d5)δ
166.0,165.6,148.5×2,136.4,135.5,135.4,133.2,130.6,127.5,126.4,125.5,125.4,
124.5,124.1,123.8,122.5,122.1,121.5,121.2,119.9,113.4,109.3,109.2,104.4,
103.8,48.8,40.1,13.5.ESI-MS m/z 525.1/527.1[M+H]+.
Iii) the preparation of 2- (1- ethyl -3- indoles) -3- (the bromo- 3- indoles of 1- benzyl -4-) maleimide (49c)
According to the preparation method of compound 24c, with compound 49c (110mg, 0.21mmol), HMDS (4.5mL,
21mmol) and MeOH (0.4mL, 10.5mmol) is raw material preparation, silica gel column chromatography separation, petroleum ether: methylene chloride=1:4
(v/v) red powder (49c) 100mg, yield 91% are eluted to obtain.1H NMR(600MHz,DMSO-d6)δ11.02(s,1H,
), imide-NH 8.05 (s, 1H, Ar-H), 7.53 (s, 1H, Ar-H), 7.47 (t, 2H, J=8.7Hz, Ar-H), 7.27 (d, 1H,
J=7.6Hz, Ar-H), 7.19 (dd, 3H, J=5.0Hz, 1.8Hz, Ar-H), 7.09 (dt, 2H, J=8.2Hz, 2.0Hz, Ar-
), H 6.99-6.95 (m, 2H, Ar-H), 6.68 (d, 1H, J=8.1Hz, Ar-H), 6.58 (t, 1H, J=7.6Hz, Ar-H),
5.42 (d, 1H, J=15.9Hz)/5.38 (d, 1H, J=15.9Hz) (Ph-CH2), 4.25 (q, 2H, J=7.2Hz ,-CH2 -
CH3), 1.35 (t, 3H, J=7.2Hz ,-CH2-CH3 ).13C NMR(150MHz,DMSO-d6)δ173.9,173.2,137.9,
137.6,136.5,134.3,133.3,132.0,129.0,127.9,127.1,126.9,126.7,125.7,124.6,
123.7,122.5,121.9,120.6,114.4,111.0×2,110.9,106.2,105.0,49.8,49.2,41.4,
15.8.ESI-MS m/z 524.1/526.1[M+H]+.
Iv) the preparation of 2- (1- ethyl -3- indoles) -3- (the bromo- 3- indoles of 4-) maleimide (49)
According to the preparation method of compound 24d, with compound 49c (110mg, 0.21mmol), DMSO (1.24mL), 1M
T-BuOK/THF solution (0.97mL, 0.97mmol) and O2For raw material preparation, silica gel column chromatography separation, petroleum ether: ethyl acetate
=3:1 (v/v) elutes to obtain red powder (49) 63mg, yield 70%.1H NMR(600MHz,DMSO-d6)δ11.65(s,1H,
), indole-NH 10.93 (s, 1H, imide-NH), 8.00 (s, 1H, Ar-H), 7.48 (d, 1H, J=8.3Hz, Ar-H), 7.45
(d, 1H, J=8.3Hz, Ar-H), 7.30 (d, 1H, J=2.8Hz, Ar-H), 7.24 (d, 1H, J=7.7Hz, Ar-H), 7.09
(t, 1H, J=7.7Hz, Ar-H), 7.01 (t, 1H, J=6.6Hz, Ar-H), 6.58 (d, 1H, J=7.9Hz, Ar-H), 6.53
(t, 1H, J=7.3Hz, Ar-H), 4.24 (q, 2H, J=7.2Hz ,-CH2 -CH3), 1.34 (t, 3H, J=7.2Hz ,-CH2-
CH3 ).13C NMR(150MHz,DMSO-d6)δ174.0,173.4,137.9,136.4,134.3,133.3,128.6,127.4,
126.4,125.8,124.1,123.5,122.4,121.8,120.4,114.1,112.2,110.8,106.5,105.1,41.3,
15.8.HR-ESIMS m/z 434.0514[M+H]+(calcd.for C22H17N3O2Br,434.0504).
The preparation of compound 50
According to the synthetic method of compound 42, by compound 49 (20mg, 0.05mmol) and HCHO (5mL, mass fraction
37%) it synthesizes, with silica gel column chromatography separation, methylene chloride: methanol=70:1 (v/v) elutes to obtain red solid N- methylol -2-
(1- ethyl -3- indoles) -3- (the bromo- 3- indoles of 4-) maleimide (50) 11mg, yield 50%.1H NMR(500MHz,
DMSO-d6) δ 11.70 (s, 1H, indole-NH), 8.03 (s, 1H, Ar-H), 7.48 (d, 1H, J=8.1Hz, Ar-H), 7.45
(d, 1H, J=8.2Hz, Ar-H), 7.34 (d, 1H, J=2.5Hz, Ar-H), 7.22 (d, 1H, J=7.5Hz, Ar-H), 7.07
(t, 1H, J=7.9Hz, Ar-H), 7.02 (t, 1H, J=7.3Hz, Ar-H), 6.56 (d, 2H, J=7.5Hz, Ar-H), 6.34
(t, 1H, J=7.0Hz ,-CH2-OH), 4.95 (d, 2H, J=7.0Hz ,-CH2 - OH), 4.27 (q, 2H, J=7.2Hz ,-CH2 -
CH3), 1.33 (t, 3H, J=7.2Hz ,-CH2-CH3 ).13C NMR(125MHz,DMSO-d6)δ171.9,171.4,137.8,
136.4,133.9,133.3,128.6,126.7,126.2,125.6,124.0,123.4,122.4,121.6,120.4,
113.8,112.1,110.8,106.1,105.0,60.7,41.2,15.6.HR-ESIMS m/z 464.0602[M+H]+
(calcd.for C23H19N3O3Br,464.0604).
The preparation of compound 51
According to the preparation method of compound 2, with compound 49 (100mg, 0.23mmol), formalin (3mL, quality point
Number 37%) and NaHCO3(97mg, 1.15mmol) is raw material preparation, silica gel column chromatography separation, petroleum ether: ethyl acetate=4:1
(v/v) elution separates to obtain red solid N- methylol -2- (1- ethyl -3- indoles) -3- (the bromo- 3- indoles of 1- methylol -4-) horse
Come acid imide (51) 67mg, yield 59%.1H NMR(500MHz,DMSO-d6) δ 8.02 (s, 1H, Ar-H), 7.68 (d, 1H, J=
8.1Hz, Ar-H), 7.48 (s, 1H, Ar-H), 7.45 (d, 1H, J=8.3Hz, Ar-H), 7.28 (d, 1H, J=7.5Hz, Ar-
), H 7.15 (d, 1H, J=7.9Hz, Ar-H), 7.06 (t, 1H, J=7.4Hz, Ar-H), 6.73 (d, 1H, J=8.2Hz, Ar-
), H 6.62 (t, 1H, J=6.8Hz, Ar-H), 6.60 (t, 1H, J=7.2Hz, indole-CH2-OH), 6.37 (t, 1H, J=
6.5Hz,imide-CH2-OH), 5.53 (d, 2H, J=7.2Hz, indole-CH2 - OH), 4.97 (d, 2H, J=6.5Hz,
imide-CH2 - OH), 4.24 (q, 2H, J=7.1Hz ,-CH2 -CH3), 1.33 (t, 3H, J=7.1Hz ,-CH2-CH3 ).13CNMR
(125MHz,DMSO-d6)δ172.0,171.5,137.4,136.5,134.6,133.5,131.3,127.2,126.2,125.9,
124.8,123.8,122.6,121.9,120.7,114.1,111.2,110.9,106.0,105.1,69.6,60.8,41.4,
15.7.HR-ESIMS m/z516.0540[M+Na]+(calcd.for C24H20N3O4BrNa,516.0535).
The preparation of compound 52
I) preparation of 1- benzyl -5- bromo indole (52a)
According to the preparation method of compound 24a, with compound 5- bromo indole (700mg, 3.59mmol), NaH (129mg,
5.38mmol, mass fraction 60%, is scattered in paraffin) and cylite (0.64mL, 5.38mmol) be raw material preparation, silicagel column
Chromatographic isolation, petroleum ether: ethyl acetate=60:1 (v/v) elutes to obtain white crystalline powder (52a) 0.88g, yield 86%.1H
NMR(600MHz,DMSO-d6) δ 7.75 (d, 1H, J=1.6Hz, Ar-H), δ 7.56 (d, 1H, J=3.3Hz, Ar-H), 7.42
(d, 2H, J=8.8Hz, Ar-H), 7.30 (t, 2H, J=7.7Hz, Ar-H), 7.24-7.16 (m, 3H, Ar-H), 6.48 (d, 1H,
J=2.2Hz, Ar-H), 5.41 (s, 2H ,-CH2-).13C NMR(150MHz,DMSO-d6)δ138.5,135.0,131.3,
130.7×2,129.1,128.0,127.6,127.5,124.2,123.2,112.8,112.4,101.3,49.8.ESI-MS m/
z 286.0/288.0[M+H]+.
Ii) the preparation of 2- (1- ethyl -3- indoles) -3- (the bromo- 3- indoles of 1- benzyl -5-) maleic anhydride (52b)
According to the preparation method of compound 24b, with compound 52a (1100mg, 3.86mmol), (COCl)2(500μL,
5.79mmol), compound 1a (783mg, 3.86mmol) and Et3N (1.07mL, 7.72mmol) is raw material preparation, pure methanol weight
Crystallize to obtain red powder (52b) 652mg, yield 32.2%.1H NMR(600MHz,DMSO-d6)δ8.06(s,1H,Ar-H),
7.99 (s, 1H, Ar-H), 7.55 (d, 1H, J=8.1Hz, Ar-H), 7.39 (d, 1H, J=8.7Hz, Ar-H), 7.33 (t, 2H, J
=7.5Hz, Ar-H), 7.28 (d, 1H, J=6.7Hz, Ar-H), 7.17 (d, 2H, J=7.4Hz, Ar-H), 7.14 (d, 1H, J=
8.8Hz, Ar-H), 7.10 (t, 1H, J=7.7Hz, Ar-H), 6.98 (s, 1H, Ar-H), 6.76 (d, 1H, J=8.1Hz, Ar-
), H 6.69 (d, 1H, J=8.2Hz, Ar-H), 5.52 (s, 2H ,-CH2- Ph), 4.33 (q, 2H, J=6.6Hz ,-CH2 -CH3),
1.39 (t, 3H, J=6.6Hz ,-CH2-CH3 ).13C NMR(150MHz,DMSO-d6)δ166.8×2,137.6,136.2,
135.2,134.8,133.2,129.5,129.2,128.2,128.0,127.6,127.5,127.4,125.8,125.3,
124.4,122.9,121.7,120.7,113.5,113.4,111.2,104.8,104.6,99.9,50.2,41.5,
16.1.ESI-MS m/z 525.1/527.0[M+H]+.
Iii) the preparation of 2- (1- ethyl -3- indoles) -3- (the bromo- 3- indoles of 1- benzyl -5-) maleimide (52c)
According to the preparation method of compound 24c, with compound 52b (110mg, 0.21mmol), HMDS (4.5mL,
21mmol) and MeOH (0.4mL, 11mmol) is raw material preparation, obtains red powder through silica gel column chromatography separation, dichloromethane eluent
Shape solid (52c) 100mg, yield 91%.1H NMR(600MHz,DMSO-d6)δ10.98(s,1H,imide-NH),7.96(s,
1H, Ar-H), 7.86 (s, 1H, Ar-H), 7.48 (d, 1H, J=8.3Hz, Ar-H), 7.34 (dt, 3H, J=7.2Hz, 1.7Hz,
), Ar-H 7.27 (t, 1H, J=7.3Hz, Ar-H), 7.14 (d, 2H, J=7.1Hz, 2H, Ar-H), 7.06 (dd, 1H, J=
6.8Hz, 2.0Hz, Ar-H), 6.90 (d, 1H, J=1.9Hz, Ar-H), 6.72 (d, 1H, J=8.0Hz, Ar-H), 6.62 (t,
1H, J=7.2Hz, Ar-H), 5.49 (s, 2H ,-CH2- Ph), 4.30 (q, 2H, J=7.2Hz ,-CH2 -CH3),1.38(t,3H,J
=7.2Hz ,-CH2-CH3 ).13C NMR(150MHz,DMSO-d6)δ173.2×2,137.9,136.0,135.0,133.9,
132.0,129.2,128.8,128.4,128.19,127.4,127.0×2,126.7,124.8,124.2×2,122.4,
121.4,120.1,113.1,112.9,110.8,105.6,105.1,50.0,41.3,16.1.ESI-MS m/z 524.1/
526.1[M+H]+.
Iv) the preparation of 2- (1- ethyl -3- indoles) -3- (the bromo- 3- indoles of 5-) maleimide (52)
According to the preparation method of compound 24d, with compound 52c (90mg, 0.172mmol), DMSO (0.85mL) and 1M
T-BuOK/THF solution (7mL, 7mmol) and O2For raw material preparation.Silica gel column chromatography separation, methylene chloride: ethyl acetate=
4:1 (v/v) elutes to obtain red powder (52) 54mg, yield 73%.1H NMR(600MHz,DMSO-d6)δ11.82(s,1H,
), indole-NH 10.92 (s, 1H, imide-NH), 7.80 (s, 1H, Ar-H), 7.77 (s, 1H, Ar-H), 7.49 (d, 1H, J=
8.3Hz, Ar-H), 7.31 (d, 1H, J=8.6Hz, Ar-H), 7.05 (d, 1H, J=8.0Hz, Ar-H), 7.03 (d, 1H, J=
8.0Hz, Ar-H), 6.79 (s, 1H, Ar-H), 6.77 (d, 1H, J=8.0Hz, Ar-H), 6.67 (t, 1H, J=7.2Hz, Ar-
), H 4.28 (q, 2H, J=7.2Hz ,-CH2 -CH3), 1.36 (t, 3H, J=7.2Hz ,-CH2-CH3 ).13C NMR(150MHz,
DMSO-d6)δ173.4,173.3,136.0,135.2,131.9,131.0,128.1,127.8,127.5,126.5,124.6,
124.0,122.4,121.4,120.1,114.2,112.4,110.7,105.8,105.3,41.3,16.1.HR-ESIMS m/
z434.0514[M+H]+(calcd.for C22H17N3O2Br,434.0504).
The preparation of compound 53
According to the synthetic method of compound 42, by compound 52 (21mg, 0.05mmol) and HCHO (5mL, mass fraction
37%) it synthesizes, with silica gel column chromatography separation, methylene chloride: methanol=70:1 (v/v) elutes to obtain red solid N- methylol -2-
(1- ethyl -3- indoles) -3- (the bromo- 3- indoles of 5-) maleimide (53) 12mg, yield 55%.1H NMR(500MHz,
DMSO-d6) δ 11.86 (s, 1H, indole-NH), 7.83 (s, 1H, Ar-H), 7.80 (s, 1H, Ar-H), 7.49 (d, 1H, J=
8.4Hz, Ar-H), 7.32 (d, 1H, J=8.7Hz, Ar-H), 7.06 (d, 1H, J=8.3Hz, Ar-H), 7.03 (d, 1H, J=
7.7Hz, Ar-H), 6.81 (s, 1H, Ar-H), 6.77 (t, 1H, J=8.2Hz, Ar-H), 6.67 (t, 1H, J=7.7Hz, Ar-
), H 6.31 (t, 1H, J=6.7Hz ,-CH2-OH), 4.95 (d, 2H, J=6.4Hz ,-CH2 - OH), 4.28 (q, 2H, J=
7.0Hz,-CH2 -CH3), 1.36 (t, 3H, J=6.8Hz ,-CH2-CH3 ).13C NMR(125MHz,DMSO-d6)δ171.4,
171.3,136.0,135.1,131.9,131.1,127.6,127.3,127.2,126.2,124.6,123.9,122.3,
121.3,120.1,114.1,112.4,110.7,105.5,105.0,60.7,41.2,15.9.HR-ESIMS m/z
464.0600[M+H]+(calcd.for C23H19N3O3Br,464.0604).
The preparation of compound 54
According to the preparation method of compound 2, with compound 53 (53mg, 0.122mmol), NaHCO3(51mg,
0.62mmol) and formalin (3mL, mass fraction 37%) is raw material preparation, silica gel column chromatography separation, petroleum ether: acetic acid second
Ester=4:1 (v/v) elutes to obtain red solid N- methylol -2- (1- ethyl -3- indoles) -3- (the bromo- 3- indoles of 1- methylol -5-)
Maleimide (54) 60mg, yield 99%.1H NMR(500MHz,DMSO-d6)δ8.04(s,1H,Ar-H),7.78(s,1H,
), Ar-H 7.50 (d, 2H, J=8.6Hz, Ar-H), 7.13 (d, 1H, J=8.6Hz, Ar-H), 7.06 (t, 1H, J=7.5Hz,
), Ar-H 6.87 (d, 1H, J=7.9Hz, Ar-H), 6.75 (t, 1H, J=6.8Hz, indole-CH2-OH),6.71(d,1H,J
=7.6Hz, Ar-H), 6.68 (s, 1H, Ar-H), 6.34 (t, 1H, J=6.4Hz, imide-CH2-OH), 5.58 (d, 2H, J=
6.8Hz,indole-CH2 - OH), 4.96 (d, 2H, J=6.4Hz, imide-CH2 - OH), 4.28 (q, 2H, J=6.9Hz ,-CH2 -
CH3), 1.35 (t, 3H, J=6.9Hz ,-CH2-CH3 ).13C NMR(125MHz,DMSO-d6)δ171.4×2,136.0,134.8,
133.6,132.0,128.2,128.1,126.9,126.6,124.8,124.3,122.5,121.4,120.4,113.3,
113.2,110.8,105.4,105.2,69.9,60.8,41.4,16.1.HR-ESIMS m/z 516.0547[M+Na]+
(calcd.for C24H20N3O4BrNa,516.0535),.
The preparation of compound 55 (compound 26d)
See the preparation of compound 26d.
The preparation of compound 56
According to the synthetic method of compound 42, by compound 55 (21mg, 0.05mmol) and HCHO (5mL, mass fraction
37%) it synthesizes, with silica gel column chromatography separation, methylene chloride: methanol=70:1 (v/v) elutes to obtain red solid N- methylol -2-
(1- ethyl -3- indoles) -3- (the bromo- 3- indoles of 6-) maleimide (56) 12mg, yield 53%.1H NMR(600MHz,
DMSO-d6) δ 11.81 (s, 1H, indole-NH), 7.85 (s, 1H, Ar-H), 7.80 (s, 1H, Ar-H), 7.58 (d, 1H, J=
1.8Hz, Ar-H), 7.50 (d, 1H, J=8.3Hz, Ar-H), 7.38 (dd, 1H, J=7.6Hz, 1.5Hz, Ar-H), 7.06 (t,
1H, J=7.6Hz, Ar-H), 6.79 (d, 1H, J=8.0Hz, Ar-H), 6.76 (dd, 1H, J=8.6Hz, 1.8Hz, Ar-H),
6.71 (d, 1H, J=3.9Hz, Ar-H), 6.69 (t, 1H, J=3.9Hz, Ar-H), 6.32 (t, 1H, J=7.0Hz ,-CH2-
OH), 4.96 (d, 2H, J=7.0Hz ,-CH2 - OH), 4.29 (q, 2H, J=7.2Hz ,-CH2 -CH3), 1.35 (t, 3H, J=
7.2Hz,-CH2-CH3 ).13C NMR(125MHz,DMSO-d6)δ171.5×2,137.5,136.1,132.3,130.7,128.2,
127.0,126.3,124.9,123.0,122.8,122.4,121.7,120.3,115.1,115.0,110.9,106.2,
105.1,60.8,41.3,15.8.HR-ESIMS m/z464.0591[M+H]+(calcd.for C23H19N3O3Br,
464.0604).
The preparation of compound 57
According to the preparation method of compound 2, with compound 56 (50mg, 0.115mmol), NaHCO3(29mg,
0.345mmol) and formalin (3mL, mass fraction 37%) is raw material preparation, silica gel column chromatography separation, petroleum ether: acetic acid second
Ester=4:1 (v/v) elutes to obtain red solid N- methylol -2- (1- ethyl -3- indoles) -3- (the bromo- 3- indoles of 1- methylol -6-)
Maleimide (57) 48mg, yield 85%.1H NMR(500MHz,DMSO-d6)δ7.98(s,1H,Ar-H),7.83(s,2H,
), Ar-H 7.49 (d, 1H, J=8.2Hz, Ar-H), 7.07 (t, 1H, J=7.7Hz, Ar-H), 6.89 (d, 1H, J=7.7Hz,
), Ar-H 6.78 (d, 1H, J=8.2Hz, Ar-H), 6.76 (t, 1H, J=6.8Hz ,-CH2- OH), 6.72 (t, 1H, J=
7.7Hz, Ar-H), 6.60 (d, 1H, J=8.2Hz, Ar-H), 6.35 (t, 1H, J=6.6Hz ,-CH2-OH),5.61(d,2H,J
=6.6Hz ,-N-CH2 - OH), 4.98 (d, 2H, J=6.6Hz ,-CH2 - OH), 4.27 (q, 2H, J=6.6Hz ,-CH2 -CH3),
1.34 (t, 3H, J=6.6Hz ,-CH2-CH3 ).13C NMR(125MHz,DMSO-d6)δ171.4×2,136.9,136.1,
133.1,132.3,128.7,126.6,126.3,125.7,123.2,123.1,122.5,121.7,120.4,115.3,
114.4,110.9,106.0,105.2,69.8,60.9,41.4,15.8.HR-ESIMS m/z 516.0544[M+Na]+
(calcd.for C24H20N3O4BrNa,516.0535).
The preparation of compound 58
I) preparation of 1- benzyl -7- bromo indole (58a)
According to the preparation method of compound 24a, with compound 7- bromo indole (700mg, 3.59mmol), NaH (129mg,
5.38mmol, mass fraction 60%, is scattered in paraffin) and cylite (0.64mL, 5.38mmol) be raw material preparation, silicagel column
Chromatographic isolation, petroleum ether: ethyl acetate=60:1 (v/v) elutes to obtain white crystalline powder (58a) 1.0g, yield 98%.1H
NMR(600MHz,DMSO-d6) δ 7.61 (d, 1H, J=7.8Hz, Ar-H), 7.54 (d, 1H, J=3.2Hz, Ar-H), 7.29 (d,
1H, J=7.5Hz, Ar-H), 7.26 (t, 2H, J=7.5Hz, Ar-H), 7.21 (d, 1H, J=7.1Hz, Ar-H), 6.95 (d,
1H, J=7.7Hz, Ar-H), 6.93 (dd, 2H, J=7.6Hz, 2.7Hz, Ar-H), 6.61 (d, 1H, J=3.2Hz, Ar-H),
5.81(s,2H,-CH2-).13C NMR(150MHz,DMSO-d6)δ140.2×2,133.3,132.4,129.1×2,127.6,
127.0,126.3,121.4×2,121.1,103.6,102.6,51.0.ESI-MS m/z 286.0/288.0[M+H]+.
Iii) the preparation of 2- (1- ethyl -3- indoles) -3- (the bromo- 3- indoles of 1- benzyl -7-) maleic anhydride (58b)
According to the preparation method of compound 24b, with compound 58a (700mg, 2.5mmol), (COCl)2(714μL,
7.5mmol), compound 1a (686mg, 3.3mmol) and Et3N (0.723mL, 5.2mmol) is raw material preparation, and pure methanol is tied again
It is brilliant to obtain red powder (58b) 380mg, yield 30%.1H NMR(600MHz,DMSO-d6)δ8.04(s,1H,Ar-H),8.01(s,
1H, Ar-H), 7.50 (d, 1H, J=8.0Hz, Ar-H), 7.31 (t, 2H, J=7.0Hz, Ar-H), 7.25 (t, 1H, J=
7.4Hz, Ar-H), 7.21 (d, 1H, J=7.6Hz, Ar-H), 7.09 (t, 1H, J=7.6Hz, Ar-H), 6.99 (d, 2H, J=
7.4Hz, Ar-H), 6.94 (d, 1H, J=8.0Hz, Ar-H), 6.77 (d, 1H, J=8.0Hz, Ar-H), 6.71 (t, 1H, J=
7.5Hz, Ar-H), 6.63 (t, 1H, J=7.8Hz, Ar-H), 5.90 (s, 2H ,-CH2- Ph), 4.31 (q, 2H, J=5.8Hz ,-
CH2 -CH3), 1.34 (t, 3H, J=5.8Hz ,-CH2-CH3 ).13C NMR(150MHz,DMSO-d6)δ166.8,166.7,
139.4,136.4,136.3,133.8,132.6,131.1,129.8,129.2,128.2,127.8,127.3,126.2,
125.9,125.8,123.0,121.8,121.4,120.9,120.8,119.4,111.2,105.8,104.6,103.9,51.7,
41.6,15.8.ESI-MS m/z 525.1/527.0[M+H]+.
Iii) the preparation of 2- (1- ethyl -3- indoles) -3- (the bromo- 3- indoles of 1- benzyl -7-) maleimide (58c)
According to the preparation method of compound 24c, with compound 58b (110mg, 0.45mmol), HMDS (4.5mL,
21mmol) and MeOH (0.4mL, 11mmol) is raw material preparation, obtains red powder through silica gel column chromatography separation, dichloromethane eluent
Shape solid (58c) 100mg, yield 91%.1H NMR(600MHz,DMSO-d6)11.04(s,1H,imide-NH),7.93(s,
1H, Ar-H), 7.92 (s, 1H, Ar-H), 7.45 (d, 1H, J=8.3Hz, Ar-H), 7.31 (t, 2H, J=7.5Hz, Ar-H),
7.25 (s, 1H, J=7.4Hz, Ar-H), 7.15 (dd, 1H, J=7.6Hz, 1.0Hz, Ar-H), 7.04 (d, 1H, J=1.1Hz,
), Ar-H 6.97 (d, 2H, J=7.2Hz, Ar-H), 6.88 (dd, 1H, J=8.0Hz, 1.0Hz, Ar-H), 6.76 (d, 1H, J=
8.0Hz, Ar-H), 6.67 (d, 1H, J=7.9Hz, Ar-H), 6.56 (t, 1H, J=7.8Hz, Ar-H), 5.88 (s, 2H ,-CH2-
), Ph 4.27 (q, 2H, J=7.2Hz ,-CH2 -CH3), 1.35 (t, 3H, J=7.2Hz ,-CH2-CH3 ).13C NMR(150MHz,
DMSO-d6)δ173.2×2,139.7,136.0,135.6,135.5,132.5,132.4,130.3,130.2,129.1,127.7
×2,126.3,126.2,125.7,122.4,121.7,121.6,121.1×2,120.2,110.8,106.5,105.1,
103.7,51.5,41.4,15.8.ESI-MS m/z 523.8/525.8[M+H]+.
Iv) the preparation of 2- (1- ethyl -3- indoles) -3- (the bromo- 3- indoles of 7-) maleimide (58)
According to the preparation method of compound 24d, with compound 58c (292mg, 0.558mmol), DMSO (0.85mL) and 1M
T-BuOK/THF solution (8.4mL, 8.4mmol) and O2For raw material preparation.Silica gel column chromatography separation, methylene chloride: acetic acid second
Ester=4:1 (v/v) elutes to obtain red powder (58) 150mg, yield 64%.1H NMR(500MHz,DMSO-d6)δ11.86(s,
1H,indole-NH),10.96(s,1H,imide-NH),7.78(s,1H,Ar-H),7.72(s,1H,Ar-H),7.46(d,1H,
J=8.2Hz, Ar-H), 7.19 (d, 1H, J=7.5Hz, Ar-H), 7.03 (t, 1H, J=7.6Hz, Ar-H), 6.82 (d, 1H, J
=8.0Hz, Ar-H), 6.76 (d, 1H, J=8.0Hz, Ar-H), 6.69 (t, 1H, J=7.5Hz, Ar-H), 6.57 (t, 1H, J=
7.7Hz, Ar-H), 4.24 (q, 2H, J=7.1Hz ,-CH2 -CH3), 1.31 (t, 3H, J=7.1Hz ,-CH2-CH3 ).13C NMR
(125MHz,DMSO-d6)δ173.1×2,135.9,134.7,132.1,130.3,128.9,127.4,127.1,126.2,
124.6,122.2,121.5,121.1,120.8,120.1,110.6,107.2,105.1,104.6,41.1,15.7.HR-
ESIMS m/z 434.0509[M+H]+(calcd.for C22H17N3O2Br,434.0504).
The preparation of compound 59
According to the synthetic method of compound 42, by compound 58 (21mg, 0.05mmol) and HCHO (5mL, mass fraction
37%) it synthesizes, with silica gel column chromatography separation, methylene chloride: methanol=70:1 (v/v) elutes to obtain red solid N- methylol -2-
(1- ethyl -3- indoles) -3- (the bromo- 3- indoles of 7-) maleimide (59) 9mg, yield 40%.1H NMR(500MHz,DMSO-
d6) δ 11.94 (s, 1H, indole-NH), 7.84 (s, 1H, Ar-H), 7.79 (s, 1H, Ar-H), 7.49 (d, 1H, J=8.3Hz,
), Ar-H 7.22 (d, 1H, J=7.5Hz, Ar-H), 7.06 (t, 1H, J=7.6Hz, Ar-H), 6.86 (d, 1H, J=8.1Hz,
), Ar-H 6.77 (d, 1H, J=8.0Hz, Ar-H), 6.73 (d, 1H, J=7.6Hz, Ar-H), 6.59 (t, 1H, J=7.8Hz,
), Ar-H 6.34 (t, 1H, J=7.0Hz, N-CH2-OH), 4.97 (d, 2H, J=7.0Hz, N-CH2 - OH), 4.27 (q, 2H, J=
7.2Hz,-CH2 -CH3), 1.33 (t, 3H, J=7.2Hz ,-CH2-CH3 ).13C NMR(125MHz,DMSO-d6)δ171.5×2,
136.1,134.9,132.4,130.6,128.7,127.4,126.8,126.3,124.9,122.5,121.7,121.4,
120.9,120.4,110.9,107.2,105.1,104.9,60.8,41.3,15.8.HR-ESIMS m/z 464.0592[M+H]+
(calcd.for C23H19N3O3Br,464.0604).
The preparation of compound 60
According to the preparation method of compound 2, with compound 59 (75mg, 0.173mmol), NaHCO3(73mg,
0.866mmol) and formalin (3mL, mass fraction 37%) is raw material preparation, silica gel column chromatography separation, petroleum ether: acetic acid second
Ester=4:1 (v/v) elutes to obtain red solid N- methylol -2- (1- ethyl -3- indoles) -3- (the bromo- 3- indoles of 1- methylol -7-)
Maleimide (60) 20mg, yield 25%.1H NMR(600MHz,CDCl3)δ7.64(s,1H,Ar-H),7.61(s,1H,Ar-
), H 7.25 (d, 1H, J=6.6Hz, Ar-H), 7.21 (d, 1H, J=7.6Hz, Ar-H), 7.07 (t, 1H, J=7.6Hz, Ar-
), H 6.90 (d, 1H, J=8.2Hz, Ar-H), 6.77 (d, 1H, J=8.0Hz, Ar-H), 6.74 (t, 1H, J=7.9Hz, Ar-
), H 6.50 (t, 1H, J=7.9Hz, Ar-H), 5.86 (d, 2H, J=7.2Hz ,-CH2 OH), 5.14 (d, 2H, J=6.1Hz ,-
CH2 ), OH 4.26 (t, 1H, J=7.2Hz ,-CH2OH), 4.17 (t, 1H, J=6.1Hz ,-CH2OH), 4.09 (q, 2H, J=
7.3Hz,-CH2 -CH3), 1.38 (t, 3H, J=7.3Hz ,-CH2-CH3 ).13C NMR(150MHz,CDCl3)δ172.0,171.7,
136.0,134.1,132.3,132.0,129.9,129.7,127.7,126.3,124.6,122.5,122.2,121.7,
121.6,120.6,109.7,106.7,105.5,103.5,71.1,61.5,41.6,15.2.HR-ESIMS m/z 516.0540
[M+Na]+(calcd.for C24H20N3O4BrNa, 516.0535) preparation of compound 61
With 6mL DMF dissolved compound 55 (300mg, 0.693mmol) in 50mL single port bottle, PPh is added3(36.3mg,
0.139mmol)、PdCl2(6.1mg, 0.0346mmol) and acrylic tributyl tin (258 μ L, 0.83mmol), argon gas protection
Under, 110 DEG C of oil baths are stirred to react 23h.It is cooled to room temperature, ether extraction is washed 3~4 times using saturation NaCl aqueous solution, with nothing
Aqueous sodium persulfate dries organic phase, and vacuum is rotated to dry.It filters and removes PdCl2, silica gel column chromatography separation, petroleum ether: ethyl acetate
=4:1 (v/v) affords red solid 2- (1- ethyl -3- indoles) -3- (6- allyl -3- indoles) maleimide (61)
171mg, yield 62%.1H NMR(600MHz,DMSO-d6)δ11.60(s,1H,indole-NH),10.90(s,1H,imide-
), NH 7.70 (d, 1H, J=2.9Hz, Ar-H), 7.70 (s, 1H, Ar-H), 7.46 (d, 1H, J=8.3Hz, Ar-H), 7.17 (s,
1H, Ar-H), 7.05 (t, 1H, J=7.1Hz, Ar-H), 6.92 (d, 1H, J=8.1Hz, Ar-H), 6.71 (t, 1H, J=
7.5Hz, Ar-H), 6.64 (d, 1H, J=8.1Hz, Ar-H), 6.47 (d, 1H, J=8.3Hz, Ar-H), 5.94-5.86 (m, 1H,
ArCH2CH=CH2),5.00-4.97(m,1H,ArCH2CH=CH2 ),4.96-4.94(m,1H,ArCH2CH=CH2 ),4.23(q,
2H, J=7.3Hz ,-CH2 -CH3), 3.32 (d, 2H, J=6.7Hz, Ar-CH2 CH=CH2), 1.30 (t, 3H, J=7.2Hz ,-
CH2-CH3 ).13C NMR(150MHz,DMSO-d6)δ173.6,173.5,138.8,137.0,136.0,133.7,131.9,
129.6,128.6,127.4,126.6,124.1,122.2,121.9,121.5,121.1,120.1,115.9,111.8,
110.6,106.0,105.5,41.2,39.0,15.8.HR-ESIMS m/z 396.1718[M+H]+(calcd.for
C25H22N3O2,396.1712).
The preparation of compound 62
With 20mL CH2Cl2Dissolved compound 61 (128mg, 0.324mmol) condenses at 40 DEG C in 50ml single-necked flask
Water flow back 0.5h, make compound all dissolve, be cooled to room temperature, be added 2- methyl-2-butene (1.2mL, 11.34mmol) and
Grubbs, 2 generation catalyst (27.5mg, 0.0324mmol), under argon gas protection, condensate return 2h, is cooled to room temperature at 40 DEG C,
Vacuum is rotated to dry.Silica gel column chromatography separation, petroleum ether: ethyl acetate=6:1 (v/v) elutes to obtain red solid 2- (1- ethyl-
3- indoles) -3- (6- isopentene group -3- indoles) maleimide (62) 91mg, yield 66%.1H NMR(600MHz,DMSO-
d6) δ 11.50 (s, 1H, indole-NH), 10.87 (s, 1H, imide-NH), 7.67 (d, 1H, J=1.7Hz, Ar-H), 7.66
(s, 1H, Ar-H), 7.47 (d, 1H, J=8.3Hz, Ar-H), 7.14 (s, 1H, Ar-H), 7.06 (t, 1H, J=7.1Hz, Ar-
), H 6.96 (d, 1H, J=8.0Hz, Ar-H), 6.74 (t, 1H, J=7.2Hz, Ar-H), 6.64 (d, 1H, J=8.2Hz, Ar-
), H 6.47 (dd, 1H, J=8.3Hz, 1.4Hz, Ar-H), 5.27-5.22 (m, 1H, ArCH2CH=C (CH3)2),4.22(q,2H,
J=7.2Hz ,-CH2 -CH3), 3.27 (d, 2H, J=7.4Hz, ArCH2 CH=C (CH3)2),1.67(s,3H,ArCH2CH=C
(CH3 )2),1.64(s,3H,ArCH2CH=C (CH3 )2), 1.29 (t, 3H, J=7.2Hz ,-CH2-CH3 ).13C NMR(150MHz,
DMSO-d6)δ172.9,172.8,136.4,135.4,134.8,131.2,131.1,128.9,128.0,126.7,125.9,
123.8,123.1,121.6,121.3,120.8,120.3,119.4,101.0,105.3,104.8,100.0,40.5,33.6,
25.4,17.5,15.0.HR-ESIMS m/z424.2029[M+H]+(calcd.for C27H26N3O2,424.2025).
The preparation of compound 63
According to the preparation method of compound 2, with compound 62 (43mg, 0.1088mmol), formalin (3mL, quality point
Number 37%) and NaHCO3(46mg, 0.544mmol) is raw material preparation, obtains dark red solid N- methylol -2- (1- ethyl -3- Yin
Diindyl) -3- (1- methylol -6- isopentene group -3- indoles) maleimide (63) 17mg, yield 34%.1H NMR(600MHz,
DMSO-d6) δ 7.90 (s, 1H, Ar-H), 7.63 (s, 1H, Ar-H), 7.48 (d, 1H, J=8.3Hz, Ar-H), 7.34 (s, 1H,
), Ar-H 7.10 (d, 1H, J=7.9Hz, Ar-H), 7.08 (d, 1H, J=8.3Hz, Ar-H), 6.79 (t, 1H, J=7.0Hz ,-
CH2OH), 6.73 (t, 1H, J=7.2Hz, Ar-H), 6.48 (q, 2H, J=8.2Hz, Ar-H), 6.38 (t, 1H, J=6.9Hz,
imide-CH2OH), 5.55 (d, 2H, J=7.0Hz, indole-CH2 ), OH 5.23 (t, 1H, J=7.2Hz, ArCH2CH=C
(CH3)2), 4.96 (d, 2H, J=6.9Hz ,-CH2 ), OH 4.22 (q, 2H, J=7.2Hz ,-CH2 -CH3), 3.28 (d, 2H, J=
7.4Hz,ArCH2 CH=C (CH3)2),1.65(s,3H,ArCH2CH=C (CH3 )2),1.63(s,3H,ArCH2CH=C (CH3 )2),
1.26 (t, 3H, J=7.2Hz ,-CH2-CH3 ).13C NMR(150MHz,DMSO-d6)δ171.6×2,136.6,136.0,
135.9,132.4,132.0,131.8,127.7,127.5,126.8,124.4,122.4,121.9,121.7,121.5,
120.4,110.8,110.6,105.6,105.4,100.0,69.5,60.8,41.2,34.5,26.1,18.2,15.6.ESI-MS
m/z 484.2[M+H]+.
The preparation of compound 64
In open quartzy bottle, with 1.0L acetone solution compound 1 (40mg, 0.1mmol), add the I of catalytic amount2,
Irradiation stirring for 24 hours, after most of solvent is evaporated in vacuo, pours into 100mL Na under 250W mercury lamp2S2O3In saturated aqueous solution, stirring
10min, ethyl acetate extract (50mL × 3 time), are associated with organic layer, and use anhydrous Na2SO4It is dry, evaporated in vacuo, silicagel column
Chromatographic isolation, petroleum ether: ethyl acetate=3:1 (v/v) elutes to obtain yellow fluorescence powder 12- ethyl -13- cyanogen methyl-1 2,13-
Dihydro -5H- indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7 (6H)-diketone (64) 28mg, yield 71%.1H NMR
(600MHz,DMSO-d6) δ 11.27 (s, 1H, indole-NH), 9.12 (d, 1H, J=8.3Hz, Ar-H), 9.11 (d, 1H, J=
8.3Hz, Ar-H), 7.96 (d, 1H, J=8.2Hz, Ar-H), 7.91 (d, 1H, J=8.2Hz, Ar-H), 7.73 (t, 1H, J=
7.7Hz, Ar-H), 7.67 (t, 1H, J=7.9Hz, Ar-H), 7.53 (t, 1H, J=7.3Hz, Ar-H), 7.43 (t, 1H, J=
7.3Hz,Ar-H),5.79(s,2H,-N-CH 2- CN), 4.75 (q, 2H, J=6.8Hz ,-CH 2-CH3), 1.10 (t, 3H, J=
6.8Hz,-CH2-CH 3).13C NMR(150MHz,DMSO-d6)δ171.0,170.9,152.0,145.5,144.4,133.1,
132.9,128.8,128.5,125.5,125.4,124.5,123.6,123.5,123.0,122.1,121.5,121.0,
116.4,113.3,113.0,43.3,31.0,14.0.HR-ESIMS m/z 391.1206[M–H]–(calcd.for
C24H15N4O2,391.1195).
The preparation of compound 65
According to the preparation method of compound 2, with compound 2 (10mg, 24.6 μm of ol) and NaHCO3(4.1mg,49.2μ
Mol it) is prepared for raw material, silica gel column chromatography separation, petroleum ether: ethyl acetate=3:1 (v/v) elutes to obtain yellow fluorescence powder 6- hydroxyl
Methyl-1 2- ethyl -13- cyanoethyl -12,13- dihydro -5H- indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7 (6H)-diketone
(65) 10.1mg, yield 94%.1H NMR(600MHz,CDCl3) δ 9.24 (d, 1H, J=7.8Hz, Ar-H), 9.22 (d, 1H, J
=7.8Hz, Ar-H), 7.66 (dt, 1H, J=7.5Hz, 1.4Hz, Ar-H), 7.65 (d, 1H, J=6.9Hz, Ar-H), 7.64
(dt, 1H, J=7.8Hz, 0.9Hz, Ar-H), 7.59 (d, 1H, J=7.8Hz, Ar-H), 7.49 (dt, 1H, J=7.8Hz,
0.9Hz, Ar-H), 7.46 (dt, 1H, J=7.5Hz, 1.4Hz, Ar-H), 5.40 (d, 2H, J=7.8Hz ,-N-CH 2-OH),
4.96 (t, 2H, J=7.8Hz, N-CH 2-CH2), CN 4.66 (q, 2H, J=7.3Hz ,-CH 2-CH3), 3.18 (t, 1H, J=
7.8Hz,NCH2-OH), 2.21 (t, 2H, J=7.8Hz, NCH2-CH 2- CN), 1.12 (t, 3H, J=7.3Hz ,-CH3).13C NMR
(150MHz,CDCl3)δ169.0,168.9,145.0,143.8,133.9,132.7,128.9,128.4,128.3,126.5,
126.1,125.4,124.5,123.3,122.5,122.4,121.5,120.2,116.4,112.2,111.7,61.8,44.4,
43.9,15.7,13.6.ESI-MS m/z 437.2[M+H]+.
The preparation of compound 66
It is raw material preparation with compound 3 (30mg, 0.072mmol), through silicagel column color according to the preparation method of compound 64
Spectrum separation, petroleum ether: ethyl acetate=3:1 (v/v) elutes to obtain yellow fluorescence powder 12- ethyl -13- cyanogen propyl -12,13- two
Hydrogen -5H- indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7 (6H)-diketone (66) 20.6mg, yield 68%.1H NMR
(600MHz,CDCl3) δ 9.25 (d, 1H, J=8.2Hz, Ar-H), 9.24 (d, 1H, J=8.3Hz, Ar-H), 7.77 (s, 1H,
), imide-NH 7.64 (t, 1H, J=7.4Hz, Ar-H), 7.63 (d, 1H, J=7.4Hz, Ar-H), 7.62 (t, 1H, J=
7.7Hz, Ar-H), 7.60 (d, 1H, J=7.8Hz, Ar-H), 7.48 (dt, 1H, J=6.8Hz, 1.7Hz, Ar-H), 7.46 (dt,
1H, J=7.4Hz, 1.7Hz, Ar-H), 4.84 (t, 2H, J=7.1Hz, N-CH 2-(CH2)2CN), 4.68 (q, 2H, J=7.1Hz,
N-CH 2-CH3), 1.77 (t, 2H, J=6.9Hz, N (CH2)2-CH 2-CN),1.26-1.24(m,2H,NCH2-CH 2-CH2CN),
1.10 (t, 3H, J=7.1Hz ,-CH2-CH 3).13C NMR(150MHz,CDCl3)δ169.5×2,145.0,144.1,133.7,
133.4,128.1,128.0,126.4,126.1,124.6,124.5,122.6,122.3,122.1,121.6,121.5,
121.2,118.2,112.2,111.8,46.9,44.1,29.8,24.0,14.7.HR-ESIMS m/z 419.1498[M–H]–
(calcd.for C26H19N4O2,419.1508).
The preparation of compound 67
According to the preparation method of compound 2, with compound 66 (10.2mg, 23.8 μm of ol) and NaHCO3(4mg,47.6μ
Mol it) is prepared for raw material, silica gel column chromatography separation, petroleum ether: ethyl acetate=5:1 (v/v) elutes to obtain yellow fluorescence powder 6- hydroxyl
Methyl-1 2- ethyl -13- cyanogen propyl -12,13- dihydro -5H- indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7 (6H)-diketone
(67) 10.5mg, yield 96%.1H NMR(600MHz,CDCl3) δ 9.25 (d, 1H, J=7.7Hz, Ar-H), 9.23 (d, 1H, J
=7.7Hz, Ar-H), 7.65-7.61 (m, 4H, Ar-H), 7.47 (t, 1H, J=7.7Hz, Ar-H), 7.44 (t, 1H, J=
6.6Hz, Ar-H), 5.41 (d, 2H, J=7.7Hz, N-CH 2- OH), 4.84 (t, 2H, J=7.7Hz, N-CH 2-(CH2)2CN),
4.68 (q, 2H, J=7.7Hz, N-CH 2-CH3), 3.17 (t, 1H, J=7.7Hz ,-OH), 1.74-1.78 (m, 4H, NCH2-CH 2-
CH 2- CN), 1.11 (t, 3H, J=7.7Hz, CH3).13C NMR(150MHz,CDCl3)δ169.1×2,144.9,144.1,
133.7,133.4,132.7,128.1,128.0,126.3,126.0,124.6,124.5,122.6,122.3,122.2,
121.6,120.3,118.2,112.2,111.8,61.8,46.9,44.1,24.0,14.7,13.6.HR-ESIMS m/z
473.1575[M+H]+(calcd.forC27H22N4O3Na,473.1590).
The preparation of compound 68
It is raw material preparation with compound 5 (40mg, 0.092mmol), through silicagel column color according to the preparation method of compound 64
Spectrum separation, petroleum ether: ethyl acetate=3:1 (v/v) elutes to obtain yellow fluorescence powder 12- ethyl -13- cyanogen butyl -12,13- two
Hydrogen -5H- indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7 (6H)-diketone (68) 28.7mg, yield 72%.1H NMR
(600MHz,CDCl3) δ 9.26 (d, 1H, J=7.7Hz, Ar-H), 9.24 (d, 1H, J=7.7Hz, Ar-H), 7.72 (s, 1H,
), imide-NH 7.64 (t, 1H, J=7.3Hz, Ar-H), 7.63 (d, 1H, J=7.4Hz, Ar-H), 7.62 (t, 1H, J=
7.7Hz, Ar-H), 7.60 (d, 1H, J=7.8Hz, Ar-H), 7.463 (dt, 1H, J=7.6Hz, 1.1Hz, Ar-H), 7.462
(dt, 1H, J=7.4Hz, 0.9Hz, Ar-H), 4.75 (t, 2H, J=6.9Hz, N-CH 2-(CH2)3), CN 4.65 (q, 2H, J=
7.4Hz,N-CH 2-CH3), 1.99 (t, 2H, J=6.8Hz, N (CH2)3-CH 2-CN),1.67(m,2H,NCH2-CH 2-(CH2)2), CN 1.10 (t, 3H, J=7.4Hz ,-CH2-CH 3),1.00-0.98(m,2H,N(CH2)2-CH 2-CH2CN).13C NMR
(150MHz,CDCl3)δ169.5×2,145.0,144.1,133.8,133.6,127.9,127.8,126.3,126.1,
124.7,124.4,122.3,122.2,122.0,121.7,121.3,121.2,118.9,112.1,111.9,47.6,44.1,
29.8,27.3,22.3,16.7.HR-ESIMS m/z 433.1663[M–H]–(calcd.for C27H21N4O2,433.1665).
The preparation of compound 69
According to the preparation method of compound 2, with compound 68 (9.8mg, 22.6 μm of ol) and NaHCO3(4mg,45.2μ
Mol it) is prepared for raw material, silica gel column chromatography separation, petroleum ether: ethyl acetate=4:1 (v/v) elutes to obtain yellow fluorescence powder 6- hydroxyl
Methyl-1 2- ethyl -13- cyanogen butyl -12,13- dihydro -5H- indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7 (6H)-diketone
(70) 10mg, yield 95%.1H NMR(600MHz,CDCl3) δ 9.26 (d, 1H, J=7.7Hz, Ar-H), 9.24 (d, 1H, J=
8.8Hz, Ar-H), 7.64-7.60 (m, 4H, Ar-H), 7.45 (t, 2H, J=7.7Hz, Ar-H), 5.41 (d, 2H, J=7.2Hz,
N-CH 2- OH), 4.75 (t, 2H, J=6.6Hz, N-CH 2-(CH2)3), CN 4.66 (q, 2H, J=6.6Hz, N-CH 2-CH3),3.15
(t, 1H, J=7.2Hz ,-OH), 1.97 (t, 2H, J=7.8Hz, N (CH2)3-CH 2-CN),1.68-1.64(m,2H,NCH2-CH 2-
(CH2)2), CN 1.10 (t, 3H, J=6.6Hz ,-CH2-CH 3),0.98(m,2H,N(CH2)2-CH 2-CH2CN).13C NMR
(150MHz,CDCl3)δ169.2×2,144.9,144.1,133.8,133.6,128.9,127.9,127.8,126.2,
126.0,124.7,122.6,122.3×2,122.1,120.5,119.3,118.9,112.2,111.9,61.8,47.5,
44.1,27.3,22.3,16.7,13.6.ESI-MS m/z 465.3[M+H]+.
The preparation of compound 70
It is raw material preparation with compound 7 (60mg, 0.15mmol), through silicagel column color according to the preparation method of compound 64
Spectrum separation, petroleum ether: ethyl acetate=2:1 (v/v) elutes to obtain yellow fluorescence powder 12,13- dicyan methyl-1 2,13- dihydro-
5H- indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7 (6H)-diketone (70) 25mg, yield 42%.1H NMR(600MHz,
DMSO-d6) δ 11.40 (s, 1H, imide-NH), 9.12 (d, 2H, J=7.8Hz, Ar-H), 8.02 (d, 2H, J=8.3Hz, Ar-
), H 7.77 (dt, 2H, J=7.3Hz, 1.1Hz, Ar-H), 7.56 (t, 2H, J=7.3Hz, Ar-H), 5.75 (s, 4H ,-CH2 -
CN).13C NMR(150MHz,DMSO-d6)δ170.0×2,144.5×2,132.3×2,128.6×2,125.1×2,123.6
×2,123.2×2,122.2×2,121.5×2,115.3×2,112.8×2,37.4×2.ESI-MS m/z 404.1[M+
H]+.
The preparation of compound 71
According to the preparation method of compound 64, with compound 2,3-di (1-cyanoethyl-1H-indol-3-yl)
Maleimide (30mg, 0.07mmol) is raw material preparation, through silica gel column chromatography separation, petroleum ether: ethyl acetate=2:1 (v/v)
Elute to obtain yellow fluorescence powder 12,13- dicyanoethyl -12,13- dihydro -5H- indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7
(6H)-diketone (71) 12mg, yield 40%.1H NMR(600MHz,DMSO-d6)δ11.27(s,1H,imide-NH),9.14(d,
2H, J=8.3Hz, Ar-H), 8.00 (d, 2H, J=8.2Hz, Ar-H), 7.69 (t, 2H, J=7.7Hz, Ar-H), 7.49 (d,
2H, J=7.7Hz, Ar-H), 5.07 (t, 4H, J=6.6Hz, N-CH2 -CH2), CN 2.64 (4H, t, J=6.6Hz, NCH2-CH2 -
CN).13C NMR(150MHz,DMSO-d6)δ171.2×2,143.8×2,133.6×2,128.3×2,125.6×2,124.5
×2,122.7×2,121.8×2,121.2×2,118.2×2,113.6×2,44.3×2,21.5×2.ESI-MS m/z
430.0[M–H]–.
The preparation of compound 72
It is raw material preparation with compound 9 (45mg, 0.09mmol), through silica gel column chromatography with the preparation method of compound 65
Separation, petroleum ether: ethyl acetate=2:1 (v/v) elutes to obtain yellow fluorescence powder 12,13- dicyan butyl -12,13- dihydro -5H-
Indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7 (6H)-diketone (74) 17mg, yield 43%.1H NMR(600MHz,DMSO-
d6) δ 11.18 (s, 1H, imide-NH), 9.15 (d, 2H, J=7.8Hz, Ar-H), 7.93 (d, 2H, J=8.2Hz, Ar-H),
7.66 (dt, 2H, J=7.8Hz, 1.0Hz, Ar-H), 7.44 (t, 2H, J=7.8Hz, Ar-H), 4.78 (t, 4H, J=7.4Hz,
N-CH 2-(CH2)3), CN 2.26 (t, 4H, J=7.3Hz, N (CH2)3-CH2 -CN),1.53-1.50(m,4H,NCH2-CH2 -
(CH2)2CN),1.11-1.09(4H,m,N(CH2)2-CH2 -CH2CN).13C NMR(150MHz,DMSO-d6)δ171.2×2,
144.6×2,133.4×2,128.0×2,125.4×2,123.7×2,122.0×2,121.4×2,120.7×2,120.3
×2,113.4×2,48.1×2,27.6×2,22.5×2,16.1×2.ESI-MS m/z 486.1[M–H]–.
The preparation of compound 73
I) 12- ethyl -12,13- dihydro -5H- indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7 (6H)-diketone (73a)
Preparation
By compound 24d (400mg, 1.13mmol), DDQ (282mg, 1.24mmol) and p-TsOH (214mg,
1.13mmol) with the dissolution of 100mL benzene, N2Flow back 30min under protective condition, solvent evaporated, and 100mL ethyl acetate re-dissolves,
Respectively with saturation NaHSO3Solution, water, salt are washed, organic layer anhydrous Na2SO4It is dry, it is evaporated rear silica gel column chromatography separation, petroleum
Ether: ethyl acetate=2:1 (v/v) elutes to obtain yellow powder (73a) 280mg, yield 70%.1H NMR(500MHz,DMSO-d6)δ
11.96 (s, 1H, indole-NH), 10.99 (s, 1H, imido-NH), 9.12 (d, 1H, J=8.1Hz, Ar-H), 9.07 (d,
1H, J=8.1Hz, Ar-H), 7.79 (d, 2H, J=8.0Hz, Ar-H), 7.59 (t, 1H, J=7.9Hz, Ar-H), 7.56 (t,
1H, J=9.0Hz, Ar-H), 7.36 (d, 1H, J=8.2Hz, Ar-H), 7.34 (d, 1H, J=8.1Hz, Ar-H), 4.94 (q,
2H, J=7.1Hz ,-CH2 -CH3), 1.42 (t, 3H, J=7.1Hz ,-CH2-CH3 ).13C NMR(125MHz,DMSO-d6)δ
171.6×2,141.5,141.0,129.6,128.6,127.3,125.1,124.7,121.7,121.4,120.7×2,
120.4,120.2,117.2,116.3,112.5,110.2,110.1,39.8,16.1.HR-ESIMS m/z 354.1249[M+
H]+(calcd.for C22H16N3O2,354.1243).
Ii) 6- (2- aminoethyl) -12- ethyl -12,13- dihydro -5H- indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7
The preparation of (6H)-diketone (73)
With 100mL 10%KOH aqueous solution suspended compound 73a (470mg, 1.33mmol), 110 DEG C of reflux 1.5h, dissolution
It for faint yellow clear solution, is cooled to room temperature, 2N hydrochloric acid acidification, ethyl acetate extracts (100mL × 3 time), organic layer is evaporated
Obtain 465mg crude product 12- ethyl -12,13- dihydrofuran [3,4-c] indoles [2,3-a] carbazole -5,7- diketone (73b), the chemical combination
Object dissolubility is very poor, but fully reacting, product are single, so direct plungeing into the next step without separation.According to compound 14
Yellow powder (73) 510mg, yield 97% is made using gained crude product 73b and 2mL ethylenediamine as raw material in preparation method.1H NMR
(500MHz,DMSO-d6) δ 9.03 (t, 2H, J=8.5Hz, Ar-H), 7.80 (d, 1H, J=8.1Hz, Ar-H), 7.74 (d, 1H,
J=8.1Hz, Ar-H), 7.57 (t, 1H, J=7.8Hz, Ar-H), 7.53 (t, 1H, J=7.6Hz, Ar-H), 7.33 (d, 1H, J
=8.1Hz, Ar-H), 7.31 (d, 1H, J=8.0Hz, Ar-H), 4.86 (q, 2H, J=6.9Hz ,-CH2 -CH3),3.75(t,2H,
J=6.1Hz ,-NCH2 CH2NH2), 2.97 (t, 2H, J=6.1Hz ,-NCH2CH2 -NH2), 1.36 (t, 3H, J=6.9Hz ,-CH2-
CH3 ).13C NMR(125MHz,DMSO-d6)δ170.1×2,141.5,140.9,129.4,128.3,127.3,127.2,
124.9,124.5,121.5,121.2,120.6×2,119.2,119.0,117.2,116.3,112.6,110.1,39.9,
39.6,38.7,16.1.HR-ESIMS m/z 397.1671[M+H]+(calcd.for C24H21N4O2,397.1665).
The preparation of compound 74
It is that yellow powder 6- is made in raw material with compound 73 (510mg, 1.26mmol) according to the preparation method of compound 16
(2- aminoethyl) -12- ethyl -12,13- dihydro -5H- indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7 (6H)-diketone hydrochloric acid
Salt (74) 540mg, yield 99%.1HNMR(600MHz,DMSO-d6) δ 12.07 (s, 1H, indole-NH), 9.11 (d, 1H, J=
8.2Hz, Ar-H), 9.08 (d, 1H, J=8.2Hz, Ar-H), 7.90 (brs, 3H ,-NH3 +), 7.84 (d, 2H, J=8.1Hz, Ar-
), H 7.63 (t, 1H, J=7.1Hz, Ar-H), 7.58 (t, 1H, J=7.7Hz, Ar-H), 7.38 (t, 1H, J=7.8Hz, Ar-
), H 7.35 (t, 1H, J=7.7Hz, Ar-H), 4.98 (q, 2H, J=6.9Hz ,-CH2 -CH3), 3.98 (t, 2H, J=5.9Hz, N-
CH2 -CH2NH3 +), 3.19 (t, 2H, J=6.0Hz, NCH2-CH2 -NH3 +), 1.41 (t, 3H, J=6.9Hz ,-CH2-CH3 ).13C
NMR(150MHz,DMSO-d6)δ170.1×2,141.6,141.1,129.6,128.5,127.5×2,124.9,124.5,
121.6,121.2,120.8,120.8,119.5,119.3,117.3,116.5,112.7,110.4,39.6,38.5,35.8,
16.1.HR-ESIMS m/z 397.1670[M-Cl]+(calcd.for C24H21N4O2,397.1665).
The preparation of compound 75
At 0 DEG C, with 15mL DMF suspension NaH in 250mL two mouth flask, be added dropwise 1mL dissolution compound 73a (40mg,
0.113mmol), low-temp reaction 10min is warmed to room temperature reaction 30min.It is cooled to 0 DEG C, ClCH is added dropwise2CH2OH(0.092mL,
1.36mol).Under 55 DEG C of oil baths, Ar gas shielded, condensate return 5h, TLC detection reaction does not carry out completely, is warming up to 85 DEG C, instead
Answer 6h.It is down to room temperature, 10mL methanol, 20mL saturated aqueous ammonium chloride is added under low temperature.Ethyl acetate extraction, organic layer is with nothing
Water Na2SO4It is dry, evaporated in vacuo.THF dissolution, silica gel column chromatography separation, petroleum ether: ethyl acetate=4:1 (v/v) elutes yellow
Color solid 6- (2- ethoxy) -12- ethyl -12,13- dihydro -5H- indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7 (6H) -
Diketone (75) 11mg, yield 25%.1H NMR(500MHz,DMSO-d6)δ11.95(s,1H,indole-NH),9.09(d,1H,J
=8.1Hz, Ar-H), 9.08 (d, 1H, J=8.1Hz, Ar-H), 7.79 (d, 1H, J=7.8Hz, Ar-H), 7.77 (d, 1H, J=
7.6Hz, Ar-H), 7.59 (t, 1H, J=7.4Hz, Ar-H), 7.56 (t, 1H, J=7.4Hz, Ar-H), 7.35 (t, 1H, J=
8.1Hz, Ar-H), 7.33 (t, 1H, J=7.4Hz, Ar-H), 4.90 (q, 2H, J=6.9Hz ,-CH2 -CH3),3.73-3.71(m,
2H,-NCH2CH2 - OH), 3.69 (t, 2H, J=5.4Hz ,-NCH2 CH2), OH 1.41 (t, 3H, J=6.9Hz ,-CH2-CH3 ).13C
NMR(125MHz,DMSO-d6)δ170.1×2,141.8,141.0,129.5,128.4,127.3,125.0,124.6,121.6,
121.3,120.7×2,119.3,119.1,117.2,116.4,112.5,110.1×2,58.8,40.5,39.5,16.1.HR-
ESIMS m/z398.1508[M+H]+(calcd.for C24H20N3O3,398.1505).
The preparation of compound 76
According to the preparation method of compound 24, with compound 73b (49mg, 0.14mmol), 4- hydroxy benzylamine (51mg,
0.42mmol) and catalytic amount Et3N is raw material, and yellow solid 6- (4- hydroxybenzyl) -12- ethyl -12,13- dihydro -5H- is made
Indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7 (6H)-diketone (76) 15mg, yield 23%.1H NMR(600MHz,DMSO-
d6) δ 9.03 (d, 1H, J=7.0Hz, Ar-H), 9.03 (d, 1H, J=6.8Hz, Ar-H), 7.77 (d, 1H, J=8.2Hz, Ar-
), H 7.70 (d, 1H, J=8.4Hz, Ar-H), 7.56 (d, 1H, J=7.0Hz, Ar-H), 7.55 (d, 1H, J=6.9Hz, Ar-
), H 7.34 (dd, 1H, J=7.0Hz, 0.9Hz, Ar-H), 7.32 (dd, 1H, J=7.0Hz, 0.9Hz, Ar-H), 7.20 (d, 2H,
J=8.2Hz, Ar-H), 6.71 (d, 2H, J=8.2Hz, Ar-H), 4.81 (q, 2H, J=7.2Hz ,-CH2 -CH3),4.63(s,
2H,-NCH2- Ar), 1.38 (t, 3H, J=7.2Hz ,-CH2-CH3 ).13CNMR(150MHz,DMSO-d6)δ169.8,169.7,
157.2,141.7,141.0,129.6×2,128.5,128.4,127.4,125.0,124.9,124.7,121.5,121.3,
120.9,120.8,119.0,118.8,117.4,116.4,115.8×2,112.6,110.1,100.0,40.7,39.6,
16.3.ESI-MS m/z 460.1[M+H]+.
The preparation of compound 77
According to the preparation method of compound 24, with compound 73b (35mg, 0.098mmol), 4- (2- aminoethyl) morpholine
(104 μ L, 0.79mmol) and catalytic amount Et3N is raw material, and yellow solid 6- (2- (4- morpholine) ethyl) ethyl-12-12- are made,
13- dihydro -5H- indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7 (6H)-diketone (77) 33mg, yield 72%.1H NMR
(500MHz,DMSO-d6)δ12.01(s,1H,indole-NH), 9.09 (t, 1H, J=8.1Hz, Ar-H), 9.07 (t, 1H, J=
7.9Hz, Ar-H), 7.81 (d, 2H, J=8.0Hz, Ar-H), 7.59 (t, 1H, J=8.0Hz, Ar-H), 7.56 (t, 1H, J=
7.8Hz, Ar-H), 7.38 (d, 1H, J=8.0Hz, Ar-H), 7.35 (t, 1H, J=8.0Hz, Ar-H), 4.94 (q, 2H, J=
7.1Hz,-CH2 -CH3), 3.79 (t, 2H, J=6.2Hz, imide-NCH2 CH2), 3.50 (t, 4H, J=4.5Hz,
morpholine-N(CH2-CH 2)2), O 2.62 (t, 2H, J=6.2Hz, imide-NCH2CH2 ), 2.46 (t, 4H, J=4.5Hz,
morpholine-N(CH 2-CH2)2), O 1.37 (t, 3H, J=7.1Hz ,-CH2-CH3 ).13C NMR(125MHz,DMSO-d6)δ
170.0×2,141.7,140.9,129.4,128.5,127.5,127.3,125.0,124.7,121.6,121.5,121.4,
121.2,120.9,119.0,117.4,116.5,112.7,110.2,66.8×2,56.6,53.7×2,39.6,34.9,
16.2.HR-ESIMS m/z 467.2088[M+H]+(calcd.for C28H27N4O3,467.2083).
The preparation of compound 78
According to the preparation method of compound 24, with compound 73b (100mg, 0.282mmol), N, N- dimethyl-ethylenediamine
(247.7 μ L, 2.256mmol) and catalytic amount Et3N is raw material, is made yellow solid 6- (2- (N, N- dimethylaminoethyl))-
12- ethyl -12,13- dihydro -5H- indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7 (6H)-diketone (78) 95.7mg, yield
80%.1H NMR(600MHz,DMSO-d6) δ 11.88 (s, 1H, indole-NH), 9.01 (d, 2H, J=7.4Hz, Ar-H),
7.76 (d, 1H, J=8.1Hz, Ar-H), 7.69 (d, 1H, J=8.3Hz, Ar-H), 7.56 (d, 1H, J=8.1Hz, Ar-H),
7.53 (d, 1H, J=7.9Hz, Ar-H), 7.33 (td, 2H, J=7.8Hz, 2.3Hz, Ar-H), 4.80 (q, 2H, J=7.1Hz ,-
CH2 -CH3), 3.63 (t, 2H, J=6.4Hz, imide-NCH2 CH2N(CH3)2), 2.49 (t, 2H, J=6.4Hz, imide-
NCH2CH2 -N(CH3)2),2.18(s,6H,-N(CH3)2), 1.38 (t, 3H, J=7.1Hz ,-CH2-CH3 ).13C NMR
(150MHz,DMSO-d6)δ169.9×2,141.6,141.0,129.5,128.4,127.4×2,125.0,124.8×2,
121.6,121.3,120.7,119.1,118.9,117.3,116.4,112.6,110.1,57.5,45.7×2,39.7,35.7,
16.2.HR-ESIMS m/z 425.1988[M+H]+(calcd.for C26H25N4O2,425.1978).
The preparation of compound 79
According to the preparation method of compound 24, with compound 73b (80mg, 0.226mmol), 2- (2- aminoethyl) pyridine
(135.3 μ L, 1.13mmol) and catalytic amount Et3N is raw material, and yellow solid 6- (2- (2- pyridine) ethyl) -12- ethyl-is made
12,13- dihydro -5H- indoles [2,3-a] pyrroles [3,4-c] carbazoles -5,7 (6H)-diketone (79) 25mg, yield 64%.
72.5mg, yield 70%.1H NMR(500MHz,DMSO-d6) δ 11.92 (s, 1H, indole-NH), 9.02 (d, 1H, J=
6.5Hz, Ar-H), 9.01 (t, 1H, J=6.5Hz, Ar-H), 8.43 (d, 1H, J=3.2Hz, Ar-H), 7.77 (t, 2H, J=
7.4Hz), 7.66 (t, 1H, J=8.0Hz, Ar-H), 7.58 (t, 1H, J=8.0Hz, Ar-H), 7.55 (t, 1H, J=7.8Hz,
), Ar-H 7.33-7.28 (m, 3H, Ar-H), 7.18 (t, 1H, J=6.3Hz, Ar-H), 4.88 (q, 2H, J=7.0Hz ,-CH2 -
CH3), 4.00 (t, 2H, J=6.5Hz, imide-NCH2 CH2), 3.13 (t, 2H, J=6.5Hz, imide-NCH2CH2 -),1.39
(t, 3H, J=7.0Hz ,-CH2-CH3 ).13C NMR(125MHz,DMSO-d6)δ169.8×2,159.0,149.7,141.6,
141.0,137.1,129.5,128.4,127.3,125.0,124.7,123.8,123.7,122.9,122.2,121.6,
121.3,120.7,119.1,118.9,117.3,116.4,112.5,110.1,39.6,37.7,36.9,16.2.HR-ESIMS
m/z 459.1831[M+H]+(calcd.for C29H23N4O2,459.1821).
The preparation of compound 80
It is that yellow solid 2- is made in raw material with compound 62 (41mg, 0.09mmol) according to the preparation method of compound 64
Isopentene group -12- ethyl -12,13- dihydro -5H- indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7 (6H)-diketone (80)
38mg, yield 90%.1H NMR(600MHz,DMSO-d6)δ11.80(s,1H,indole-NH),10.95(s,1H,imide-
), NH 9.06 (d, 1H, J=7.6Hz, Ar-H), 8.88 (d, 1H, J=8.1Hz, Ar-H), 7.75 (d, 1H, J=8.3Hz, Ar-
), H 7.58 (td, 1H, J=7.1Hz, 1.1Hz, Ar-H), 7.50 (s, 1H, Ar-H), 7.33 (t, 1H, J=7.5Hz, Ar-H),
7.13 (dd, 1H, J=8.1Hz, 1.3Hz, Ar-H), 5.40 (t, 1H, J=7.5Hz, ArCH2CH=C (CH3)2),4.87(q,
2H, J=7.1Hz ,-CH2 -CH3), 3.48 (d, 2H, J=7.5Hz, ArCH2 CH=C (CH3)2),1.75(s,6H,ArCH2CH=C
(CH3 )2), 1.39 (t, 3H, J=7.2Hz ,-CH2-CH3 ).13C NMR(150MHz,DMSO-d6)δ170.7,170.6,141.0,
140.0,139.9,131.5,128.6,127.5,126.2,124.0,123.5,122.8,120.7,119.6,119.1,
118.8,118.4,116.3,115.1,110.3,109.0,106.5,33.6,28.3,25.1,17.2,15.2.HR-ESIMS
m/z 422.1879[M+H]+(calcd.for C27H24N3O2,422.1869).
The preparation of compound 81
According to the preparation method of compound 2, with compound 80 (30mg, 0.071mmol) and formalin (3mL, quality point
Number 37%) it is that yellow solid 2- isopentene group -6- methylol -12- ethyl -12,13- dihydro -5H- indoles [2,3- is made in raw material
A] pyrroles [3,4-c] carbazole -5,7 (6H)-diketone (81) 13mg, yield 25%.1H NMR(600MHz,DMSO-d6)δ11.78
(s, 1H, indole-NH), 9.03 (d, 1H, J=7.8Hz, Ar-H), 8.86 (d, 1H, J=8.1Hz, Ar-H), 7.72 (d, 1H,
J=8.3Hz, Ar-H), 7.57 (t, 1H, J=7.0Hz, Ar-H), 7.51 (s, 1H, Ar-H), 7.34 (t, 1H, J=7.4Hz,
), Ar-H 7.14 (d, 1H, J=8.2Hz, Ar-H), 6.28 (t, 1H, J=7.0Hz ,-CH2OH), 5.44 (t, 1H, J=7.6Hz,
ArCH2CH=C (CH3)2), 4.92 (d, 2H, J=6.1Hz ,-CH2 ), OH 4.80 (q, 2H, J=7.2Hz ,-CH2 -CH3),3.53
(d, 2H, J=7.5Hz, ArCH2 CH=C (CH3)2),1.78(s,6H,ArCH2CH=C (CH3 )2), 1.39 (t, 3H, J=
7.2Hz,-CH2-CH3 ).13C NMR(150MHz,DMSO-d6)δ168.6×2,141.3,140.3,140.2,131.8,128.8,
127.7,126.6,124.1,123.6,123.0×2,120.8,112.0,118.6,118.1,117.7,116.5,115.4,
110.6,109.3,59.4,38.8,33.9,25.4,17.5,15.4.HR-ESIMS m/z 450.1821[M-H]-
(calcd.for C28H24N3O3,450.1812).
The preparation of compound 82
I) preparation of N- methyl -2,3- dibromo-maleimide (82a)
In 50mL two-mouth bottle, NaH (30mg, 0.75mmol, mass fraction 60%, be scattered in paraffin) is used into 5mL
DMF, which suspends, to be stirred, and 2, the 3- dibromo-maleimide (127.5mg, 0.5mmol) of 5mL DMF dissolution is added dropwise at -5 DEG C, low temperature is anti-
It after answering 30min, is added dropwise iodomethane (47 μ L, 0.75mmol), low-temp reaction 30min, saturation NH is added dropwise4Cl solution terminates reaction,
CH2Cl2Extraction, organic layer are evaporated, and silica gel column chromatography separation, petroleum ether: ethyl acetate=30:1 (v/v) elutes to obtain white crystal
(82a) 92mg, yield 69%.1HNMR(600MHz,CDCl3)δ3.12(s,3H,-CH3).13C NMR(150MHz,CDCl3)δ
164.1×2,129.5×2,25.6.ESI-MS m/z 267.9[M+H]+.
Ii) the preparation of N- methyl -2,3- two (the chloro- 3- indoles of 6-) maleimide (82)
Magnesium wire (200mg, 8.35mmol) is placed in 50mL two-mouth bottle, is suspended stir with 5mLTHF at room temperature, bromine is added dropwise
For ethane (620 μ L, 8.35mmol), 20min is reacted at room temperature, 45 DEG C is risen to the reaction was continued 30min, the dissolution of 8mL toluene is added dropwise
6- chloro-indole (1.27g, 8.35mmol) reacts 1h, and the 82a (448mg, 1.67mmol) of 8mL toluene dissolution is slowly added dropwise, and drop finishes
110 DEG C of reflux 2h are risen to, are down at -5 DEG C, saturation NH is added dropwise4Cl solution terminates reaction, ethyl acetate extraction, and organic layer is concentrated,
Silica gel column chromatography separation, petroleum ether: ethyl acetate=3:1 (v/v) elutes to obtain red solid powder (82) 300mg, yield 44%.1H
NMR(500MHz,DMSO-d6)δ11.80(s,2H,indole-NH),7.80(s,2H,Ar-H),7.43(s,2H,Ar-H),
6.71 (d, 2H, J=8.6Hz, Ar-H), 6.65 (d, 2H, J=8.6Hz, Ar-H), 3.02 (s, 3H ,-CH3).13C NMR
(125MHz,DMSO-d6)δ171.9×2,136.8×2,130.7×2,127.4×2,126.8×2,124.4×2,122.3
×2,120.1×2,112.0×2,106.0×2,24.4.HR-ESIMS m/z 410.0467[M+H]+(calcd.for
C21H14N3O2Cl2,410.0463).
The preparation of compound 83
In 25mL two-mouth bottle, with 10mL DMF dissolved compound 82 (257mg, 0.63mmol), under -5 DEG C of stirring conditions
It is added NaH (28mg, 0.69mmol, mass fraction 60%, be scattered in paraffin), after low-temp reaction 30min, EtI is slowly added dropwise
(108mg, 0.69mmol), low-temp reaction 30min.Saturation NH is added dropwise4Cl solution terminates reaction, ethyl acetate extraction, organic layer
Concentration, silica gel column chromatography separation, petroleum ether: ethyl acetate=4:1 (v/v) elutes to obtain orange red powder N- methyl -2- (1- second
The chloro- 3- indoles of base -6-) -3- (the chloro- 3- indoles of 6-) maleimide (83) 100mg, yield 38%.1H NMR(500MHz,
DMSO-d6) δ 11.84 (d, 1H, J=2.2Hz, indole-NH), 7.83 (d, 1H, J=2.2Hz, Ar-H), 7.79 (s, 1H,
), Ar-H 7.64 (d, 1H, J=1.6Hz, Ar-H), 7.45 (d, 1H, J=1.7Hz, Ar-H), 6.81 (d, 1H, J=8.8Hz,
), Ar-H 6.72 (dd, 1H, J=8.3Hz, 1.7Hz, Ar-H), 6.66-6.64 (m, 2H, Ar-H), 4.25 (q, 2H, J=
7.1Hz,-CH 2-CH3),3.03(s,3H,N-CH3), 1.31 (t, 3H, J=7.1Hz ,-CH2-CH3 ).13C NMR(125MHz,
DMSO-d6)δ172.0,171.9,137.1,136.5,132.9,131.0,127.7,127.3,127.0,126.9,125.1,
124.3,122.9,122.6,120.5,120.3,112.2,110.8,106.0,105.6,41.4,24.6,15.8.HR-ESIMS
m/z 438.0780[M+H]+(calcd.for C23H18N3O2Cl2,438.0776).
The preparation of compound 84
I) preparation of 2- (the chloro- 3- indoles of 1- ethyl -6-) -3- (the chloro- 3- indoles of 6-) maleic anhydride (84a)
In 50mL single port bottle, with 10mL ethyl alcohol suspended compound 83 (100mg, 0.23mmol), it is added 10mL 5M's
KOH solution is cooled to room temperature after the 8h that flows back at 78 DEG C, the acidification of 6N hydrochloric acid, ethyl acetate extraction, organic layer anhydrous slufuric acid is added dropwise
Sodium is dry, vacuum concentration, and silica gel column chromatography separation, dichloromethane eluent obtain Orange red solid (84a) 58mg, yield 60%.1H
NMR(600MHz,DMSO-d6) δ 12.06 (d, 1H, J=2.8Hz, indole-NH), 7.92 (d, 1H, J=3.3Hz, Ar-H),
7.88 (s, 1H, Ar-H), 7.69 (d, 1H, J=1.6Hz, Ar-H), 7.49 (d, 1H, J=1.6Hz, Ar-H), 6.85 (d, 1H, J
=8.8Hz, Ar-H), 6.79 (dd, 1H, J=8.2Hz, 1.6Hz, Ar-H), 6.73 (dd, 1H, J=8.2Hz, 1.6Hz, Ar-
), H 6.70 (d, 1H, J=8.8Hz, Ar-H), 4.26 (q, 2H, J=7.1Hz ,-CH2 -CH3), 1.31 (t, 3H, J=7.1Hz ,-
CH2-CH3 ).13C NMR(150MHz,DMSO-d6)δ166.8,166.7,137.2,136.7,134.0,132.3,128.8,
128.1,127.7,127.4,124.7,124.0,123.2,122.9,121.0,120.7,112.5,111.1,105.4,
104.8,41.6,15.7.ESI-MS m/z 425.0/427.0[M+H]+.
Ii) the preparation of 2- (the chloro- 3- indoles of 1- ethyl -6-) -3- (the chloro- 3- indoles of 6-) maleimide (84)
According to the preparation method of compound 24c, with compound 84a (53mg, 0.125mmol), HMDS (2.6mL,
12.5mmol) and MeOH (0.25mL, 6.25mmol) is raw material, and orange red powder (84) 52mg, yield 98% is made.1H NMR
(500MHz,DMSO-d6) δ 11.80 (s, 1H, indole-NH), 10.97 (s, 1H, imide-NH), 7.81 (d, 1H, J=
2.8Hz, Ar-H), 7.79 (s, 1H, Ar-H), 7.62 (s, 1H, Ar-H), 7.44 (s, 1H, Ar-H), 6.80 (d, 1H, J=
8.8Hz, Ar-H), 6.71 (dd, 1H, J=8.8Hz, 1.1Hz, Ar-H), 6.69 (d, 1H, J=8.8Hz, Ar-H), 6.65 (dd,
1H, J=8.8Hz, 1.7Hz, Ar-H), 4.25 (q, 2H, J=7.1Hz ,-CH2 -CH3), 1.31 (t, 3H, J=7.1Hz ,-CH2-
CH3 ).13C NMR(125MHz,DMSO-d6)δ173.2×2,137.0,136.5,132.9,130.9,128.3,127.7,
127.2,126.9,125.2,124.5,122.9,122.6,120.4,120.2,112.1,110.0,106.0,105.6,41.4,
15.8.HR-ESIMS m/z 424.0629[M+H]+(calcd.for C22H16N3O2Cl2,424.0620).
The preparation of compound 85
According to the preparation method of compound 2, with compound 84 (20mg, 47 μm of ol), formalin (3mL, mass fraction
And NaHCO 37%)3(11.9mg, 140 μm of ol) are raw material preparation, silica gel column chromatography separation, petroleum ether: ethyl acetate=2:1
(v/v) red solid N- methylol -2- (the chloro- 3- indoles of 1- ethyl -6-) -3- (the chloro- 3- indoles of 1- methylol -6-) horse is eluted to obtain
Come acid imide (85) 22mg, yield 97%.1H NMR(500MHz,DMSO-d6)δ8.00(s,1H,Ar-H),7.80(s,1H,Ar-
), H 7.68 (s, 1H, Ar-H), 7.64 (s, 1H, Ar-H), 6.86 (d, 1H, J=8.6Hz, Ar-H), 6.74 (t, 1H, J=
7.2Hz,indole-CH2-OH), 6.70 (d, 1H, J=8.7Hz, Ar-H), 6.67 (d, 1H, J=8.6Hz, Ar-H), 6.55
(d, 1H, J=8.6Hz, Ar-H), 6.33 (t, 1H, J=7.0Hz, imide-CH2-OH), 5.60 (d, 2H, J=7.2Hz,
indole-CH2 - OH), 4.95 (d, 2H, J=7.0Hz, imide-CH2 - OH), 4.25 (q, 2H, J=7.2Hz ,-CH2 -CH3),
1.29 (t, 3H, J=7.2Hz ,-CH2-CH3 ).13C NMR(125MHz,DMSO-d6)δ171.3×2,136.6×2,133.5,
133.1,127.8,127.4×2,127.3,125.3,125.2,122.9,122.7,120.8,120.6,111.6,110.9,
105.7,105.4,69.9,60.9,41.5,15.8.HR-ESIMS m/z 506.0656[M+Na]+(calcd.for
C24H19N3O4Cl2Na,506.0650).
The preparation of compound 86
According to the preparation method of compound 82, with compound 82a (710mg, 2.64mmol), Mg (317mg,
13.2mmol), bromic ether (982 μ L, 13.2mmol) and 4- bromo indole (2g, 132mmol) are raw material preparation, silica gel column chromatography
Separation, methylene chloride: ethyl acetate=9:1 (v/v) elutes to obtain solid N- methyl -2,3- two (the bromo- 3- indoles of 4-) maleimide
Amine (86) 500mg, yield 30%.1H NMR(500MHz,DMSO-d6)δ11.84(s,2H,indole-NH),7.84(d,2H,J
=7.4Hz, Ar-H), 7.42 (d, 2H, J=8.1Hz, Ar-H), 7.18 (d, 2H, J=7.5Hz, Ar-H), 7.02 (t, 2H, J=
7.8Hz,Ar-H),3.07(s,3H,-CH3).13C NMR(125MHz,DMSO-d6)δ172.3×2,137.8×2,137.3×
2,130.4×2,127.1×2,126.1×2,123.6×2,113.9×2,112.4×2,104.8×2,24.8.ESI-MS
m/z 519.9/521.9/523.9[M+Na]+.
The preparation of compound 87
According to the preparation method of compound 83, with compound 86 (506mg, 1.02mmol), NaH (81mg, 2.04mmol,
Mass fraction 60%, is scattered in paraffin) and iodoethane (90 μ L, 1.2mmol) be raw material preparation, silica gel column chromatography separation, stone
Oily ether: ethyl acetate=2:1 (v/v) affords Orange red solid N- methyl -2- (the bromo- 3- indoles of 1- ethyl -4-) -3- (4-
Bromo- 3- indoles) maleimide (87) 182mg, yield 34%.1H NMR(500MHz,DMSO-d6)δ11.85(s,1H,
), indole-NH 7.92 (s, 1H, Ar-H), 7.85 (d, 1H, J=2.7Hz, Ar-H), 7.52 (d, 1H, J=8.3Hz, Ar-H),
7.41 (d, 1H, J=8.1Hz, Ar-H), 7.19 (dd, 2H, J=7.2Hz, 1.6Hz, Ar-H), 7.06 (t, 1H, J=7.9Hz,
), Ar-H 7.02 (t, 1H, J=7.8Hz, Ar-H), 4.22 (q, 2H, J=7.2Hz ,-CH2 -CH3),3.06(s,3H,-NCH3),
1.34 (t, J=7.2Hz, 3H ,-CH2-CH3 ).13C NMR(125MHz,DMSO-d6)δ172.3×2,137.7×2,135.3,
134.7,132.7,130.4,126.3,126.1,124.2,124.1,123.6,123.5,114.1,113.9,111.9,
110.4,104.2,103.5,41.4,24.8,15.8.ESI-MS m/z 525.9/527.9/529.9[M+H]+.
The preparation of compound 88
I) preparation of 2- (the bromo- 3- indoles of 1- ethyl -4-) -3- (the bromo- 3- indoles of 4-) maleic anhydride (88a)
It is raw material preparation, silicagel column color with compound 87 (100mg, 0.23mmol) according to the preparation method of compound 84a
It composes (dichloromethane eluent) and obtains Orange red solid (88a) 58mg, yield 60%.1H NMR(600MHz,DMSO-d6)δ12.06(s,
1H, indole-NH), 8.00 (s, 1H, Ar-H), 7.95 (d, 1H, J=2.7Hz, Ar-H), 7.57 (d, 1H, J=8.2Hz, Ar-
), H 7.46 (d, 1H, J=8.1Hz, Ar-H), 7.25 (dd, 2H, J=7.2Hz, 7.1Hz, Ar-H), 7.10 (t, 1H, J=
7.9Hz, Ar-H), 7.06 (t, 1H, J=7.9Hz, Ar-H), 4.25 (q, 2H, J=7.2Hz ,-CH2 -CH3),1.35(t,3H,J
=7.2Hz ,-CH2-CH3 ).13C NMR(150MHz,DMSO-d6)δ166.7×2,137.8,137.3,136.9,136.3,
133.6,131.4,125.8,125.6,124.7,124.6,124.0×2,113.9,113.7,112.3,110.7,102.9,
102.2,41.6,15.8.ESI-MS m/z 513.1/515.0/517.1[M+H]+.
Ii) the preparation of 2- (the bromo- 3- indoles of 1- ethyl -4-) -3- (the bromo- 3- indoles of 4-) maleimide (88)
According to the preparation method of compound 24c, with compound 88a (126mg, 0.32mmol), HMDS (6.7mL,
32mmol) and MeOH (0.64mL, 16mmol) is raw material preparation, and silica gel column chromatography separation, dichloromethane eluent obtain orange red toner
Last 88 (118mg, yields 94%).1H NMR(500MHz,DMSO-d6)δ11.83(s,1H,indole-NH),10.98(s,1H,
), imide-NH 7.92 (s, 1H, Ar-H), 7.85 (d, 1H, J=2.7Hz, Ar-H), 7.52 (t, 1H, J=8.0Hz, Ar-H),
7.41 (d, 1H, J=8.0Hz, Ar-H), 7.20 (t, 1H, J=7.5Hz, Ar-H), 7.18 (d, 1H, J=7.5Hz, Ar-H),
7.06 (d, 1H, J=7.9Hz, Ar-H), 7.01 (t, 1H, J=7.8Hz, Ar-H), 4.21 (q, 2H, J=7.2Hz ,-CH2 -
CH3), 1.35 (t, 3H, J=7.2Hz ,-CH2-CH3 ).13C NMR(125MHz,DMSO-d6)δ173.5×2,137.7,137.2,
135.8,135.3,132.6,130.3,126.4,124.1,124.0,123.5,114.2,113.9,113.7,111.9,
110.3,104.4,103.7,100.0,41.4,15.8.ESI-MS m/z 512.1/514.0/516.1[M+H]+.
The preparation of compound 89
According to the preparation method of compound 1, with compound 88 (36mg, 70.5 μm of ol), formalin (3mL, mass fraction
And NaHCO 37%)3(30mg, 352 μm of ol) are raw material preparation, silica gel column chromatography separation, petroleum ether: ethyl acetate=1:2 (v/
V) orange/yellow solid N- methylol -2- (the bromo- 3- indoles of 1- ethyl -4-) -3- (the bromo- 3- indoles of 1- methylol -4-) horse is eluted to obtain
Come acid imide (89) 39mg, yield 97%.1H NMR(500MHz,DMSO-d6)δ7.99(s,1H,Ar-H),7.92(s,1H,Ar-
), H 7.61 (d, 1H, J=8.2Hz, Ar-H), 7.53 (d, 1H, J=8.2Hz, Ar-H), 7.24 (d, 1H, J=7.8Hz, Ar-
), H 7.21 (d, 1H, J=7.6Hz, Ar-H), 7.09 (t, 1H, J=8.0Hz, Ar-H), 7.06 (t, 1H, J=7.6Hz, Ar-
), H 6.69 (t, 1H, J=7.3Hz ,-CH2OH), 6.40 (t, 1H, J=7.0Hz ,-CH2OH), 5.56 (d, 2H, J=7.3Hz ,-
CH2 ), OH 4.97 (d, 2H, J=7.0Hz ,-CH2 ), OH 4.02 (q, 2H, J=7.1Hz ,-CH2 -CH3), 1.17 (t, 3H, J=
7.1Hz,-CH2-CH3 ).13C NMR(125MHz,DMSO-d6)δ171.6×2,137.2,137.1,135.5,135.0,133.2,
132.9,126.8,126.3,124.7,124.2,123.8,123.6,114.0,113.9,111.0,110.4,103.9,
103.3,69.7,60.3,41.5,15.8.ESI-MS m/z 554.1/556/1/558.1[M–H2O+H]+.
The preparation of compound 90
According to the preparation method of compound 82, with compound 5- bromo indole (2g, 13.2mmol), Mg (317mg,
13.2mmol) and compound 82a (710mg, 2.64mmol) is raw material preparation, silica gel column chromatography separation, petroleum ether: ethyl acetate
=3:1 (v/v) elutes to obtain Orange red solid N- methyl -2,3- bis- (the bromo- 3- indoles of 5-) maleimide (90) 500mg, yield
30%.1H NMR(500MHz,DMSO-d6)δ11.91(s,2H,indole-NH),7.80(s,2H,Ar-H),7.36(d,2H,J
=8.6Hz, Ar-H), 7.10 (d, 2H, J=8.6Hz, Ar-H), 6.84 (s, 2H, Ar-H), 3.04 (s, 3H ,-CH3).13C NMR
(125MHz,DMSO-d6)δ171.9×2,135.2×2,130.9×2,127.5×2,127.3×2,124.7×2,123.6
×2,114.2×2,112.4×2,105.5×2,24.5.HR-ESIMS m/z 497.9458[M+H]+(calcd.for
C21H14N3O2Br2,497.9453).
The preparation of compound 91
According to the preparation method of compound 84, with compound 90 (506mg, 1.2mmol), NaH (81mg, 2.04mmol, matter
Measure score 60%, be scattered in paraffin) and EtI (90 μ L, 1.2mmol) be raw material prepare, silica gel column chromatography separate, petroleum ether:
Ethyl acetate=3:1 (v/v) elutes to obtain Orange red solid N- methyl -2- (the bromo- 3- indoles of 1- ethyl -5-) -3- (the bromo- 3- Yin of 5-
Diindyl) maleimide (91) 200mg, yield 36%.1H NMR(500MHz,DMSO-d6)δ11.95(s,1H,indole-NH),
7.88 (s, 1H, Ar-H), 7.75 (d, 1H, J=1.4Hz, Ar-H), 7.48 (d, 1H, J=8.1Hz, Ar-H), 7.37 (d, 1H, J
=8.5Hz, Ar-H), 7.18 (d, 1H, J=8.5Hz, Ar-H), 7.09 (d, 1H, J=7.9Hz, Ar-H), 6.99 (s, 1H, Ar-
), H 6.68 (s, 1H, Ar-H), 4.24 (q, 2H, J=7.1Hz ,-CH2 -CH3),3.03(s,3H,-CH3), 1.31 (t, 3H, J=
7.1Hz,-CH2-CH3 ).13C NMR(125MHz,DMSO-d6)δ172.0,171.9,135.4,134.8,133.0,131.3,
128.1,127.9,127.1,126.8,124.8×2,124.0,123.7,114.3,112.8×2,112.6,105.6,
105.0,41.5,24.6,16.0.HR-ESIMS m/z 525.9776[M+H]+(calcd.for C23H18N3O2Br2,
525.9766).
The preparation of compound 92
I) preparation of 2- (the bromo- 3- indoles of 1- ethyl -5-) -3- (the bromo- 3- indoles of 5-) maleic anhydride (92a)
It is raw material preparation, silicagel column with compound 91 (120mg, 0.229mmol) according to the preparation method of compound 84a
Chromatographic isolation, dichloromethane eluent obtain red solid (92a) 88mg, yield 75%.1H NMR(600MHz,DMSO-d6)δ12.16
(s, 1H, indole-NH), 7.97 (d, 1H, J=1.4Hz, Ar-H), 7.87 (s, 1H, Ar-H), 7.53 (d, 1H, J=8.7Hz,
), Ar-H 7.40 (d, 1H, J=8.5Hz, Ar-H), 7.23 (d, 1H, J=8.8Hz, Ar-H), 7.16 (d, 1H, J=8.4Hz,
), Ar-H 7.01 (s, 1H, Ar-H), 6.72 (s, 1H, Ar-H), 4.28 (q, 2H, J=7.2Hz ,-CH2 -CH3),1.33(t,3H,J
=7.2Hz ,-CH2-CH3 ).13C NMR(150MHz,DMSO-d6)δ166.8,166.7,135.5,134.9,134.0,132.4,
129.1,128.0,127.7,126.8,125.2×2,124.2,124.0,114.6,113.3,113.0×2,104.8,
104.2,41.7,16.0.ESI-MS m/z ESI-MS m/z 512.9/514.9/516.9[M+H]+.
Ii) the preparation of 2- (the bromo- 3- indoles of 1- ethyl -5-) -3- (the bromo- 3- indoles of 5-) maleimide (92)
According to the preparation method of compound 23c, with compound 92a (88mg, 0.172mmol), HMDS (4mL,
17.2mmol) and MeOH (0.5mL, 8.6mmol) is raw material preparation, and silica gel column chromatography separation, dichloromethane eluent obtain red solid
Body 92 (85mg, yield 97%).1H NMR(500MHz,DMSO-d6)δ11.93(s,1H,indole-NH),10.98(s,1H,
), imide-NH 7.86 (d, 1H, J=2.8Hz, Ar-H), 7.77 (s, 1H), 7.48 (d, 1H, J=8.7Hz, Ar-H), 7.35
(d, 1H, J=8.5Hz, Ar-H), 7.15 (dd, 1H, J=8.7Hz, 1.8Hz, Ar-H), 7.08 (dd, 1H, J=8.6Hz,
1.9Hz, Ar-H), 6.94 (d, 1H, J=7.8Hz, Ar-H), 6.68 (d, 1H, J=1.7Hz, Ar-H), 4.25 (q, 2H, J=
7.2Hz,-CH2 -CH3), 1.32 (t, 3H, J=7.2Hz ,-CH2-CH3 ).13C NMR(125MHz,DMSO-d6)δ173.2,
173.1,135.3,134.7,133.0,131.2,128.5,128.1,127.4,127.2,124.8,124.7,123.9,
123.8,114.3,112.8,112.7,112.5,105.4,105.0,41.5,16.0.HR-ESIMS m/z 511.9617[M+
H]+(calcd.forC22H16N3O2Br2,511.9609).
The preparation of compound 93
According to the preparation method of compound 2, with compound 92 (55mg, 107.6 μm of ol), formalin (3mL, quality point
Number 37%) and NaHCO3(45mg, 538 μm of ol) are raw material preparation, silica gel column chromatography separation, petroleum ether: ethyl acetate=1:2
(v/v) orange/yellow solid N- methylol -2- (the bromo- 3- indoles of 1- ethyl -5-) -3- (the bromo- 3- indoles of 1- methylol -5-) is eluted to obtain
Maleimide (93) 58mg, yield 95%.1HNMR(500MHz,DMSO-d6)δ8.04(s,1H,Ar-H),7.71(s,1H,
), Ar-H 7.55 (d, 1H, J=8.7Hz, Ar-H), 7.50 (d, 1H, J=8.7Hz, Ar-H), 7.18 (dt, 2H, J=8.9Hz,
1.5Hz, Ar-H), 7.12 (d, 1H, Ar-H, J=1.5Hz), 6.58 (d, 1H, Ar-H J=1.5Hz), 5.60 (s, 2H,
indole-CH2 -OH),4.97(s,2H,imide-CH2 - OH), 4.23 (q, 2H, J=7.1Hz ,-CH2 -CH3),3.78(s,1H,
N-CH2-OH),3.15(s,1H,N-CH2-OH), 1.29 (t, 3H, J=7.1Hz ,-CH2-CH3 ).13C NMR(125MHz,DMSO-
d6)δ171.2×2,134.9,134.8,133.9,133.2,128.2,128.1,127.6,127.5,127.0,125.0,
124.1,124.0,113.5,113.2,113.1,112.8,104.9,104.8,69.9,60.9,41.5,16.0.HR-ESIMS
m/z 593.9647[M+Na]+(calcd.for C24H19N3O4Br2Na,593.9640).
The preparation of compound 94
According to the preparation method of compound 82, with 6- bromo indole (850mg, 5.58mmol), Mg (134mg, 5,58mmol)
It is raw material with compound 82 (300mg, 1.12mmol), Orange red solid N- methyl -2,3- bis- (the bromo- 3- indoles of 6-) Malaysia is made
Acid imide (94) 180mg, yield 30%.1H NMR(600MHz,DMSO-d6)δ11.83(s,2H,indole-NH),7.78(d,
2H, J=7.7Hz, Ar-H), 7.58 (d, 2H, J=7.7Hz, Ar-H), 6.78 (d, 1H, J=7.8Hz, Ar-H), 6.77 (d,
1H, J=7.8Hz, Ar-H), 6.68 (s, 1H, Ar-H), 6.67 (s, 1H, Ar-H), 3.02 (s, 3H ,-CH3).13C NMR
(150MHz,DMSO-d6)δ172.0×2,137.4×2,130.8×2,127.5×2,124.8×2,122.9×2,122.8
×2,115.1×2,115.0×2,106.1×2,24.6.HR-ESIMS m/z 497.9458[M+H]+(calcd.for
C21H14N3O2Br2,497.9453).
The preparation of compound 95
According to the preparation method of compound 83, with compound 94 (155mg, 0.312mmol), NaH (14mg,
0.343mmol, mass fraction 60%, is scattered in paraffin) and EtI (28 μ L, 0.343mmol) be raw material preparation, silicagel column color
Spectrum separation, petroleum ether: ethyl acetate=4:1 (v/v) elutes to obtain Orange red solid N- methyl -2- (the bromo- 3- Yin of 1- ethyl -6-
Diindyl) -3- (the bromo- 3- indoles of 6-) maleimide (95) 56mg, yield 34%.1H NMR(500MHz,DMSO-d6)δ11.81(s,
1H, indole-NH), 7.79 (s, 1H, Ar-H), 7.76 (s, 1H, Ar-H), 7.57 (s, 1H, Ar-H), 6.82 (d, 1H, J=
8.6Hz, Ar-H), 6.75 (t, 2H, J=7.7Hz, Ar-H), 6.61 (d, 1H, J=8.6Hz, Ar-H), 4.24 (q, 2H, J=
7.2Hz,-CH2 -CH3),3.02(s,3H,-NCH3), 1.29 (t, 3H, J=7.2Hz ,-CH2-CH3 ).13CNMR(125MHz,
DMSO-d6)δ171.9,171.8,137.4,136.8,132.6,130.8,127.6,126.9,125.2,124.4,123.1,
122.9,122.8,122.7,115.2,115.0,114.9,113.5,105.9,105.4,41.3,24.4,15.7.HR-ESIMS
m/z 525.9771[M+H]+(calcd.for C23H18N3O2Br2,525.9766).
The preparation of compound 96
I) preparation of 2- (the bromo- 3- indoles of 1- ethyl -6-) -3- (the bromo- 3- indoles of 6-) maleic anhydride (96a)
It is raw material preparation, silicagel column color with compound 95 (240mg, 0.46mmol) according to the preparation method of compound 84a
Spectrum separation, dichloromethane eluent obtain Orange red solid 96a (144mg, yield 61%).1H NMR(600MHz,DMSO-d6)δ
12.04 (s, 1H, indole-NH), 7.89 (d, 1H, J=1.5Hz, Ar-H), 7.87 (s, 1H, Ar-H), 7.82 (s, 1H, Ar-
), H 7.63 (s, 1H, Ar-H), 6.91 (d, 1H, J=8.6Hz, Ar-H), 6.85 (d, 1H, J=8.6Hz, Ar-H), 6.80 (d,
1H, J=8.6Hz, Ar-H), 6.67 (d, 1H, J=8.6Hz, Ar-H), 4.27 (q, 2H, J=7.1Hz ,-CH2 -CH3),1.30
(t, 3H, J=7.1Hz ,-CH2-CH3 ).13C NMR(150MHz,DMSO-d6)δ166.8,166.7,137.7,137.1,133.9,
132.2,128.8,128.1,124.9,124.2,123.6,123.5,123.3,123.2,115.8,115.5×2,114.0,
105.4,104.8,41.6,15.7.ESI-MS m/z 535.1/537.0/539.1[M+Na]+.
Ii) the preparation of 2- (the bromo- 3- indoles of 1- ethyl -6-) -3- (the bromo- 3- indoles of 6-) maleimide (96)
According to the preparation method of compound 24c, with compound 96a (100mg, 0.195mmol), HMDS (4mL,
17.2mmol) and MeOH (0.5mL, 8.6mmol) is raw material preparation, and silica gel column chromatography separation, dichloromethane eluent obtain red solid
Body 96 (97mg, yield 97%).1H NMR(500MHz,DMSO-d6)δ11.82(s,1H,indole-NH),11.00(s,1H,
), imide-NH 7.79 (d, 1H, J=0.9Hz, Ar-H), 7.78 (s, 1H, Ar-H), 7.76 (d, 1H, J=7.5Hz, Ar-H),
7.57 (d, 1H, J=7.6Hz, Ar-H), 6.82 (dd, 1H, J=8.6Hz, 1.6Hz, Ar-H), 6.76 (dd, 1H, J=8.6Hz,
1.7Hz, Ar-H), 6.73 (d, 1H, J=8.5Hz, Ar-H), 6.63 (d, 1H, J=8.6Hz, Ar-H), 4.25 (q, 2H, J=
7.2Hz,-CH2 -CH3), 1.30 (t, 3H, J=7.2Hz ,-CH2-CH3 ).13C NMR(125MHz,DMSO-d6)δ173.2×2,
137.5,136.9,132.8,130.9,128.3,127.6,125.4,124.7,123.2,123.0,122.9,122.8,
115.3,115.1,114.9,113.6,106.0,105.5,41.4,15.8.HR-ESIMS m/z 511.9617[M+H]+
(calcd.for C22H16N3O2Br2,511.9609).
The preparation of compound 97
According to the preparation method of compound 2, with compound 96 (14mg, 27.4 μm of ol), formalin (3mL, mass fraction
And NaHCO 37%)3(12mg, 137 μm of ol) are raw material preparation, silica gel column chromatography separation, petroleum ether: ethyl acetate=3:1 (v/
V) red solid N- methylol -2- (the bromo- 3- indoles of 1- ethyl -6-) -3- (the bromo- 3- indoles of 1- methylol -6-) Malaysia is eluted to obtain
Acid imide (97) 14.1mg, yield 90%.1HNMR(500MHz,DMSO-d6)δ7.98(s,1H,Ar-H),7.82(s,1H,Ar-
), H 7.78 (s, 2H, Ar-H), 6.85-6.82 (m, 2H, Ar-H), 6.79 (d, 1H, J=8.8Hz, Ar-H), 6.74 (t, 1H, J
=7.5Hz, indole-CH2-OH), 6.51 (d, 1H, J=8.5Hz, Ar-H), 6.32 (t, 1H, J=6.0Hz, imide-CH2-
OH), 5.59 (d, 2H, J=7.5Hz, indole-CH2 - OH), 4.95 (d, 2H, J=6.0Hz, imide-CH2 -OH),4.25(q,
2H, J=6.8Hz ,-CH2 -CH3), 1.29 (d, 3H, J=6.8Hz ,-CH2-CH3 ).13CNMR(125MHz,DMSO-d6)δ
171.3,171.2,137.0,136.9,133.4,133.0,127.8,127.2,125.5,125.4,123.4,123.3,
123.2,123.0×2,115.4,114.5,113.8,105.6,105.4,69.8,60.9,41.4,15.8.HR-ESIMS m/z
593.9650[M+Na]+(calcd.for C24H19N3O4Br2Na,593.9640).
The preparation of compound 98
According to the preparation method of compound 82, with 7- bromo indole (850mg, 5.6mmol), Mg (134mg, 5.6mmol) and
Compound 82a (286mg, 1.1mmol) is raw material, and Orange red solid N- methyl -2,3- bis- (the bromo- 3- indoles of 7-) Malaysia acyl is made
Imines (98) 180mg, yield 32%.1H NMR(500MHz,DMSO-d6)δ11.94(s,2H,indole-NH),7.77(d,2H,
J=2.7Hz, Ar-H), 7.20 (d, 2H, J=7.5Hz, Ar-H), 6.77 (d, 2H, J=8.0Hz, Ar-H), 6.60 (t, 2H, J
=7.8Hz, Ar-H), 3.04 (s, 3H ,-CH3).13CNMR(125MHz,DMSO-d6)δ171.8×2,134.7×2,130.5×
2,127.7×2,127.4×2,124.9×2,121.3×2,120.6×2,107.0×2,104.8×2,24.5.HR-
ESIMS m/z 497.9464[M+H]+(calcd.for C21H14N3O2Br2,497.9453).
The preparation of compound 99
According to the preparation method of compound 83, with compound 98 (317mg, 0.638mmol), NaH (28.1mg,
0.702mmol, mass fraction 60%, is scattered in paraffin) and EtI (57 μ L, 0.702mmol) be raw material preparation, silicagel column color
Spectrum separation, petroleum ether: ethyl acetate=5:1 (v/v) elutes to obtain Orange red solid N- methyl -2- (the bromo- 3- Yin of 1- ethyl -7-
Diindyl) -3- (the bromo- 3- indoles of 7-) maleimide (99) 110mg, yield 33%.1H NMR(500MHz,DMSO-d6)δ11.96
(s, 1H, indole-NH), 7.83 (s, 1H, Ar-H), 7.77 (s, 1H, Ar-H), 7.24 (d, 1H, J=7.5Hz, Ar-H),
7.20 (d, 1H, J=7.5Hz, Ar-H), 6.95 (d, 1H, J=7.9Hz, Ar-H), 6.64 (t, 1H, J=6.7Hz, Ar-H),
6.62 (d, 1H, J=6.6Hz, Ar-H), 6.57 (t, 1H, J=7.8Hz, Ar-H), 4.59 (q, 2H, J=7.2Hz ,-CH2 -
CH3),3.04(s,3H,-NCH3), 1.31 (d, 3H, J=7.2Hz ,-CH2-CH3 ).13C NMR(125MHz,DMSO-d6)δ
171.7×2,134.8×2,131.9,130.8,129.8,128.7,127.5,127.0,126.6,124.9,121.5,
121.3,121.1,120.6,106.9,105.6,104.8,103.4,43.5,24.5,17.9.HR-ESIMS m/z
525.9772[M+H]+(calcd.for C23H18N3O2Br2,525.9766).
The preparation of compound 100
I) preparation of 2- (bromo- 3 indoles of 1- ethyl -7-) -3- (the bromo- 3- indoles of 7-) maleic anhydride (100a)
It is raw material preparation, silicagel column color with compound 99 (200mg, 0.38mmol) according to the preparation method of compound 84a
Spectrum separation, dichloromethane eluent obtain Orange red solid 100a (84mg, yield 43%).1H NMR(600MHz,DMSO-d6)δ
12.23 (s, 1H, indole-NH), 7.90 (d, 1H, J=2.5Hz, Ar-H), 7.87 (s, 1H, Ar-H), 7.29 (d, 1H, J=
7.5Hz, Ar-H), 7.26 (d, 1H, J=7.3Hz, Ar-H), 7.00 (d, 1H, J=8.0Hz, Ar-H), 6.71-6.68 (m, 1H,
), Ar-H 6.68-6.62 (m, 2H, Ar-H), 4.60 (q, 2H, J=7.1Hz ,-CH2 -CH3), 1.32 (t, 3H, J=7.1Hz ,-
CH2-CH3 ).13C NMR(150MHz,DMSO-d6)δ166.6,166.5,135.9,135.1,132.2,130.0,129.5,
128.1,127.8,126.7,125.5,122.1,122.0,121.4,121.0,106.4,105.2,104.9,103.7,43.8,
17.9.ESI-MS m/z 512.9/514.9/516.9[M+H]+.
Ii) the preparation of 2- (the bromo- 3- indoles of 1- ethyl -7-) -3- (the bromo- 3- indoles of 7-) maleimide (100)
According to the preparation method of compound 24c, with compound 100a (150mg, 0.293mmol), HMDS (4mL,
17.2mmol) and MeOH (0.5mL, 8.6mmol) is raw material preparation, and silica gel column chromatography separation, dichloromethane eluent obtain red solid
Body 100 (123mg, yield 82%).1H NMR(500MHz,DMSO-d6)δ11.94(s,1H,indole-NH),11.03(s,1H,
), imide-NH 7.80 (s, 1H, Ar-H), 7.76 (s, 1H, Ar-H), 7.23 (d, 1H, J=7.6Hz, Ar-H), 7.19 (d, 1H,
J=7.4Hz, Ar-H), 6.92 (d, 1H, J=8.0Hz, Ar-H), 6.64 (d, 1H, J=7.9Hz, Ar-H), 6.62 (t, 1H, J
=7.9Hz, Ar-H), 6.56 (t, 1H, J=7.7Hz, Ar-H), 4.58 (d, 2H, J=7.1Hz ,-CH2 -CH3),1.32(t,3H,
J=7.1Hz ,-CH2-CH3 ).13C NMR(125MHz,DMSO-d6)δ172.9,172.8,134.8×2,131.9,130.8,
129.9,129.2,127.5,127.2,127.1,124.8,121.4,121.3,121.1,120.6,106.9,105.6,
104.8,103.3,43.5,17.9.HR-ESIMS m/z 511.9613[M+H]+(calcd.for C22H16N3O2Br2,
511.9609).
The preparation of compound 101
According to the preparation method of compound 2, with compound 100 (55mg, 107 μm of ol), formalin (3mL, mass fraction
And NaHCO 37%)3(45mg, 537 μm of ol) are raw material preparation, silica gel column chromatography separation, petroleum ether: ethyl acetate=3:1 (v/
V) red solid N- methylol -2- (the bromo- 3- indoles of 1- ethyl -7-) -3- (the bromo- 3- indoles of 1- methylol -7-) Malaysia is eluted to obtain
Acid imide (101) 20.2mg, yield 33%.1HNMR(500MHz,DMSO-d6)δ12.06(s,1H,indole-NH),7.87(s,
1H), 7.82 (s, 1H, Ar-H), 7.26 (d, 2H, J=7.6Hz, Ar-H), 7.22 (d, 1H, J=7.4Hz, Ar-H), 6.95
(d, 1H, J=8.0Hz, Ar-H), 6.65 (d, 1H, J=7.8Hz, Ar-H), 6.63 (d, 1H, J=6.0Hz, Ar-H), 5.82
(t, 1H, J=7.0Hz ,-CH2OH), 4.97 (d, 2H, J=7.0Hz ,-CH2 ), OH 4.62 (q, 2H, J=7.0Hz ,-CH2 -
CH3), 1.33 (t, 3H, J=7.0Hz ,-CH2-CH3 ).13C NMR(125MHz,DMSO-d6)δ170.5,170.4,134.3×2,
134.2,131.3,130.4,129.2,128.2,126.9,126.9,126.4×2,126.1×2,120.9,120.8,
119.9,104.8,104.2,60.1,42.9,17.2.HR-ESIMS m/z 541.9725[M+H]+(calcd.for
C23H18N3O3Br2,541.9715).
The preparation of compound 102
I) preparation of N- methyl -2- (3- indoles) -3- bromine maleimide (102a)
With THF (5mL) suspension magnesium chips (360mg, 15mmol) in 50mL two-mouth bottle, be slowly added dropwise bromoethane (1.12mL,
15mmol), be stirred at room temperature after 20min and be warming up to 45 DEG C of stirring 20min, be added dropwise THF (5mL) dissolution indoles (1.75g,
15mmol), continue to stir 30min.It is down to room temperature, the compound 82a (2g, 7.5mmol) of THF (10mL) dissolution, room temperature is added dropwise
It is stirred overnight.TLC is detected to end of reaction, and saturated aqueous ammonium chloride (50mL) quenching reaction, ethyl acetate extraction is slowly added dropwise
It takes (2 times × 100mL), saturated common salt washes (2 times × 100mL), merges organic phase, and dry with anhydrous sodium sulfate, vacuum rotation
Solvent is evaporated off, silica gel column chromatography separation, petroleum ether: ethyl acetate=4:1 (v/v) elutes to obtain orange solids (102a) 2.2g,
Yield 96%.1H NMR(500MHz,DMSO-d6) δ 12.12 (s, 1H, indole-NH), 8.06 (d, 1H, J=8.0Hz, Ar-
), H 7.91 (d, 1H, J=8.0Hz, Ar-H), 7.55 (dt, 1H, J=8.0Hz, 0.6Hz, Ar-H), 7.23 (dt, 1H, J=
7.9Hz, 0.9Hz, Ar-H), 7.15 (dt, 1H, J=7.7Hz, 1.0Hz, Ar-H), 3.01 (s, 3H ,-NCH3).13C NMR
(125MHz,DMSO-d6)δ169.7,167.1,138.2,137.1,131.6,125.1,123.1,122.8,121.0,114.1,
112.9,104.4,25.1.ESI-MS m/z 304.9[M+H]+.
Ii) the preparation of N- methyl -2- (1- tertiary butyl oxycarbonyl -3- indoles) -3- bromine maleimide (102b)
At 0 DEG C, in 250mL single port bottle, with THF (80mL) dissolved compound 102a (2g, 6.58mmol), catalysis is added
(Boc) of THF (20mL) dissolution is slowly added dropwise in the DMAP of amount2O (2.9g, 13.16mmol), is warmed to room temperature, is stirred to react 2h.
TLC is detected to end of reaction, and vacuum revolving removes solvent, with silica gel column chromatography separation, petroleum ether: ethyl acetate=10:1 (v/
V) yellow solid (102b) 2.5g, yield 94% are eluted to obtain.1H NMR(500MHz,DMSO-d6) δ 8.13 (d, 1H, J=8.4Hz,
), Ar-H 8.08 (s, 1H, Ar-H), 7.77 (d, 1H, J=7.9Hz, Ar-H), 7.43 (dt, 1H, J=7.9Hz, 0.9Hz, Ar-
), H 7.36 (dt, 1H, J=7.7Hz, 1.0Hz, Ar-H), 3.02 (s, 3H ,-NCH3),1.65(s,9H,-C(CH3)3).13C NMR
(125MHz,DMSO-d6)δ168.9,166.4,149.0,136.3,135.1,129.4,127.2,125.8,123.7,123.0,
122.1,115.5,109.0,85.7,28.1,25.3.ESI-MS m/z 405.0[M+H]+.iii) N- methyl -2- (the tertiary fourth of 1-
Base oxygen carbonyl -3- indoles) -3- (3- indoles) maleimide (102c) preparation
According to the synthetic method of compound 102a, by compound 102b (1.8g, 4.46mmol), magnesium chips (321mg,
13.37mmol), bromoethane (1mL, 13.37mmol) and indoles (1.57g, 13.37mmol) synthesis, silica gel column chromatography separation, stone
Oily ether: ethyl acetate=4:1 (v/v) elutes to obtain yellow solid (102c) 1.6g, yield 81%.1H NMR(500MHz,DMSO-
d6) δ 11.83 (s, 1H, indole-NH), 8.03 (d, 1H, J=8.3Hz, Ar-H), 7.91 (s, 1H, Ar-H), 7.85 (d, 1H,
J=2.8Hz, Ar-H), 7.37 (d, 1H, J=8.1Hz, Ar-H), 7.18 (t, 1H, J=7.7Hz), 6.98 (t, 1H, J=
7.6Hz, Ar-H), 6.87 (d, 1H, J=8.2Hz, Ar-H), 6.86 (d, 1H, J=8.3Hz, Ar-H), 6.82 (t, 1H, J=
7.5Hz, 1H, Ar-H), 6.67 (t, 1H, J=7.6Hz, Ar-H), 3.04 (s, 3H ,-NCH3),1.60(s,9H,-C(CH3)3)
.13C NMR(125MHz,DMSO-d6)δ171.6,171.5,149.1,136.6,134.7,132.5,131.0,128.4,
128.1,125.5,125.0,123.4,122.9,122.4,121.7,121.2,120.3,115.1,112.4,111.2,
105.7,85.0,28.0,24.5.ESI-MS m/z 442.2[M+H]+.
Iv) the preparation of p-methyl benzenesulfonic acid phenethyl ester (102d)
At 0 DEG C, benzyl carbinol (2g, 16.3mmol) is dissolved with methylene chloride (50mL) in 250mL two-mouth bottle, three second are added
The paratoluensulfonyl chloride (4.67g, 24.5mmol) of methylene chloride (20mL) dissolution, drop is added dropwise in amine (3.38mL, 24.5mmol)
Finish, be warmed to room temperature, reaction is overnight.TLC is detected to end of reaction, and vacuum revolving removes solvent, with silica gel column chromatography separation, petroleum
Ether: ethyl acetate=25:1 (v/v) elutes to obtain yellow solid (102d) 3.6g, yield 80%.ESI-MS m/z 277.1[M+H]+.
V) N- methyl -2- (1- tertiary butyl oxycarbonyl -3- indoles) -3- (1- phenethyl -3- indoles) maleimide
The preparation of (102e)
In tri- mouthfuls of reaction flasks of 25mL, with DMF (5mL) sodium hydride suspension, (11mg, 0.272mmol, content 60% are dispersed in
In paraffin oil), after -5 DEG C of stirring 30min, the compound 102c (60mg, 0.136mmol) of DMF (5mL) dissolution is slowly added dropwise, it is low
Temperature continues to stir 45min, and the compound 102d (100 μ L, 0.272mmol) of DMF (2mL) dissolution is slowly added dropwise, is warmed to room temperature, instead
It should stay overnight.TLC is detected to end of reaction, is cooled to 0 DEG C, and saturated aqueous ammonium chloride (50mL) quenching reaction, second is slowly added dropwise
Acetoacetic ester extracts (3 times × 100mL), and brine is washed (2 times × 100mL), merges organic phase, and dry with anhydrous sodium sulfate, vacuum
Revolving removes solvent, and silica gel column chromatography separation, petroleum ether: ethyl acetate=7:1 (v/v) elutes to obtain red solid 47mg, yield
63%.1H NMR(500MHz,DMSO-d6) δ 8.03 (d, 1H, J=8.4Hz, Ar-H), 7.93 (s, 1H, Ar-H), 7.72 (s,
1H, Ar-H), 7.47 (d, 1H, J=8.3Hz, Ar-H), 7.22 (t, 1H, J=6.6Hz, Ar-H), 7.18 (m, 2H, Ar-H),
7.14 (m, 2H, Ar-H), 7.03-6.98 (dt, 1H, J=7.8Hz, 0.9Hz, Ar-H), 6.81 (m, 3H, Ar-H), 6.66 (dd,
1H, J=7.0Hz, 7.1Hz, Ar-H), 4.47 (t, 2H, J=7.1Hz, N-CH2 -CH2Ph),3.01(s,3H,-NCH3),2.99
(t, 2H, J=7.1Hz, NCH2-CH2 -Ph),1.61(s,9H,-C(CH3)3).13C NMR(125MHz,DMSO-d6)δ171.5,
171.4,149.2,138.7,136.2,134.7,133.7,131.7,129.2×2,128.7×2,128.6,128.2,
126.9,126.1,125.1,123.3,122.8,122.6,121.7,121.4,120.5,115.1,111.2,110.9,
104.9,85.1,47.8,36.1,28.1×3,24.5.ESI-MS m/z 546.3[M+H]+.
Vi) the preparation of N- methyl -2- (3- indoles) -3- (1- phenethyl -3- indoles) maleimide (102f)
With toluene (10mL) dissolved compound 102e (34mg, 0.062mmol) in 100mL single port bottle, silica gel is added
(200mg), is heated to reflux 2h.It is cooled to room temperature, TLC is detected to end of reaction, and vacuum revolving removes solvent, silica gel column chromatography point
From, petroleum ether: ethyl acetate=3:1 (v/v) elutes to obtain red solid (102f) 26mg, yield 94%.1H NMR(500MHz,
DMSO-d6) δ 11.68 (s, 1H, indole-NH), 7.76 (s, 1H, Ar-H), 7.63 (s, 1H, Ar-H), 7.45 (d, 1H, J=
8.3Hz, Ar-H), 7.36 (d, 1H, J=8.1Hz, Ar-H), 7.25 (d, 1H, J=7.8Hz, Ar-H), 7.24 (d, 2H, J=
7.2Hz, Ar-H), 7.18-7.16 (m, 3H, Ar-H), 6.99 (d, 1H, J=7.9Hz, Ar-H), 6.95 (d, 1H, J=7.8Hz,
), Ar-H 6.75 (d, 1H, J=8.3Hz, Ar-H), 6.73 (d, 1H, J=8.0Hz, Ar-H), 6.64 (d, 1H, J=8.1Hz,
), Ar-H 6.60 (d, 1H, J=8.1Hz, Ar-H), 4.46 (t, 2H, J=7.3Hz, N-CH2 -CH2), Ph 3.03 (t, 2H, J=
7.3Hz,NCH2-CH2 -Ph),3.01(s,3H,-NCH3).13C NMR(125MHz,DMSO-d6)δ172.2,172.1,138.8,
136.4,136.0,134.7,132.3,129.6,129.2×2,128.7×2,127.4,126.9,126.7,126.4,
125.8,122.1,121.6,121.4,119.9,119.7,112.2,110.6,106.1,105.3,47.7,36.2,
24.4.ESI-MS m/z446.3[M+H]+.
Vii) 6- methyl-1 2- phenethyl -12,13- dihydro -5H- indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7
The preparation of (6H)-diketone (102)
According to the preparation method of compound 73a, by compound 102f (406mg, 0.912mmol), DDQ (269mg,
It 1.19mmol) is synthesized with p-TsOH (154mg, 0.81mmol), silica gel column chromatography separation, petroleum ether: ethyl acetate=3:1 (v/
V) yellow solid (102) 340mg, yield 84% are eluted to obtain.1H NMR(500MHz,DMSO-d6)δ11.83(s,1H,indole-
), NH 9.03 (d, 1H, J=8.0Hz, Ar-H), 9.00 (d, 1H, J=7.8Hz, Ar-H), 7.77 (d, 1H, J=8.1Hz, Ar-
), H 7.55 (t, 1H, J=7.5Hz, Ar-H), 7.50 (d, 1H, J=8.1Hz, Ar-H), 7.44 (t, 1H, J=7.0Hz, Ar-
), H 7.33 (t, 1H, J=6.9Hz, Ar-H), 7.27 (t, 1H, J=6.9Hz, Ar-H), 7.03-7.00 (m, 5H, Ar-H),
5.07 (t, 2H, J=7.4Hz, N-CH2 -CH2Ph),3.05(s,3H,NCH3), 3.03 (t, 2H, J=7.4Hz, NCH2-CH2 -
Ph).13C NMR(125MHz,DMSO-d6)δ170.1×2,141.7,141.6,138.4,129.8,129.6,129.5,128.7
×2,128.6,128.5,127.4,127.2,126.8,124.8,124.7,121.5,120.8,120.7×2,119.7,
117.5,116.6,112.6,110.6,45.8,36.9,24.1.ESI-MS m/z 444.2[M+H]+.
The preparation of compound 103
I) preparation of 12- phenethyl -12,13- dihydrofuran [3,4-c] indoles [2,3-a] carbazole -5,7- diketone (103a)
According to the synthetic method of compound 73b, closed by compound 102 (200mg, 0.45mmol) and KOH (5M, 30mL)
At obtaining yellow solid (103a) 164mg, yield 84%.Since the dissolubility of product is very poor, and react more complete, therefore without
It isolates and purifies to direct plunge into and react in next step.
Ii) 12- phenethyl -12,13- dihydro -5H- indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7 (6H)-diketone
(103) preparation
According to the synthetic method of compound 23c, by compound 103a (20mg, 0.047mmol), HMDS (500 μ L,
It 2.35mmol) is synthesized with methanol (50 μ L, 1.18mmol), silica gel column chromatography separation, petroleum ether: ethyl acetate=3:1 (v/v) is washed
Take off to obtain yellow solid (103) 16mg, yield 90%.1H NMR(500MHz,DMSO-d6)δ11.83(s,1H,indole-NH),
11.02 (s, 1H, imide-NH), 9.08 (d, 1H, J=7.8Hz, Ar-H), 9.06 (d, 1H, J=7.8Hz, Ar-H), 7.79
(d, 1H, J=8.1Hz, Ar-H), 7.62 (d, 1H, J=8.3Hz, Ar-H), 7.56 (t, 1H, J=7.6Hz, Ar-H), 7.47
(t, 1H, J=7.7Hz, Ar-H), 7.35 (t, 1H, J=7.5Hz, Ar-H), 7.30 (t, 1H, J=7.5Hz, Ar-H), 7.10-
6.98 (m, 5H, Ar-H), 5.20 (t, 2H, J=7.1Hz, N-CH2 -CH2- Ph), 3.07 (t, 2H, J=7.1Hz, N-CH2-CH2 -
Ph).13C NMR(125MHz,DMSO-d6)δ171.6,171.5,141.6,141.5,138.2,133.0,129.5×2,
128.9,128.4×2,127.3,127.1,126.7,124.9,124.7,123.5,121.6,121.4,120.7×2,
120.3,117.4,116.6,112.5,110.6,45.8,36.5.ESI-MS m/z 430.2[M+H]+.
The preparation of compound 104
It is raw material preparation, silica gel column chromatography with compound 103 (18mg, 0.06mmol) according to the preparation method of compound 2
Separation, petroleum ether: ethyl acetate=3:1 (v/v) elutes to obtain yellow fluorescence powder 6- methylol -12- phenethyl -12,13- two
Hydrogen -5H- indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7 (6H)-diketone (104) 21mg, yield 80%.1H NMR
(500MHz,DMSO-d6) δ 11.92 (s, 1H, indole-NH), 9.07 (d, 1H, J=7.9Hz, Ar-H), 9.06 (d, 1H, J=
7.8Hz, Ar-H), 7.79 (d, 1H, J=8.1Hz, Ar-H), 7.58 (d, 1H, J=8.2Hz, Ar-H), 7.56 (d, 1H, J=
8.1Hz, Ar-H), 7.47 (t, 1H, J=7.6Hz, Ar-H), 7.35 (t, 1H, J=7.4Hz, Ar-H), 7.30 (t, 1H, J=
7.4Hz, Ar-H), 7.00-6.97 (m, 5H), 6.29 (t, 1H, J=7.0Hz ,-CH2OH), 5.16 (t, 2H, J=6.8Hz, N-
CH2 -CH2), Ph 5.04 (d, 2H, J=7.0Hz ,-CH2 ), OH 3.08 (t, 2H, J=6.8Hz, NCH2-CH2 -Ph).13C NMR
(125MHz,DMSO-d6)δ169.5,169.4,141.6,141.5,138.2,130.0,129.4×2,128.9,128.4,
127.4,127.2,126.7,124.9,124.7,124.5,123.5,121.4,121.3,120.8,120.7,119.1,
117.4,116.6,112.6,110.6,60.2,45.8,36.4.ESI-MS m/z 460.2[M+H]+.
The preparation of compound 105
According to the synthetic method of compound 14, by compound 103a (40mg, 0.09mmol) and ethylenediamine (75 μ L,
It 0.9mmol) synthesizes, silica gel column chromatography separation, methylene chloride: methanol=50:1 (v/v) elutes to obtain yellow solid 6- (2- ammonia second
Base) -12- phenethyl -12,13- dihydro -5H- indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7 (6H)-diketone (105) 34mg,
Yield 80%.1H NMR(500MHz,DMSO-d6) δ 12.07 (s, 1H, indole-NH), 9.08 (d, 1H, J=7.2Hz, Ar-
), H 9.07 (d, 1H, J=7.9Hz, Ar-H), 7.83 (d, 1H, J=8.0Hz, Ar-H), 7.62 (d, 1H, J=8.1Hz, Ar-
), H 7.58 (t, 1H, J=7.8Hz, Ar-H), 7.47 (t, 1H, J=7.3Hz, Ar-H), 7.35 (t, 1H, J=7.3Hz, Ar-
), H 7.30 (t, 1H, J=7.2Hz, Ar-H), 7.01 (m, 5H, Ar-H), 5.23 (t, 2H, J=6.6Hz, N-CH2 -CH2-Ph),
3.90 (t, 2H, J=5.7Hz, N-CH2 -CH2NH2), 3.10 (t, 2H, J=5.7Hz, NCH2-CH2 -NH2), 3.09 (t, 2H, J=
6.6Hz,N-CH2-CH2 -Ph).13C NMR(125MHz,DMSO-d6)δ170.2×2,141.7,141.6,138.2,129.5×
2,128.8,128.4×2,127.4,127.2,126.7,124.7,124.6,121.9,121.4,120.9,120.7,119.4,
119.3,117.5,116.7,112.7,111.6,110.7,45.9,40.9,40.9,36.5.ESI-MS m/z 473.3[M+H]+.
The preparation of compound 106
According to the synthetic method of compound 16, yellow solid 6- (2- ammonia is made by compound 105 (25mg, 0.05mmol)
Ethyl) -12- phenethyl -12,13- dihydro -5H- indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7 (6H)-dione hydrochloride
(106) 173mg, yield 90%.1H NMR(500MHz,DMSO-d6) δ 12.24 (s, 1H, indole-NH), 9.05 (d, 1H, J=
7.5Hz, Ar-H), 9.04 (d, 1H, J=7.0Hz, Ar-H), 8.21 (brs, 3H ,-NH3 +), 7.87 (d, 1H, J=8.1Hz, Ar-
), H 7.56 (d, 1H, J=7.7Hz, Ar-H), 7.55 (d, 1H, J=8.1Hz, Ar-H), 7.45 (d, 1H, J=7.3Hz, Ar-
), H 7.34 (t, 1H, J=7.5Hz, Ar-H), 7.28 (t, 1H, J=7.4Hz, Ar-H), 7.03-6.93 (m, 5H), 5.23 (t,
2H, J=6.4Hz, N-CH2 -CH2), Ph 3.97 (t, 2H, J=6.4Hz, N-CH2 -CH2NH3 +), 3.18 (t, 2H, J=6.4Hz,
NCH2-CH2 -NH3 +), 3.07 (t, 2H, J=6.4Hz, NCH2-CH2 -Ph).13C NMR(125MHz,DMSO-d6)δ170.1×2,
141.8,141.6,138.2,129.8,129.4,128.7,128.3,127.4,127.1,126.6,124.6,124.5,
121.4,120.9,121.2,120.7,120.6,119.3×2,117.4,116.7,112.8,110.7,110.6.45.8,
38.2,36.6,35.7.ESI-MSm/z 473.2[M–Cl]+.
The preparation of compound 107
According to the synthetic method of compound 14, by compound 103a (25mg, 0.06mmol) and 1,3- propane diamine (99 μ L,
It 1.2mmol) synthesizes, silica gel column chromatography separation, methylene chloride: methanol=50:1 (v/v) elutes to obtain yellow solid 6- (3- ammonia third
Base) -12- phenethyl -12,13- dihydro -5H- indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7 (6H)-diketone (107) 22mg,
Yield 75%.1H NMR(500MHz,DMSO-d6) δ 12.19 (s, 1H, indole-NH), 9.05 (d, 1H, J=7.8Hz, Ar-
), H 9.03 (d, 1H, J=7.8Hz, Ar-H), 7.87 (d, 1H, J=8.1Hz, Ar-H), 7.57 (dt, 1H, J=8.1Hz,
1.1Hz, Ar-H), 7.54 (d, 1H, J=8.1Hz, Ar-H), 7.45 (dt, 1H, J=8.1Hz, 1.1Hz, Ar-H), 7.35 (dt,
1H, J=8.1Hz, 1.1Hz, Ar-H), 7.28 (t, 1H, J=7.9Hz, Ar-H), 7.05-7.03 (m, 5H, Ar-H), 5.20 (t,
2H, J=7.0Hz, N-CH2 -CH2), Ph 3.76 (t, 2H, J=6.6Hz, N-CH2 -(CH2)2NH2), 3.07 (t, 2H, J=
7.0Hz,NCH2-CH2 - Ph), 2.90 (t, 2H, J=6.6Hz, N (CH2)2-CH2 -NH2),2.04–2.00(m,2H,NCH2-CH2 -
CH2NH2).13C NMR(125MHz,DMSO-d6)δ170.2×2,141.9,141.7,138.4,130.0,129.6×2,
128.9,128.5×2,127.5,127.3,126.8,124.8,124.6,121.5,121.4,120.8×2,119.1×2,
117.6,116.8,112.9,110.7,45.9,37.5,36.7,35.2,27.4.ESI-MS m/z 487.1[M+H]+.
The preparation of compound 108
According to the synthetic method of compound 16, yellow solid 6- (3- ammonia is made by compound 107 (23mg, 0.05mmol)
Propyl) -12- phenethyl -12,13- dihydro -5H- indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7 (6H)-dione hydrochloride
(108) 20mg, yield 90%.1H NMR(500MHz,DMSO-d6) δ 12.18 (s, 1H, indole-NH), 9.06 (d, 2H, J=
7.9Hz,Ar-H),8.01(brs,3H,-NH3 +), 7.85 (d, 1H, J=8.1Hz, Ar-H), 7.59 (d, 1H, J=8.1Hz, Ar-
), H 7.56 (d, 1H, J=8.1Hz, Ar-H), 7.45 (t, 1H, J=7.6Hz, Ar-H), 7.34 (t, 1H, J=7.5Hz, Ar-
), H 7.29 (t, 1H, J=7.5Hz, Ar-H), 7.04-6.97 (m, 5H), 5.22 (t, 2H, J=6.8Hz, N-CH2 -CH2Ph),
3.77 (d, 2H, J=6.8Hz, N-CH2 -(CH2)2NH3 +), 3.07 (t, 2H, J=6.7Hz, NCH2-CH2 -Ph),2.93(t,2H,
J=6.7Hz, N (CH2)2-CH2 -NH3 +),2.05–1.97(m,2H,NCH2-CH2 -CH2NH3 +).13C NMR(125MHz,DMSO-
d6)δ170.2,170.1,141.8,141.6,138.3,130.0,129.8,129.5,128.8,128.4,127.4,127.3,
127.2,126.7,124.7,124.5,121.4,121.2,120.7×2,119.0×2,117.5,116.7,112.8,
110.7,45.8,37.4,36.5,35.1,27.3.ESI-MS m/z 487.1[M–Cl]+.
The preparation of compound 109
According to the synthetic method of compound 24, by compound 103a (21mg, 0.049mmol), 4- (2- aminoethyl)-morpholine
The synthesis of the triethylamine of (50 μ L, 0.49mmol) and catalytic amount, silica gel column chromatography separation, methylene chloride: methanol=50:1 (v/v) is washed
Take off to obtain yellow solid 6- (2- (4- morpholine) ethyl) -12- phenethyl -12,13- dihydro -5H- indoles [2,3-a] pyrroles [3,4-c]
Carbazole -5,7 (6H)-diketone (109) 19mg, yield 80%.1H NMR(500MHz,DMSO-d6)δ11.91(s,1H,indole-
), NH 9.05 (d, 1H, J=7.9Hz, Ar-H), 9.04 (d, 1H, J=7.8Hz, Ar-H), 7.78 (d, 1H, J=8.1Hz),
7.57 (d, 1H, J=7.8Hz, Ar-H), 7.57 (t, 1H, J=7.3Hz, Ar-H), 7.46 (d, 1H, J=7.2Hz, Ar-H),
7.34 (t, 1H, J=7.2Hz, Ar-H), 7.29 (t, 1H, J=7.4Hz, Ar-H), 7.03-7.01 (m, 5H, Ar-H), 5.16
(t, 2H, J=7.0Hz, N-CH2 -CH2), Ph 3.78 (t, 2H, J=6.5Hz, imide-N-CH2 -CH2-morpholine),
3.50 (t, 4H, J=3.9Hz, morpholine-N (CH2-CH2 )2), O 3.07 (t, 2H, J=7.0Hz, NCH2-CH2 -Ph),
2.61 (t, 2H, J=6.5Hz, imide-NCH2-CH2 - morpholine), 2.47 (t, 4H, J=3.9Hz, morpholine-N
(CH 2-CH2)2O).13C NMR(125MHz,DMSO-d6)δ170.0,169.9,141.6,141.5,138.2,130.0,129.8,
129.5×2,128.8,128.7,128.4×2,127.4,127.2,126.7,124.6,121.4,121.3,120.8,
120.1,119.0,117.4,116.7,112.6,110.6,66.6×2,56.5×2,53.6,45.8,36.5,34.9.ESI-
MS m/z 543.2[M+H]+.
The preparation of compound 110
According to the synthetic method of compound 24, by compound 103a (23mg, 0.054mmol), 4- (2- aminoethyl)-piperazine
The synthesis of the triethylamine of (60 μ L, 0.54mmol) and catalytic amount, silica gel column chromatography separation, methylene chloride: methanol=50:1 (v/v) is washed
Take off to obtain yellow solid 6- (2- piperazine ethyl) -12- phenethyl -12,13- dihydro -5H- indoles [2,3-a] pyrroles [3,4-c] click
Azoles -5,7 (6H)-diketone (110) 16mg, yield 80%.1HNMR(500MHz,DMSO-d6)δ12.12(s,1H,indole-NH),
10.24 (s, 1H, piperazin-NH), 9.04 (d, 1H, J=7.1Hz, Ar-H), 9.03 (d, 1H, J=6.9Hz, Ar-H),
7.83 (d, 1H, J=8.1Hz, Ar-H), 7.58-7.52 (m, 2H, Ar-H), 7.44 (t, 1H, J=7.5Hz, Ar-H), 7.33
(t, 1H, J=7.4Hz, Ar-H), 7.28 (t, 1H, J=7.4Hz, Ar-H), 7.05-6.94 (m, 5H, Ar-H), 5.19 (t, 2H,
J=7.0Hz, N-CH2 -CH2), Ph 3.80 (t, 2H, J=6.5Hz, imide-N-CH2 -CH2-piperazine),3.07(t,
2H, J=7.0Hz, NCH2-CH2 - Ph), 3.01 (t, 4H, J=4.4Hz, piperazine-N (CH 2-CH2)2NH),2.75(t,
4H, J=4.4Hz, piperazine-N (CH2-CH 2)2), NH 2.48 (t, 2H, J=6.5Hz, imide-NCH2-CH2 -
piperazine).13C NMR(125MHz,DMSO-d6)δ170.0,169.9,141.7,141.6,138.2,129.9,129.5
×2,128.7,128.4×2,127.4,127.1,126.7,124.7,124.5,121.4,121.2,120.7,120.6,
119.0,118.9,117.4,116.6,112.7,110.6,55.6×2,53.6,49.5×2,43.1,36.5,34.8.ESI-
MS m/z 542.3[M+H]+.
The preparation of compound 111
According to the synthetic method of compound 24, by the chloro- 6- fluorophenethylamine of compound 103a (15mg, 0.035mmol), 2-
The synthesis of the triethylamine of (20 μ L, 0.35mmol) and catalytic amount, silica gel column chromatography separation, methylene chloride: methanol=50:1 (v/v) is washed
Take off to obtain yellow solid 6- (the chloro- 6- fluorobenzene ethyl of 2-) -12- phenethyl -12,13- dihydro -5H- indoles [2,3-a] pyrroles [3,4-
C] carbazole -5,7 (6H)-diketone (111) 13mg, yield 68%.1H NMR(500MHz,DMSO-d6)δ11.93(s,1H,
), indole-NH 9.00 (d, 1H, J=7.8Hz, Ar-H), 8.98 (d, 1H, J=7.9Hz, Ar-H), 7.78 (d, 1H, J=
8.1Hz, Ar-H), 7.60 (d, 1H, J=8.4Hz, Ar-H), 7.55 (t, 1H, J=7.6Hz, Ar-H), 7.46 (t, 1H, J=
7.4Hz, Ar-H), 7.35 (t, 1H, J=7.7Hz, Ar-H), 7.29 (d, 1H, J=7.6Hz, Ar-H), 7.25 (m, 2H, Ar-
), H 7.11 (dd, J=7.1Hz, 5.9Hz, 1H), 7.08-6.95 (m, 5H, Ar-H), 5.17 (t, 2H, J=7.0Hz, N-CH2 -
CH2), Ph 3.94 (t, 2H, J=6.5Hz, imide-N-CH2 -CH2-C6H3), FCl 3.19 (t, 2H, J=6.5Hz, imide-
NCH2-CH2 -C6H3), FCl 3.07 (t, 2H, J=7.0Hz, NCH2-CH2 -Ph).13C NMR(125MHz,DMSO-d6)δ169.8,
169.7,161.8(d,1JCF=244Hz), 141.6 (d,3JCF=11Hz), 138.2,135.0,129.8 (d,2JCF=11Hz),
129.4×2,128.7,128.4×2,127.4,127.2,126.7,125.8×2,124.8,124.7,124.6,124.5×
2,121.4(d,2JCF=22Hz), 120.8,120.7,119.0,118.9,117.4,116.6,114.7 (d,2JCF=23Hz),
112.6,110.6,45.8,36.9,36.5,25.9.ESI-MS m/z 586.2[M+H]+.
The preparation of compound 112
According to the synthetic method of compound 24, by compound 103a (15mg, 0.035mmol), 1- (2- amino-ethyl) piperazine
The synthesis of the triethylamine of pyridine (50 μ L, 0.47mmol) and catalytic amount, silica gel column chromatography separation, methylene chloride: methanol=50:1 (v/v)
Elute to obtain yellow solid 6- (2- piperidinoethyl) -12- phenethyl -12,13- dihydro -5H- indoles [2,3-a] pyrroles [3,4-c] click
Azoles -5,7 (6H)-diketone (112) 17mg, yield 67%.1HNMR(500MHz,DMSO-d6)δ11.92(s,1H,indole-NH),
9.04 (d, 1H, J=8.2Hz, Ar-H), 9.02 (d, 1H, J=8.5Hz, Ar-H), 7.78 (d, 1H, J=8.1Hz, Ar-H),
7.56 (d, 1H, J=7.3Hz, Ar-H), 7.54 (d, 1H, J=8.0Hz, Ar-H), 7.45 (d, 1H, J=7.2Hz, Ar-H),
7.34 (d, 1H, J=7.3Hz, Ar-H), 7.28 (d, 1H, J=7.3Hz, Ar-H), 7.08-6.96 (m, 5H, Ar-H), 5.14
(t, 2H, J=6.6Hz, N-CH2 -CH2), Ph 3.77 (t, 2H, J=5.4Hz, imide-N-CH2 -CH2-piperidine),
3.06 (t, 2H, J=6.6Hz, NCH2-CH2 - Ph), 2.65 (t, 2H, J=6.5Hz, imide-NCH2-CH2 -piperidine),
2.49 (t, 4H, J=3.1Hz, piperidine-N (CH 2-CH2)2CH2),1.45(m,4H,piperidine-N(CH2-CH 2)2CH2), 1.34 (t, 2H, J=3.4Hz, piperidine-N (CH2-CH2)2CH 2).13C NMR(125MHz,DMSO-d6)δ
169.9×2,141.6,141.5,138.2,129.8,129.4×2,128.7,128.4×2,127.4,127.1,126.7,
124.7,124.6,121.4,121.3,120.7,120.6,119.1,119.0,117.4,116.5,112.6,110.6,56.5
×2,54.2,45.8,36.5,25.9,25.6×2,24.1.ESI-MS m/z 541.2[M+H]+.
The preparation of compound 113
According to the synthetic method of compound 24, by compound 103a (23mg, 0.054mmol), 4- methyl-1-piperazine ethanamine
The synthesis of the triethylamine of (50 μ L, 0.55mmol) and catalytic amount, silica gel column chromatography separation, methylene chloride: methanol=50:1 (v/v) is washed
De- yellow solid 6- (2- (4- methyl piperazine) ethyl) -12- phenethyl -12,13- dihydro -5H- indoles [2,3-a] pyrroles [3,
4-c] carbazole -5,7 (6H)-diketone (113) 19mg, yield 65%.1H NMR(500MHz,DMSO-d6)δ11.94(s,1H,
), indole-NH 9.06 (d, 1H, J=7.3Hz, Ar-H), 9.05 (d, 1H, J=7.0Hz, Ar-H), 7.79 (d, 1H, J=
8.2Hz, Ar-H), 7.59 (d, 1H, J=7.7Hz, Ar-H), 7.56 (d, 1H, J=7.7Hz, Ar-H), 7.46 (t, 1H, J=
7.6Hz, Ar-H), 7.35 (t, 1H, J=7.5Hz, Ar-H), 7.07-6.97 (m, 5H, Ar-H), 5.17 (t, 2H, J=6.8Hz,
N-CH2 -CH2), Ph 3.79 (t, 2H, J=6.3Hz, N-CH2 -CH2- piperazine), 3.07 (t, 2H, J=6.9Hz, NCH2-
CH2 - Ph), 2.62 (t, 2H, J=6.5Hz, NCH2-CH2 - piperazine), 2.48 (t, 4H, J=4.5Hz, piperazine-
N(CH 2-CH2)2NCH3), 2.35 (t, 4H, J=4.5Hz, piperazine-N (CH2-CH 2)2NCH3),2.15(s,3H,
piperazine-N(CH2-CH2)2NCH 3).13C NMR(125MHz,DMSO-d6)δ169.9×2,141.6×2,138.2,
129.9,129.5×2,128.7,128.4×2,127.5,127.2,126.7,124.7,124.6,121.4,121.3,
120.8,120.7,119.1,119.0,117.4,116.7,112.6,110.6,55.9×2,54.8×2,52.6,45.8,
45.6,36.5,35.2.ESI-MS m/z 556.3[M+H]+.
The preparation of compound 114
According to the synthetic method of compound 24, by compound 103a (40mg, 0.093mmol), ethanol amine (102 μ L,
It 1.86mmol) is synthesized with the triethylamine of catalytic amount, silica gel column chromatography separation, methylene chloride: methanol=50:1 (v/v) elutes yellow
Color solid 6- (2- ethoxy) -12- phenethyl -12,13- dihydro -5H- indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7
(6H)-diketone (114) 28mg, yield 67%.1H NMR(500MHz,DMSO-d6)δ11.86(s,1H,indole-NH),9.06
(d, 1H, J=8.0Hz, Ar-H), 9.04 (d, 1H, J=7.9Hz, Ar-H), 7.78 (d, 1H, J=8.1Hz, Ar-H), 7.57
(t, 1H, J=7.3Hz, Ar-H), 7.53 (d, 1H, J=8.1Hz, Ar-H), 7.45 (t, 1H, J=7.3Hz, Ar-H), 7.35
(d, 1H, J=7.0Hz, Ar-H), 7.28 (t, 1H, J=7.5Hz, Ar-H), 7.07-7.00 (m, 5H, Ar-H), 5.12 (t, 2H,
J=6.6Hz, N-CH2 -CH2), Ph 4.93 (t, 1H, J=5.7Hz ,-OH), 3.72 (t, 2H, J=5.7Hz, N-CH2 -CH2OH),
3.69 (t, 2H, J=5.7Hz ,-CH2 ), OH 3.07 (t, 2H, J=6.6Hz, NCH2-CH2 -Ph).13C NMR(125MHz,DMSO-
d6)δ170.2×2,141.7,141.6,138.4,129.8,129.5×2,128.8,128.5×2,127.5,127.2,
126.8,124.9,124.8,121.5,121.4,120.8,120.7,119.3×2,117.5,116.7,112.6,110.6,
58.9,45.9,45.8,36.6.ESI-MS m/z 474.3[M+H]+The preparation of compound 115
According to the synthetic method of compound 24, by compound 103a (30mg, 0.07mmol), 3- hydroxypropylamine (100 μ L,
It 1.4mmol) is synthesized with the triethylamine of catalytic amount, silica gel column chromatography separation, methylene chloride: methanol=50:1 (v/v) elutes yellow
Color solid 6- (3- hydroxypropyl) -12- phenethyl -12,13- dihydro -5H- indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7
(6H)-diketone (115) 24mg, yield 70%.1H NMR(500MHz,DMSO-d6)δ11.93(s,1H,indole-NH),9.07
(d, 1H, J=7.9Hz, Ar-H), 9.05 (d, 1H, J=7.9Hz, Ar-H), 7.80 (d, 1H, J=8.1Hz, Ar-H), 7.58
(dd, 1H, J=8.3Hz, 1.1Hz, Ar-H), 7.57 (t, 1H, J=7.7Hz, Ar-H), 7.48 (dt, 1H, J=8.1Hz,
1.1Hz, Ar-H), 7.35 (d, J=8.3Hz, 1H, Ar-H), 7.29 (t, 1H, J=7.5Hz, Ar-H), 7.08-7.01 (m, 5H,
), Ar-H 5.15 (t, 2H, J=7.1Hz, N-CH2 -CH2), Ph 4.59 (t, 1H, J=5.1Hz, N (CH2)2CH2-OH),3.73(t,
2H, J=7.2Hz, N-CH2 -CH2CH2OH),3.53–3.51(m,2H,N(CH2)2-CH2 - OH), 3.07 (t, 2H, J=7.1Hz,
NCH2-CH2 -Ph),1.88–1.83(m,2H,NCH2-CH2 -CH2OH).13C NMR(125MHz,DMSO-d6)δ170.2×2,
141.8,141.7,138.4,129.9,129.6×2,128.8,128.5×2,127.5,127.3,126.9,124.9,
124.8,121.6,121.4,120.8,120.7,119.2×2,117.5,116.8,112.9,110.7,59.3×2,45.9,
36.6,32.3.ESI-MS m/z 488.1[M+H]+.
The preparation of compound 116
I) preparation of p-methyl benzenesulfonic acid (1- naphthalene second) ester (116a)
According to the synthetic method of compound 102d, by naphthyl ethyl alcohol (5g, 0.029mmol), paratoluensulfonyl chloride (11.65g,
It 0.061mmol) is synthesized with triethylamine (8.46mL, 0.061mmol), silica gel column chromatography separation, petroleum ether: ethyl acetate=3:1
(v/v) white solid 9.6g, yield 85% are eluted to obtain.ESI-MS m/z 278.1[M+H]+.
Ii) N- methyl -2- (1- tertiary butyl oxycarbonyl -3- indoles) -3- (1- (1- naphthylethyl) -3- indoles) maleimide
The preparation of (116b)
According to the synthetic method of compound 102e, by compound 102c (1g, 2.27mmol), sodium hydride (200mg,
4.54mmol) synthesized with compound 116a (1.13g, 3.41mmol).Silica gel column chromatography separation, petroleum ether: ethyl acetate=4:1
(v/v) red solid (116b) 563mg, yield 41% are eluted to obtain.1H NMR(500MHz,DMSO-d6) δ 8.08 (d, 1H, J=
8.0Hz, Ar-H), 8.07 (d, 1H, J=8.0Hz, Ar-H), 7.97 (s, 1H, Ar-H), 7.94 (d, 1H, J=7.8Hz, Ar-
), H 7.80 (d, 1H, J=8.2Hz, Ar-H), 7.74 (s, 1H, Ar-H), 7.59 (dd, 1H, J=8.3Hz, 1.4Hz, Ar-H),
7.56 (d, 1H, J=6.9Hz, Ar-H), 7.44 (d, 1H, J=8.3H, Ar-H), 7.38 (t, 1H, J=7.2Hz, Ar-H),
7.24 (d, 1H, J=7.2Hz, Ar-H), 7.19 (d, 1H, J=7.1Hz, Ar-H), 7.04 (t, 1H, J=7.6Hz, Ar-H),
6.95 (d, 1H, J=8.0Hz, Ar-H), 6.89 (d, 1H, J=7.9Hz, Ar-H), 6.85 (d, 1H, J=7.9Hz, Ar-H),
6.74 (t, 1H, J=7.6Hz, Ar-H), 4.58 (t, 2H, J=7.3Hz, N-CH2 -CH2- Nap), 3.46 (t, 2H, J=7.3Hz,
NCH2-CH2 -Nap),3.04(s,3H,NCH3),1.64(s,9H,-C(CH3)3).13C NMR(125MHz,DMSO-d6)δ171.5
×2,149.3,136.4,134.9,134.8,134.0,133.9,131.9,131.8,129.3,128.4,128.3,127.8,
127.4,126.9,126.3,125.9,125.2,124.0,123.6,123.0,122.8,122.0,121.7,120.7,
115.3,111.3,110.9,105.1,85.2,47.2,33.3,28.2×3,24.9.ESI-MS m/z596.2[M+H]+.
Iii) the preparation of N- methyl -2- (3- indoles) -3- (1- (1- naphthylethyl) -3- indoles) maleimide (116c)
According to the synthetic method of compound 102f, closed by compound 116b (100mg, 0.168mmol) and silica gel (400mg)
At silica gel column chromatography separation, petroleum ether: ethyl acetate=4:1 (v/v) elutes to obtain yellow solid (116c) 79mg, yield 95%.1H
NMR(500MHz,DMSO-d6) δ 11.72 (d, 1H, J=2.5Hz, indole-NH), 8.09 (d, 1H, J=8.2Hz, Ar-H),
7.94 (s, 1H, Ar-H), 7.80 (d, 1H, J=8.2Hz, Ar-H), 7.75 (d, 1H, J=2.8Hz, Ar-H), 7.62 (s, 1H,
), Ar-H 7.58 (t, 1H, J=7.7Hz, Ar-H), 7.54 (t, 1H, J=7.7Hz, Ar-H), 7.43-7.40 (m, 2H, Ar-H),
7.36 (dd, 1H, J=8.2Hz, 7.0Hz, Ar-H), 7.25 (d, 1H, J=7.0Hz, Ar-H), 7.01 (dt, 2H, J=7.5Hz,
1.1Hz, Ar-H), 6.84 (d, 1H, J=8.0Hz, Ar-H), 6.80 (d, 1H, J=8.1Hz, Ar-H), 6.69 (dt, 1H, J=
7.5Hz, 1.1Hz, Ar-H), 6.66 (dt, 1H, J=7.5Hz, 1.1Hz, Ar-H), 4.57 (t, 2H, J=7.3Hz, N-CH2 -
CH2- Nap), 3.51 (t, 2H, J=7.3Hz, NCH2-CH2 -Nap),3.02(s,3H,NCH3).13C NMR(125MHz,DMSO-
d6)δ172.3,172.2,136.6,136.2,134.9,134.0,132.5,131.9,129.9,129.3,127.7,127.5,
126.9,126.4,126.3,126.0,125.7,124.1,122.3×2,121.9,121.6,120.1,119.9,112.4,
110.6,106.2,105.6,47.2,33.3,24.5.ESI-MS m/z 496.2[M+H]+.
Iv) 6- methyl-1 2- (1- naphthylethyl) -12,13- dihydro -5H- indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7
The preparation of (6H)-diketone (116)
According to the synthetic method of compound 102, by compound 116c (400mg, 0.808mmol), DDQ (238mg,
It 1.05mmol) is synthesized with p-TsOH (154mg, 0.81mmol), silica gel column chromatography separation, petroleum ether: ethyl acetate=4:1 (v/
V) yellow solid (116) 270mg, yield 65% are eluted to obtain.1H NMR(600MHz,DMSO-d6)δ11.85(s,1H,indole-
), NH 9.07 (d, 1H, J=7.9Hz, Ar-H), 9.00 (d, 1H, J=7.8Hz, Ar-H), 8.00 (d, 1H, J=7.9Hz, Ar-
), H 7.83 (d, 1H, J=7.3Hz, Ar-H), 7.73 (d, 1H, J=8.1Hz, Ar-H), 7.62 (d, 1H, J=8.1Hz, Ar-
), H 7.60 (dt, 1H, J=7.7Hz, 1.1Hz, Ar-H), 7.48-7.40 (m, 2H, Ar-H), 7.39 (t, 1H, J=7.7Hz,
), Ar-H 7.33 (t, 1H, J=7.7Hz, Ar-H), 7.23 (d, 1H, J=7.7Hz, Ar-H), 7.22 (d, 1H, J=8.1Hz,
), Ar-H 7.16 (t, 1H, J=7.4Hz, Ar-H), 7.02 (d, 1H, J=6.6Hz, Ar-H), 5.24 (t, 2H, J=7.0Hz, N-
CH2 -CH2- Nap), 3.53 (t, 2H, J=7.0Hz, NCH2-CH2 -Nap),3.12(s,3H,NCH3).13C NMR(150MHz,
DMSO-d6)δ170.2,170.1,141.8,141.7,134.5,133.8,132.0,129.9,129.0,128.8,127.6,
127.5×2,127.0,126.6,126.1,125.7,124.8,124.7,123.8,121.6×2,120.9,120.7,
119.4,119.3,117.7,117.0,112.6,110.2,45.3,33.4,24.1.ESI-MS m/z 494.2[M+H]+.
The preparation of compound 117
I) 12- (1- naphthylethyl) -12,13- dihydrofuran [3,4-c] indoles [2,3-a] carbazole -5,7- diketone (117a)
Preparation
According to the synthetic method of compound 73b, closed by compound 116 (200mg, 0.45mmol) and KOH (5M, 30mL)
At obtaining yellow solid (117a) 164mg, yield 84%.Since the dissolubility of product is very poor, and react more complete, therefore without
It isolates and purifies to direct plunge into and react in next step.
Ii) 12- (1- naphthylethyl) -12,13- dihydro -5H- indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7 (6H)-two
The preparation of ketone (117)
According to the synthetic method of compound 23c, by compound 117a (26mg, 0.054mmol), HMDS (500 μ L,
It 2.35mmol) is synthesized with methanol (50 μ L, 1.18mmol), silica gel column chromatography separation, petroleum ether: ethyl acetate=4:1 (v/v) is washed
Take off to obtain yellow solid (117) 22mg, yield 87%.1H NMR(500MHz,DMSO-d6)δ11.91(s,1H,indole-NH),
11.03 (s, 1H, imide-NH), 9.10 (d, 1H, J=7.9Hz, Ar-H), 9.04 (d, 1H, J=7.8Hz, Ar-H), 8.00
(d, 1H, J=8.0Hz, Ar-H), 7.80 (d, 1H, J=7.3Hz, Ar-H), 7.75 (d, 1H, J=7.5Hz, Ar-H), 7.62
(d, 1H, J=8.1Hz, Ar-H), 7.60 (t, 1H, J=7.8Hz, Ar-H), 7.47-7.42 (m, 2H, Ar-H), 7.37 (t, 1H,
J=7.7Hz, Ar-H), 7.33-7.30 (m, 2H, Ar-H), 7.25 (d, 1H, J=7.6Hz, Ar-H), 7.15 (t, 1H, J=
7.8Hz, Ar-H), 7.05 (d, 1H, J=7.0Hz, Ar-H), 5.32 (t, 2H, J=7.0Hz, N-CH2 -CH2-Nap),3.54(t,
2H, J=7.0Hz, NCH2-CH2 -Nap).13C NMR(125MHz,DMSO-d6)δ171.7,171.6,141.8,134.5,
133.8,132.0,130.2,129.1,129.0,127.7,127.6,127.5,127.1,126.6,126.4,126.1,
125.7,125.0,124.9,123.8,121.8,121.7,120.9,120.8,120.5,120.4,117.6,117.0,
112.6,110.3,45.4,33.3.ESI-MS m/z 480.3[M+H]+The preparation of compound 118
According to the synthetic method of compound 2, by compound 117 (20mg, 0.04mmol) and formaldehyde (3mL, mass fraction
37%) it synthesizes, silica gel column chromatography separation, petroleum ether: ethyl acetate=4:1 (v/v) elutes to obtain yellow solid 6- methylol -12-
(1- naphthylethyl) -12,13- dihydro -5H- indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7 (6H)-diketone (118) 16mg is received
Rate 80%.1H NMR(600MHz,DMSO-d6) δ 11.90 (s, 1H, imide-NH), 9.08 (d, 1H, J=7.9Hz, Ar-H),
9.00 (d, 1H, J=7.4Hz, Ar-H), 7.96 (d, 1H, J=7.6Hz, Ar-H), 7.77 (d, 1H, J=8.4Hz, Ar-H),
7.72 (d, 1H, J=8.2Hz, Ar-H), 7.59 (d, 1H, J=8.1Hz, Ar-H), 7.56 (d, J=7.4Hz, 1H), 7.45-
7.39 (m, 2H), 7.36 (t, 1H, J=7.5Hz, Ar-H), 7.29 (t, 1H, J=7.8Hz, Ar-H), 7.22 (t, 2H, J=
7.0Hz, Ar-H), 7.10 (t, 1H, J=7.6Hz, Ar-H), 6.98 (d, 1H, J=6.9Hz, Ar-H), 6.30 (t, 1H, J=
6.6Hz,-CH2OH), 5.26 (t, 2H, J=6.9Hz, N-CH2 -CH2- Nap), 5.03 (d, 2H, J=6.6Hz ,-CH2 OH),
3.53 (t, 2H, J=6.9Hz, NCH2-CH2 -Nap).13C NMR(150MHz,DMSO-d6)δ169.4,169.3,141.7,
141.6,134.3,133.6,131.9,130.1,128.9×2,127.5,127.4,127.0,126.4,126.3,126.0,
125.5,124.6,124.5,123.7,122.3,121.5,121.4,120.8,120.6,119.1,119.0,117.5,
116.8,112.6,110.2,60.3,45.3,33.2.ESI-MS m/z 510.2[M+H]+.
The preparation of compound 119
According to the synthetic method of compound 14, by compound 117a (36mg, 0.074mmol) and ethylenediamine (500 μ L,
It 7.5mmol) synthesizes, silica gel column chromatography separation, methylene chloride: methanol=3:1 (v/v) elutes to obtain yellow solid 6- (2- ammonia second
Base) -12- (1- naphthylethyl) -12,13- dihydro -5H- indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7 (6H)-diketone (119)
35mg, yield 90%.1H NMR(500MHz,DMSO-d6) δ 9.10 (d, 1H, J=7.9Hz, Ar-H), 9.02 (d, 1H, J=
7.7Hz, Ar-H), 8.02 (dd, 1H, J=6.7Hz, 2.2Hz, Ar-H), 7.82 (dd, 1H, J=6.4Hz, 2.5Hz, Ar-H),
7.81 (d, 1H, J=8.3Hz, Ar-H), 7.62 (d, 1H, J=8.2Hz, Ar-H), 7.61 (t, 1H, J=7.6Hz, Ar-H),
7.48 (dd, 2H, J=6.6Hz, 3.2Hz, Ar-H), 7.40 (t, 1H, J=7.7Hz, Ar-H), 7.31 (t, 1H, J=8.1Hz,
), Ar-H 7.23 (t, 1H, J=8.2Hz, Ar-H), 7.20 (d, 1H, J=7.8Hz, Ar-H), 7.11 (t, 1H, J=8.1Hz,
), Ar-H 6.96 (d, 1H, J=6.9Hz, Ar-H), 5.33 (t, 2H, J=6.1Hz, N-CH2-CH2- Nap), 3.93 (t, 2H, J=
6.7Hz,N-CH2 -CH2NH2), 3.54 (t, 2H, J=6.1Hz, NCH2-CH2 - Nap), 3.14 (t, 2H, J=6.7Hz, NCH2-
CH2 -NH2).13C NMR(125MHz,DMSO-d6)δ170.3,170.2,142.0,141.9,134.5,133.8,132.0,
130.0,129.1,129.0,127.7,127.6,127.1,126.6,126.4,126.1,125.7,124.8,124.7,
123.8,121.6,121.5,121.0,120.7,119.6,119.5,117.7,117.1,112.9,110.3,45.4,39.1,
37.1,33.5.ESI-MS m/z 523.4[M+H]+.
The preparation of compound 120
According to the synthetic method of compound 16, by the ethyl acetate solution of compound 119 (23mg, 0.04mmol) and hydrochloric acid
(3N, 3mL) synthesizes to obtain 20mg yellow solid 6- (2- aminoethyl) -12- (1- naphthylethyl) -12,13- dihydro -5H- indoles [2,3-
A] pyrroles [3,4-c] carbazole -5,7 (6H)-dione hydrochloride (120), yield 90%.1H NMR(500MHz,DMSO-d6)δ
12.16 (s, 1H, indole-NH), 9.07 (d, 1H, J=7.9Hz, Ar-H), 9.00 (d, 1H, J=7.6Hz, Ar-H), 8.13
(s,3H,-NH3 +), 8.00 (d, 1H, J=5.6Hz, Ar-H), 7.79 (d, 2H, J=7.7Hz, Ar-H), 7.59 (d, 1H, J=
8.0Hz, Ar-H), 7.56 (d, 1H, J=7.5Hz, Ar-H), 7.45 (d, 1H, J=7.5Hz, Ar-H), 7.43 (d, 1H, J=
7.5Hz, Ar-H), 7.36 (t, 1H, J=7.4Hz, Ar-H), 7.28 (t, 1H, J=7.6Hz, Ar-H), 7.22 (d, 1H, J=
7.4Hz, Ar-H), 7.18 (t, 1H, J=6.8Hz, Ar-H), 7.07 (t, 1H, J=7.5Hz, Ar-H), 6.92 (d, 1H, J=
6.9Hz, Ar-H), 5.33 (t, 2H, J=6.9Hz, N-CH2 -CH2- Nap), 3.97 (t, 2H, J=6.7Hz, N-CH2 -CH2NH3 +), 3.52 (t, 2H, J=6.9Hz, NCH2-CH2 - Nap), 3.19 (t, 2H, J=6.7Hz, NCH2-CH2 -NH3 +).13C NMR
(125MHz,DMSO-d6)δ170.1,170.0,141.8×2,134.3,133.6,131.8,129.8,129.0,128.8,
127.5,127.4,127.0,126.5,126.0,125.5,124.6,124.5,123.7,121.4,121.3,120.8,
120.6,119.4,119.3,117.6,116.9,112.8,110.2,45.3,38.3,35.7,33.4.ESI-MS m/z
523.3[M–Cl]+.
The preparation of compound 121
According to the synthetic method of compound 14, by compound 117a (25mg, 0.05mmol), 1,3- propane diamine (60 μ L,
0.78mmol) synthesize to obtain 25mg yellow solid 6- (3- aminopropyl) -12- (1- naphthylethyl) -12,13- dihydro -5H- indoles [2,3-
A] pyrroles [3,4-c] carbazole -5,7 (6H)-diketone (121), yield 90%.1H NMR(500MHz,DMSO-d6)δ12.16(s,
1H, indole-NH), 9.08 (d, 1H, J=8.0Hz, Ar-H), 9.01 (d, 1H, J=7.7Hz, Ar-H), 7.97 (d, 1H, J=
7.4Hz, Ar-H), 7.81-7.79 (m, 2H, Ar-H), 7.62 (t, 1H, J=7.5Hz, Ar-H), 7.61 (d, 1H, J=7.6Hz,
), Ar-H 7.59 (t, 1H, J=7.5Hz, Ar-H), 7.48-7.42 (m, 2H, Ar-H), 7.37 (t, 1H, J=7.4Hz, Ar-H),
7.31 (t, 1H, J=7.6Hz, Ar-H), 7.23 (t, 1H, J=7.7Hz, Ar-H), 7.21 (t, 1H, J=7.4Hz, Ar-H),
7.11 (t, 1H, J=7.8Hz, Ar-H), 6.99 (d, 1H, J=7.0Hz, Ar-H), 5.33 (t, 2H, J=6.8Hz, N-CH2 -
CH2- Nap), 3.79 (t, 2H, J=7.2Hz, N-CH2 -(CH2)2-NH2), 3.54 (t, 2H, J=6.8Hz, NCH2-CH2 -Nap),
2.91 (t, 2H, J=7.2Hz, N (CH2)2-CH2 -NH2),2.11–1.93(m,2H,NCH2-CH2 -CH2NH2).13C NMR
(125MHz,DMSO-d6)δ170.3,170.2,142.0,141.9,134.5,133.8,132.0,130.1,129.0×2,
127.7,127.6,127.5,127.1,126.6,126.1,125.7,124.8,124.7,123.8,121.6,121.5,
120.9,120.7,119.2,119.1,117.7,117.1,112.9,110.4,45.9,45.4,37.6,35.2,27.4.ESI-
MS m/z 537.4[M+H]+.
The preparation of compound 122
According to the synthetic method of compound 16, by the ethyl acetate solution of compound 121 (25mg, 0.04mmol) and hydrochloric acid
(3N, 3mL) synthesizes to obtain yellow solid 6- (3- aminopropyl) -12- (1- naphthylethyl) -12,13- dihydro -5H- indoles [2,3-a] pyrrole
Cough up [3,4-c] carbazole -5,7 (6H)-dione hydrochloride (122) 20mg, yield 90%.1H NMR(500MHz,DMSO-d6)δ
12.14 (s, 1H, indole-NH), 9.07 (d, 1H, J=7.8Hz, Ar-H), 9.01 (d, 1H, J=7.8Hz, Ar-H), 7.99
(s,3H,-NH3 +), 7.96 (d, 1H, J=9.0Hz, Ar-H), 7.78 (d, 2H, J=7.9Hz, Ar-H), 7.59 (d, 1H, J=
8.0Hz, Ar-H), 7.56 (d, 1H, J=7.9Hz, Ar-H), 7.46-7.40 (m, 2H, Ar-H), 7.35 (t, 1H, J=7.5Hz,
), Ar-H 7.28 (d, 1H, J=7.2Hz, Ar-H), 7.24 (d, 1H, J=7.9Hz, Ar-H), 7.22 (d, 1H, J=7.2Hz,
), Ar-H 7.11 (t, 1H, J=7.5Hz, Ar-H), 6.98 (d, 1H, J=6.8Hz, Ar-H), 5.34 (t, 2H, J=6.8Hz, N-
CH2 -CH2- Nap), 3.81 (t, 2H, J=7.2Hz, N-CH2 -(CH2)2-NH3 +), 3.52 (t, 2H, J=6.8Hz, NCH2-CH2 -
), Nap 2.93 (t, 2H, J=7.2Hz, N (CH2)2-CH2 -NH3 +),2.05–1.99(m,2H,NCH2-CH2 -CH2NH2).13C NMR
(125MHz,DMSO-d6)δ170.1,170.0,141.8,141.7,134.3,133.6,131.8,130.0,129.3,128.9
×2,127.5,127.4,127.0,126.4,125.9,125.5,124.6,124.5,123.6,121.4,121.3,120.8,
120.6,119.1,119.0,117.6,116.9,112.7,110.3,45.3,37.4,35.1,33.3,27.3.ESI-MS m/z
573.3[M–Cl]+.
The preparation of compound 123
According to the synthetic method of compound 24, by compound 117a (20mg, 0.04mmol), 4- (2- aminoethyl)-morpholine
The synthesis of the triethylamine of (50 μ L, 0.42mmol) and catalytic amount, silica gel column chromatography separation, methylene chloride: methanol=3:1 (v/v) is washed
Take off to obtain yellow solid 6- (2- morpholine ethyl) -12- (1- naphthylethyl) -12,13- dihydro -5H- indoles [2,3-a] pyrroles [3,4-c]
Carbazole -5,7 (6H)-diketone (123) 19mg, yield 76%.1HNMR(500MHz,DMSO-d6)δ11.90(s,1H,indole-
), NH 9.07 (d, 1H, J=8.0Hz, Ar-H), 9.00 (d, 1H, J=7.8Hz, Ar-H), 7.97 (d, 1H, J=7.7Hz, Ar-
), H 7.79 (dd, 1H, J=6.9Hz, 2.4Hz, Ar-H), 7.72 (d, 1H, J=8.1Hz, Ar-H), 7.60 (d, 1H, J=
8.2Hz, Ar-H), 7.57 (t, 1H, J=7.7Hz, Ar-H), 7.47-7.40 (m, 2H, Ar-H), 7.36 (t, 1H, J=7.5Hz,
), Ar-H 7.29 (d, 1H, J=6.9Hz, Ar-H), 7.25 (d, 1H, J=8.6Hz, Ar-H), 7.23 (t, 1H, J=7.3Hz,
), Ar-H 7.14 (t, 1H, J=7.7Hz, Ar-H), 7.02 (d, 1H, J=6.9Hz, Ar-H), 5.28 (t, 2H, J=6.4Hz, N-
CH2 -CH2- Nap), 3.80 (t, 2H, J=5.8Hz, N-CH2 -CH2- morpholine), 3.54 (t, 2H, J=6.4Hz, NCH2-
CH2 - Nap), 3.56 (t, 4H, J=3.9Hz, morpholine-N (CH2-CH 2)2), O 2.63 (t, 2H, J=5.8Hz, imide-
NCH2-CH2 - morpholine), 2.49 (t, 4H, J=3.9Hz, morpholine-N (CH2 -CH2)2O).13C NMR
(125MHz,DMSO-d6)δ169.9,169.8,141.7,134.4,133.6,131.9,129.9,128.9×2,127.5,
127.4,127.0,126.4,126.0,125.6,124.7,124.6,123.7,121.5,121.4,120.8,120.6,119.1
×2,117.6,116.9,112.5,110.2,66.6×2,56.5,53.6×2,45.3,34.9,33.2.ESI-MS m/z
593.3[M+H]+.
The preparation of compound 124
According to the synthetic method of compound 24, by compound 117a (20mg, 0.042mmol), 4- (2- aminoethyl) piperazine
The synthesis of the triethylamine of (45 μ L, 0.42mmol) and catalytic amount, silica gel column chromatography separation, methylene chloride: methanol=10:1 (v/v) is washed
Take off to obtain yellow solid 6- (2- piperazine ethyl) -12- (1- naphthylethyl) -12,13- dihydro -5H- indoles [2,3-a] pyrroles [3,4-c]
Carbazole -5,7 (6H)-diketone (124) 20mg, yield 80%.1H NMR(500MHz,DMSO-d6) δ 9.05 (d, 1H, J=7.9Hz,
), Ar-H 8.97 (d, 1H, J=7.6Hz, Ar-H), 7.94 (d, 1H, J=8.0Hz, Ar-H), 7.84 (d, 1H, J=8.0Hz,
), Ar-H 7.80 (d, 1H, J=7.8Hz, Ar-H), 7.59 (d, 1H, J=8.7Hz, Ar-H), 7.57 (d, 1H, J=7.6Hz,
), Ar-H 7.46-7.39 (m, 2H, Ar-H), 7.35 (dd, 1H, J=11.4Hz, 4.3Hz, Ar-H), 7.23 (dd, 1H, J=
8.1Hz, 1.2Hz, Ar-H), 7.20 (t, 1H, J=7.6Hz, Ar-H), 7.11 (d, 1H, J=8.2Hz, Ar-H), 7.10 (t,
1H, J=8.2Hz, Ar-H), 6.98 (d, 1H, J=6.9Hz, Ar-H), 5.33 (t, 2H, J=6.6Hz, N-CH2 -CH2-Nap),
3.78 (t, 2H, J=6.5Hz, N-CH2 -CH2- piperazine), 3.56 (t, 2H, J=6.6Hz, NCH2-CH2 -Nap),2.97
(t, 4H, J=5.1Hz, piperazine-N (CH 2-CH2)2), NH 2.70 (t, 4H, J=5.1Hz, piperazine-N (CH2-
CH 2)2), NH 2.68 (t, 2H, J=6.5Hz, NCH2-CH2 -piperazine).13C NMR(125MHz,DMSO-d6)δ170.1,
170.0,142.0,141.8,134.6,134.3,133.7,133.3,131.9,131.5,130.0,129.0×2,128.1,
127.6,127.0,126.5,126.0,125.6,124.7,123.8,121.5,120.8,120.6,119.2,119.0,
117.6,116.9,112.9,110.2,55.9×2,50.0,45.4×2,43.5,35.0,33.5.ESI-MS m/z 592.3
[M+H]+.
The preparation of compound 125
According to the synthetic method of compound 24, by the chloro- 6- fluorophenethylamine of compound 117a (20mg, 0.042mmol), 2-
The synthesis of the triethylamine of (30 μ L, 0.42mmol) and catalytic amount, silica gel column chromatography separation, methylene chloride: methanol=25:1 (v/v) is washed
Take off to obtain yellow solid 6- (the chloro- 6- fluorobenzene ethyl of 2-) -12- (1- naphthylethyl) -12,13- dihydro -5H- indoles [2,3-a] pyrroles
[3,4-c] carbazole -5,7 (6H)-diketone (125) 12mg, yield 60%.1HNMR(500MHz,DMSO-d6)δ11.90(s,1H,
), indole-NH 9.02 (d, 1H, J=7.8Hz, Ar-H), 8.95 (d, 2H, J=7.8Hz, Ar-H), 7.95 (d, 1H, J=
8.2Hz, Ar-H), 7.80 (d, 1H, J=7.9Hz, Ar-H), 7.73 (d, 1H, J=8.1Hz, Ar-H), 7.62 (d, 1H, J=
8.1Hz, Ar-H), 7.58 (t, 1H, J=7.5Hz, Ar-H), 7.47 (t, 1H, J=7.2Hz, Ar-H), 7.42 (dd, 1H, J=
8.2Hz, 1.8Hz, Ar-H), 7.36 (t, 1H, J=7.5Hz, Ar-H), 7.31 (d, 1H, J=7.3Hz, Ar-H), 7.29-7.27
(m, 2H, Ar-H), 7.23 (t, 1H, J=7.0Hz, Ar-H), 7.17 (d, 1H, J=7.1Hz, Ar-H), 7.15 (t, 1H, J=
7.0Hz, Ar-H), 7.14 (dd, 1H, J=7.4Hz, 1.2Hz, Ar-H), 7.07 (d, 1H, J=6.9Hz, Ar-H), 5.29 (t,
2H, J=6.8Hz, N-CH2 -CH2- Nap), 3.95 (t, 2H, J=6.7Hz, N-CH2 -CH2-C6H3), FCl 3.54 (t, 2H, J=
6.8Hz,NCH2-CH2 - Nap), 3.21 (t, 2H, J=6.7Hz, NCH2-CH2 -C6H3FCl).13C NMR(125MHz,DMSO-d6)
δ169.9,169.8,162.7(d,1JCF=244Hz), 141.8 (d,3JCF=11Hz), 135.1,134.8,134.5,133.7,
133.4,132.0,130.1,129.9(d,3JCF=11Hz), 128.9,128.8,127.6,127.5,127.1,126.5,
126.1,125.9,125.7,124.9,124.8,123.8,122.8,121.6(d,2JCF=22Hz), 120.9,120.8,
119.1,119.0,117.7,117.0,114.9(d,2JCF=23Hz), 112.6,110.3,90.3,45.4,36.5,33.3,
29.4.ESI-MS m/z636.2[M+H]+.
The preparation of compound 126
According to the synthetic method of compound 24, by compound 117a (20mg, 0.042mmol), 1- (2- amino-ethyl) piperazine
The synthesis of the triethylamine of pyridine (50 μ L, 0.42mmol) and catalytic amount, silica gel column chromatography separation, methylene chloride: methanol=10:1 (v/v)
Elute to obtain yellow solid 6- (2- piperidinoethyl) -12- (1- naphthylethyl) -12,13- dihydro -5H- indoles [2,3-a] pyrroles [3,4-
C] carbazole -5,7 (6H)-diketone (126) 19mg, yield 67%.1H NMR(500MHz,DMSO-d6)δ11.89(s,1H,
), indole-NH 9.05 (d, 1H, J=7.9Hz, Ar-H), 8.97 (d, 1H, J=7.6Hz, Ar-H), 7.95 (d, 1H, J=
8.9Hz, Ar-H), 7.78 (d, 1H, J=7.4Hz, Ar-H), 7.71 (d, 1H, J=8.1Hz, Ar-H), 7.59 (d, 1H, J=
8.2Hz, Ar-H), 7.56 (t, 1H, J=7.6Hz, Ar-H), 7.44-7.40 (m, 2H, Ar-H), 7.34 (t, 1H, J=7.5Hz,
), Ar-H 7.26 (d, 1H, J=7.0Hz, Ar-H), 7.20 (d, 1H, J=8.0Hz, Ar-H), 7.18 (d, 1H, J=7.5Hz,
), Ar-H 7.13 (t, 1H, J=7.5Hz, Ar-H), 7.00 (d, 1H, J=6.8Hz, Ar-H), 5.29 (t, 2H, J=6.8Hz, N-
CH2 -CH2- Nap), 3.73 (t, 2H, J=6.6Hz, N-CH2 -CH2- piperidine), 3.51 (t, 2H, J=6.8Hz, NCH2-
CH2 - Nap), 2.58 (t, 2H, J=6.2Hz, NCH2-CH2 - piperidine), 2.44 (t, 4H, J=3.3Hz,
piperidine-N(CH 2-CH2)2CH2),1.45–1.41(m,4H,piperidine-N(CH2-CH 2)2CH2),1.33(t,2H,J
=4.4Hz, piperidine-N (CH2-CH2)2CH 2).13C NMR(125MHz,DMSO-d6)δ169.9,169.8,141.7,
141.6,135.1,134.4,133.6,131.9,129.9,128.9,128.8,127.5,127.4,127.4,126.9,
126.4,126.0,125.6,125.1,124.7,124.6,123.7,121.4,121.4,120.7,120.6,119.1,
119.0,117.5,116.9,112.5,110.1,56.6×2,54.3,45.2,35.2,33.3,25.9×2,24.3.ESI-MS
m/z 591.3[M+H]+.
The preparation of compound 127
According to the synthetic method of compound 24, by compound 117a (22mg, 0.046mmol), 4- methyl-1-piperazine ethanamine
The synthesis of the triethylamine of (50 μ L, 0.55mmol) and catalytic amount, silica gel column chromatography separation, methylene chloride: methanol=10:1 (v/v) is washed
Take off to obtain yellow solid 6- (2- (4- methyl piperazine) ethyl) -12- (1- naphthylethyl) -12,13- dihydro -5H- indoles [2,3-a] pyrrole
Cough up [3,4-c] carbazole -5,7 (6H)-diketone (127) 22mg, yield 80%.1H NMR(500MHz,DMSO-d6)δ11.95(s,
1H, indole-NH), 9.06 (d, 1H, J=7.0Hz, Ar-H), 8.98 (d, 1H, J=7.2Hz, Ar-H), 7.95 (d, 1H, J=
6.7Hz, Ar-H), 7.78 (d, 1H, J=6.8Hz, Ar-H), 7.73 (d, 1H, J=8.1Hz, Ar-H), 7.62-7.54 (m, 2H,
), Ar-H 7.42 (d, 2H, J=7.8Hz, Ar-H), 7.34 (t, 1H, J=7.8Hz, Ar-H), 7.27 (t, 1H, J=7.3Hz,
), Ar-H 7.20 (d, 2H, J=6.9Hz, Ar-H), 7.11 (d, 1H, J=7.6Hz, Ar-H), 7.01 (d, 1H, J=7.6Hz,
), Ar-H 5.27 (t, 2H, J=6.3Hz, N-CH2 -CH2- Nap), 3.75 (t, 2H, J=6.3Hz, N-CH2 -CH2-
), piperazine 3.51 (t, 2H, J=6.3Hz, NCH2-CH2 - Nap), 2.60 (d, 2H, J=5.8Hz, NCH2-CH2 -
), piperazine 2.48 (t, 4H, J=4.6Hz, piperazine-N (CH 2-CH2)2NCH3), 2.25 (t, 4H, J=4.6Hz,
piperazine-N(CH2-CH 2)2NCH3),2.07(s,3H,piperazine-N(CH2-CH2)2NCH3 ).13C NMR
(125MHz,DMSO-d6)δ169.9,169.8,141.7,141.6,134.4,133.6,131.8,129.9,128.9,127.5,
127.4,126.9,126.4,125.9,125.6,124.7,124.6,123.7,121.4,121.4,120.8,120.6,
119.15,119.0,117.5,116.9,112.6,110.1,56.1,55.1×2,53.0×2,46.1,45.3,35.2,
33.3.ESI-MS m/z 605.4[M+H]+.
The preparation of compound 128
According to the synthetic method of compound 24, by compound 117a (30mg, 0.063mmol), ethanol amine (55 μ L,
It 0.94mmol) is synthesized with the triethylamine of catalytic amount, silica gel column chromatography separation, methylene chloride: methanol=50:1 (v/v) elutes yellow
Color solid 6- (2- ethoxy) -12- (1- naphthylethyl) -12,13- dihydro -5H- indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7
(6H)-diketone (128) 26mg, yield 89%.1H NMR(500MHz,DMSO-d6)δ11.95(s,1H,indole-NH),9.11
(d, 1H, J=7.8Hz, Ar-H), 9.05 (d, 1H, J=7.9Hz, Ar-H), 8.02 (d, 1H, J=7.7Hz, Ar-H), 7.83
(d, 1H, J=8.1Hz, Ar-H), 7.75 (d, 1H, J=8.1Hz, Ar-H), 7.63 (d, 1H, J=8.0Hz, Ar-H), 7.59
(t, 1H, J=7.8Hz, Ar-H), 7.47 (m, 2H, Ar-H), 7.38 (t, 1H, J=7.5Hz, Ar-H), 7.34 (t, 1H, J=
7.8Hz, Ar-H), 7.26-7.24 (m, 2H, Ar-H), 7.15 (t, 1H, J=7.8Hz, Ar-H), 7.00 (d, 1H, J=7.2Hz,
), Ar-H 5.32 (t, 2H, J=7.0Hz, N-CH2 -CH2- Nap), 4.94 (t, 1H, J=6.1Hz, N-CH2 -CH2-OH),4.2
(brs,-OH), 3.80 (t, 2H, J=6.1Hz, NCH2-CH2 - OH), 3.56 (t, 2H, J=7.0Hz, NCH2-CH2 -Nap).13C
NMR(125MHz,DMSO-d6)δ170.3,170.2,141.9,134.5,133.8,132.0,130.1,129.1,129.0,
127.7,127.6,127.5,127.1,126.6,126.1,125.7,124.9,124.8,123.8,121.6,121.6,
120.9,120.8,119.8,119.4,117.7,117.0,112.7,112.4,110.3,58.9,45.4,40.7,
33.4.ESI-MS m/z 524.4[M+H]+.
The preparation of compound 129
According to the synthetic method of compound 24, by compound 117a (25mg, 0.052mmol), 3- hydroxypropylamine (50 μ L,
It 0.52mmol) is synthesized with the triethylamine of catalytic amount, silica gel column chromatography separation, methylene chloride: methanol=50:1 (v/v) elutes yellow
Color solid 6- (3- hydroxypropyl) -12- (1- naphthylethyl) -12,13- dihydro -5H- indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7
(6H)-diketone (129) 24mg, yield 80%.1HNMR(500MHz,DMSO-d6)δ11.91(s,1H,indole-NH),9.10
(d, 1H, J=7.9Hz, Ar-H), 9.04 (d, 1H, J=7.7Hz, Ar-H), 8.01 (d, 1H, J=8.0Hz, Ar-H), 7.82
(dd, 2H, J=7.6Hz, 3.2Hz, Ar-H), 7.74 (d, 1H, J=8.1Hz, Ar-H), 7.62 (d, 1H, J=8.2Hz, Ar-
), H 7.59 (dt, 1H, J=8.2Hz, 1.2Hz, Ar-H), 7.48-7.43 (m, 2H, Ar-H), 7.39 (dt, 1H, J=7.8Hz,
1.1Hz, Ar-H), 7.34 (t, 1H, J=7.8Hz, Ar-H), 7.27 (d, 1H, J=8.1Hz, Ar-H), 7.27 (t, 1H, J=
7.6Hz, Ar-H), 7.14 (t, 1H, J=7.7Hz, Ar-H), 7.03 (d, 1H, J=6.6Hz, Ar-H), 5.30 (t, 2H, J=
6.9Hz,N-CH2 -CH2-Nap),4.57(brs,-OH), 3.77 (t, 2H, J=7.2Hz, N-CH2 -CH2CH2OH),3.54(t,
2H, J=6.9Hz, NCH2-CH2 - Nap), 3.53 (t, 2H, J=6.2Hz, N (CH2)2-CH2 -OH),1.90–1.84(m,2H,
NCH2-CH2 -CH2OH).13CNMR(125MHz,DMSO-d6)δ170.2,170.1,141.8,134.5,133.8,132.0,
130.1,129.1,129.0,127.7,127.6,127.1,126.6,126.1,125.7,124.9,124.8,123.8,
121.7,121.6,120.9,120.8,119.3,119.3,117.7,117.0,112.7,112.4,110.3,59.3,45.4,
35.5,33.3,32.3.ESI-MS m/z 538.5[M+H]+.
The preparation of compound 130
Under argon gas protection, in two mouthfuls of reaction flasks of 25mL, it is added staurosporine (46.6mg, 0.1mmol), with 3mL dichloro
Methane dissolution, is added dropwise excessive triethylamine, is then added to fluorophenylsulfonyl chloride, and reaction 4h is stirred at room temperature, and adds water to terminate and reacts, and two
Chloromethanes extraction, and use anhydrous Na2SO4It is dry, evaporated in vacuo, after by gel column chromatography separation, methanol elute to obtain 3 '-N- pairs
Fluorobenzene sulphonyl staurosporine (130) 52.0mg, yield 83.3%.1H NMR(600MHz,CDCl3) δ 9.40 (d, 1H, J=
7.4Hz, Ar-H), 7.92 (m, 2H, Ar-H), 7.85 (d, 1H, J=7.3Hz, Ar-H), 7.72 (d, 1H, J=7.8Hz, Ar-
), H 7.47 (t, 1H, J=7.3Hz, Ar-H), 7.46 (t, 1H, J=7.3Hz, Ar-H), 7.43 (d, 2H, J=7.3Hz, Ar-
), H 7.32 (m, 2H, J=7.3Hz, Ar-H), 7.06 (d, 1H, J=7.8Hz, Ar-H), 6.84 (brs, 1H ,-NH), 6.56 (m,
1H, H-1'), 4.95 (d, 1H, J=16.0Hz, H-7a), 4.89 (d, 1H, J=16.0Hz, H-7b), 4.53 (dd, 1H, J=
12.4Hz,5.5Hz,H-3'),3.94(s,1H,H-4'),2.71(s,3H,4'-OCH3),2.47(s,3H,3'-NCH3),2.43
(m,1H,H-1'a),2.37(s,3H,H-6'),2.27(m,1H,H-2'b);13C NMR(150MHz,CDCl3)δ173.5,
164.6(d,1JC-F=247.2Hz), 138.4,136.5,136.5,132.5,130.5,129.7 × 2 (d,3JC-F=9.2Hz),
126.9,126.3,125.5,125.3,124.8,123.6,121.7,120.8,120.2,119.2,116.8×2(d,2JC-F=
13.7Hz),116.3,114.6,112.2,107.6,94.7,86.5,82.4,60.3,52.1,46.0,30.8,29.1,
28.3.ESI-MS m/z 625.3[M+H]+。
The preparation of compound 131
According to the synthetic method of compound 130, by staurosporine (46.6mg, 0.1mmol), triethylamine and to chlorobenzenesulfonyl
Chlorine synthesis.By gel column chromatography separation, methanol elute 3 '-N- to chlorobenzenesulfonyl staurosporine (131) 51.3mg, yield
80.1%.1H NMR(600MHz,CDCl3) δ 9.41 (d, 1H, J=7.7Hz, Ar-H), 7.86 (d, 1H, J=7.8Hz, Ar-H),
7.84 (d, 2H, J=8.2Hz, Ar-H), 7.72 (d, 1H, J=8.7Hz, Ar-H), 7.61 (d, 2H, J=8.2Hz, Ar-H),
7.48 (t, 1H, J=8.3Hz, Ar-H), 7.44 (t, 1H, J=6.8Hz, Ar-H), 7.36 (t, 1H, J=7.8Hz, Ar-H),
7.34 (t, 1H, J=7.8Hz, Ar-H), 7.09 (d, 1H, J=8.2, Ar-H), 6.61 (br s, 1H ,-NH), 6.58 (dd, 1H,
J=9.2Hz, 4.1Hz, H-1'), 4.93 (m, 2H, H-7), 4.52 (ddd, 1H, J=12.8Hz, 5.5Hz, 1.9Hz, H-3'),
3.96(s,1H,H-4'),2.72(s,3H,4'-OCH3),2.48(s,1H,3'-NCH3),2.44(m,1H,H-2'a),2.41(s,
3H,H-6'),2.26(m,1H,H-2'a).13C NMR(150MHz,CDCl3)δ173.3,139.8,138.5,137.7,136.5,
132.5,130.5,129.9×2,128.5×2,126.9,126.3,125.6,125.3,124.8,123.7,121.7,
120.8,120.3,119.3,116.4,114.7,112.2,107.6,94.7,86.6,82.4,60.4,52.2,45.9,30.8,
29.2,28.3.ESI-MS m/z 641.4/643.4[M+H]+。
The preparation of compound 132
According to the synthetic method of compound 130, by staurosporine (46.6mg, 0.1mmol), triethylamine and brosyl
Chlorine synthesis.3 '-N- brosyl staurosporine (132) 52.6mg, yield are eluted to obtain by gel column chromatography separation, methanol
76.8%.1H NMR(600MHz,CDCl3) δ 9.40 (d, 1H, J=7.1Hz, Ar-H), 7.99 (d, 1H, J=6.9Hz, Ar-H),
7.83 (d, 1H, J=7.7Hz, Ar-H), 7.72 (d, 1H, J=8.3Hz, Ar-H), 7.61 (d, 2H, J=6.9Hz, Ar-H),
7.47 (t, 1H, J=7.7Hz, Ar-H), 7.42 (t, 1H, J=7.2Hz, Ar-H), 7.34 (t, 2H, J=7.1Hz, Ar-H),
7.04 (d, 2H, J=7.7, Ar-H), 6.51 (br s, 1H ,-NH), 4.99 (d, 1H, J=18.0Hz, H-7a), 4.92 (d, 1H,
J=16.4Hz, H-7b), 4.50 (dd, 1H, J=5.5Hz, 12.7Hz, H-3'), 3.91 (s, 1H, H-4'), 2.69 (s, 3H,
4'-OCH3),2.47(s,1H,3'-NCH3), 2.45 (t, 1H, J=12.6Hz, H-2'a), 2.35 (s, 3H, H-6'), 2.45 (t,
1H, J=12.4Hz, H-2'a);13C NMR(150MHz,CDCl3)δ173.4,138.4,132.9×2,138.3,136.4,
132.5,130.5,128.6×2,128.2,126.8,126.3,125.5,125.3,124.7,123.6,121.7,120.7,
120.3,119.0,116.2,114.6,112.2,107.7,94.6,86.6,82.4,60.3,52.2,46.1,30.8,29.1,
28.3.ESI-MS m/z 685.3/687.3[M+H]+。
The preparation of compound 133
According to the synthetic method of compound 130, closed by staurosporine (46.6mg, 0.1mmol), triethylamine and benzene sulfonyl chloride
At.3 '-N- benzene sulfonyl staurosporine (133) 50.4mg, yield 83.2% are eluted to obtain by gel column chromatography separation, methanol.1H
NMR(600MHz,CDCl3) δ 9.40 (d, 1H, J=7.8Hz, Ar-H), 7.91 (d, 2H, J=7.4Hz, Ar-H), 7.87 (d,
1H, J=7.3Hz, Ar-H), 7.70 (d, 1H, J=7.8Hz, Ar-H), 7.64 (t, 2H, J=7.8Hz, Ar-H), 7.46 (t,
1H, J=7.8Hz, Ar-H), 7.42 (t, 1H, J=7.8Hz, Ar-H), 7.34 (t, 1H, J=7.3Hz, Ar-H), 7.32 (t,
1H, J=7.3Hz, Ar-H), 7.07 (d, 1H, J=8.2Hz, Ar-H), 6.71 (brs, 1H ,-NH), 6.69 (dd, 1H, J=
9.2Hz, 4.6Hz, H-1'), 4.94 (m, 2H, H-7), 4.54 (dd, 2H, J=12.8Hz, 5.5Hz, H-3'), 3.91 (s, 1H,
H-4'),2.73(s,3H,4'-OCH3),2.45(s,3H,3'-NCH3),2.43(br m,1H,H-2'a),2.39(s,3H,H-
6'),2.25(br m,1H,H-2'b).13C NMR(150MHz,CDCl3)δ173.3,139.1,138.4,136.4,133.3,
132.4,130.4,129.5×2,127.0×2,126.8,126.2,125.4,125.1,124.7,123.6,121.5,
120.6,120.2,119.1,116.2,114.5,112.1,107.5,94.6,86.2,82.4,60.3,51.9,45.9,30.7,
29.1,28.1.ESI-MS m/z 607.3[M+H]+。
The preparation of compound 134
Argon gas protection under, in two mouthfuls of reaction flasks of 25mL, be added 3'-N- to fluorobenzoyl staurosporine (15.0mg,
0.025mmol), it is dissolved with 1mL methanol, bromo-succinimide (5.0mg, 0.027mmol) then is added, reaction is stirred at room temperature
2h adds water to terminate reaction, methylene chloride extraction, and uses anhydrous Na2SO4It is dry, evaporated in vacuo, after by gel column chromatography separation,
Methanol elute the bromo- 3 '-N- of 3- to fluorobenzoyl staurosporine (134) 8.4mg, yield 49.0%.1H NMR(600MHz,
CDCl3) δ 9.51 (s, 1H, Ar-H), 7.86 (d, 1H, J=7.8Hz, Ar-H), 7.75 (d, 1H, J=7.3Hz, Ar-H), 7.46
(t, 2H, J=7.8Hz, Ar-H), 7.43 (m, 2H, J=7.3Hz, Ar-H), 7.36 (t, 1H, J=7.8Hz, Ar-H), 7.34
(d, 1H, J=7.8Hz, Ar-H), 7.09 (d, 2H, J=7.3Hz, Ar-H), 7.02 (br s, 1H ,-NH), 6.66 (br s, 1H,
), H-1' 5.18 (d, 1H, J=7.8Hz, H-3'), 4.93 (br s, 2H, H-7), 4.17 (s, 1H, H-4'), 2.82 (s, 3H,
4'-OCH3), 2.71 (dt, 1H, J=12.5Hz, 3.2Hz, H-2'a), 2.56 (s, 3H, 3'-NCH3), 2.44 (dt, 1H, J=
12.5Hz,3.2Hz,H-2'b),2.36(s,3H,H-6').13C NMR(150MHz,CDCl3)δ171.6,171.4,163.5(d
,1JC-F=247.2Hz), 138.5 × 2,132.9,132.1,131.5,130.4,129.4 × 2 (d,3JC-F=6.9Hz),
129.0,128.1,126.8,125.4,125.1,124.6,121.8,120.8,119.2,115.7×2(d,2JC-F=
13.7Hz),115.5,115.0,112.3,109.1,94.7,84.7,82.6,60.5,49.8,46.2,34.6,29.2,
28.1.ESI-MS m/z 667.3/669.3[M+H]+。
The preparation of compound 135
I) preparation of compound 135a
In two mouthfuls of reaction flasks of the 25mL for being filled with oxygen, it is added staurosporine (6.6mg, 0.1mmol), it is molten with 3mL DMSO
Excessive potassium tert-butoxide is added in solution, reacts at room temperature 6h, and water is added to terminate reaction, and ethyl acetate extracts three times, evaporated in vacuo, by
Cross gel column chromatography separation, methanol elutes to obtain 7- oxygen subunit staurosporine (135a) 42.5mg, yield 88.6%.1H NMR
(600MHz,DMSO-d6) δ 11.04 (s, 1H ,-NH), 9.21 (d, 1H, J=8.8Hz, Ar-H), 9.08 (d, 1H, J=7.7Hz,
), Ar-H 8.03 (d, 1H, J=8.8Hz, Ar-H), 7.71 (t, 1H, J=8.8Hz, Ar-H), 7.60 (t, 1H, J=7.7Hz,
), Ar-H 7.51 (t, 1H, J=7.7Hz, Ar-H), 7.41 (t, 1H, J=7.7Hz, Ar-H), 7.33 (d, 1H, J=7.7Hz,
Ar-H),6.77(br s,1H,H-1'),4.14(m,1H,H-3'),3.38(s,1H,H-4'),3.36(s,3H,4'-OCH3),
2.55(m,2H,H-2'),2.34(s,1H,3'-NCH3),1.22(s,3H,H-6').13C NMR(150MHz,DMSO-d6)δ
171.4,171.2,142.1,139.2,132.3,131.7,127.5,126.5,126.4,125.6,124.4,122.8,
121.2,121.1,120.6,120.2,117.2,116.4,115.8,109.2,92.1,84.5,81.3,57.4,51.5,
33.6,30.4,30.1.ESI-MS m/z481.1[M+H]+。
Ii) the preparation of compound 135
According to the synthetic method of compound 130, by 135a (10.0mg, 0.021mmol), triethylamine and to fluorobenzoyl chloride
Synthesis.By gel column chromatography separation, methanol elute 7- -3 '-N- of oxygen subunit to fluorobenzoyl staurosporine (135)
10.8mg, yield 86.1%.1H NMR(600MHz,CDCl3) δ 9.33 (d, 1H, J=7.7Hz, Ar-H), 9.17 (d, 1H, J=
7.8Hz, Ar-H), 7.73 (d, 1H, J=7.7Hz, Ar-H), 7.68 (t, 1H, J=7.4Hz, Ar-H), 7.56 (t, 1H, J=
7.8Hz, Ar-H), 7.51 (t, 1H, J=7.8Hz, Ar-H), 7.42 (t, 1H, J=7.8Hz, Ar-H), 7.41 (d, 2H, J=
7.7Hz, Ar-H), 7.41 (t, 1H, J=7.8Hz, Ar-H), 7.11 (d, 2H, J=7.4Hz, Ar-H), 6.72 (br s, 1H, H-
1'), 5.20 (d, 1H, J=5.8Hz, H-3'), 4.16 (s, 1H, H-4'), 2.86 (s, 3H, 4'-OCH3),2.80(m,1H,H-
2'a),2.53(s,3H,3'-NCH3),2.38(m,1H,H-2'b),2.35(s,3H,H-6').13C NMR(150MHz,CDCl3)
δ169.8,169.6,163.8(d,1JC-F=270.0Hz), 139.3,139.2,137.8,133.2 × 2,130.3,129.6 × 2
(d,3JC-F=6.9Hz), 127.0 × 2 (d,2JC-F=13.7Hz), 126.5,126.3,123.8,122.5,121.4,121.3,
121.0,119.4,117.4,116.3,114.7,111.3,108.2,94.7,86.0,82.5,60.1,51.9,30.7,28.9,
28.3.ESI-MS m/z 603.2[M+H]+。
The preparation of compound 136
According to the synthetic method of compound 130, by 135a (10.0mg, 0.021mmol), triethylamine and parachlorobenzoyl chloride
Synthesis.By gel column chromatography separation, methanol elute 7- -3 '-N- of oxygen subunit to chlorobenzoyl staurosporine (136)
10.6mg, yield 82.3%.1H NMR(600MHz,CDCl3) δ 9.38 (d, 1H, J=7.7Hz, Ar-H), 9.24 (d, 1H, J=
7.8Hz, Ar-H), 7.94 (t, 1H, J=7.4Hz, Ar-H), 7.76 (t, 1H, J=7.8Hz, Ar-H), 7.61 (t, 1H, J=
7.8Hz, Ar-H), 7.54 (d, 2H, J=7.7Hz, Ar-H), 7.52 (d, 2H, J=7.7Hz, Ar-H), 7.51 (br s, 1H ,-
), NH 7.41 (t, 1H, J=7.8Hz, Ar-H), 7.40 (d, 1H, J=7.8Hz, Ar-H), 7.11 (d, 1H, J=7.4Hz, Ar-
), H 6.80 (br s, 1H, H-1'), 5.26 (dd, 1H, J=5.4Hz, 12.3Hz, H-3'), 4.22 (s, 1H, H-4'), 2.88
(s,3H,4'-OCH3), 2.83 (dt, 1H, J=3.2Hz, 10.8Hz, H-2'a), 2.74 (dt, 1H, J=3.2Hz, 10.8Hz,
H-2'b),2.58(s,3H,3'-NCH3),2.44(s,3H,H-6').13C NMR(150MHz,CDCl3)δ171.4,169.9,
169.7,139.5,137.9,136.3,131.6,130.2,129.0,128.6,129.6×2,127.1×2,126.5,
126.4,123.8,122.6,121.4,121.3,121.0,119.5,117.4,116.4,111.7,111.6,108.3,94.8,
84.7,82.5,60.5,49.7,30.4,29.0,28.1.ESI-MS m/z619.5/621.5[M+H]+。
The preparation of compound 137
According to the synthetic method of compound 130, by 135a (10.0mg, 0.021mmol), triethylamine and parabromobenzoyl chloride
Synthesis.By gel column chromatography separation, methanol elute 7- -3 '-N- of oxygen subunit to Bromophenacyl staurosporine (137)
11.1mg, yield 80.3%.1H NMR(500MHz,CDCl3) δ 9.34 (d, 1H, J=7.7Hz, Ar-H), 9.19 (d, 1H, J=
7.8Hz, Ar-H), 7.74 (t, 1H, J=7.4Hz, Ar-H), 7.71 (t, 1H, J=7.8Hz, Ar-H), 7.56 (t, 1H, J=
7.8Hz, Ar-H), 7.54 (d, 2H, J=7.7Hz, Ar-H), 7.52 (d, 2H, J=7.7Hz, Ar-H), 7.51 (br s, 1H ,-
), NH 7.41 (t, 1H, J=7.8Hz, Ar-H), 7.40 (d, 1H, J=7.8Hz, Ar-H), 7.29 (d, 1H, J=7.4Hz, Ar-
), H 6.71 (br s, 1H, H-1'), 5.21 (dd, 1H, J=5.5Hz, 12.4Hz, H-3'), 4.15 (s, 1H, H-4'), 2.84
(s,3H,4'-OCH3), 2.80 (dt, 1H, J=3.2Hz, 10.8Hz, H-2'a), 2.67 (dt, 1H, J=3.2Hz, 10.8Hz,
H-2'b),2.53(s,3H,3'-NCH3),2.35(s,3H,H-6').13C NMR(150MHz,CDCl3)δ171.4,170.0,
169.7,139.4,137.8,134.8,131.5,130.1,129.0,128.6,128.7×2,127.1×2,126.5,
126.3,126.2,123.8,122.5,121.4,121.3,121.1,119.5,117.4,116.3,111.6,108.3,94.7,
84.7,82.5,60.4,49.7,34.4,28.9,28.1.ESI-MS m/z663.5/665.5[M+H]+。
The preparation of compound 138
According to the synthetic method of compound 130, by 135a (10.0mg, 0.021mmol), triethylamine and to iodobenzoyl chloride
Synthesis.By gel column chromatography separation, methanol elute 7- -3 '-N- of oxygen subunit to iodobenzene formyl staurosporine (138)
11.6mg, yield 78.5%.1H NMR(600MHz,CDCl3) δ 9.38 (d, 1H, J=7.7Hz, Ar-H), 9.24 (d, 1H, J=
7.8Hz, Ar-H), 7.94 (t, 1H, J=7.4Hz, Ar-H), 7.76 (t, 1H, J=7.8Hz, Ar-H), 7.61 (t, 1H, J=
7.8Hz, Ar-H), 7.54 (d, 2H, J=7.7Hz, Ar-H), 7.52 (t, 2H, J=7.7Hz, Ar-H), 7.51 (br s, 1H ,-
), NH 7.41 (t, 1H, J=7.8H, Ar-H), 7.40 (d, 1H, J=7.8Hz, Ar-H), 7.11 (d, 1H, J=7.4Hz, Ar-
), H 6.80 (dd, 1H, J=3.7Hz, 9.2Hz, H-1'), 5.26 (dd, 1H, J=5.5Hz, 12.4Hz, H-3'), 4.22 (s,
1H,H-4'),2.88(s,3H,4'-OCH3), 2.83 (dt, 1H, J=3.2Hz, 10.8Hz, H-2'a), 2.74 (dt, 1H, J=
3.2Hz,10.8Hz,H-2'b),2.58(s,3H,3'-NCH3),2.44(s,3H,H-6').13C NMR(150MHz,CDCl3)δ
171.4,170.0,169.8,139.5,137.9,136.3,131.9,130.2,129.0,128.6,129.6×2,127.1×
2,126.5,126.4,123.8,122.6,121.4,121.3,121.0,120.9,119.5,117.4,116.4,111.7,
108.3,94.8,84.7,82.5,60.5,49.7,30.4,29.0,28.1.ESI-MS m/z 711.5[M+H]+.
The preparation of compound 139
Argon gas protection under, in two mouthfuls of reaction flasks of 25mL, be added 3'-N- to fluorobenzoyl staurosporine (20.0mg,
0.034mmol), it is dissolved with 1mL DMSO, the 2N NaOH solution of 0.03mL is then added, reaction 4h is stirred at room temperature, water is added to terminate
Reaction, ethyl acetate extraction, and use anhydrous Na2SO4It is dry, evaporated in vacuo, after by gel column chromatography separation, methanol elute 7
Alpha-hydroxy -3 '-N- is to fluorobenzoyl staurosporine (139) 7.6mg, yield 37.0%.1H NMR(600MHz,CDCl3)δ9.00
(d, 1H, J=7.7Hz, Ar-H), 8.64 (d, 1H, J=7.7Hz ,-NH), 7.50 (t, 1H, J=8.2Hz, Ar-H), 7.49 (t,
2H, J=8.2Hz, Ar-H), 7.44 (t, 2H, J=7.3Hz, Ar-H), 7.37 (t, 1H, J=7.7Hz, Ar-H), 7.36 (t,
1H, J=7.7Hz, Ar-H), 7.25 (d, 1H, J=7.7Hz, Ar-H), 7.19 (t, 1H, J=7.7Hz, Ar-H), 7.11 (t,
2H, J=7.7Hz, Ar-H), 7.10 (s, 1H, H-7), 6.71 (br s, 1H ,-OH), 6.47 (br s, 1H, H-1'), 5.19 (d,
1H, J=8.2Hz, H-3'), 3.84 (s, 1H, H-4'), 2.70 (s, 3H, 4'-OCH3),2.35(m,1H,H-2'a),2.24(m,
1H,H-2'b),2.19(s,3H,3'-NCH3),2.04(s,3H,H-6').13C NMR(150MHz,CDCl3)δ173.3,
171.5,163.6(d,1JC-F=247.2Hz), 136.5 × 2,132.5,132.2,130.6,129.5 × 2 (d,3JC-F=
6.9Hz),126.7,126.4,125.5,125.2,124.9,123.8,121.6,120.6,120.3,119.2,116.3,
115.8×2(d,2JC-F=13.7Hz), 114.6,112.4,107.6,94.7,84.8,82.5,79.4,60.5,49.8,
34.5,29.2,28.2.ESI-MS m/z 605.3[M+H]+.
The preparation of compound 140 and 141
According to the synthetic method of compound 139, by 3'-N- to chlorobenzoyl staurosporine (20.0mg, 0.034mmol),
DMSO and NaOH solution synthesis.By gel column chromatography separation, methanol elute 7-3 '-N- of Alpha-hydroxy to chlorobenzoyl cross spore
Alkali (140) 7.2mg (yield 35.1%) and 7-3 '-N- of beta-hydroxy is to chlorobenzoyl staurosporine (141) 5.4mg (yield
26.3%).
Compound 140:1H NMR(600MHz,DMSO-d6) δ 9.25 (d, 1H, J=7.8Hz, Ar-H), 8.87 (s, 1H ,-
), NH 8.46 (d, 1H, J=7.7Hz, Ar-H), 7.99 (d, 1H, J=7.8Hz, Ar-H), 7.68 (d, 2H, J=7.8Hz, Ar-
), H 7.52 (d, 2H, J=7.3Hz, Ar-H), 7.50 (t, 1H, J=8.0Hz, Ar-H), 7.49 (t, 2H, J=7.3Hz, Ar-
), H 7.34 (t, 1H, J=7.8Hz, Ar-H), 7.31 (t, 1H, J=7.8Hz, Ar-H), 7.19 (s, 1H ,-OH), 6.54 (d,
1H, J=10.0Hz, H-7), 6.44 (d, 1H, J=8.0Hz, H-1'), 5.19 (d, 1H, J=9.2Hz, H-3'), 4.50 (s,
1H,H-4'),2.84(s,3H,4'-OCH3),2.73(m,1H,H-2'a),2.67(m,1H,H-2'b),2.54(s,3H,3'-
NCH3),2.48(s,3H,H-6').13C NMR(150MHz,DMSO-d6)δ171.0,171.1,137.4,136.6,134.8,
133.8,132.5,130.6,129.1×2,128.6×2,126.9,126.5,125.6,125.2,124.8,123.7,
121.6,120.7,120.3,119.3,116.4,114.7,112.5,109.6,95.1,84.7,82.7,79.1,60.6,
49.8,34.5,29.9,27.0.ESI-MS m/z605.3/607.3[M+H]+。
Compound 141:1H NMR(600MHz,CDCl3) δ 9.25 (d, 1H, J=7.8Hz, Ar-H), 8.46 (d, 1H, J=
7.7Hz ,-NH), 7.72 (d, 1H, J=7.8Hz, Ar-H), 7.49 (t, 1H, J=7.8Hz, Ar-H), 7.46 (t, 2H, J=
7.8Hz, Ar-H), 7.40 (d, 2H, J=7.3Hz, Ar-H), 7.38 (d, 2H, J=7.3Hz, Ar-H), 7.35 (t, 2H, J=
7.8Hz, Ar-H), 7.22 (d, 1H, J=7.8Hz, Ar-H), 6.68 (s, 1H, H-7), 6.66 (s, 1H ,-OH), 6.41 (d, 1H,
J=8.0Hz, H-1'), 5.19 (d, 1H, J=9.2Hz, H-3'), 4.21 (s, 1H, H-4'), 2.81 (s, 3H, 4'-OCH3),
2.71(m,1H,H-2'a),2.61(m,1H,H-2'b),2.51(s,3H,3'-NCH3),1.66(s,3H,H-6').13C NMR
(150MHz,CDCl3)δ171.3,171.2,136.9,136.4,133.4,132.5,130.9,130.6,129.0×2,128.6
×2,126.9,126.5,125.6,125.2,124.8,123.7,121.6,120.7,120.3,119.3,115.9,115.6,
112.5,107.8,94.7,84.7,82.4,79.4,60.7,49.8,34.5,29.3,28.1.ESI-MS m/z 605.3/
607.3[M+H]+。
The preparation of compound 142 and 143
According to the synthetic method of compound 139, by 3'-N- to trifluoromethylbenzoyl staurosporine (20.0mg,
0.031mmol), DMSO and NaOH solution synthesis.By gel column chromatography separation, methanol elute 7-3 '-N- of Alpha-hydroxy to three
Methyl fluoride benzoyl staurosporine (142) 7.5mg (yield 36.6%) and 7-3 '-N- of beta-hydroxy are to trifluoromethylbenzoyl cross
Spore alkali (143) 5.4mg (yield 26.3%).
Compound 142:1H NMR(600MHz,CDCl3) δ 8.93 (d, 1H, J=7.4Hz, Ar-H), 8.62 (d, 1H, J=
7.4Hz ,-NH), 7.69 (m, 3H, Ar-H), 7.60 (d, 1H, J=7.9Hz, Ar-H), 7.51 (m, 2H, Ar-H), 7.43 (t,
2H, J=7.8Hz, Ar-H), 7.37 (t, 2H, J=7.8Hz, Ar-H), 7.16 (d, 1H, J=7.8Hz, Ar-H), 6.89 (s,
1H,H-7),6.87(m,1H,H-1'),6.49(br s,1H,-OH),5.19(m,1H,H-3'),3.90(s,1H,H-4'),
2.70(s,3H,4'-OCH3),2.54(m,1H,H-2'a),2.35(m,1H,H-2'b),2.09(s,3H,3'-NCH3),2.06
(s,3H,H-6').13C NMR(150MHz,CDCl3)δ170.2,170.1,141.1,139.7,138.3,134.8×2,
132.8,130.1,128.8×2(q,2JC-F=27.0Hz), 127.9,127.1,127.3,126.7,125.8,125.3 (q,3JC-F=8.0Hz), 125.1,124.6,122.7 (q,1JC-F=270.0Hz), 121.8,120.1 (q,3JC-F=7.1Hz),
119.6,115.0,114.7,113.2,109.0,94.5,83.0,82.0,78.2,60.3,48.8,33.7,29.3,
28.2.ESI-MS m/z 655.2[M+H]+。
Compound 143:1H NMR(600MHz,DMSO-d6) δ 9.28 (d, 1H, J=7.4Hz, Ar-H), 8.88 (s, 1H ,-
), NH 8.51 (d, 1H, J=6.6Hz, Ar-H), 7.99 (d, 1H, J=7.7Hz, Ar-H), 7.83 (d, 1H, J=7.1Hz, Ar-
), H 7.70 (d, 1H, J=7.3Hz, Ar-H), 7.66 (d, 1H, J=7.3Hz, Ar-H), 7.49 (m, 3H, Ar-H), 7.34 (t,
1H, J=8.3Hz, Ar-H), 7.30 (m, 2H, Ar-H), 7.09 (d, 1H, J=9.0Hz, H-7), 6.46 (br s, 1H ,-OH),
6.45 (m, 1H, H-1'), 5.09 (d, 1H, J=10.0Hz, H-3'), 4.53 (s, 1H, H-4'), 2.90 (s, 3H, 4'-OCH3),
2.78(m,1H,H-2'a),2.73(s,3H,3'-NCH3),2.57(m,1H,H-2'b),2.39(s,3H,H-6').13C NMR
(150MHz,DMSO-d6)δ170.9,170.8,139.8,137.1,138.3,134.8×2,132.8,130.1,128.7×2
(q,2JC-F=27.0Hz), 127.9,127.1,127.3,126.7,125.8,125.0 (q,3JC-F=8.0Hz), 125.1,
124.6,122.6(1JC-F=270.0Hz), 121.8,120.1 (q,3JC-F=7.1Hz), 119.6,115.0,114.7,113.2,
109.0,94.5,83.0,82.0,78.3,60.3,48.9,33.8,29.2,28.1.ESI-MS m/z 655.2[M+H]+。
The preparation of compound 144 and 145
According to the synthetic method of compound 139, synthesized by 130 (25.0mg, 0.040mmol), DMSO and NaOH solution.Through
Cross gel column chromatography separation, methanol elute 7-3 '-N- of Alpha-hydroxy to fluorobenzene sulphonyl staurosporine (144) 8.4mg (yield
32.8%) and 7-3 '-N- of beta-hydroxy are to fluorobenzene sulphonyl staurosporine (145) 6.0mg (yield 23.4%).
Compound 144:1H NMR(600MHz,DMSO-d6) δ 9.22 (d, 1H, J=7.9Hz, Ar-H), 8.86 (s, 1H ,-
), NH 8.45 (d, 1H, J=8.6Hz, Ar-H), 9.07 (m, 2H, Ar-H), 7.99 (d, 1H, J=8.4Hz, Ar-H), 7.56 (m,
2H, Ar-H), 7.50 (m, 3H, Ar-H), 7.34 (t, 1H, J=7.3Hz, Ar-H), 7.30 (d, 1H, J=7.7Hz, H-7),
6.95 (m, 1H, H-1'), 6.44 (br s, 1H ,-OH), 4.53 (d, 1H, J=13.4Hz, H-3'), 4.18 (s, 1H, H-4'),
2.63(s,3H,4'-OCH3),2.59(s,3H,3'-NCH3),2.57(m,1H,H-2'a),2.43(m,1H,H-2'b),2.40
(s,3H,H-6').13C NMR(150MHz,DMSO-d6)δ170.3,163.5(d,1JC-F=85.7Hz), 138.8,136.5,
134.9,130.2×2(d,3JC-F=9.9Hz), 129.6,126.0,125.6,125.6,125.4,123.5,123.4,
123.4,122.6,120.3,119.7,118.8,117.0×2(d,2JC-F=19.1Hz), 115.1,114.8,113.0,
109.1,94.8,85.1,82.1,60.3,51.8,40.1,30.60,29.0,26.9.ESI-MS m/z 641.2[M+H]+。
Compound 145:1H NMR(600MHz,CDCl3) δ 9.19 (d, 1H, J=8.2Hz, Ar-H), 8.37 (d, 1H, J=
7.9Hz ,-NH), 7.87 (m, 2H, Ar-H), 7.65 (d, 1H, J=8.3Hz, Ar-H), 7.44 (ddd, 1H, J=1.3,7.3,
8.0Hz, Ar-H), 7.36 (ddd, 1H, J=1.5,6.9,8.1Hz, Ar-H), 7.31 (d, 1H, J=7.3Hz, Ar-H), 7.29
(dt, 2H, J=2.8,8.2Hz, Ar-H), 7.26 (m, 1H, Ar-H), 7.24 (t, 1H, J=7.4Hz, Ar-H), 6.99 (d, 1H,
J=8.1Hz, Ar-H), 6.82 (s, 1H, H-7), 6.48 (dd, 1H, J=4.5,8.9Hz, H-1'), 6.27 (s, 1H ,-OH),
4.49 (ddd, 1H, J=2.1,5.5,13.0Hz, H-3'), 3.87 (s, 1H, H-4), 2.57 (s, 3H, 4'-OCH3),2.44(s,
3H,3'-NCH3), 2.34 (dt, 1H, J=4.6,13.3Hz, H-2'a), 2.27 (s, 3H, H-6'), 2.22 (m, 1H, H-2'b)
.13C NMR(150MHz,CDCl3)δ171.3,165.4(d,1JC-F=254.9Hz), 138.8,136.8,135.3,133.5,
130.7,129.7×2(d,3JC-F=9.2Hz), 127.2,126.6,125.8,125.7,124.1,123.9,123.2,
120.9,120.4,118.1,115.9×2(d,2JC-F=22.8Hz), 115.8,115.5,112.0,107.7,94.7,86.6,
82.3,79.3,60.4,52.1,33.7,29.3,28.2.ESI-MS m/z641.2[M+H]+。
The preparation of compound 146 and 147
According to the synthetic method of compound 139, synthesized by 131 (25.0mg, 0.039mmol), DMSO and NaOH solution.Through
Cross gel column chromatography separation, methanol elute 7-3 '-N- of Alpha-hydroxy to chlorobenzenesulfonyl staurosporine (146) 8.2mg (yield
32.0%) and 7-3 '-N- of beta-hydroxy are to chlorobenzenesulfonyl staurosporine (147) 5.9mg (yield 23.0%).
Compound 146:1H NMR(600MHz,CDCl3) δ 8.63 (d, 2H, J=7.7Hz, Ar-H), 8.23 (s, 1H ,-
), NH 7.84 (m, 2H, Ar-H), 7.61 (m, 2H, Ar-H), 7.49 (d, 1H, J=8.4Hz, Ar-H), 7.43 (t, 1H, J=
7.3, Ar-H), 7.36 (t, 1H, J=7.7Hz, Ar-H), 6.87 (t, 1H, J=7.7Hz, Ar-H), 6.80 (d, 1H, J=
7.7Hz, Ar-H), 6.79 (dd, 1H, J=3.7,11.7Hz, Ar-H), 6.54 (d, 1H, J=7.7Hz, H-7), 6.53 (m, 1H,
), H-1' 5.43 (br s, 1H ,-OH), 4.53 (dd, 1H, J=6.3,12.4Hz, H-3'), 3.60 (s, 1H, H-4'), 2.58
(s,3H,4'-OCH3),2.47(s,3H,3'-NCH3), 2.34 (m, 1H, H-2'a), 2.22 (dt, 1H, J=4.2,12.3Hz, H-
2'b),1.92(s,3H,H-6').13C NMR(150MHz,CDCl3)δ173.3,139.7,138.3,138.0,135.8,
133.7,130.4,129.9×2,128.5×2,126.7,125.9,125.5,124.6,124.4,124.3,122.5,
120.7,119.6,117.9,116.3,114.9,111.0,107.1,94.3,86.2,82.2,80.3,59.7,52.2,30.6,
29.2,28.7.ESI-MS m/z 657.6/659.6[M+H]+.Compound 147:1H NMR(600MHz,CDCl3)δ9.14(d,
1H, J=7.9Hz, Ar-H), 8.28 (d, 1H, J=7.8Hz ,-NH), 7.76 (br d, 2H, J=8.0Hz, Ar-H), 7.62 (d,
1H, J=8.5Hz, Ar-H), 7.54 (br d, 2H, J=8.7Hz, Ar-H), 7.40 (t, 1H, J=7.3Hz, Ar-H), 7.30
(t, 1H, J=7.8Hz, Ar-H), 7.25 (m, 2H, Ar-H), 7.19 (t, 1H, J=7.7Hz, Ar-H), 7.06 (s, 1H, H-7),
6.92 (d, 1H, J=8.0Hz, Ar-H), 6.41 (dd, 1H, J=4.5,8.9Hz, H-1'), 6.16 (s, 1H ,-OH), 4.44
(dd, J=5.4,11.9Hz H-3'), 3.79 (s, 1H, H-4'), 2.51 (s, 3H, 4'-OCH3),2.43(s,3H,3'-NCH3),
2.28 (m, 1H, J=4.2,13.2Hz, H-2'a), 2.19 (m, 1H, H-2'b), 2.15 (s, 3H, H-6')13C NMR
(150MHz,CDCl3)δ171.5,139.7,138.6,137.7,136.7,133.5,130.6,119.9×2,118.4×2,
127.0,126.4,135.7,125.6,124.1,123.9,123.1,120.8,120.3,118.0,115.6,115.5,
111.8,107.7,94.6,86.6,82.2,79.3,60.2,52.1,30.6,29.2,28.2.ESI-MSm/z 657.6/
659.6[M+H]+.
The preparation of compound 148 and 149
According to the synthetic method of compound 139, synthesized by 132 (25.0mg, 0.036mmol), DMSO and NaOH solution.Through
Cross gel column chromatography separation, methanol elutes to obtain 7 Alpha-hydroxy -3 '-N- brosyl staurosporine (148) 7.8mg (yields
And 7 beta-hydroxy -3 '-N- brosyl staurosporine (149) 5.5mg (yield 21.5%) 30.5%).
Compound 148:1H NMR(600MHz,CDCl3) δ 8.90 (s, 1H, Ar-H), 8.66 (d, 1H, J=7.4Hz ,-
), NH 8.59 (d, 1H, J=7.8Hz, Ar-H), 7.77 (m, 4H, Ar-H), 7.46 (d, 1H, J=8.1Hz, Ar-H), 7.42 (d,
1H, J=8.5Hz, Ar-H), 7.36 (t, 1H, J=7.7Hz, Ar-H), 6.82 (dd, 1H, J=3.5,9.8Hz, Ar-H), 6.78
(m, 2H, Ar-H), 6.56 (d, 1H, J=10.9Hz, H-7), 6.46 (t, 1H, J=7.2Hz, H-1'), 5.78 (d, 1H, J=
11.1Hz ,-OH), 4.52 (dd, 1H, J=6.2,12.8Hz, H-3'), 3.56 (s, 1H, H-4'), 2.56 (s, 3H, 4'-
OCH3),2.48(s,3H,3'-NCH3), 2.35 (m, 1H, H-2'a), 2.19 (dt, 1H, J=2.5,13.5Hz, H-2'b), 2.86
(s,3H,H-6').13C NMR(150MHz,CDCl3)δ173.2,138.5,138.2,135.6,133.8,132.9×2,
130.3,128.6×2,128.1,126.5,125.8,125.4,124.8,124.4,124.2,122.4,120.6,119.5,
117.9,116.2,114.8,110.8,107.0,94.2,86.2,82.4,80.5,59.6,52.2,30.5,29.1,
28.7.ESI-MS m/z 701.5/703.5[M+H]+.Compound 149:1H NMR(600MHz,CDCl3) δ 9.07 (d, 1H, J=
7.8Hz, Ar-H), 8.36 (d, 1H, J=7.8Hz ,-NH), 7.77 (m, 4H, Ar-H), 7.64 (d, 1H, J=8.2Hz, Ar-H),
7.43 (t, 1H, J=6.8Hz, Ar-H), 7.37 (d, 1H, J=3.9Hz, Ar-H), 7.31 (m, 2H, Ar-H), 7.13 (t, 1H, J
=7.7Hz, Ar-H), 7.08 (s, 1H, H-7), 6.99 (d, 1H, J=8.1Hz, Ar-H), 6.51 (dd, 1H, J=4.0,
9.2Hz, H-1'), 6.34 (s, 1H ,-OH), 4.49 (ddd, 1H, J=1.9,5.5,12.8Hz, H-3'), 3.86 (s, 1H, H-
4'),2.58(s,3H,4'-OCH3),2.48(s,3H,3'-NCH3),2.44(m,1H,H-2'a),2.25(s,3H,H-6'),
2.22(m,1H,H-2'b).13C NMR(150MHz,CDCl3)δ171.6,138.7,138.3,136.7,134.4,132.9×2,
130.6,128.5×2,128.2,127.1,126.1,126.5,125.7,125.7,124.2,123.1,120.9,120.3,
118.0,115.7,115.6,111.8,107.6,94.6,86.6,82.3,79.4,60.3,52.1,33.7,29.3,
28.2.ESI-MS m/z 701.5/703.5[M+H]+。
The preparation of compound 150
According to the synthetic method of compound 139, by 3'-N- to iodobenzene sulphonyl staurosporine (25.0mg, 0.034mmol),
DMSO and NaOH solution synthesis.By gel column chromatography separation, methanol elute 7-3 '-N- of Alpha-hydroxy to iodobenzene sulphonyl cross spore
Alkali (150) 8.1mg (yield 31.7%).1H NMR(600MHz,CDCl3) δ 8.65 (d, 1H, J=7.4Hz, Ar-H), 8.60 (d,
1H, J=7.9Hz, Ar-H), 8.57 (s, 1H ,-NH), 7.99 (m, 2H, Ar-H), 7.60 (m, 2H, Ar-H), 7.47 (d, 1H, J
=8.0Hz, Ar-H), 7.43 (t, 1H, J=7.3Hz, Ar-H), 7.36 (t, 1H, J=7.3Hz, Ar-H), 6.83 (t, 1H, J=
7.8Hz, Ar-H), 6.79 (t, 2H, J=8.0Hz, Ar-H), 6.54 (d, 1H, J=11.8Hz, H-7), 6.49 (t, 1H, J=
7.8Hz, H-1'), 5.62 (d, 1H, J=12.2Hz ,-OH), 4.50 (dd, 1H, J=5.8,12.8Hz, H-3'), 3.57 (s,
1H,H-4'),2.57(s,3H,4'-OCH3),2.47(s,1H,3'-NCH3), 2.34 (m, 1H, H-2'a), 2.20 (dt, 1H, J=
3.2,12.4Hz,H-2'b),1.90(s,3H,H-6').13C NMR(150MHz,CDCl3)δ173.5,139.3×2,138.8×
2,138.3,135.7,133.8,130.4,128.5×2,126.6×2,125.8,125.4,124.4,122.4,120.6,
119.6,117.9,116.3,114.9,110.9,109.4,100.5,94.3,86.2,82.2,80.4,59.6,52.3,30.6,
29.1,28.7.ESI-MS m/z 749.6[M+H]+.
The preparation of compound 151 and 152
According to the synthetic method of compound 139, synthesized by 133 (25.0mg, 0.034mmol), DMSO and NaOH solution.Through
Cross gel column chromatography separation, methanol elutes to obtain 7 Alpha-hydroxy -3 '-N- benzene sulfonyl staurosporine (151) 7.9mg (yield 30.8%)
With 7 beta-hydroxy -3 '-N- benzene sulfonyl staurosporine (152) 5.4mg (yield 21.1%).
Compound 151:1H NMR(600MHz,CDCl3) δ 8.66 (s, 1H ,-NH), 8.63 (t, 2H, J=7.4Hz, Ar-
), H 7.91 (d, 2H, J=7.4Hz, Ar-H), 7.70 (t, 1H, J=7.8Hz, Ar-H), 7.64 (m, 2H, Ar-H), 7.40 (m,
2H, Ar-H), 7.34 (t, 1H, J=7.4Hz, Ar-H), 6.77 (m, 2H, Ar-H), 6.73 (d, 1H, J=7.6Hz, Ar-H),
6.54 (d, 1H, J=10.0Hz, H-7), 6.48 (d, 1H, J=8.0Hz, H-1'), 5.75 (d, 1H, J=10.0Hz ,-OH),
4.53 (dd, 1H, J=12.8,5.5Hz, H-3'), 3.48 (s, 1H, H-4'), 2.58 (s, 3H, 4'-OCH3),2.42(s,3H,
3'-NCH3),2.36(m,1H,H-2'a),2.18(m,1H,H-2'b),1.82(s,3H,H-6').13CNMR(150MHz,
CDCl3)δ173.5,139.5,138.2,135.7,133.7,133.2,130.4,129.6×2,127.0×2,126.6,
125.7,125.3,124.7,124.3,124.2,122.4,120.5,119.5,117.8,116.1,114.8,110.8,
107.0,94.2,85.8,82.2,80.4,59.4,52.1,30.5,29.0,28.6.ESI-MS m/z 623.2[M+H]+.
Compound 152:1H NMR(600MHz,CDCl3) δ 9.19 (d, 1H, J=7.8Hz, Ar-H), 8.38 (d, 1H, J=
7.4Hz ,-NH), 7.88 (d, 2H, J=7.3Hz, Ar-H), 7.70 (d, 1H, J=7.8Hz, Ar-H), 7.62 (m, 3H, Ar-H),
7.43 (t, 1H, J=7.8Hz, Ar-H), 7.36 (t, 1H, J=7.8Hz, Ar-H), 7.30 (t, 1H, J=7.3Hz, Ar-H),
7.24 (t, 1H, J=7.3Hz, Ar-H), 6.99 (d, 1H, J=7.9Hz, ArH), 6.83 (s, 1H, H-7), 6.47 (dd, 1H, J
=9.2,4.6Hz, H-1'), 6.31 (br s, 1H ,-OH), 4.50 (ddd, 1H, J=1.9,5.3,13.0Hz, H-3'), 3.83
(s,1H,H-4'),2.61(s,3H,4'-OCH3),2.42(s,3H,3'-NCH3),2.34(m,1H,H-2'a),2.29(s,3H,
H-6'),2.22(m,1H,H-2'b).13C NMR(150MHz,CDCl3)δ171.3,139.2,138.8,136.8,133.4,
133.2,130.7,129.5×2,127.2,127.1×2,126.6,125.6,125.8,125.7,124.1,124.0,
123.3,120.9,120.4,118.1,115.6,112.0,107.7,94.7,86.3,82.4,79.4,60.3,52.1,20.7,
29.3,28.1.ESI-MS m/z 623.2[M+H]+。
The preparation of compound 153
According to the synthetic method of compound 130, by staurosporine (46.6mg, 0.1mmol), triethylamine and to fluorobenzoyl
Chlorine synthesis.By gel column chromatography separation, methanol elute 3 '-N- to fluorobenzoyl staurosporine (153) 53.8mg, yield
91.5%.1H NMR(600MHz,CDCl3) δ 9.45 (d, 1H, J=8.2Hz, Ar-H), 7.87 (d, 1H, J=7.8Hz, Ar-H),
7.78 (d, 1H, J=7.8Hz, Ar-H), 7.48 (t, 1H, J=7.8Hz, Ar-H), 7.46 (t, 1H, J=7.3Hz, Ar-H),
7.43 (m, 2H, J=7.3Hz, Ar-H), 7.37 (t, 1H, J=7.3Hz, Ar-H), 7.33 (t, 1H, J=7.3Hz, Ar-H),
7.21 (d, 1H, J=7.3Hz, Ar-H), 7.10 (d, 2H, J=7.3Hz, Ar-H), 6.94 (br s, 1H ,-NH), 6.66 (br
S, 1H, H-1'), 5.17 (d, 1H, J=7.8Hz, H-3'), 4.97 (d, 1H, J=16.0Hz, H-7a), 4.93 (d, 1H, J=
16.0Hz,H-7b),4.21(s,1H,H-4'),2.84(s,3H,4'-OCH3),2.72(m,1H,H-2'a),2.65(m,1H,H-
2'b),2.53(s,3H,3'-NCH3),2.45(s,3H,H-6').13C NMR(150MHz,CDCl3)δ173.5,171.5,
163.6(d,1JC-F=247.2Hz), 136.6 × 2,132.5,132.2,130.6,129.4 × 2 (d,3JC-F=6.9Hz),
126.9,126.4,125.5,125.1,124.8,123.7,121.6,120.6,120.2,119.2,116.3,115.8×2(d
,2JC-F=13.7Hz), 114.6,112.4,107.8,94.7,84.8,82.4,60.5,49.8,46.1,34.6,29. 2,
28.2.ESI-MS m/z 589.2[M+H]+。
The preparation of compound 154
According to the synthetic method of compound 134, by compound 153 (15.0mg, 0.025mmol) and chlorosuccinimide
(7.5mg, 0.056mmol) synthesis.By gel column chromatography separation, methanol elute the chloro- 3 '-N- of 3- to fluorobenzoyl cross spore
Alkali (154) 10.5mg, yield 33.2%.1H NMR(600MHz,CDCl3) δ 9.38 (s, 1H, Ar-H), 7.89 (d, 1H, J=
7.8Hz, Ar-H), 7.77 (d, 1H, J=7.3Hz, Ar-H), 7.48 (d, 2H, J=7.8Hz, Ar-H), 7.43 (d, 2H, J=
7.3, Ar-H), 7.36 (t, 1H, J=7.8Hz, Ar-H), 7.35 (d, 1H, J=7.8Hz, Ar-H), 7.12 (t, 2H, J=
7.3Hz, Ar-H), 7.10 (br s, 1H ,-NH), 6.74 (br s, 1H, H-1'), 5.20 (d, 1H, J=7.8Hz, H-4'),
4.98(br s,2H,H-7),4.22(s,1H,H-3'),2.86(s,3H,4'-OCH3),2.75(m,1H,H-2'a),2.62(m,
1H,H-2'b),2.57(s,3H,3'-NCH3),2.44(s,3H,H-6').13C NMR(150MHz,CDCl3)δ173.0,
171.5,163.6(d,1JC-F=247.2Hz), 134.8 × 2,132.8,132.2,130.4,129.3 × 2 (d,3JC-F=
6.9Hz),127.1,126.1,125.7,125.4,124.7,124.6,121.7,120.8,119.2,115.9×2(d,2JC-F
=13.7Hz), 115.4,115.0,112.4,108.6 × 2,94.8,84.7,82.5,60.5,49.8,46.1,34.5,29.2,
28.1.ESI-MS m/z 623.3/625.3[M+H]+。
The preparation of compound 155
According to the synthetic method of compound 139, by compound 153 (20.0mg, 0.034mmol), DMSO and NaOH solution
Synthesis.By gel column chromatography separation, methanol elute 7-3 '-N- of beta-hydroxy to fluorobenzoyl staurosporine (155) 7.6mg,
Yield 37.0%.1HNMR (600MHz, DMSO) δ 9.28 (d, 1H, J=7.7Hz, Ar-H), 8.52 (d, 1H, J=7.7Hz ,-
), NH 7.77 (d, 1H, J=7.7Hz, Ar-H), 7.50 (t, 1H, J=8.2Hz, Ar-H), 7.49 (t, 1H, J=8.2Hz, Ar-
), H 7.44 (d, 2H, J=7.3Hz, Ar-H), 7.39 (t, 1H, J=7.7Hz, Ar-H), 7.37 (t, 1H, J=7.7Hz, Ar-
), H 7.35 (t, 1H, J=7.7Hz, Ar-H), 7.11 (d, 2H, J=7.7Hz, Ar-H), 7.06 (s, 1H, H-7), 6.71 (br
S, 1H ,-OH), 6.50 (br s, 1H, H-1'), 5.20 (d, 1H, J=8.2Hz, H-3'), 4.26 (s, 1H, H-4'), 2.87 (s,
3H,4'-OCH3),2.74(m,1H,H-2'a),2.68(m,1H,H-2'b),2.54(s,3H,3'-NCH3),1.67(s,3H,H-
6');13C NMR(150MHz,DMSO)δ171.0,170.9,163.9(d,1JC-F=247.2Hz), 137.1 × 2,135.4,
133.5,130.2,129.9×2(d,3JC-F=6.9Hz), 126.1 × 2,125.8,124.0,123.9,123.1,120.7,
120.2,119.3×2,116.1,115.7×2(d,2JC-F=13.7Hz), 113.9,112.7,109.6,95.2,82.7,
82.7,78.9,61.0,49.9,34.6,29.9,27.5;ESI-MSm/z 604.2[M+H]+。
The preparation of compound 156
According to the synthetic method of compound 130, by 135a (48.0mg, 0.1mmol), triethylamine and to trifluoromethylbenzene first
Acyl chlorides synthesis.By gel column chromatography separation, methanol elute 7- -3 '-N- of oxygen subunit to trifluoromethylbenzoyl staurosporine
(156) 59.5mg, yield 91.3%.1H NMR(600MHz,CDCl3) δ 9.34 (d, 1H, J=7.7Hz, Ar-H), 9.17 (d,
1H, J=7.8Hz, Ar-H), 7.91 (d, 2H, J=7.7Hz, Ar-H), 7.71 (t, 1H, J=7.4Hz, Ar-H), 7.66 (t,
1H, J=7.8Hz, Ar-H), 7.63 (t, 1H, J=7.8Hz, Ar-H), 7.53 (t, 2H, J=7.7Hz, Ar-H), 7.52 (br
S, 1H ,-NH), 7.41 (t, 1H, J=7.8Hz, Ar-H), 7.40 (d, 1H, J=7.8Hz, Ar-H), 7.12 (d, 1H, J=
7.4Hz, Ar-H), 6.60 (dd, 1H, J=3.7Hz, 9.2Hz, H-1'), 4.56 (dd, 1H, J=5.5Hz, 12.4Hz, H-3'),
3.83(s,1H,H-4'),2.74(s,3H,4'-OCH3),2.47(m,1H,H-2'a),2.42(s,3H,3'-NCH3),2.38(m,
1H,H-2'b),2.26(s,3H,H-6').13C NMR(150MHz,CDCl3)δ169.8,169.6,167.8,139.3,139.2,
137.8×2,133.2×2,131.4(q,2JC-F=27.3Hz), 130.0,129.6 × 2,127.1 × 2,126.5 (q,3JC-F=
8.4Hz),126.3,123.8(q,1JC-F=270.0Hz), 122.5,121.4,121.3,121.0 (q,3JC-F=7.8Hz),
119.4,117.4,116.4,114.7,111.3,108.2,94.7,86.0,82.5,60.1,51.9,30.7,28.9,28.3;
ESI-MS m/z 653.2[M+H]+。
The preparation of compound 157
According to the synthetic method of compound 130, by staurosporine (46.6mg, 0.1mmol), triethylamine and to iodobenzene sulphonyl
Chlorine synthesis.By gel column chromatography separation, methanol elute 3 '-N- to iodobenzene sulphonyl staurosporine (157) 62.1mg, yield
84.8%.1H NMR(600MHz,CDCl3) δ 9.42 (d, 1H, J=7.8Hz, Ar-H), 7.99 (d, 2H, J=6.9Hz, Ar-H),
7.89 (d, 1H, J=7.8Hz, Ar-H), 7.72 (d, 1H, J=8.3Hz, Ar-H), 7.61 (d, 2H, J=6.9Hz, Ar-H),
7.48 (t, 1H, J=7.3Hz, Ar-H), 7.45 (t, 1H, J=7.3Hz, Ar-H), 7.37 (t, 1H, J=7.8Hz, Ar-H),
7.35 (t, 1H, J=7.8Hz, Ar-H), 7.10 (d, 1H, J=8.2Hz, Ar-H), 6.61 (br s, 1H ,-NH), 6.57 (dd,
1H, J=4.6Hz, 9.2Hz, H-1'), 4.99 (d, 1H, J=16.5Hz, H-7a), 4.92 (d, 1H, J=16.5Hz, H-7b),
4.50(m,1H,H-4'),3.96(s,1H,H-3'),2.72(s,3H,4'-OCH3),2.47(s,1H,3'-NCH3),2.45(m,
1H,H-2'a),2.43(s,3H,H-6'),2.45(m,1H,H-2'a);13C NMR(150MHz,CDCl3)δ173.3,138.9×
2,138.5,136.6×2,132.5,130.5,128.4×2,127.0,126.4,125.6,125.3,124.8,123.7,
121.7,120.8,120.3,119.3,116.4,114.7,112.3,107.7,100.6,94.7,86.6,82.5,60.5,
52.2,46.0,30.9,29.2,28.2.ESI-MS m/z 733.3[M+H]+。
The preparation of compound 158
I) preparation of (3- indoles) maleimide of N- methyl -3,4- two (158a)
According to the synthetic method of compound 82, by magnesium wire (128mg, 5.3mmol), bromic ether (396 μ L, 5.3mmol)
It is synthesized with indoles (622mg, 5.3mmol), silica gel column chromatography separation, petroleum ether: ethyl acetate=3:1 (v/v) elutes red
Solid (158a) 263mg, yield 73%.1H NMR(600MHz,DMSO-d6)δ11.70(s,2H,indole-NH),7.77(d,
2H, J=2.3Hz, Ar-H), 7.38 (d, 2H, J=8.2Hz, Ar-H), 6.98 (t, 2H, J=7.7Hz, Ar-H), 6.82 (d,
2H, J=7.8Hz, Ar-H), 6.64 (t, 2H, J=7.8Hz, Ar-H), 3.04 (s, 3H ,-CH3).13C NMR(150MHz,
DMSO-d6)δ172.4×2,136.6×2,129.7×2,127.6×2,125.9×2,122.2×2,121.5×2,119.9
×2,112.3×2,106.2×2,24.5.ESI-MS m/z 342.1[M+H]+。
Ii) the preparation of (3- indoles) maleic anhydride of 3,4- bis- (158b)
According to the synthetic method of compound 84a, closed by the KOH solution of compound 158a (120mg, 0.35mmol) and 10%
At silica gel column chromatography separation, dichloromethane eluent obtain red solid (158b) 104mg, yield 90%.1H NMR(600MHz,
DMSO-d6) δ 11.93 (d, 2H, J=2.8Hz, indole-NH), 7.86 (d, 2H, J=2.8Hz, Ar-H), 7.44 (d, 2H, J
=8.2Hz, Ar-H), 7.04 (t, 2H, J=8.2Hz, Ar-H), 6.87 (d, 2H, J=7.7Hz, Ar-H), 6.71 (t, 2H, J=
7.7Hz,Ar-H).13C NMR(150MHz,DMSO-d6)δ167.1×2,136.7×2,131.1×2,125.8×2,125.5
×2,122.6×2,121.7×2,120.4×2,112.7×2,105.5×2.ESI-MS m/z 329.1[M+H]+。
Iii) the preparation of (3- indoles) maleimide of 3,4- bis- (158c)
According to the preparation method of compound 1, by compound 158b (100mg, 0.3mmol), HMDS (6.4mL,
30.5mmol), orange red powder (158c) 70mg, yield 71% is made in MeOH (0.61mL, 15.2mmol).1H NMR
(600MHz,DMSO-d6) δ 11.65 (brs, 2H, indole-NH), 10.89 (brs, 1H, imide-NH), 7.72 (d, 2H, J=
2.8Hz, Ar-H), 7.36 (d, 2H, J=8.2Hz, Ar-H), 6.96 (dt, 2H, J=8.2Hz, 1.0Hz, Ar-H), 6.79 (d,
2H, J=7.8Hz, Ar-H), 6.61 (dt, 2H, J=8.2Hz, 1.0Hz, Ar-H)13C NMR(150MHz,DMSO-d6)δ
173.6×2,136.4×2,129.6×2,128.2×2,125.9×2,122.1×2,121.4×2,119.8×2,112.3
×2,106.1×2.ESI-MS m/z 328.2[M+H]+。
IV) N- methylol -3,4- two (1- methylol -3- indoles) maleimide (158) preparation
According to the preparation method of compound 4, from 158c (76.5mg, 0.23mmol), NaHCO3(98mg, 1.17mmol) and
Red powder solid (158) 96mg, yield 99% is made in formalin (3mL, mass fraction 37%).1H NMR(600MHz,
DMSO-d6) δ 7.95 (s, 2H, Ar-H), 7.55 (d, 2H, J=8.2Hz, Ar-H), 7.03 (t, 2H, J=7.3Hz, Ar-H),
6.76 (d, 2H, J=8.2Hz, Ar-H), 6.64 (t, 2H, J=7.3Hz, Ar-H), 5.60 (s, 4H, indole-CH2 -OH),
4.98(s,2H,imide-CH2 -OH).13C NMR(150MHz,DMSO-d6)δ171.6×2,136.0×2,132.4×2,
127.6×2,127.0×2,122.4×2,121.5×2,120.6×2,111.4×2,105.9×2,69.7,60.9×
2.HR-ESIMS m/z 440.1236[M+H]+(calcd.for C23H19N3O5Na, 440.1222) preparation of compound 159
According to the preparation method of compound 14, reacted by compound 8b (30mg, 0.055mmol) and ethylenediamine (0.5mL),
Silica gel column chromatography separation, methylene chloride: methanol=8:1 (v/v) elutes to obtain two (1- of dark red solid N- (2- aminoethyl) -2,3-
Cyanogen propyl -3- indoles) maleimide (159) 30mg, yield 94%.1H NMR(600MHz,DMSO-d6)δ7.76(s,2H,
), Ar-H 7.50 (d, 2H, J=8.2Hz, Ar-H), 7.07 (t, 2H, J=7.6Hz, Ar-H), 6.89 (d, 2H, J=7.9Hz,
), Ar-H 6.72 (s, 2H, Ar-H), 4.28 (t, 4H, J=5.5Hz ,-N-CH2 -(CH2)2CN), 3.63 (t, 2H, J=5.7Hz ,-
N-CH2 -CH2NH2), 2.86 (t, 2H, J=5.7Hz ,-NCH2-CH2 -NH2), 2.37 (t, J=6.8Hz, 4H, N (CH2)2-CH2 -
CN),2.03-1.98(m,4H,N-CH2-CH2 -CH2CN).13C NMR(150MHz,DMSO-d6)δ171.9×2,136.3×2,
132.4×2,127.4×2,126.0×2,122.5×2,121.9×2,120.3×2,120.1×2,110.6×2,105.7
×2,54.0,45.0×2,39.9,26.0×2,14.2×2.ESI-MS m/z 505.1[M+H]+.
The preparation of compound 160
According to the preparation method of compound 24, by compound 8b (60mg, 0.129mmol), 4- (2- aminoethyl) morpholine
(120 μ L, 0.909mmol) and catalytic amount Et3N synthesis, silica gel column chromatography separation, methylene chloride: methanol=30:1 (v/v) elution
Obtain red solid N- (2- (4- morpholine) ethyl) -2,3- bis- (1- cyanogen propyl -3- indoles) maleimide (160) 44mg, yield
59%.1H NMR(500MHz,DMSO-d6) δ 7.77 (s, 2H, Ar-H), 7.51 (d, 2H, J=8.3Hz, Ar-H), 7.07 (t,
2H, J=7.6Hz, Ar-H), 6.87 (d, 2H, J=8.0Hz, Ar-H), 6.73 (t, 2H, J=7.5Hz, Ar-H), 4.27 (t,
4H, J=6.6Hz ,-N-CH2 -(CH2)2), CN 3.69 (t, 2H, J=6.0Hz ,-N-CH2 -CH2-morpholine),3.52(t,
4H, J=4.5Hz, morpholine-N (CH2CH 2)2), O 2.53 (t, 2H, J=6.0Hz ,-NCH2-CH2 -morpholine),
2.42 (t, 4H, J=5.3Hz, N (CH2)2-CH2 - CN), 2.37 (t, 4H, J=3.9Hz, morpholine-N (CH 2CH2)2O),
2.03-1.98(m,4H,NCH2-CH2 -CH2CN).13C NMR(125MHz,DMSO-d6)δ171.8×2,136.3×2,132.5
×2,127.2×2,126.0×2,122.5×2,121.8×2,120.4×2,120.2×2,110.6×2,105.6×2,
66.7×2,56.4,53.6×2,45.0×2,35.3,26.0×2,14.2×2.ESI-MS m/z 575.2[M+H]+.
The preparation of compound 161
According to the synthetic method of compound 24, by compound 8b (60mg, 0.129mmol), 4- (2- aminoethyl) piperazine
(100 μ L, 0.90mmol) and catalytic amount Et3N synthesis, silica gel column chromatography separation, methylene chloride: methanol=10:1 (v/v) elution
Obtain red solid N- (2- piperazine ethyl) -2,3- bis- (1- cyanogen propyl -3- indoles) maleimide (161) 44mg, yield 75%.1H
NMR(600MHz,DMSO-d6) δ 7.77 (s, 2H, Ar-H), 7.51 (d, 2H, J=8.3Hz, Ar-H), 7.07 (t, 2H, J=
7.6Hz, Ar-H), 6.87 (d, 2H, J=8.0Hz, Ar-H), 6.73 (t, 2H, J=7.5Hz, Ar-H), 4.27 (t, 4H, J=
6.5Hz,-N-CH2 -(CH2)2), CN 3.67 (t, 4H, J=6.1Hz, piperazine-N (CH 2CH2)2NH),2.73(t,4H,J
=4.9Hz, piperazine-N (CH2CH 2)2), NH 2.52 (t, 2H, J=6.1Hz, imide-NCH 2-CH2-piperazine),
2.43 (t, 2H, J=4.9Hz, imide-NCH2-CH 2- piperazine), 2.37 (t, 4H, J=7.1Hz, N (CH2)2-CH2 -
CN),1.99-2.02(m,4H,NCH2-CH2 -CH2CN).13C NMR(150MHz,DMSO-d6)δ171.8×2,136.3×2,
132.5×2,127.3×2,126.0×2,122.5×2,121.8×2,120.3×2,120.2×2,110.6×2,105.6
×2,56.4,53.2×2,45.3×2,45.0×2,35.4,26.0×2,14.2×2.ESI-MS m/z 574.2[M+H]+.
The preparation of compound 162
With 6ml dry pyridine dissolved compound 8b (55mg, 0.119mmol), be added hydroxylamine hydrochloride (17mg,
0.238mmol), 1.5h is reacted at lower 100 DEG C of nitrogen protection.TLC is detected to reaction and is no longer carried out, and is cooled to room temperature, and revolving is extremely
It is dry.Silica gel column chromatography separation, methylene chloride: methanol=15:1 (v/v) elutes to obtain two (1- cyanogen third of red solid N- hydroxyl -2,3-
Base -3- indoles) maleimide (162) 51mg, yield 89%.1H NMR(600MHz,DMSO-d6)δ10.46(s,1H,-OH),
7.78 (s, 2H, Ar-H), 7.51 (d, 2H, J=8.3Hz, Ar-H), 7.07 (t, 2H, J=7.6Hz, Ar-H), 6.86 (d, 2H, J
=8.0Hz, Ar-H), 6.72 (t, 2H, J=7.5Hz, Ar-H), 4.28 (t, 4H, J=6.5Hz ,-N-CH2 -(CH2)2CN),
2.37 (t, 4H, J=7.1Hz, N (CH2)2-CH2 -CN),2.04-1.98(m,4H,NCH2-CH2 -CH2CN).13C NMR
(150MHz,DMSO-d6)δ168.6×2,136.3×2,132.6×2,125.9×2,124.7×2,122.5×2,121.8
×2,120.4×2,120.3×2,110.7×2,105.5×2,45.0×2,26.0×2,14.2×2.ESI-MS m/z
478.2[M+H]+.
The preparation of compound 163
According to the synthetic method of compound 162, by compound 26e (55mg, 0.13mmol) and hydroxylamine hydrochloride (25mg,
It 0.25mmol) synthesizes, silica gel column chromatography separation, methylene chloride: methanol=20:1 (v/v) elutes to obtain red solid N- hydroxyl -2-
(1- ethyl -3- indoles) -3- (the bromo- 3- indoles of 6-) maleimide (162) 58mg, yield 99%.1H NMR(600MHz,
DMSO-d6)δ11.83(s,1H,indole-NH),10.50(brs,1H,-OH),7.84(s,1H,Ar-H),7.79(s,1H,
), Ar-H 7.57 (s, 1H, Ar-H), 7.47 (d, 1H, J=8.2Hz, Ar-H), 7.03 (t, 1H, J=7.6Hz, Ar-H), 6.76
(t, 1H, J=7.6Hz, Ar-H), 6.74 (d, 1H, J=7.1Hz, Ar-H), 6.68 (t, 1H, J=6.2Hz, Ar-H), 6.67
(d, 1H, J=8.1Hz, Ar-H), 4.25 (q, 2H, J=7.0Hz ,-CH2 -CH3), 1.32 (t, 3H, J=7.1Hz ,-CH2-
CH3 ).13C NMR(150MHz,DMSO-d6)δ168.7×2,137.3,136.0,132.3,130.7,126.1,125.2,
124.7,124.3,122.9,122.7,122.3,121.6,120.2,114.9×2,110.7,106.1,105.0,41.2,
15.7.HR-ESIMS m/z 450.0459[M+H]+(calcd.for C22H16N3O3Br,449.0375).
The preparation of compound 164
According to the preparation method of compound 24, by compound 26e (30mg, 0.069mmol), 4- (2- aminoethyl) morpholine
(64 μ L, 0.484mmol) and catalytic amount Et3N synthesis, silica gel column chromatography separation, methylene chloride: methanol=25:1 (v/v) elution
Obtain red solid N- (2- (4- morpholine) ethyl) -2- (1- ethyl -3- indoles) -3- (the bromo- 3- indoles of 6-) maleimide (164)
33mg, yield 88%.1H NMR(500MHz,DMSO-d6)δ11.78(s,1H,indole-NH),7.81(s,1H,Ar-H),
7.76 (s, 1H, Ar-H), 7.56 (d, 1H, J=1.5Hz, Ar-H), 7.46 (d, 1H, J=8.3Hz, Ar-H), 7.03 (t, 1H, J
=7.6Hz, Ar-H), 6.78 (d, 1H, J=7.7Hz, Ar-H), 6.74 (dd, 1H, J=8.4Hz, 1.6Hz, Ar-H), 6.69
(d, 1H, J=8.4Hz, Ar-H), 6.67 (t, 1H, J=8.2Hz, Ar-H), 4.24 (q, 2H, J=7.2Hz ,-CH2 -CH3),
3.67 (t, 2H, J=6.5Hz, imide-NCH2 CH2), 3.51 (t, 4H, J=4.2Hz, morpholine-N (CH2-CH 2)2O),
2.52 (t, 2H, J=6.5Hz, imide-NCH2CH2 ), 2.40 (t, 4H, J=4.2Hz, morpholine-N (CH 2-CH2)2O),
1.32 (t, 3H, J=7.2Hz ,-CH2-CH3 ).13C NMR(125MHz,DMSO-d6)δ171.9,171.8,137.3,136.0,
132.1,130.5,127.7,126.4,126.2,124.7,122.9,122.6,122.3,121.6,120.1,114.9,
114.8,110.7,106.2,105.1,66.6×2,56.3,53.6×2,41.2,35.3,15.7.HR-ESIMS m/z
547.1354[M+H]+(calcd.for C28H27N4O3Br,546.1267).
The preparation of compound 165
According to the synthetic method of compound 24, by compound 26e (30mg, 0.069mmol), 4- (2- aminoethyl) piperazine
(93 μ L, 0.712mmol) and catalytic amount Et3N synthesis, silica gel column chromatography separation, methylene chloride: methanol=8:1 (v/v) elutes
Red solid N- (2- piperazine ethyl) -2- (1- ethyl -3- indoles) -3- (the bromo- 3- indoles of 6-) maleimide (165) 55mg,
Yield 99%.1H NMR(500MHz,DMSO-d6)δ11.78(s,1H,indole-NH),7.81(s,1H,Ar-H),7.76(d,
1H, J=2.6Hz, Ar-H), 7.57 (d, 1H, J=1.5Hz, Ar-H), 7.48 (d, 1H, J=8.3Hz, Ar-H), 7.04 (t,
1H, J=7.6Hz, Ar-H), 6.78 (d, 1H, J=8.0Hz, Ar-H), 6.76 (dd, 1H, J=8.4Hz, 1.6Hz, Ar-H),
6.69 (d, 1H, J=8.5Hz, Ar-H), 6.68 (t, 1H, J=7.8Hz, Ar-H), 4.25 (q, 2H, J=7.1Hz ,-CH2 -
CH3), 3.67 (d, 2H, J=6.2Hz, imide-NCH2 CH2-),3.15(brs,1H,piperazine-NH),3.03(t,4H,J
=4.9Hz, piperazine-N (CH 2-CH2)2), NH 2.64 (t, 4H, J=4.9Hz, piperazine-N (CH2-CH 2)2NH),
2.60 (t, 2H, J=5.8Hz, imide-NCH2CH2 ), 1.32 (t, 3H, J=7.2Hz ,-CH2-CH3 ).13C NMR(125MHz,
DMSO-d6)δ171.9,171.8,137.3,136.0,132.2,130.6,127.7,126.4,126.1,124.7,122.9,
122.6,122.3,121.6,120.2,114.9,114.8,110.8,106.2,105.1,55.5×2,49.6,43.5×2,
41.2,35.3,15.7.HR-ESIMS m/z 546.1515[M+H]+(calcd.for C28H28N5O2Br,545.1426).
The preparation of compound 166
According to the synthetic method of compound 64, by compound 8 (50.0mg, 0.108mmol) and I2(2.0mg,
It 0.008mmol) synthesizes, silica gel column chromatography separation, petroleum ether: ethyl acetate=3:1 (v/v) elutes to obtain yellow powder 12,13- bis-
Cyanogen propyl -6H- indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone (166) 23mg, yield 45%.1H NMR
(600MHz,DMSO-d6) δ 11.2 (s, 1H ,-NH), 9.14 (d, 2H, J=7.8Hz, Ar-H), 7.89 (d, 2H, J=8.2Hz,
), Ar-H 7.66 (t, 2H, J=7.8Hz, Ar-H), 7.44 (t, 2H, J=7.8Hz, Ar-H), 4.81 (t, 4H, J=6.9Hz, N-
CH 2-(CH2)2), CN 2.13 (t, 4H, J=6.9Hz, N (CH2)2-CH 2-CN),1.71(m,4H,NCH2-CH 2-CH2CN).13C
NMR(150MHz,DMSO-d6)δ171.2×2,144.3×2,133.2×2,128.1×2,125.5×2,123.9×2,
122.2×2,121.6×2,120.5×2,120.2×2,113.3×2,47.5×2,24.2×2,14.2×2.HR-ESIMS
m/z 458.1604[M–H]–(calcd.for C28H20N5O2,458.1617).
The preparation of compound 167
At 0 DEG C, staurosporine (60mg, 0.129mmol) is dissolved with THF (5mL), addition diisopropylethylamine (64 μ L,
0.38mmol) with triphosgene (19mg, 0.064mmol), 2h is stirred at room temperature, pours into ice water, ethyl acetate extraction (2 times ×
30mL), brine washes (2 times × 30mL), with the dry organic phase of anhydrous sodium sulfate, rotates to dry.Crude product is dissolved in THF (3mL),
Diisopropylethylamine (127 μ L, 0.77mmol), imidazoles (18mg, 0.25mmol) and to dimethylamino naphthyridine (31.5mg,
0.258mmol), be stirred to react 2h for 60 DEG C, pour into ice water, ethyl acetate extract (2 times × 30mL), brine wash (2 times ×
30mL), it with the dry organic phase of anhydrous sodium sulfate, rotates to dry.Silica gel column chromatography separation, methylene chloride: methanol=50:1 (v/v)
Afford faint yellow solid: 3 '-N- (1- imidazole carboxamide) staurosporine (167) 56mg, yield 80%.[α]D 18+176(c
0.07,CHCl3);1H NMR(500MHz,DMSO-d6) δ 9.31 (d, J=7.9Hz, 1H, ArH), 8.68 (s, 1H, ArH), 8.61
(s, 1H, NH), 8.07 (d, J=7.8Hz, 1H, ArH), 8.01 (d, J=8.5Hz, 1H, ArH), 7.79 (brs, 1H, ArH),
7.59 (d, J=8.2Hz, 1H, ArH), 7.51 (t, J=8.2Hz, 1H, ArH), 7.49 (t, J=8.2Hz, 1H, ArH), 7.37
(t, J=7.7Hz, 1H, ArH), 7.35 (brs, 1H, ArH), 7.31 (t, J=7.5Hz, 1H, ArH), 7.04 (dd, J=8.5,
5.6Hz,1H,H-1'),5.00(s,2H,H-7),4.68(m,1H,H-3'),4.50(brs,1H,H-4'),2.94-2.99(m,
1H,H-2'a),2.89(s,3H,3'-NCH3),2.61(s,3H,6'-CH3),2.36-2.43(m,1H,H-2'b),2.39(s,
3H,6'-CH3).13C NMR(125MHz,DMSO-d6)δ172.0,150.8,138.6,137.2,136.3,132.6,129.5,
125.9,125.8,125.5,125.5,125.3,123.9,122.8,121.7,120.6,119.7,119.6,119.5,
115.2,114.3,113.2,109.0,94.7,83.2,82.1,60.2,52.3,45.5,33.2,28.9,27.0.HRESI-MS
m/z 561.2242[M+H]+(calcd for C32H29N6O4,561.2245).
The preparation of compound 168
Staurosporine (186mg, 0.4mmol) is dissolved with 10mL methylene chloride, 1mL triethylamine and N are added at room temperature,
N '-thiocarbonyldiimidazole (214mg, 1.2mmol), ambient temperature overnight reaction.Reaction solution pours into 20mL ice water, methylene chloride extraction
It takes, is concentrated after the dry organic phase of anhydrous sodium sulfate, silica gel column chromatography separation, methylene chloride: methanol=20:1 (v/v) affords
3 '-N- (the thio formyl of 1- imidazoles) staurosporine (168) 180mg, yield 78%.1H NMR(500MHz,DMSO-d6)δ9.32
(d, J=7.9Hz, 1H), 8.63 (s, 1H, NH), 8.12 (s, 1H, ArH), 8.07 (d, J=7.7Hz, 1H, ArH), 8.03 (d, J
=8.5Hz, 1H, ArH), 7.64 (d, J=7.2Hz, 1H, ArH), 7.59 (brs, 1H, ArH), 7.51 (t, J=7.4Hz, 1H,
), ArH 7.50 (t, J=7.7,1H, ArH), 7.37 (t, J=7.4Hz, 1H, ArH), 7.32 (t, J=7.5Hz, 1H, ArH),
7.13(brs,1H,ArH),7.06(brs,1H,H-1'),5.47(brs,1H,H-3'),5.01(s,2H,H-7),4.79(brs,
1H,H-4'),3.06(s,3H,3'-NCH3),3.02-3.09(m,1H,H-2'a),2.73(s,3H,4'-OCH3),2.44(s,
3H,6'-CH3),2.41-2.47(m,1H,H-2'b);13C NMR(125MHz,DMSO-d6)δ179.3,171.9,138.8,
137.7,136.2,132.7,129.3,129.0,125.8,125.4,125.2×2,123.9,122.7,121.6,120.5,
119.9,119.6,119.6,115.3,114.3,113.5,108.9,94.8,81.9×2,60.4,58.1,45.5,38.2,
29.4,27.1;HRESI-MS m/z 577.2031[M+H]+(calcd for C32H29N6O3S,577.2022).
The preparation of compound 169
Compound 168 (80mg, 0.14mmol) is dissolved in 10mL acetonitrile, is added iodomethane (86 μ L, 1.39mmol), room
Temperature reaction 24 hours.Reaction solution is directly concentrated, with 50mL petroleum ether: the mixed solution of methylene chloride=4:1 (v/v) wash it is pure to obtain the final product
The iodomethane salt 75mg of the imidazole fragment of compound 168, yield 76%;HRESI-MS m/z 591.2164[M-I]+(calcd
for C33H31N6O3S,591.2173).Tryptamines (2.0g, 12.5mmol) is dissolved in 20mL tetrahydrofuran, is down to 10 DEG C, successively
Triethylamine (3.5mL, 25mmol) He Shuding oxygen formic anhydride (3.03g, 15.0mmol) is added, 10 DEG C are reacted 1 hour, by reaction solution
It pours into 100mL ice water, ethyl acetate extraction, is concentrated after the dry organic phase of anhydrous sodium sulfate, flash column chromatography separation, petroleum
Ether: ethyl acetate=2:1 (v/v) affords N- [2- (3- indoles) ethyl] t-butyl carbamate 3.16g, yield 97%;
ESI-MS m/z 261.3[M+H]+.N- [2- (3- indoles) ethyl] t-butyl carbamate (1.8g, 6.92mmol) is dissolved in
110mL THF/H2O (10:1) is down to 0 DEG C, and DDQ (3.1g, 13.8mmol) is added and reacts two hours at this temperature.Reaction
Liquid pours into 200mL ethyl acetate, be washed till with saturated sodium bicarbonate solution it is colourless, ethyl acetate layer with anhydrous sodium sulfate it is dry after
Concentration, flash column chromatography separation, petroleum ether: ethyl acetate=1:1 (v/v) affords N- [2- oxygen subunit -2- (3- indoles) second
Base] t-butyl carbamate 1.2g, yield 63%;ESI-MS m/z 275.4[M+H]+.By N- [2- oxygen subunit -2- (3- Yin
Diindyl) ethyl] t-butyl carbamate (200mg, 0.73mmol) 5mL trifluoroacetic acid dissolves, react one hour at 10 DEG C, addition
Benzene (5mL × 3 time) is azeotroped off trifluoroacetic acid and obtains N- [2- oxygen subunit -2- (3- indoles) ethyl] trifluoroacetic acid ammonium 185mg,
Yield 93%.The iodomethane salt (75.0mg, 0.105mmol) of the imidazole fragment of compound 168 is dissolved in 2mL DMF, is added
Triethylamine (73.0 μ L, 0.525mmol) and N- [2- oxygen subunit -2- (3- indoles) ethyl] trifluoroacetic acid ammonium (85.4mg,
0.315mmol, 3.0equiv), it reacts at room temperature 24 hours.Reaction solution is diluted with 10mL ethyl acetate, anhydrous with the salt pickling of 1N
It is concentrated after sodium sulphate is dry.Half preparation HPLC separation, MeOH:H2O=9:1 (v/v) affords 3 '-N- [N- (2- oxygen subunit-
2- (3- indoles) ethyl) aminothio formyl] staurosporine (169) 40mg, yield 56%.[α]D 18+248(c 0.07,
CHCl3);1H NMR(500MHz,DMSO-d6) δ 12.02 (d, J=2.0Hz, 1H, NH), 9.30 (d, J=8.0Hz, 1H, ArH),
8.59 (s, 1H, NH), 8.49 (d, J=2.9Hz, 1H, ArH), 8.19 (d, J=7.0Hz, 1H, ArH), 8.05 (d, J=
7.8Hz, 1H, ArH), 7.98 (d, J=8.5Hz, 1H, ArH), 7.92 (t, J=6.0Hz, 1H, NH), 7.72 (d, J=8.3Hz,
1H, ArH), 7.52 (d, J=7.2Hz, 1H, ArH), 7.49 (t, J=7.5Hz, 2H, ArH), 7.36 (t, J=7.4Hz, 1H,
), ArH 7.31 (t, J=7.5Hz, 1H, ArH), 7.25 (dt, J=7.7,1.6Hz, 1H, ArH), 7.21 (dt, J=7.6,
1.5Hz, 1H, ArH), 7.07 (t, J=7.4Hz, 1H, H-1'), 5.94 (d, J=12.2Hz, 1H, H-3'), 4.97-5.09 (m,
2H,H-3”),5.01(s,2H,H-7),4.51(brs,1H,H-4'),2.96(s,3H,3'-NCH3),2.84(s,3H,4'-
OCH3),2.72-2.76(m,1H,H-2'a),2.36(s,3H,6'-CH3), 2.31 (ddd, J=12.5,12.5,6.5Hz 1H,
H-2'b);13C NMR(125MHz,DMSO-d6)δ190.2,182.5,172.1,139.1,136.5,136.4,133.4,
132.8,129.2,125.7,125.5×2,125.1,125.1,123.9,123.0,122.7,121.9,121.5,121.3,
120.4,119.6,119.4,115.4,114.3×2,113.9,112.3,109.2,95.1,83.1,82.5,60.5,54.3,
52.0,45.6,32.8,29.6,27.8;HRESI-MS m/z 683.2462[M+H]+(calcd for C39H35N6O4S,
683.2441).
The preparation of compound 170
Bromoacetophenone (1.97g, 10.0mmol) is dissolved with 40mL chloroform, addition hexamethylenetetramine (1.47g,
10.5mmol), it reacts at room temperature 4 hours.Filter residue 80mL methanol is dissolved after reaction solution filtering, 4mL concentrated hydrochloric acid is added, reflux is anti-
It answers 3 hours.After reaction solution concentration, recrystallizing methanol obtains compound N-(2- oxygen subunit -2- phenethyl) ammonium chloride 1.5g, yield
88%;ESI-MS m/z 136.3[M-Cl]+.By the iodomethane salt of the imidazole fragment of compound 168 (49.0mg,
It 0.068mmol) is dissolved in 2mL DMF, triethylamine (47.2 μ L, 0.34mmol) and N- (2- oxygen subunit -2- phenethyl) chlorine is added
Change ammonium (34.9mg, 0.204mmol), reacts at room temperature 24 hours.Reaction solution is diluted with 10mL ethyl acetate, with the salt pickling of 1N,
It is concentrated after the dry organic phase of anhydrous sodium sulfate.Flash column chromatography separation, petroleum ether: ethyl acetate=1:1 (v/v) affords
3 '-N- [N- (2- oxygen subunit -2- phenethyl) aminothio formyl] staurosporine (170) 18.0mg, yield 41%.[α]D 18+
257(c 0.07,CHCl3);1H NMR(600MHz,DMSO-d6) δ 9.29 (d, J=8.1Hz, 1H, ArH), 8.61 (s, 1H,
), NH 8.06 (d, J=7.8Hz, 1H, ArH), 8.04 (d, J=7.7Hz, 2H, ArH), 8.00 (d, J=8.5Hz, 1H, ArH),
7.74 (d, J=8.2Hz, 1H, ArH), 7.68 (t, J=7.3Hz, 1H, ArH), 7.58 (t, J=7.6Hz, 2H, ArH), 7.49
(t, J=7.6Hz, 2H, ArH), 7.36 (t, J=7.4Hz, 1H, ArH), 7.30 (t, J=7.5Hz, 1H, ArH), 7.08 (t, J
=7.7Hz, 1H, H-1'), 5.85 (m, 1H, H-3'), 5.02-5.15 (m, 2H, H-3 "), 5.01 (s, 2H, H-7), 4.51
(brs,1H,H-4'),2.93(s,3H,3'-NCH3),2.85(s,3H,4'-OCH3),2.70-2.74(m,1H,H-2'a),2.34
(s,3H,6'-CH3), 2.28 (ddd, J=13.0,13.0,7.2Hz, 1H, H-2'b);13CNMR(150MHz,DMSO-d6)δ
195.4,182.5,171.9,139.1,136.3,135.5,133.4,132.8,129.0,128.8×2,127.8×2,
125.7,125.4,125.0,124.9,123.8,122.6,121.4,120.3,119.5,119.4,115.3,114.2,
114.0,109.1,94.9,82.7,82.3,60.4,54.4,51.9,45.5,32.9,29.6,27.6;HRESI-MS m/z
644.2351[M+H]+(calcd for C37H34N5O4S,644.2332).
The preparation of compound 171
Compound 167 (50mg, 0.089mmol) is dissolved in 10mL acetonitrile, is added iodomethane (55 μ L, 0.89mmol),
Room temperature reaction 24 hours.Reaction solution is directly concentrated, with 50mL petroleum ether: the mixed solution of methylene chloride=4:1 (v/v) wash it is pure i.e.
Obtain the imidazole salts 48mg of compound 167, yield 77%;HRESI-MS m/z 575.2393[M–I]+(calcd for
C33H31N6O4,575.2401).The iodomethane salt (48.0mg, 0.068mmol) of the imidazole fragment of compound 167 is dissolved in 2mL
In DMF, triethylamine (47.2 μ L, 0.34mmol) and N- [2- oxygen subunit -2- (3- indoles) ethyl] trifluoroacetic acid ammonium is added
(55.2mg, 0.204mmol) is reacted at room temperature 24 hours.Reaction solution is diluted with 10mL ethyl acetate, anhydrous with the salt pickling of 1N
It is concentrated after the dry organic phase of sodium sulphate.Flash column chromatography separation, methylene chloride: ethyl acetate=1:3 (v/v) affords 3 '-
N- [N- (2- oxygen subunit -2- (3- indoles) ethyl) carbamyl] staurosporine (171) 36.0mg, yield 79%.[α]D 18+105
(c 0.07,CHCl3);1H NMR(600MHz,DMSO-d6) δ 12.08 (d, J=2.5Hz, 1H, NH), 9.29 (d, J=8.0Hz,
1H, ArH), 8.61 (s, 1H, NH), 8.49 (d, J=3.1Hz, 1H, ArH), 8.21 (d, J=7.7Hz, 1H, ArH), 8.04 (d,
J=7.9Hz, 1H, ArH), 7.96 (d, J=8.4Hz, 1H, ArH), 7.70 (d, J=8.4Hz, 2H, ArH), 7.52 (d, J=
8.0Hz, 1H, ArH), 7.48 (t, J=7.6Hz, 2H, ArH), 7.35 (t, J=7.4Hz, 1H, ArH), 7.30 (t, J=
7.5Hz, 1H, ArH), 7.24 (t, J=7.3Hz, 1H, ArH), 7.21 (t, J=7.6Hz, 1H, ArH), 7.02 (t, J=
7.6Hz, 1H, H-1'), 6.84 (t, J=5.3Hz, 1H, NH), 5.00 (s, 2H, H-7), 4.85 (d, J=12.5Hz, 1H, H-
3'), 4.50 (d, J=5.7Hz, 2H, H-3 "), 4.24 (brs, 1H, H-4'), 2.84 (s, 3H, 3'-NCH3),2.75(s,3H,
4'-OCH3),2.61-2.65(m,1H,H-2'a),2.30(s,3H,6'-CH3), 2.22 (ddd, J=12.5,12.5,7.0Hz,
1H,H-2'b);13C NMR(150MHz,DMSO-d6)δ192.0,172.2,158.4,139.2,136.6,136.5,133.5,
132.9,129.4,125.9,125.7,125.6,125.2×2,124.0,123.1,122.8,122.0,121.6,121.4,
120.5,119.7,119.5,115.4,114.3×2,114.0,112.4,109.3,95.1,84.1,82.7,60.6,49.1,
47.6,45.7,30.0,29.7,27.6;HRESI-MS m/z667.2661[M+H]+(calcd for C39H35N6O5,
667.2669).
The preparation of compound 172
The iodomethane salt (48.0mg, 0.068mmol) of the imidazole fragment of compound 167 is dissolved in 2mL DMF, is added three
Ethamine (47.2 μ L, 0.34mmol) and N- (2- oxygen subunit -2- phenethyl) ammonium chloride (34.9mg, 0.204mmol), room temperature reaction
24 hours.Reaction solution is diluted with 10mL ethyl acetate, and with the salt pickling of 1N, anhydrous sodium sulfate is concentrated after drying organic phase.Quickly
Pillar layer separation, methylene chloride: ethyl acetate=2:1 (v/v) affords 3 '-N- [N- (2- oxygen subunit -2- phenethyl) amino
Formyl] staurosporine (172) 20.0mg, yield 47.0%.[α]D 18+174(c 0.07,CHCl3);1H NMR(600MHz,
DMSO-d6) δ 9.28 (d, J=7.9Hz, 1H, ArH), 8.60 (s, 1H, NH), 8.04 (t, J=8.2Hz, 1H, ArH), 8.03
(d, J=8.1Hz, 1H, ArH), 8.03 (d, J=8.3Hz, 1H, ArH), 7.96 (t, J=8.7Hz, 1H, ArH), 7.70 (d, J
=8.5Hz, 1H, ArH), 7.68 (t, J=7.6Hz, 1H, ArH), 7.58 (d, J=7.6Hz, 1H, ArH), 7.57 (d, J=
7.6Hz, 1H, ArH), 7.49 (t, J=6.8Hz, 2H, ArH), 7.35 (t, J=7.5Hz, 1H, ArH), 7.30 (t, J=
7.5Hz, 1H, ArH), 7.02 (t, J=7.6Hz, 1H, H-1'), 6.90 (t, J=5.3Hz, 1H, NH), 5.00 (s, 2H, H-7),
4.81 (d, J=12.5Hz, 1H, H-3'), 4.59 (d, J=5.6Hz, 2H, H-3 "), 4.20 (brs, 1H, H-4'), 2.83 (s,
3H,3'-NCH3),2.72(s,3H,4'-OCH3),2.59-2.63(m,1H,H-2'a),2.29(s,3H,6'-CH3),2.20
(ddd, J=12.5,12.5,6.9Hz, 1H, H-2'b);13CNMR(150MHz,DMSO-d6)δ196.9,172.2,158.2,
139.2,136.5,135.4,133.6,132.9,129.3,129.0×2,128.0×2,125.8,125.6,125.1×2,
123.9,122.8,121.6,120.5,119.7,119.5,115.4,114.3,114.0,109.2,95.0,84.0,82.6,
60.6,49.1,47.7,45.6,30.0,29.7,27.5;HRESI-MS m/z 628.2568[M+H]+(calcd for
C37H34N5O5,628.2560).
The preparation of compound 173
According to the preparation method of compound 169, by the imidazole fragment of compound 168 iodomethane salt (15.0mg,
0.021mmol) with DMF, Et3N and the synthesis of 4- (2- piperazine ethyl) morpholine.Half preparation HPLC separation, MeOH:H2O=4:1 (v/v)
Afford 3 '-N- [4- (2- (4- morpholine) ethyl) the thio formyl of piperazine] staurosporine (173) 8.0mg, yield 47.1%.
[α]D 20+101°(c 0.07,CHCl3);1H NMR(600MHz,DMSO-d6) δ 9.29 (d, J=7.9Hz, 1H, ArH), 8.52
(s, 1H, NH), 8.03 (d, J=7.8Hz, 1H, ArH), 7.94 (d, J=8.6Hz, 1H, ArH), 7.56 (d, J=8.2Hz, 1H,
), ArH 7.48 (t, J=7.8Hz, 1H, ArH), 7.45 (t, J=7.8Hz, 1H, ArH), 7.34 (t, J=7.4Hz, 1H, ArH),
7.27 (t, J=7.5Hz, 1H, ArH), 7.00 (dd, J=8.7,5.5Hz, 1H, H-1'), 5.23-5.27 (m, 1H, H-3'),
4.98(s,2H,H-7),4.68(brs,1H,H-4'),3.91(brs,4H,morpholine-N(CH2-CH2 )2O),3.50-
3.75(m,16H,-N(CH2 -CH2 )2N,piperazine-CH2 -CH2 -morpholine,-N(CH2 -CH2)2O),3.01(s,3H,
3'-NCH3),2.94-2.98(m,1H,H-2'a),2.56(s,3H,4'-OCH3),2.44(s,3H,6'-CH3),2.37-2.41
(m,1H,H-2'b);13C NMR(150MHz,DMSO-d6)δ193.5,172.0,138.5,136.2,132.4,129.6,
125.8,125.5,125.2,125.1,123.9,122.7,121.4,120.4,119.5,119.4,115.2,114.2,
113.1,108.8,94.9,83.0,82.2,63.3×2,59.9,56.3,51.6×2,51.0×2,49.8×2,49.2,
47.6,45.5,37.3,29.2,27.6;ESI-MS m/z 708.4[M+H]+.
The preparation of compound 174
According to the preparation method of compound 169, by the imidazole fragment of compound 168 iodomethane salt (18.0mg,
0.021mmol) with DMF, Et3N and 2,6- difluorobenzene synthetic methylamine.Flash column chromatography separation, methylene chloride: ethyl acetate=4:
1 (v/v) affords 3 '-N- [N- (2,6- difluorobenzyl) aminothio formyl] staurosporine (174) 8.0mg, yield
48.0%.[α]D 20+128°(c 0.07,CHCl3);1H NMR(600MHz,DMSO-d6) δ 9.27 (d, J=7.9Hz, 1H,
), ArH 8.60 (s, 1H, NH), 8.04 (d, J=7.8Hz, 1H, ArH), 7.99 (d, J=8.5Hz, 1H, ArH), 7.93 (t, J=
4.2Hz, 1H, NH), 7.70 (d, J=8.3Hz, 1H, ArH), 7.47 (t, J=7.6Hz, 2H, ArH), 7.39 (m, 1H, ArH),
7.35 (t, J=7.5Hz, 1H, ArH), 7.29 (t, J=7.5Hz, 1H, ArH), 7.06 (t, J=7.7Hz, 2H, ArH), 7.03-
7.06 (m, 1H, H-1'), 5.90 (d, J=12.5Hz, 1H, H-3'), 4.99 (s, 2H, H-7), 4.75-4.88 (m, 2H, H-
3”),4.47(brs,1H,H-4'),2.82(s,3H,3'-NCH3),2.74(s,3H,4'-OCH3),2.66-2.71(m,1H,H-
2'a),2.35(s,3H,6'-CH3),2.20-2.27(m,1H,H-2'b);13C NMR(150MHz,DMSO-d6)δ181.6,
172.0,161.3×2(dd,1JC-F=247.7Hz,3JC-F=8.2Hz), 139.0,136.4,132.8,129.6 (t,3JC-F=
10.5Hz),129.2,125.7,125.4,125.1,125.0,123.8,122.7,121.5,120.4,119.6,119.4,
115.3,114.3(t,2JC-F=18.1Hz), 114.2,113.9,111.5 × 2 (d,2JC-F=20.1Hz), 109.2,95.0,
83.0,82.4,60.3,54.2,45.5,38.3,32.9,29.5,27.7;ESI-MS m/z 652.3[M+H]+.
The preparation of compound 175
According to the preparation method of compound 169, by the imidazole fragment of compound 168 iodomethane salt (18.0mg,
0.021mmol) with DMF, Et3The chloro- 4- fluorobenzene synthetic methylamine of N and 3-.Flash column chromatography separation, methylene chloride: ethyl acetate=
4:1 (v/v) affords 3 '-N- [N- (the chloro- 4- benzyl of 3-) aminothio formyl] staurosporine (175) 8.0mg, yield
48.0%.[α]D 20+166°(c 0.07,CHCl3);1H NMR(600MHz,DMSO-d6) δ 9.28 (d, J=7.9Hz, 1H,
), ArH 8.62 (s, 1H, NH), 8.26 (t, J=4.5Hz, 1H, NH), 8.05 (d, J=7.8Hz, 1H, ArH), 8.00 (d, J=
8.5Hz, 1H, ArH), 7.71 (d, J=8.2Hz, 1H, ArH), 7.51 (d, J=7.1Hz, 1H, ArH), 7.48 (t, J=
7.7Hz, 2H, ArH), 7.38 (t, J=7.8Hz, 1H, ArH), 7.32-7.37 (m, 2H, ArH), 7.29 (t, J=7.5Hz, 1H,
), ArH 7.07 (t, J=7.6Hz, 1H, H-1'), 5.92 (d, J=12.9Hz, 1H, H-3'), 5.00 (s, 2H, H-7), 4.79-
4.87(m,2H,H-3”),4.50(brs,1H,H-4'),2.88(s,3H,3'-NCH3),2.79(s,3H,4'-OCH3),2.68-
2.72(m,1H,H-2'a),2.36(s,3H,6'-CH3), 2.26 (ddd, J=12.9,12.9,6.9Hz, 1H, H-2'b);13C
NMR(150MHz,DMSO-d6)δ182.1,172.0,156.1(d,1JC-F=244.8Hz), 139.1,137.8,136.4,
132.8,129.2,129.1(d,3JC-F=7.4Hz), 127.9 (d,3JC-F=7.4Hz), 125.7,125.4,125.1,125.0,
123.8,122.7,121.5,120.4,119.6,119.4,119.0(d,2JC-F=17.8Hz), 116.6 (d,2JC-F=
20.9Hz),115.3,114.2,113.9,109.2,95.0,83.0,82.4,60.4,54.4,45.5,35.9,33.0,29.6,
27.7;ESI-MS m/z 668.4/670.4[M+H]+.
The preparation of compound 176
According to the preparation method of compound 169, by the imidazole fragment of compound 168 iodomethane salt (18.0mg,
0.021mmol) with DMF, Et3The chloro- 6- fluorophenethylamine synthesis of N and 2-.Flash column chromatography separation, methylene chloride: ethyl acetate=
4:1 (v/v) affords 3 '-N- [N- (the chloro- 6- fluorobenzene ethyl of 2-) aminothio formyl] staurosporine (176) 6.0mg, yield
35.0%.[α]D 20+96°(c 0.07,CHCl3);1H NMR(600MHz,DMSO-d6) δ 9.29 (d, J=8.0Hz, 1H, ArH),
8.60 (s, 1H, NH), 8.06 (d, J=7.7Hz, 1H, ArH), 8.01 (d, J=8.5Hz, 1H, ArH), 7.75 (t, J=
5.4Hz, 1H, NH), 7.69 (d, J=8.3Hz, 1H, ArH), 7.48 (m, 1H, ArH), 7.36 (t, J=7.5Hz, 1H, ArH),
7.27-7.32 (m, 3H, ArH), 7.15-7.19 (m, 1H, ArH), 7.06 (dd, J=8.3,6.6Hz, 1H, H-1'), 5.98 (d,
J=12.1Hz, 1H, H-3'), m, 1H, H-3 " a), 5.00 (s, 2H, H-7), 4.39 (brs, 1H, H-4'), 3.89-3.96 are (
3.70-3.76(m,1H,H-3”b),3.03-3.16(m,2H,H-4”),2.77(s,3H,3'-NCH3),2.68(s,3H,4'-
OCH3),2.67-2.71(m,1H,H-2'a),2.40(s,3H,6'-CH3), 2.25 (ddd, J=12.9,12.9,6.4Hz, 1H,
H-2'b);13C NMR(150MHz,DMSO-d6)δ181.8,172.0,161.4(d,1JC-F=246.5Hz), 138.9,136.3,
134.7(d,3JC-F=6.6Hz), 132.7,129.3,128.9 (d,3JC-F=10.4Hz), 125.7,125.4 × 2,125.3 (d
,2JC-F=25.6Hz), 125.1 × 2,123.8,122.7,121.5,120.4,119.5,119.4,115.2,114.3 (d,2JC-F
=22.3Hz), 114.2,113.7,109.2,95.0,83.3,82.4,60.2,53.9,45.5,43.9,32. 6,29.4,
27.7,26.2;ESI-MS m/z 682.4/684.4[M+H]+.
The preparation of compound 177
According to the preparation method of compound 169, by the imidazole fragment of compound 168 iodomethane salt (18.0mg,
0.021mmol) with DMF, Et3The synthesis of N and 2- m-trifluoromethyl phenyl ethylamine.Flash column chromatography separation, methylene chloride: ethyl acetate
=4:1 (v/v) affords 3 '-N- [N- (2- m-trifluoromethyl phenethyl) aminothio formyl] staurosporine (177)
6.0mg, yield 35.0%.[α]D 20+132°(c 0.07,CHCl3);1HNMR(600MHz,DMSO-d6) δ 9.29 (d, J=
8.0Hz, 1H, ArH), 8.61 (s, 1H, NH), 8.05 (d, J=7.8Hz, 1H, ArH), 7.99 (d, J=8.5Hz, 1H, ArH),
7.71 (t, J=5.6Hz, 1H, NH), 7.70 (d, J=8.0Hz, 1H, ArH), 7.52-7.58 (m, 4H, ArH), 7.48 (t, J=
6.3Hz, 2H, ArH), 7.36 (t, J=7.4Hz, 1H, ArH), 7.30 (t, J=7.5Hz, 1H, ArH), 7.06 (t, J=
7.3Hz, 1H, H-1'), 5.95 (d, J=12.4Hz, 1H, H-3'), 5.00 (s, 2H, H-7), 4.44 (brs, 1H, H-4'),
3.86-3.92(m,1H,H-3”a),3.74-3.80(m,1H,H-3”b),3.98-3.10(m,2H,H-4”),2.76(s,3H,
3'-NCH3),2.70(s,3H,4'-OCH3),2.65-2.70(m,1H,H-2'a),2.38(s,3H,6'-CH3),2.24(ddd,J
=12.9,12.9,6.8Hz, 1H, H-2'b);13C NMR(150MHz,DMSO-d6)δ181.5,172.0,141.0,139.0,
136.3,133.1,132.8,129.4,129.3(q,2JC-F=27.2Hz), 128.9,125.7,125.4,125.2 (q,3JC-F=
5.0Hz),125.1,125.0,123.8,123.4(q,1JC-F=274.7Hz) 122.9 (q,3JC-F=5.7Hz), 122.7,
121.5,120.4,119.5,119.4,115.3,114.2,113.8,109.2,95.0,83.1,82.4,60.2,53.9,
46.4,45.4,34.3,32.6,29.5,27.6;ESI-MS m/z 698.3[M+H]+.
The preparation of compound 178
According to the preparation method of compound 169, by the imidazole fragment of compound 168 iodomethane salt (18.0mg,
0.021mmol) with DMF, Et3N and benzylamine synthesis.Flash column chromatography separation, methylene chloride: ethyl acetate=1:1 (v/v) elution
Obtain 3 '-N- (the thio formyl of N- Benzylamino) staurosporine (178) 9.0mg, yield 73.2%.[α]D 20+54°(c
0.07,CHCl3);1H NMR(600MHz,DMSO-d6) δ 9.28 (d, J=8.0Hz, 1H, ArH), 8.58 (s, 1H, NH), 8.20
(brs, 1H, NH), 8.05 (d, J=7.9Hz, 1H, ArH), 8.00 (d, J=8.3Hz, 1H, ArH), 7.70 (d, J=8.0Hz,
1H, ArH), 7.48 (t, J=7.8Hz, 2H, ArH), 7.36 (t, J=7.8Hz, 1H, ArH), 7.28-7.33 (m, 5H, ArH),
7.21-7.25 (m, 1H, ArH), 7.06 (t, J=7.4Hz, H-1'), 5.98 (d, J=13.5Hz, 1H, H-3'), 5.00 (s,
2H, H-7), 4.89 (d, J=5.6Hz, 2H, H-3 "), 4.49 (s, 1H, H-4'), 2.89 (s, 3H, 3'-NCH3),2.72(s,
3H,4'-OCH3),2.68-2.74(m,1H,H-2'a),2.38(s,3H,6'-CH3),2.24-2.30(m,1H,H-2'b);13C
NMR(150MHz,DMSO-d6)δ182.2,172.0,139.8,139.0,136.4,132.8,129.2,128.2×2,127.2
×2,126.6,125.7,125.4,125.1,125.1,123.8,122.7,121.5,120.4,119.6,119.4,115.3,
114.2,113.8,109.2,95.1,83.2,82.5,60.4,54.3,48.4,45.6,32.9,29.5,27.8;ESI-MS m/
z 616.3[M+H]+.
The preparation of compound 179
According to the preparation method of compound 169, by the imidazole fragment of compound 168 iodomethane salt (18.0mg,
0.021mmol) with DMF, Et3N and 4-Methoxybenzylamine synthesis.Flash column chromatography separation, methylene chloride: ethyl acetate=1:1
(v/v) 3 '-N- [N- (4- mehtoxybenzyl) aminothio formyl] staurosporine (179) 9.0mg, yield are afforded
69.8%.[α]D 20+40°(c 0.07,CHCl3);1H NMR(600MHz,DMSO-d6) δ 9.28 (d, J=7.9Hz, 1H, ArH),
8.58 (s, 1H, NH), 8.13 (t, J=5.4Hz, 1H, NH), 8.05 (d, J=7.8Hz, 1H, ArH), 7.99 (d, J=8.5Hz,
1H, ArH), 7.69 (d, J=8.2Hz, 1H, ArH), 7.48 (t, J=7.5Hz, 2H, ArH), 7.35 (t, J=7.4Hz, 1H,
), ArH 7.30 (t, J=7.6Hz, 1H, ArH), 7.27 (d, J=8.6Hz, 2H, ArH), 7.05 (t, J=7.5Hz, 1H, H-
1'), 6.88 (d, J=8.6Hz, 2H, ArH), 5.00 (s, 2H, H-7), 4.80 (d, J=12.5Hz, 1H, H-3'), 4.47
(brs,1H,H-4'),3.73(brs,2H,H-3”),2.86(s,3H,3'-NCH3),2.74(s,3H,4'-OCH3),2.67-
2.73(m,1H,H-2'a),2.37(s,3H,6'-CH3),2.23-2.29(m,1H,H-2'b);13C NMR(150MHz,DMSO-
d6)δ182.0,172.0,158.2,139.0,136.4,132.8,131.7,129.3,128.6×2,125.7,125.5,
125.2,125.1,123.9,122.7,121.5,120.4,119.6,119.4,115.3,114.2,113.8,113.6×2,
109.2,95.1,83.2,82.5,60.4,55.2,54.3,47.9,45.6,32.8,29.5,27.8;ESI-MSm/z 646.3
[M+H]+.
The preparation of compound 180
According to the preparation method of compound 171, by the imidazole fragment of compound 167 iodomethane salt (15.0mg,
0.021mmol) with DMF, Et3N and the synthesis of 4- (2- piperazine ethyl) morpholine.Flash column chromatography separation, methylene chloride: ethyl acetate
=1:3 (v/v) affords 3 '-N- [4- (2- (4- morpholine) ethyl) piperazine formyl] staurosporine (180) 8.0mg, yield
55.1%.[α]D 20+72°(c 0.07,CHCl3);1H NMR(600MHz,DMSO-d6) δ 9.29 (d, J=7.9Hz, 1H, ArH),
8.58 (s, 1H, NH), 8.06 (d, J=7.5Hz, 1H, ArH), 8.00 (d, J=8.5Hz, 1H, ArH), 7.59 (d, J=
8.3Hz, 1H, ArH), 7.50 (t, J=7.6Hz, 1H, ArH), 7.47 (t, J=7.7Hz, 1H, ArH), 7.36 (t, J=
7.5Hz, 1H, ArH), 7.30 (t, J=7.7Hz, 1H, ArH), 6.97 (dd, J=8.8,5.2Hz, 1H, H-1'), 5.00 (s,
2H, H-7), 4.44 (ddd, J=13.0,4.9,2.2Hz, 1H, H-3'), 4.36 (brs, 1H, H-4'), 3.79 (brs, 4H ,-N
(CH2-CH2 )2O),3.33(brs,8H,-N(CH2 -CH2 )2N),3.14(brs,8H,piperazine-CH2 -CH2 -
morpholine,-N(CH2 -CH2)2O),2.78-2.83(m,1H,H-2'a),2.71(s,3H,3'-NCH3),2.55(s,3H,
4'-OCH3),2.39(s,3H,6'-CH3),2.28-2.34(m,1H,H-2'b);13C NMR(150MHz,DMSO-d6)δ172.4,
163.6,139.0,136.7,133.0,130.0,126.1,126.0,125.8,125.6,124.2,123.1,122.0,
120.9,119.9,119.8,115.4,114.5,113.7,109.4,95.1,84.4,82.7,64.2×2,60.3,52.3×
2,51.8×2,51.3,51.1,50.6,45.9,44.4×2,33.4,29.4,27.8;ESI-MS m/z 708.4[M+H]+.
The preparation of compound 181
According to the preparation method of compound 171, by the imidazole fragment of compound 167 iodomethane salt (15.0mg,
0.021mmol) with DMF, Et3N and 2,6- difluorobenzene synthetic methylamine.Flash column chromatography separation, methylene chloride: ethyl acetate=1:
2 (v/v) afford 3 '-N- [N- (2,6- difluorobenzyl) carbamyl] staurosporine (181) 9.0mg, yield 67.6%.
[α]D 20+48°(c 0.07,CHCl3);1H NMR(600MHz,DMSO-d6) δ 9.28 (d, J=7.9Hz, 1H, ArH), 8.60 (s,
1H, NH), 8.04 (d, J=7.7Hz, 1H, ArH), 7.95 (d, J=8.6Hz, 1H, ArH), 7.65 (d, J=8.2Hz, 1H,
), ArH 7.45-7.48 (m, 2H, ArH), 7.33-7.38 (m, 2H, ArH), 7.29 (t, J=7.5Hz, 1H, ArH), 7.06 (t, J
=7.8Hz, 2H, ArH), 6.98 (t, J=7.6Hz, 1H, H-1'), 6.93 (t, J=4.6Hz, 1H, NH), 4.99 (s, 2H, H-
7), 4.82 (d, J=12.7Hz, 1H, H-3'), 4.34-4.44 (m, 2H, H-3 "), 4.21 (brs, 1H, H-4'), 2.73 (s,
3H,3'-NCH3),2.61(s,3H,4'-OCH3),2.55-2.60(m,1H,H-2'a),2.31(s,3H,6'-CH3),2.16
(ddd, J=13.0,13.0,6.7Hz, 1H, H-2'b);13C NMR(150MHz,DMSO-d6)δ172.1,161.3×2(dd,1JC-F=247.5Hz,3JC-F=9.2Hz), 157.7,139.1,136.4,132.8,129.5 (t,3JC-F=11.0Hz),
129.3,125.8,125.5,125.2,125.1,123.8,122.7,121.5,120.4,119.6,119.4,115.6(t,2JC-F=18.1Hz), 115.3,114.2,113.8,111.5 × 2 (d,2JC-F=19.9Hz), 109.1,95.0,84.0,82.5,
60.3,48.9,45.6,32.7,29.9,29.5,27.5;ESI-MS m/z 636.5[M+H]+.
The preparation of compound 182
According to the preparation method of compound 169, by the imidazole fragment of compound 168 iodomethane salt (50.0mg,
0.070mmol) with DMF, Et3The synthesis of N and 2S- hydroxyl -1- propylamine.Half preparation HPLC separation, MeOH:H2O=4:1 (v/v) elution
Obtain 3 '-N- [N- (2S- hydroxypropyl) aminothio formyl] staurosporine (182) 12.0mg, yield 28.5%.[α]D 20+
31°(c 0.07,CHCl3);1H NMR(600MHz,DMSO-d6) δ 9.30 (d, J=8.0Hz, 1H, ArH), 8.59 (s, 1H,
), NH 8.05 (d, J=7.8Hz, 1H, ArH), 8.00 (d, J=8.5Hz, 1H, ArH), 7.69 (d, J=8.2Hz, 1H, ArH),
7.48 (t, J=7.6Hz, 1H, ArH), 7.47 (d, J=7.6Hz, 1H, ArH), 7.35 (t, J=7.4Hz, 1H, ArH), 7.30
(t, J=7.5Hz, 1H, ArH), 7.06 (t, J=7.6Hz, 1H, H-1'), 5.99 (d, J=12.8Hz, 1H, H-3'), 5.01
(s,2H,H-7),4.75(s,1H,OH),4.45(s,1H,H-4'),3.97(brs,1H,H-4”),3.61-3.66(m,1H,H-
3”a),3.40-3.46(m,1H,H-3”b),2.85(s,3H,3'-NCH3),2.71(s,3H,4'-OCH3),2.66-2.71(m,
1H,H-2'a),2.39(s,3H,6'-CH3), 2.24-2.30 (m, 1H, H-2'b), 1.07 (d, J=6.2Hz, 3H, H-5 ");13C
NMR(150MHz,DMSO-d6)δ181.7,172.0,138.9,136.3,132.7,129.3,125.7,125.4,125.1×2,
123.8,122.7,121.5,120.4,119.5,119.4,115.3,114.2,113.7,109.1,95.0,83.3,82.4,
64.6,60.2,54.0,53.1,45.5,32.5,29.4,27.7,21.2;ESI-MS m/z 584.7[M+H]+.
The preparation of compound 183
By Fradcarbazole C (16.0mg, 0.032mmol) with 5mL methanol dissolve, be added 100.0 μ L triethylamines and
100mg hydroxylamine hydrochloride, ambient temperature overnight reaction.Reaction solution is diluted with ethyl acetate, the dry concentration of anhydrous sodium sulfate after 1N salt pickling.
Half preparation HPLC separation, MeOH:H2O=9:1 (v/v) affords 3 '-N- (N- hydroxyl amino iminomethyl) staurosporine
(183) 12.0mg, yield 71.8%.[α]D 20+15°(c 0.07,MeOH);1H NMR(600MHz,DMSO-d6)δ10.32(s,
1H, NH), 9.27 (d, J=7.9Hz, 1H, ArH), 8.63 (s, 1H, NH), 8.30 (s, 1H, NH), 8.05 (d, J=7.8Hz,
1H, ArH), 7.94 (d, J=8.5Hz, 1H, ArH), 7.70 (d, J=8.2Hz, 1H, ArH), 7.50 (t, J=7.3Hz, 2H,
), ArH 7.36 (t, J=7.4Hz, 1H, ArH), 7.30 (t, J=7.5Hz, 1H, ArH), 6.98 (t, J=7.6Hz, 1H, H-
1'), 5.00 (s, 2H, H-7), 4.47 (brs, 1H, H-3'), 4.18 (brs, 1H, H-4'), 3.16 (s, 1H, OH), 2.93 (s,
3H,3'-NCH3),2.73(s,3H,4'-OCH3),2.70-2.75(m,1H,H-2'a),2.35(s,3H,6'-CH3),2.27-
2.32(m,1H,H-2'b);13C NMR(150MHz,DMSO-d6)δ172.0,158.6,139.4,136.4,132.9,128.9,
125.8,125.5,125.1,124.9,123.9,122.7,121.5,120.5,119.7,119.5,115.4,114.4,
114.3,109.1,95.0,82.5,82.0,60.6,52.0,45.6,31.6,29.4,27.2;ESI-MS m/z 525.2[M+
H]+.
The preparation of compound 184
By staurosporine (46.6mg, 0.1mmol) with 5mL methylene chloride dissolve, sequentially add be added catalytic amount DMAP,
It is small that dicyclohexylcarbodiimide (24.7mg, 0.12mmol) and Chlorambucil (36.4mg, 0.12mmol) react 2 at room temperature
When, it pours into ice water, methylene chloride extraction is concentrated after anhydrous sodium sulfate is dry, silica gel column chromatography separation, petroleum ether: acetic acid second
Ester=1:1 (v/v) affords 3 '-N- [4- [4- (N, N- bis- (2- chloroethyl) amino) phenyl] butyryl] staurosporine (184)
60.1mg, yield 80%.[α]D 20+99°(c 0.07,CHCl3);1H NMR(CD3OD) δ 9.27 (d, J=8.0Hz, 1H, ArH),
7.85 (d, J=7.7Hz, 1H, ArH), 7.73 (d, J=8.5Hz, 1H, ArH), 7.40-7.44 (m, 2H, ArH), 7.27-7.30
(m, 2H, ArH), 7.22 (d, J=8.1Hz, 1H, ArH), 7.03 (d, J=8.5Hz, 2H, ArH), 6.65 (dd, J=9.0,
4.9Hz, 1H, H-1'), 6.59 (d, J=8.5Hz, 2H, ArH), 5.10-5.14 (m, 1H, H-3'), 4.86-4.95 (m, 2H, H-
7), 3.95 (brs, 1H, H-4'), 3.65 (t, J=6.7Hz, 4H ,-N (CH2 -CH2Cl)2), 3.57 (t, J=6.7Hz, 4H ,-N
(CH2-CH2 Cl)2),2.76(s,3H,3'-NCH3), 2.56 (t, J=7.9Hz, 2H, H-2 "), 2.43 (s, 3H, 4'-OCH3),
2.43-2.49(m,1H,H-2'a),2.39(s,3H,6'-CH3), 2.30-2.33 (m, 1H, H-2'b), 1.90 (t, J=
7.8Hz,2H,H-4"),1.53-1.56(m,2H,H-3");13C NMR(CD3OD)δ175.0,174.5,144.9,139.1,
137.0,133.1,131.0,130.8,130.0×2,126.7,126.6,125.9,125.5,124.9,123.8,121.8,
121.0,120.3,119.2,116.4,114.9,112.9,112.6×2,108.4,95.1,85.1,82.9,60.7,53.9×
2,48.9,46.5,40.9×2,34.1,31.7,29.3,28.4,26.0,25.3;ESI-MS m/z752.2/754.3/756.2
[M+H]+.
The preparation of compound 185
I) preparation of N- benzyloxymethyl -2- (3- indoles) -3- bromine maleimide (185a)
2,3- dibromo-maleimide (2.55g, 10.0mmol) is placed in 100mL there-necked flask, with the DMF that 30mL is dry
Dissolution, nitrogen protection are down to 0 DEG C, and sodium hydride is added in two portions, and (480mg, 12mmol, 60% mass fraction are dispersed in paraffin
In).The chloromethyl benzyl methyl ether (2.08mL, 15mmol) of the dry DMF dissolution of 10mL is added after 1h, is warmed to room temperature reaction 2h.Afterwards
It is down to 0 DEG C, 20mL saturated ammonium chloride solution is added and terminates reaction, ethyl acetate extracts, dense after the dry organic phase of anhydrous sodium sulfate
Contracting, pressurize pillar layer separation petroleum ether: ethyl acetate=50:1 (v/v) elutes to obtain compound N-benzyloxymethyl -2,3- dibromo
Maleimide 3.55g, yield 94%.ESIMSm/z 395.4,397.3,399.5[M+Na]+.By magnesium wire (432mg,
It 18.0mmol) is placed in the dry there-necked flask of 100mL, the dry tetrahydrofuran of 4mL, argon gas displacement, rear anhydrous importing bromine is added
Ethane (1.35mL, 18.0mmol) rises to 40 DEG C of reaction 30min after reacting at room temperature 15min.With conduit introduce indoles (2.11g,
18.0mmol), 1h is reacted.N- benzyloxymethyl -2,3- dibromo-maleimide (3.29g, 8.9mmol) is added afterwards, room temperature is anti-
Answer 4h.20mL saturated ammonium chloride solution is added and terminates reaction, ethyl acetate extracts, it is concentrated after the dry organic phase of anhydrous sodium sulfate,
Pressurize pillar layer separation, petroleum ether: ethyl acetate=4:1 (v/v) affords compound 185a 3.46g, yield 94%.1H-
NMR(600MHz,DMSO-d6) δ 8.93 (brs, 1H, NH), 8.03 (t, J=7.8Hz, 1H, ArH), 7.99 (t, J=7.8Hz,
1H, ArH), 7.44 (d, J=7.8Hz, 1H, ArH), 7.37 (s, 1H, ArH), 7.27-7.36 (m, 5H, ArH), 7.25 (d, J=
7.8Hz,1H,ArH),5.17(s,2H,PhCH2OCH2 N),4.67(s,2H,PhCH2 OCH2N);13C NMR(150MHz,DMSO-
d6)δ168.8,166.2,137.8,137.8,136.6,131.5,128.2×2,127.6,127.5×2,124.5,122.6,
122.4,120.6,114.1,112.4,103.7,70.5,67.5;ESIMS m/z 433.0,435.0[M+Na]+.
Ii) the preparation of N- benzyloxymethyl -2- (1- tertbutyloxycarbonyl -3- indoles) -3- bromine maleimide (185b)
Compound 185a (3.15g, 8.39mmol) is dissolved with 50mL tetrahydrofuran, 3.81mL tert-butoxy formic acid is added
Acid anhydride (i.e. di-tert-butyl dicarbonic acid ester Boc2O, 16.78mmol) and 100mg to dimethylamino naphthyridine, react at room temperature 4h.It is directly dense
Pillar layer separation after contracting, petroleum ether: ethyl acetate=20:1 (v/v) affords compound 185b 3.90g, yield 91%.1H-NMR(600MHz,CDCl3) δ 8.23 (s, 1H, ArH), 8.20 (d, J=8.2Hz, 1H, ArH), 7.80 (dd, J=7.3,
8.2Hz, 1H, ArH), 7.41 (t, J=7.3,1H, ArH), 7.26 (d, J=7.3Hz, 1H, ArH), 7.30-7.36 (m, 5H,
ArH),5.17(s,2H,PhCH2OCH2 N),4.68(s,2H,PhCH2 OCH2N),1.71(s,9H,-C(CH3)3);13C NMR
(150MHz,CDCl3)δ168.2,165.6,148.9,137.4,136.7,135.4,130.0,128.5×2,127.9,127.6
×2,126.8,125.4,123.3,122.5,120.9,115.4,108.4,85.2,71.9,67.8,28.1×3;ESIMS m/
z 511.2,513.0[M+H]+.
Iii) N- benzyloxymethyl -2- (1- tertbutyloxycarbonyl -3- indoles) -3- (3- indoles) maleimide (185c)
Preparation
Magnesium wire (366.7mg, 15.32mmol) is placed in the dry there-necked flask of 100mL, the dry tetrahydro furan of 4mL is added
It mutters, argon gas displacement, rear anhydrous importing bromoethane (1.15mL, 15.32mmol) rises to 40 DEG C of reactions after reacting at room temperature 15min
30min.Indoles (1.8g, 15.32mmol) is introduced with conduit, reacts 1h.Compound 185b (3.9g, 7.66mmol) is added afterwards,
React at room temperature 4h.20mL saturated ammonium chloride solution is added and terminates reaction, ethyl acetate extracts, after the dry organic phase of anhydrous sodium sulfate
Concentration, pressurize pillar layer separation, petroleum ether: ethyl acetate=4:1 (v/v) affords compound 185c (3.98g, yield
95%).1H-NMR(600MHz,CDCl3) δ 8.60 (brs, 1H, NH), 8.19 (d, J=7.8Hz, 1H, ArH), 8.09 (s, 1H,
ArH),8.02(s,1H,ArH);7.81 (t, J=7.8Hz, 1H, ArH);7.29~7.41 (m, 5H, ArH);7.16 (dt, J=
8.0,3.0Hz, 1H, ArH), 7.10 (t, J=8.2Hz, 1H, ArH), 7.05 (d, J=7.8,1H, ArH), 6.77~6.83 (m,
3H,ArH),5.23(s,2H,PhCH2OCH2 N),4.72(s,2H,PhCH2 OCH2N),1.68(s,9H,-C(CH3)3);13C NMR
(150MHz,CDCl3)δ171.4,171.2,149.2,137.6,136.0,135.0,131.6,129.9,128.6,128.4×
2,128.0,127.8,127.7×2,125.3,124.6,124.4,122.7,122.6,121.7,121.6,120.7,115.0,
111.6,110.7,106.4,84.5,71.7,67.3,28.1×3;ESIMS m/z 546.2[M–H]–.
Iv the)) preparation of 6-O- triisopropylsilyl-D- glucal (185d)
0.206mL perchloric acid is added slowly in 40mL acetic anhydride, stirs 30min at 40 DEG C, after cool the temperature to 30 DEG C,
10gD- glucose is slowly added to and stirs 30min.Reaction solution is cooled to 10 DEG C, 3.1g red phosphorus, 5.8mL bromine and 3.6mL
Water is successively slowly added to, after be warming up to 30 DEG C continue stir 2h.Reaction solution is quenched with 50mL ice water, ethyl acetate extraction, ester layer
It is concentrated after being dried with anhydrous sodium sulfate.Concentrate 50mL ethyl acetate dissolves, and 0 DEG C is cooled to, by 16.1g zinc powder, 212mg
CuSO4·5H2O and 1.06g sodium acetate is mixed with the aqueous acetic acid of 130mL 60%, is added in reaction solution.0 DEG C of reaction 1h
After be warmed to room temperature reaction 1h, reaction solution is filtered, after be extracted with ethyl acetate, ester layer with anhydrous sodium sulfate it is dry after be concentrated, add
Compression leg chromatographic isolation, petroleum ether: ethyl acetate=3:1 (v/v) affords 10.4g 3,4,6- tri- (O- acetyl group)-D- grape
Glycal (two step yields 68%), ESIMS m/z 273.2 [M+H]+.By 5.2g 3,4,6- tri- (O- acetyl group)-D- glucal
(19.1mmol) is dissolved with 100mL methanol, and 300mg sodium methoxide is added, and reacts at room temperature 1h, and reaction solution adjusts pH with resin cation
It is 7, is concentrated after filtering, pressurization column chromatography (ethyl acetate elution) obtains 2.5g D- glucal, yield 90%;ESIMS m/z
147.1[M+H]+.By 5.6g D- glucal (38.4mmol) 100mL pyridinium dissolution, it is cooled to 0 DEG C, 11.34mL is added
Tri isopropyl chlorosilane (54.22mmol) and 15.6g imidazoles (230.4mmol) react at room temperature 2h, are quenched with 50mL ice water, second
Acetoacetic ester extraction is concentrated after ester layer anhydrous sodium sulfate drying, and pressurize pillar layer separation, petroleum ether: ethyl acetate=5:1 (v/
V) 5.2g compound 185d, yield 46% are afforded.1H-NMR(600MHz,CDCl3) δ 6.30 (d, J=6.0,1H, H-1),
4.72-4.74 (m, 1H, H-2), 4.27-4.29 (m, 1H, H-4), 4.09 (dd, J=12.0,4.8Hz, 1H, H-6a), 3.98
(dd, J=12.0,4.8Hz, 1H, H-6b), 3.85 (dd, J=6.0,3.6Hz, 1H, H-3), 3.81-3.84 (1H, m, H-5),
3.35(brs,1H,OH),2.35(brs,1H,OH),1.12-1.16(m,3H,-Si(CH(CH3)2)3), 1.08 (d, J=
6.0Hz,18H,-Si(CH(CH 3)2)3).ESIMSm/z 303.2[M+H]+.
V) preparation of compound 185e
1.43g compound 185d (4.7mmol) is placed in 100mL there-necked flask, is protected with argon gas, 20mL drying is added
Methylene chloride dissolution, is down to -5 DEG C, sodium hydride (751mg, 31.3mmol, 60% are dispersed in paraffin) is added in two portions, rises to 0
DEG C reaction 20min, be slowly increased to room temperature reaction 1.5h.Again -5 DEG C are down to, Tritox (5.59mL, 56.4mmol) is dissolved in
In 10mL dry methylene chloride, it is introduced into reaction solution with conduit, is warmed to room temperature reaction overnight.Reaction solution is down to-
It 78 DEG C, is added dropwise boron trifluoride ether (17.3mL, 141mmol), reacts 6h at this temperature, the rear bicarbonate that 20mL saturation is added
Sodium solution is slowly increased to room temperature, and methylene chloride extraction is concentrated after anhydrous sodium sulfate is dry, and pressurize pillar layer separation, petroleum ether:
Ethyl acetate=20:1 (v/v) elutes to obtain 1.1g compound 185e, yield 52%.[α]D 20+121°(c 2.02,CH2Cl2);1H-
NMR(600MHz,CDCl3) δ 7.02 (brs, 1H, NH), 6.45 (d, J=4.8,1H, H-1), 4.92-4.94 (m, 1H, H-2),
4.46-4.48 (m, 1H, H-4), 4.16-4.18 (m, 1H, H-3), 4.06 (dd, J=12.0,5.4Hz, 1H, H-6a), 3.96
(dd, J=12.0,5.4Hz, 1H, H-6b), 3.84-3.86 (m, 1H, H-5), 3.17 (brs, 1H, OH), 1.12-1.16 (m,
3H,-Si(CH(CH3)2)3), 1.08 (d, J=6.0Hz, 18H ,-Si (CH (CH 3)2)3);13C-NMR(150MHz,CDCl3):δ
162.3,145.8,97.3,92.6,74.5,67.1,63.4,45.8,17.8×3,11.7×6;ESIMS m/z 444.0[M–
H]–.
Vi) the preparation of compound 185f
1.1g compound 185e (2.4mmol) is dissolved in 30mL methylene chloride, is down to 0 DEG C, be added sodium hydride (244mg,
10.2mmol, 60% is dispersed in paraffin), be slowly increased to room temperature reaction 3h, after be down to 0 DEG C, water is added and terminates reaction, dichloromethane
Alkane extraction is concentrated after anhydrous sodium sulfate is dry, and pressurize pillar layer separation, petroleum ether: ethyl acetate=4:1 (v/v) elutes
595mg compound 185f, yield 75%.[α]D 20+108°(c 3.00,CH2Cl2);1H-NMR(500MHz,CDCl3)δ6.58
(d, J=7.2,1H, H-1), 5.96 (brs, 1H, NH), 4.85-4.87 (m, 2H, H-2and H-4), 4.34 (1H, dd, J=
7.2,4.2Hz, H-3), 4.06 (dd, J=10.2,3.6Hz, 1H, H-6a), 3.96 (dd, J=10.2,3.6Hz, 1H, H-6b),
3.80-3.82(m,1H,H-5),1.12-1.16(m,3H,-Si(CH(CH3)2)3), 1.08 (d, J=6.0Hz, 18H ,-Si (CH
(CH 3)2)3);13C-NMR(125MHz,CDCl3):δ158.7,147.2,98.5,74.0,71.0,61.7,46.1,17.9×3,
11.9×6;ESIMS m/z 326.0[M–H]-.
Vii) the preparation of compound 185g
595mg compound 185f (1.8mmol) is transferred in two-mouth bottle, the dissolution of 20mL methylene chloride is added, is down to -5
DEG C, it is added sodium hydride (218mg, 9.1mmol, 60% are dispersed in paraffin), is warmed to room temperature reaction two hours, it is rear that sulfuric acid two is added
Methyl esters (0.87mL, 9.1mmol) reacts at room temperature 16h, and ice water is added and terminates reaction, methylene chloride extracts, and anhydrous sodium sulfate is dry
After be concentrated, pressurize pillar layer separation, petroleum ether: ethyl acetate=6:1 (v/v) elutes to obtain 600mg compound 185g, yield
97%.[α]D 20+75°(c 1.00,CH2Cl2);1H-NMR(500MHz,CDCl3) δ 6.68 (d, J=7.2Hz, 1H, H-1),
4.93 (1H, dd, J=7.2,4.8Hz, H-2), 4.74-4.76 (m, 1H, H-4), 4.09 (dd, J=13.2,3.6Hz, 1H, H-
6a), 4.07-4.10 (m, 1H, H-3), 3.98 (dd, J=13.2,3.6Hz, 1H, H-6b), 3.61-3.63 (m, 1H, H-5),
2.84(s,3H,N-CH3),1.12-1.16(m,3H,-Si(CH(CH3)2)3), 1.08 (d, J=6.0Hz, 18H ,-Si (CH
(CH 3)2)3);13C-NMR(125MHz,CDCl3)δ157.3,148.5,96.0,74.4,67.7,61.6,51.0,28.8,17.9
×3,11.9×6.ESIMS m/z 342.2[M+H]+.
Viii) the preparation of mixture 185h
415mg compound 185g (1.22mmol) is dissolved in 20mL tetrahydrofuran, is down to 0 DEG C, the dissolution of 20mL water is added
Mercuric acetate (781mg, 2.44mmol), solution becomes yellow, be warmed to room temperature reaction 2h.It is down to 0 DEG C, 60mL water is added, it is rear slow
It is slow that sodium borohydride (371mg, 9.76mmol) is added, there is black generation, carbon dioxide to solution is passed through after 10min and is in neutrality.It takes out
It is extracted with ethyl acetate after filter, is concentrated after anhydrous sodium sulfate is dry, pressurize pillar layer separation, petroleum ether: ethyl acetate=2:1
(v/v) a pair of unsegregated C-1 epimer 185h (337mg, yield 77%) is afforded.1H-NMR(600MHz,
CDCl3) δ 5.31 (m, 1H, H-1), 5.15 (dd, J=6.0,4.8Hz, 1H, H-1), 4.63 (t, J=8.4Hz, 1H, H-4),
4.57 (t, J=8.4Hz, 1H, H-4), 4.03-3.97 (m, 2H, H-6a), 3.91-3.94 (m, 2H, H-6b), 3.86-3.90
(m,2H,H-3),3.78-3.81(m,1H,H-5),3.58-3.61(m,1H,H-5),2.86(s,3H,N-CH3),2.83(s,
3H,N-CH3),2.22-2.26(m,1H,H-2a),2.04-2.08(m,1H,H-2a),1.96-2.01(m,1H,H-2b),1.81
(ddd, J=13.2,8.4,6.0Hz, 1H, H-2b), 1.07-1.12 (m, 6H ,-Si (CH(CH3)2)3), 1.05 (d, J=
7.2Hz,36H,-Si(CH(CH 3)2)3);13C-NMR(150MHz,CDCl3)δ158.4,158.0,91.7,90.6,74.7,
69.0,68.8,68.1,63.2,63.1,53.9,52.9,31.2,29.9,29.2,28.9,18.0×3,17.8×3,12.4×
6,12.0×6;ESIMS m/z 360.2[M+H]+.
Ix) the preparation of compound 185i and 185j
712.5mg compound 185c (1.253mmol) is placed in tri- mouthfuls of reaction flasks of 250mL, 20mL dry four is added
Hydrogen furans dissolution, argon gas protection, is cooled to -78 DEG C, be added the dry tetrahydrofuran dissolution of 10mL triphenylphosphine (655mg,
2.515mmol), 0.5mL DIAD (2.515mmol) is dissolved in 10mL tetrahydrofuran after, is added dropwise to reaction solution, it is anti-at -78 DEG C
The compound 185h (300mg, 0.835mmol) that 10mL tetrahydrofuran dissolves is added after answering 1h, rises to room after -78 DEG C of reaction 2h
Warm reaction overnight.The ammonium chloride solution that saturation is added terminates reaction, is concentrated after ethyl acetate extraction, pressurize pillar layer separation, stone
Oily ether: ethyl acetate=4:1 (v/v) affords 202mg compound 185i (yield 27%) 210mg compound 185j (yield
28%).
185i:[α]D 20+14.1°(c 0.59,CH2Cl2);1H NMR(600MHz,CDCl3) δ 8.15 (d, J=7.8Hz,
1H, ArH), 8.11 (s, 1H, ArH), 7.77 (s, 1H, ArH), 7.40-7.10 (m, 9H, ArH), 6.86 (t, J=7.8Hz, 1H,
), ArH 6.80-6.77 (m, 2H, ArH), 5.72 (dd, J=10.8,1.8Hz, 1H, H-1'), 5.23 (s, 2H, PhCH2OCH2 N),
4.59 (dd, J=9.0,7.2Hz, 1H, H-4'), 4.72 (s, 2H, PhCH2 OCH2N),4.06-4.08(m,1H,H-3'),4.01
(dd, J=12.0,1.8Hz, 1H, H-6'a), 3.95 (dd, J=12.0,2.4Hz, 1H, H-6'b), 3.82-3.84 (m, 1H, H-
5'),2.87(s,3H,N-CH3),2.39-2.41(m,1H,H-2'a),2.27-2.30(m,1H,H-2'b),1.69(s,9H,-C
(CH 3)3),1.04-1.10(m,3H,-Si(CH(CH3)2)3), 1.02 (d, J=6.0Hz ,-Si (CH (CH 3)2)3);13CNMR
(150MHz,CDCl3)δ171.1,171.0,158.5,149.1,137.6,135.7,135.1,130.5,129.0,128.6,
128.3×2,127.7,127.6×2,126.5,125.7,124.6,123.2,122.4×2,121.7,121.5,121.0,
115.1,110.6,110.4,107.0,84.6,79.4,78.3,71.7,67.3,67.0,62.9,55.7,29.5,29.3,
28.1×3,17.8×3,11.8×6;ESIMS m/z 889.6[M+H]+,911.6[M+Na]+;HR-ESIMS m/z
889.4195[M+H]+(calcd for C50H61N4O9Si,889.4208).
185j:[α]D 20-9.1°(c 0.10,CH2Cl2);1H NMR(600MHz,CDCl3) δ 8.15 (d, J=7.2Hz,
1H,ArH),8.13(s,1H,ArH),7.63(s,1H,ArH),7.39-7.42(m,3H,ArH),7.28-7.32(m,3H,
), ArH 7.22-7.25 (m, 1H, ArH), 7.15-7.19 (m, 2H, ArH), 6.95 (t, J=7.2Hz, 1H, ArH), 6.78 (t, J
=7.8Hz, 1H, ArH), 6.70 (d, J=7.8Hz, 1H, ArH), 6.10 (dd, J=10.7,4.5Hz, 1H, H-1'), 5.23
(s,2H,PhCH2OCH2 ), N 4.75 (t, J=7.8Hz, 1H, H-4'), 4.72 (s, 2H, PhCH2 OCH2N),3.99-4.03(m,
1H,H-3'),3.85-3.93(m,2H,H-6'),3.80-3.83(m,1H,H-5'),2.87(s,3H,N-CH3),2.40-2.44
(m,1H,H-2'a),2.06-2.11(m,1H,H-2'b),1.69(s,9H,-C(CH 3)3),1.06-1.12(m,3H,-Si(CH
(CH3)2)3), 1.02 (d, J=6.0Hz, 18H ,-Si (CH (CH 3)2)3);13C NMR(150MHz,CDCl3)δ171.2,171.0,
157.3,149.2,137.8,136.0,135.4,130.8,129.4,128.5×3,127.9,127.8×2,127.3,
126.7,126.0,124.7,123.3,122.5×2,122.0,121.7,115.4,110.6,110.4,107.1,84.8,
78.6,72.5,71.8,68.8,67.4,63.6,53.7,29.8,29.2,28.2×3,18.0×3,11.9×6.ESIMS m/
z 889.5[M+H]+.
X) preparation of compound 185l and 188b
Compound 185i (311mg, 0.350mmol) is dissolved with 40mL toluene, 3.0g silica gel is added, is heated to reflux 5h.
It is cooled to room temperature and is filtered with silica gel, ethyl acetate affords compound 185k (262mg, yield 95%);HR-ESIMS m/z
787.3499[M–H]-(calcd for C45H51N4O7Si,787.3572).With compound 185j (210mg) for raw material, with same
188a (180mg, yield 96%) is made in the method for sample, HR-ESIMS m/z 787.3496 [M-H]-(calcd for
C45H51N4O7Si,787.3572).262mg compound 185k (0.333mmol) 30mL tetrahydrofuran is dissolved, is down to 0 DEG C,
Tetrabutyl ammonium fluoride (1.0mL, 1.0mmol, 1.0M tetrahydrofuran solution) Deprotection is added, reacts at room temperature 1h, ethyl acetate
It washes, is concentrated after ethyl acetate layer anhydrous sodium sulfate drying, pressurize pillar layer separation, petroleum ether after dilution: ethyl acetate=
1:2 (v/v) affords 179mg compound 185l, yield 85%.With 188a (179mg) for raw material, it is made in the same way
188b (136mg, yield 95%).
185l:[α]D 20-2.5°(c 0.01,CH2Cl2);1H NMR(600MHz,CDCl3)δ9.40(s,1H,NH),7.67
(d, J=3.0Hz, 1H, ArH), 7.59 (s, 1H, ArH), 7.36-7.37 (m, 2H, ArH), 7.27-7.32 (m, 4H, ArH),
7.22-7.24 (m, 1H, ArH), 7.17-7.17 (m, 2H, ArH), 7.04 (t, J=7.8Hz, 1H, ArH), 6.87-6.90 (m,
2H, ArH), 6.76 (t, J=7.8Hz, 1H, ArH), 5.67 (dd, J=10.2,1.2Hz, 1H, H-1'), 5.14 (s, 2H,
PhCH2OCH2 N),4.67(s,2H,PhCH2 OCH2), N 4.30 (t, J=7.8Hz, 1H, H-4'), 3.86-3.87 (m, 1H, H-
3'), 3.81 (dd, J=12.0,2.4Hz, 1H, H-6'a), 3.72-3.75 (m, 1H, H-5'), 3.64 (dd, J=12.0,
2.4Hz,1H,H-6'b),2.77(s,3H,N-CH3),2.24-2.29(m,1H,H-2'a),2.12-2.16(m,1H,H-2'b)
;13C NMR(150MHz,CDCl3):δ171.7,171.6,158.6,137.7,136.3,136.0,129.7,129.2,128.5
×2,128.0,127.8×2,127.7,126.6,126.5,124.9,123.3,122.9,122.6,122.2,121.5,
120.4,111.8,110.0,107.6,106.5,78.9,77.6,71.7,67.2,62.1,60.5,55.7,29.6,28.8;
HR-ESIMS m/z 631.2216[M-H]-(calcd for C36H31N4O7,631.2193).
188b:[α]D 20-10°(c 0.10,CH2Cl2);1H NMR(600MHz,CDCl3)δ8.90(s,1H,NH),7.80
(m, 1H, ArH), 7.46-7.21 (m, 10H, ArH), 7.80 (d, J=3.0Hz, 1H, ArH), 7.45-7.46 (m, 2H, ArH),
7.38-7.40(m,3H,ArH),7.34-7.36(m,1H,ArH),7.29-7.32(m,2H,ArH),7.20-7.25(m,2H,
), ArH 7.07-7.10 (m, 1H, ArH), 7.01 (t, J=7.2Hz, 1H, ArH), 6.72-6.74 (m, 2H, ArH), 6.05 (dd,
J=10.4,5.4Hz, 1H, H-1'), 5.14 (s, 2H, PhCH2OCH2 N),4.71(s,2H,PhCH2 OCH2), N 4.60 (t, J=
8.4Hz, 1H, H-4'), 3.92-3.97 (brs, 1H, H-3'), 3.69 (dd, J=12.0,2.4Hz, 1H, H-6'a), 3.60
(dd, J=12.0,4.2Hz, 1H, H-6'b), 3.52-3.54 (m, 1H, H-5'), 2.80 (s, 3H, N-CH3),2.39-2.43
(m,1H,H-2'a),2.25-2.30(m,1H,H-2'b);13C NMR(150MHz,CDCl3):δ171.7×2,157.3,
137.8,136.4,135.8,129.7,129.1,128.5×2,127.9,127.8×2,127.7,127.0,126.8,
124.3,123.3,123.0,122.7,122.3,121.6,120.4,112.0,110.1,107.6,106.5,78.4,76.5,
71.8,68.9,62.1,59.2,53.2,29.8,28.9;HR-ESIMS m/z 631.2218[M-H]-(C36H31N4O7, calculate
Value 631.2193)
Xi) the preparation of compound 185m and 188c
30mg compound 185l (0.047mmol) is dissolved in 1750mL acetone, 3mg catalysis of iodine, 250w high-pressure mercury is added
Light irradiation reacts 12h, and solution becomes green fluorescence from red, and saturated sodium thiosulfate solution, ethyl acetate extraction are added after concentration
It takes, is concentrated after anhydrous sodium sulfate is dry, pressurize pillar layer separation, petroleum ether: ethyl acetate=1:1 (v/v) elutes to obtain product
185m (17mg, yield 57%).With compound 188b (136mg) for raw material, compound 188c is made in the same way
(70mg, yield 51%).
185m:[α]D 20+71.7°(c 0.05,CH2Cl2);1H NMR(600MHz,CDCl3)δ11.0(s,1H,NH),
9.23 (d, J=7.8Hz, 1H, ArH), 8.77 (d, J=7.8Hz, 1H, ArH), 7.54-7.57 (m, 1H, ArH), 7.46-7.48
(m,2H,ArH),7.39-7.41(m,2H,ArH),7.35-7.38(m,2H,ArH),7.28-7.31(m,3H,ArH),6.97
(d, J=8.4Hz, 1H, ArH), 6.16 (dd, J=9.0,1.8Hz, 1H, H-1'), 5.18 (t, J=7.8Hz, 1H, H-4'),
5.13-5.17(m,2H,PhCH2OCH2 N),4.80(s,2H,PhCH2 OCH2), N 4.40 (d, J=12.0Hz, 1H, H-3'),
4.10-4.13(m,2H,H-6'),3.35-3.38(m,1H,H-5'),2.91(s,3H,N-CH3),2.29-2.34(m,1H,H-
2'a),1.98-2.01(m,1H,H-2'b);13C NMR(150MHz,CDCl3):δ169.5,169.0,158.7,140.7,
139.7,137.5,129.7,128.6×2,128.3,128.1×3,128.0,127.6,127.2,126.2,125.0,
122.7,121.7,120.7,120.5,119.5,118.4,118.1,111.2,108.6,79.3,78.3,71.9,66.8,
66.2,60.9,56.2,29.7,29.0;ESIMS m/z 629.3[M-H]-.
188c:[α]D 20-25.7°(c 0.16,CH2Cl2);1H NMR(600MHz,DMSO-d6)δ11.4(s,1H,NH),
9.22 (d, J=7.8Hz, 1H, ArH), 9.10 (d, J=7.8Hz, 1H, ArH), 7.95 (d, J=8.4Hz, 1H, ArH), 7.79
(d, J=8.4Hz, 1H, ArH), 7.73-7.74 (m, 1H, ArH), 7.67-7.68 (m, 1H, ArH), 7.61-7.64 (m, 2H,
), ArH 7.46 (t, J=7.8Hz, 1H, ArH), 7.40 (t, J=7.2Hz, 1H, ArH), 7.32 (d, J=7.2Hz, 1H, ArH),
7.31 (t, J=7.8Hz, 1H, ArH), 7.24 (t, J=7.2Hz, 1H, ArH), 6.94 (dd, J=11.4,4.8Hz, 1H, H-
1'), 5.45 (t, J=5.4Hz, 1H, H-4'), 5.20 (s, 2H, PhCH2OCH2 N),4.83-4.85(m,1H,H-3'),4.77-
4.79(m,1H,OH),4.69(s,2H,PhCH2 OCH2N),4.44-4.48(m,1H,H-5'),3.90-3.96(m,2H,H-6'),
2.67(s,3H,N-CH3),2.48-2.52(m,1H,H-2'a),2.43-2.46(m,1H,H-2'b);13C NMR(150MHz,
DMSO-d6)δ169.6,169.5,157.2,141.2,140.0,138.4,132.3,132.1,129.3×2,129.1,128.8
×2,128.1×3,128.0,125.3,124.9,122.6,122.0,121.5 121.3,120.3,118.8,118.2,
112.8,79.5,75.1,70.1,67.3,65.6,61.4,53.4,29.6,29.0;ESIMS m/z 629.2[M-H]-.
Xii) the preparation of compound 185o and 188e
307mg triphenylphosphine (1.171mmol) and 159mg imidazoles (2.342mmol) 20mL methylene chloride are dissolved, drop
It to 0 DEG C, is added 287mg iodine (2.342mmol), stirs 1h.Compound 185m (123mg, 0.195mmol) is used into 20mL dichloromethane
Alkane dissolution, is slowly added into reaction solution, is warmed to room temperature reaction 6h.After be down to 0 DEG C, water quenching, methylene chloride extraction, nothing is added
It is concentrated after aqueous sodium persulfate is dry, pressurize pillar layer separation, petroleum ether: ethyl acetate=2:1 (v/v) affords compound 185n
(80mg, yield 56%);HR-ESIMS m/z 741.1221[M+H]+(C36H30N4O6I, calculated value 741.1210).With chemical combination
Object 188c (70mg) is raw material, compound 188d (54mg, yield 65%) is made in the same way, HR-ESIMS m/z
741.1225[M+H]+(calcd forC36H30N4O6I,741.1210).30mg compound 185n (0.041mmol) is used into 10mL
Tetrahydrofuran dissolution, is down to 0 DEG C, is added 0.4mL DBU (2.67mmol), and 0 DEG C of reaction 1h rises to 40 DEG C of reaction 1h.Reaction solution
It is diluted with ethyl acetate, is concentrated after washing, pressurize pillar layer separation, petroleum ether: ethyl acetate=1:1 (v/v) affording
It closes object 185o (22.3mg, yield 89%).With compound 188d (54mg) for raw material, compound 188e is made in the same way
(40mg, yield 90%).
185o:[α]D 20+141.3°(c 0.34,CH2Cl2);1H NMR(600MHz,DMSO-d6)δ12.1(s,1H,NH),
9.22 (d, J=7.8Hz, 1H, ArH), 9.08 (d, J=8.4Hz, 1H, ArH), 7.86 (d, J=8.4Hz, 1H, ArH), 7.71
(d, J=8.4Hz, 1H, ArH), 7.60-7.63 (m, 2H, ArH), 7.47 (d, J=7.2Hz, 1H, ArH), 7.41-7.36 (m,
3H, ArH), 7.31 (t, J=7.2Hz, 2H, ArH), 7.24 (t, J=7.2Hz, 1H, ArH), 7.20 (dd, J=12.0,
2.4Hz, 1H, H-1'), 5.40 (d, J=9.6,1H, H-4'), 5.15-5.19 (m, 2H, PhCH2OCH2 N),5.07-5.09(m,
2H,H-6'),4.67(s,2H,PhCH2 OCH2N),4.33-4.36(m,1H,H-3'),2.69(s,3H,N-CH3),2.44-2.51
(m,1H,H-2'a),2.10-2.14(m,1H,H-2'b);13C NMR(150MHz,DMSO-d6)δ169.6,169.5,157.0,
152.9,142.2,140.6,138.4,129.8,129.4,128.8×2,128.2,128.1×3,128.0,125.6,
124.9,123.7,122.5,121.8,121.4,120.5,119.2,118.8,118.4,113.7,112.9,101.2,81.0,
71.4,70.9,67.3,53.1,28.8,28.0;ESIMS m/z 611.3[M-H]-.
188e:[α]D 20-21.4°(c 0.7,CH2Cl2);1H NMR(600MHz,CDCl3)δ9.62(s,1H,NH),9.27
(d, J=8.4Hz, 1H, ArH), 9.10 (d, J=8.4Hz, 1H, ArH), 7.62-7.66 (m, 1H, ArH), 7.51-7.56 (m,
2H, ArH), 7.38-7.46 (m, 4H, ArH), 7.29-7.36 (m, 3H, ArH), 7.22 (t, J=7.2Hz, 1H, ArH), 6.27
D, J=2.0Hz, 1H, H-6 ' a), (dd, J=11.4,2.4Hz, 1H, H-1 '), 5.43 (5.30 (d, J=2.0Hz, 1H, H-6 '
b),5.16-5.22(m,2H,PhCH2OCH2 ), N 5.07 (d, 1H, J=7.2Hz, H-4 '), 4.73 (s, 2H, PhCH2 OCH2N),
4.14-4.18(m,1H,H-3′),2.76(s,3H,N-CH3),2.47-2.53(m,1H,H-2′a),2.38-2.42(m,1H,H-
2′b);13C NMR(150MHz,CDCl3)δ169.4,169.2,156.7,151.3,140.8,139.7,137.7,129.3,
128.5×2,128.2,128.0×3,127.8,127.5,126.3,125.3,122.6,122.2,121.9,121.6,
121.0,119.5,119.3,118.8,111.9,108.7,100.1,81.9,71.6,70.1,66.9,54.4,32.8,29.2;
ESIMS m/z 611.4[M-H]-.
Xiii) the preparation of compound 185p and 188f
By 30mg compound 185o (0.05mmol) tetrahydrofuran/methanol 10mL/1mL dissolution, it is cooled to 0 DEG C, is added
22mg potassium tert-butoxide (0.2mmol), solution become red from yellow, are slowly increased to that 2h is stirred at room temperature, 38mg iodine is added
(0.15mmol), solution colour are deepened, reaction overnight.It is cooled to 0 DEG C, is poured into saturated sodium thiosulfate solution, acetic acid second
Ester extraction is concentrated after anhydrous sodium sulfate is dry, and pressurize pillar layer separation, petroleum ether: ethyl acetate=1:2 (v/v) elutes to produce
Object 185p (20mg, yield 54%).With compound 188e (40mg) for raw material, compound 188f is made in the same way
(20mg, yield 42%).
185p:[α]D 20+45.9°(c 0.05,CH2Cl2);1H NMR(600MHz,DMSO-d6) δ 9.28 (d, J=
7.8Hz, 1H, ArH), 9.03 (d, J=7.8Hz, 1H, ArH), 8.11 (d, J=9.0Hz, 1H, ArH), 8.07 (d, J=
8.4Hz, 1H, ArH), 7.70-7.66 (m, 2H, ArH), 7.56 (t, J=7.2Hz, 1H, ArH), 7.47 (t, J=7.2Hz, 1H,
), ArH 7.36-7.40 (m, 2H, ArH), 7.31 (t, J=7.2Hz, 2H, ArH), 7.24 (t, J=7.2Hz, 1H, ArH), 7.08
(dd, J=9.6,7.2Hz, 1H, H-1'), 5.91 (d, J=12.0Hz, 1H, H-4'), 5.26 (s, 2H, PhCH2OCH 2),4.70
(s,2H,PhCH 2OCH2), 1H, d, J=12.6Hz, H-6 ' a), 4.63 (4.48-4.51 (m, 1H, H-3 '), 3.79 (1H, d, J=
12.6Hz,H-6′b),2.99(s,3H,N-CH3),2.58-2.63(m,1H,H-2′a),2.36-2.42(m,1H,H-2′b);13C
NMR(150MHz,DMSO-d6)δ169.2,169.0,156.7,138.1,135.5,132.4,131.0,128.9,128.5×2,
127.9,127.8×2,127.5,126.2,126.0,125.4,122.7,121.9,121.4,119.7,119.1,118.5,
117.9,116.7,112.5,108.0,93.5,77.7,71.8,70.5,67.0,53.2,29.8,27.8,9.3;ESIMS m/z
761.1[M+Na]+.
188f:[α]D 20-73.4°(c 0.21,CH2Cl2);1H NMR(600MHz,CDCl3) δ 9.41 (d, J=8.4Hz,
1H, ArH), 9.23 (d, J=8.4Hz, 1H, ArH), 8.05 (d, J=8.4Hz, 1H, ArH), 7.61 (t, J=7.2Hz, 2H,
), ArH 7.49 (t, J=7.2Hz, 1H, ArH), 7.43-7.46 (m, 4H, ArH), 7.30 (t, J=7.2Hz, 2H, ArH), 7.22
(t, J=7.2Hz, 1H, ArH), 6.63 (dd, J=10.8,6.0Hz, 1H, H-1 '), 5.34 (s, 2H, PhCH2OCH 2),5.31
(d, J=9.0Hz, 1H, H-4 '), 4.73 (s, 2H, PhCH 2OCH2), d, J=11.4Hz, 1H, H-6 ' a), 4.52 (4.27-4.32
M, 1H, H-2 ' a), 1H, d, J=11.4Hz, H-6 ' b), (m, 1H, H-3 '), 3.96 (2.84-2.89 (2.80 (s, 3H, N-
CH3),2.41-2.48(m,1H,H-2′b);13C NMR(150MHz,CDCl3)δ169.4,169.2,155.4,141.7,137.8
×2,131.8,128.7,128.4×2,128.0,127.9×2,127.8,127.6,126.6,126.1,125.1,122.8,
122.3,121.7,121.3,119.7×2,115.0,114.1,107.1,92.2,79.4,73.5,71.6,67.0,53.4,
29.5,29.0,14.2;ESIMS m/z 761.1[M+Na]+.
Vix) the preparation of compound 185q and 188g
25mg compound 185p (0.034mmol) is dissolved in 20mL benzene, AIBN (3mg) He Siding is added in argon gas protection
Base stannane (0.1mL), is heated to reflux 1h.It is cooled to room temperature concentration, pressurize pillar layer separation, petroleum ether: ethyl acetate=1:2
(v/v) product 185q (17mg, yield 80%) is eluted to obtain.With compound 188f (20mg) for raw material, it is made in the same way
Compound 188g (15mg, yield 96%).
185q:[α]D 20+87.3°(c 0.29,CH2Cl2);1H NMR(600MHz,CDCl3) δ 9.35 (d, J=7.2Hz,
1H, ArH), 9.10 (d, J=7.8Hz, 1H, ArH), 7.64-7.57 (m, 3H, ArH), 7.47-7.42 (m, 4H, ArH), 7.35
(t, J=7.2Hz, 1H, ArH), 7.31 (t, J=7.8Hz, 2H, ArH), 7.23 (t, J=7.2Hz, 1H, ArH), 6.49 (dd, J
=9.6,7.2Hz, 1H, H-1'), 5.63 (d, J=9.6Hz, 1H, H-4'), 5.25-5.33 (m, 2H, PhCH2OCH 2),4.76
(s,2H,PhCH 2OCH2),4.32-4.35(m,1H,H-3'),3.10(s,3H,N-CH3),2.69-2.73(m,1H,H-2'a),
2.36-2.40(m,1H,H-2'b),1.94(s,3H,6'-CH3);13C NMR(150MHz,CDCl3)δ169.4,169.2,
157.3,140.1,138.1,137.7,130.1,128.9,128.5×2,128.0×2,127.8,127.6,127.5,
126.7,126.3,124.7,122.2,122.1,121.5,121.0,119.6,118.5,117.5,112.3,107.8,94.0,
77.2,71.7,71.4,66.9,52.7,29.6,26.2,24.6;ESIMS m/z 613.5[M+H]+.
188g:[α]D 20-24.0°(c 0.19,CH2Cl2);1H NMR(600MHz,CDCl3) δ 9.40 (d, J=7.8Hz,
1H, ArH), 9.24 (d, J=7.8Hz, 1H, ArH), 8.09 (d, J=7.8Hz, 1H, ArH), 7.72-7.74 (m, 1H, ArH),
7.59-7.62 (m, 2H, ArH), 7.53-7.55 (m, 1H, ArH), 7.43-7.47 (m, 3H, ArH), 7.31 (t, J=7.8Hz,
2H, ArH), 7.25 (t, J=7.2Hz, 1H, ArH), 6.59 (dd, J=9.6,6.6Hz, 1H, H-1'), 5.37 (s, 2H,
PhCH2OCH 2), 5.11 (d, J=8.4Hz, 1H, H-4'), 4.77 (s, 2H, PhCH 2OCH2),4.26-4.31(m,1H,H-3'),
2.79-2.85(m,1H,H-2'a),2.77(s,3H,N-CH3),2.42-2.48(m,1H,H-2'b),2.08(s,3H,6'-
CH3);13C NMR(150MHz,CDCl3)δ169.5,169.3,155.8,142.1,137.7×2,131.0,128.9,128.7,
128.4×2,127.9×2,127.8,127.7,127.6,126.6,125.8,124.6,122.3,122.2,121.6,
119.7,119.5,116.4,114.1,107.5,93.3,79.0,71.9,71.6,67.0,53.0,30.0,29.7,29.5;
ESIMS m/z 635.2[M+Na]+.
Xx) the preparation of compound 185 and 188
Compound 185q (10mg, 0.016mmol) is dissolved in 20mL ethyl acetate: in methanol=1:1 (v/v), argon gas is set
The hydroxide palladium carbon of 5mg 20%, rear hydrogen displacement, reaction overnight are added after changing.It is concentrated after being filtered with silica gel, half prepares HPLC
Separation, MeOH:H2O=9:1 (v/v) elute 4 '-O- demethyls-(4 '-O, 3 '-N) carbonyl -7- oxygen subunit -3 ', 4 '-bis- tables
Staurosporine (185) 7mg, yield 89%.With compound 188g (15mg) for raw material, mapping [4 '-O- are made in the same way
Demethyl-(4 '-O, 3 '-N) carbonyl -7- oxygen subunit] staurosporine (188) 11.3mg, yield 96%.
185:[α]D 20+33.5°(c 0.04,CH2Cl2);1H NMR(600MHz,DMSO-d6)δ11.2(s,1H,NH),
9.22 (d, J=7.8Hz, 1H, ArH), 9.00 (d, J=7.8Hz, 1H, ArH), 8.08 (d, J=7.8Hz, 1H, ArH), 7.95
(d, J=7.8Hz, 1H, ArH), 7.65 (t, J=7.8Hz, 1H, ArH), 7.63 (t, J=7.2Hz, 1H, ArH), 7.49 (t, J
=7.8Hz, 1H, ArH), 7.42 (t, J=7.8Hz, 1H, ArH), 6.99 (dd, J=10.2,6.6Hz, 1H, H-1'), 5.76
(d, J=9.6Hz, 1H, H-4'), 4.43-4.46 (m, 1H, H-3'), 2.99 (s, 3H, N-CH3), 2.80 (ddd, J=9.6,
6.0,2.4Hz, 1H, H-2'a), 2.18 (ddd, J=9.6,6.0,2.4Hz, 1H, H-2'b), 1.80 (s, 3H, 6'-CH3);13C
NMR(150MHz,DMSO-d6)δ171.2×2,157.4,140.4,135.9,130.2,129.1,127.8,127.7,125.8,
125.3,124.3,122.0×2,121.5,121.4,120.7,117.6,116.5,114.4,114.3,94.1,77.9,
71.4,52.4,29.5,24.9×2;ESIMS m/z 491.3[M-H]-.
188:[a]D 20-50.2°(c 0.08,CH2Cl2);1H NMR(600MHz,DMSO-d6) δ 9.23 (d, J=9.0Hz,
1H, ArH), 9.04 (d, J=10.2Hz, 1H, ArH), 8.09 (d, J=9.6Hz, 1H, ArH), 7.88 (d, J=10.8Hz, 1H,
), ArH 7.64 (t, J=9.0Hz, 1H, ArH), 7.57-7.60 (m, 1H, ArH), 7.41-7.44 (m, 2H, ArH), 7.01 (dd,
J=12.0,7.2Hz, 1H, H-1'), 5.33 (d, J=10.8Hz, 1H, H-4'), 4.32-4.36 (m, 1H, H-3'), 2.93-
2.99(m,1H,H-2'a),2.57(s,3H,N-CH3),2.04-2.11(m,1H,H-2'b),2.05(s,3H,6'-CH3);13C
NMR(150MHz,DMSO-d6)δ170.8,170.5,155.7,141.4,137.7,130.0,128.2,127.3,126.7,
125.0,124.7,123.5,121.3,121.1×2,121.0,119.9,117.5,116.7,115.8,109.4,92.6,
79.0,75.3,52.0,29.8,28.3×2;ESIMS m/z 515.2[M+Na]+.
The preparation of compound 186,187,189,190
Compound 185 (15mg, 0.030mmol) is dissolved in 10mL methanol, be down to 0 DEG C of addition sodium borohydride (7.6mg,
0.2mmol), it is warmed to room temperature reaction two hours, solution is become colorless by yellow, and saturated ammonium chloride is added after being diluted with ethyl acetate
Solution, ethyl acetate extraction are evaporated after anhydrous sodium sulfate is dry.Crude product is dissolved in 5mL glacial acetic acid, addition zinc powder (20mg,
0.32mmol), 40 DEG C are risen to react 1.5 hours, is cooled to room temperature, is diluted with ethyl acetate, saturated sodium bicarbonate solution washing
Afterwards, it is concentrated after anhydrous sodium sulfate is dry.Partly prepare HPLC chromatogram separation, acetonitrile: water=2:3 (v/v) elutes to obtain 4 '-O- of 5.2mg
Demethyl-(4 '-O, 3 '-N) carbonyl -3 ', 4 '-bis- table staurosporines (186) (yield 36%) and 5.2mg 5- deoxidation -7- oxygen are sub-
Base -4 '-O- demethyl-(4 '-O, 3 '-N) carbonyl -3 ', 4 '-bis- table staurosporines (187) (yield 36%).With compound 188
(11mg) is raw material, and 4.0mg mapping [4 '-O- demethyls-(4 '-O, 3 '-N) carbonyl] staurosporine is made in the same way
(189) (yield 38%) and 4.0mg mapping [5- deoxidation -7- oxygen -4 '-O- of subunit demethyl-(4 '-O, 3 '-N) carbonyl] cross
Spore alkali (190) (yield 38%).
186:[α]D 20+101.0°(c 0.10,MeOH);1H NMR(600MHz,CDCl3) δ 9.32 (d, J=8.0Hz, 1H,
), ArH 7.97 (d, J=7.7Hz, 1H, ArH), 7.68 (d, J=8.3Hz, 1H, ArH), 7.56 (m, 1H, ArH), 7.52-7.58
(m, 2H, ArH), 7.43-7.48 (m, 2H, ArH), 7.38 (t, J=7.5Hz, 1H, ArH), 6.57 (s, 1H, NH), 6.49 (dd,
J=9.6,6.8Hz, 1H, H-1'), 5.59 (d, J=9.4Hz, 1H, H-4'), 5.04 (d, J=16.7Hz, 1H, H-7a), 4.92
(d, J=16.7Hz, 1H, H-7b), 4.28-4.30 (m, 1H, H-3'), 3.06 (s, 3H, N-CH3),2.49-2.55(m,1H,H-
2'a),2.22-2.28(m,1H,H-2'b),1.94(s,3H,6'-CH3);13CNMR(125MHz,CDCl3)δ172.7,157.4,
139.2,137.2,133.2,129.3,127.2,126.3,125.8×2,125.5,123.5,122.1,121.8,120.8,
120.3,117.8,115.8,113.0,107.5,93.9,77.2,71.7,52.9,46.1,29.6,26.2,24.7;HR-
ESIMS m/z 479.1738[M+H]+(calcd for C28H23N4O4 479.1719).
187:[α]D 20+102.6°(c 0.05,MeOH);1H NMR(600MHz,CDCl3) δ 9.60 (d, J=7.7Hz, 1H,
), ArH 7.98 (d, J=7.7Hz, 1H, ArH), 7.61 (d, J=8.4Hz, 1H, ArH), 7.56 (t, J=7.7Hz, 1H, ArH),
7.54 (t, J=8.4Hz, 1H, ArH), 7.51 (d, J=8.4Hz, 1H, ArH), 7.44 (t, J=7.3Hz, 1H, ArH), 7.40
(t, J=7.4Hz, 1H, ArH), 6.50 (dd, J=9.4,6.9Hz, 1H, H-1'), 6.40 (s, 1H, NH), 5.67 (d, J=
9.5Hz, 1H, H-4'), 4.99-5.07 (m, 2H, H-5), 4.30 (d, J=9.5Hz, 1H, H-3'), 3.08 (s, 3H, N-CH3),
2.59-2.64(m,1H,H-2'a),2.37-2.43(m,1H,H-2'b),1.90(s,3H,6'-CH3);13C NMR(150MHz,
CDCl3)δ173.1,157.5,139.3,137.3,134.7,128.2,127.7,126.8,126.2×2,125.9,123.2,
122.0,121.5,121.1,119.6,118.9,115.3,111.9,108.4,94.0,77.2,71.8,52.9,45.7,
29.6,26.4,24.4;HR-ESIMS m/z 479.1706[M+H]+(calcd for C28H23N4O4,479.1719).
189:[α]D 20-72.8°(c 0.10,MeOH);1H NMR(600MHz,DMSO-d6) δ 9.23 (d, J=7.6Hz,
1H, ArH), 8.67 (s, 1H, NH), 8.06 (d, J=8.5Hz, 1H, ArH), 8.03 (d, J=7.4Hz, 1H, ArH), 7.79 (d,
J=8.4Hz, 1H, ArH), 7.50-7.53 (m, 2H, ArH), 7.37-7.40 (m, 1H, ArH), 7.29-7.32 (m, 1H, ArH),
6.96 (dd, J=9.9,6.3Hz, 1H, H-1'), 5.31 (d, J=8.8Hz, 1H, H-4'), 4.95-5.03 (m, 2H, H-7),
4.34 (ddd, J=12.1,8.8,5.1Hz, 1H, H-3'), 2.90-2.94 (m, 1H, H-2'a), 2.58 (s, 3H, N-CH3),
2.03(s,3H,6'-CH3),1.97-2.02(m,1H,H-2'b);13C NMR(150MHz,DMSO-d6)δ171.7,155.7,
140.4,136.5,133.0,128.7,125.8,125.6,125.1,125.0,124.7,122.4,121.3,121.1,
120.4,119.7,116.7,115.9,115.5,108.8,92.6,79.2,75.5,52.1,45.4,29.6,28.8,28.3;
HR-ESIMS m/z 479.1708[M+H]+(calcd for C28H23N4O4 479.1719).
190:[α]D 20-75.6°(c 0.10,MeOH);1H NMR(600MHz,DMSO-d6) δ 9.51 (d, J=7.9Hz,
1H, ArH), 8.62 (s, 1H, NH), 8.10 (d, J=7.8Hz, 1H, ArH), 8.01 (d, J=8.5Hz, 1H, ArH), 7.84 (d,
J=8.2Hz, 1H, ArH), 7.56 (t, J=7.7Hz, 1H, ArH), 7.45-7.48 (m, 1H, ArH), 7.38 (t, J=7.4Hz,
1H, ArH), 7.30 (t, J=7.5Hz, 1H, ArH), 6.96 (dd, J=9.8,6.3Hz, 1H, H-1'), 5.29 (d, J=
8.7Hz, 1H, H-4'), 4.96-5.01 (m, 2H, H-5), 4.34 (ddd, J=12.1,8.8,5.1Hz, 1H, H-3'), 2.91-
2.96(m,1H,H-2'a),2.59(3H,s,N-CH3),2.05-2.10(m,1H,H-2'b),1.99(s,3H,6'-CH3);13C
NMR(150MHz,DMSO-d6)δ171.9,155.8,140.4,136.6,134.4,127.0,126.6,125.70,125.5,
125.1×2,122.1,121.9,120.6,120.1,119.4,117.6,116.1,114.3,109.3,92.6,79.2,
75.5,52.2,44.9,29.5,28.8,28.3;HR-ESIMS m/z 479.1722[M+H]+(calcd for C28H23N4O4
479.1719).
The preparation of compound 191
I) preparation of 6-O- triisopropylsilyl-L- glucal (191a)
0.041mL perchloric acid is added slowly in 40mL acetic anhydride, stirs 30min at 40 DEG C, after cool the temperature to 30 DEG C,
2gL- glucose is added slowly and continues to stir 30min.Reaction solution is cooled to 10 DEG C, be successively slowly added to 0.62g red phosphorus,
1.16mL bromine and 0.72mL water are warming up to 30 DEG C and continue to stir 2h.With 10mL ice water quenching reaction, ethyl acetate extraction, nothing
It is concentrated after aqueous sodium persulfate is dry.Concentrate 50mL ethyl acetate dissolves, and 0 DEG C is cooled to, by 3.22g zinc powder, 42.4mg
CuSO4·5H2The aqueous acetic acid of O and 0.21g sodium acetate 60% volume fraction of 30mL is added in reaction solution after mixing, and 0
DEG C reaction 1h after be warmed to room temperature reaction 1h.Reaction solution is filtered, filtrate is extracted with ethyl acetate, dense after anhydrous sodium sulfate is dry
Contracting, pressurize pillar layer separation, petroleum ether: ethyl acetate=3:1 (v/v) affords 2.5g 3,4,6- tri- (O- acetyl group)-L-
Glucal, two step yields 82%;ESIMS m/z 273.3[M+H]+.By 3,4,6- tri- (O- acetyl group)-L- glucal
(2.5g, 9.19mmol) is dissolved with 100mL methanol, and 60mg sodium methoxide is added, and reacts at room temperature 1h, reaction solution resin cation tune
Saving pH is 7, is concentrated after filtering, and pressurization pillar layer separation (ethyl acetate elution) obtains 1.3gL- glucal, yield 97%;
ESIMS m/z 147.2[M+H]+.Compound L-glucal (1.3g, 8.9mmol) 30mL pyridinium dissolution, is cooled to 0 DEG C,
Tri isopropyl chlorosilane (3.78ml, 17.8mmol) and imidazoles (3.61g, 53.4mmol) is added, 2h is reacted at room temperature, with 50mL ice
Water quenching is gone out, and ethyl acetate extraction is concentrated after anhydrous sodium sulfate is dry, and pressurize pillar layer separation, petroleum ether: ethyl acetate=5:1
(v/v) compound 191a 1.41g, yield 52% are afforded.1H-NMR(500MHz,CDCl3) δ 6.27 (d, J=6.0Hz,
1H, H-1), 4.67-4.70 (m, 1H, H-2), 4.26 (brs, 1H, H-4), 4.04 (dd, J=12.0,4.8Hz, 1H, H-6a),
3.98 (dd, J=12.0,4.8Hz, 1H, H-6b), 3.79-3.82 (m, 2H, H-3and H-5), 1.09-1.16 (m, 3H,
((CH3)2CH)3), Si- 1.06 (d, J=6.0Hz, 18H, ((CH 3)2CH)3Si-).13C-NMR(125MHz,CDCl3)δ143.9,
102.5,76.5,72.5,69.4,64.4,17.8×3,11.8×6;ESIMS m/z 325.1[M+Na]+.
Ii) the preparation of compound 191b
1.41g compound 191a (4.7mmol) is placed in 100mL there-necked flask, the lower addition 20mL drying of argon gas protection
Methylene chloride stirs molten, is down to -5 DEG C, sodium hydride is added in two portions, and (740mg, 18.5mmol, 60% mass fraction are dispersed in paraffin
In), 0 DEG C of reaction 20min is risen to, room temperature is slowly increased to the reaction was continued 1.5h.Again -5 DEG C are down to, by Tritox (5.51mL,
It 55.6mmol) is dissolved in the dry methylene chloride of 10mL, is introduced into reaction solution with conduit, is warmed to room temperature reaction overnight.
Reaction solution is down to -78 DEG C, is added dropwise boron trifluoride ether (17.0mL, 139mmol), reacts 6h at this temperature, it is rear to be added
20mL saturated sodium bicarbonate solution quenching reaction is slowly increased to room temperature, and methylene chloride extraction is concentrated after anhydrous sodium sulfate is dry,
Pressurize pillar layer separation, petroleum ether: ethyl acetate=20:1 (v/v) affords 0.88g compound 191b, yield 42%.
[α]D 20-71.6°(c 0.90,CH2Cl2);1H-NMR(500MHz,CDCl3) δ 7.02 (brs, 1H, NH), 6.45 (d, J=6.0,
1H, H-1), 4.93 (dd, J=6.0,5.0Hz, 1H, H-2), 4.46-4.49 (m, 1H, H-4), 4.16-4.18 (m, 1H, H-3),
4.06 (dd, J=12.0,5.4Hz, 1H, H-6a), 3.96 (dd, J=12.0,5.4Hz, 1H, H-6b), 3.82-3.86 (m, 1H,
H-5),1.10-1.17(m,3H,((CH3)2CH)3), Si- 1.07 (d, J=6.0Hz, 18H, ((CH 3)2CH)3Si-);13C-NMR
(125MHz,CDCl3)δ162.4,145.8,97.3,92.6,74.6,67.3,63.5,45.9,17.9×3,11.8×6;
ESIMS m/z446.1/448.2/490.1[M+H]+.
Iii) the preparation of compound 191c
Compound 191b (0.88g, 1.98mmol) is dissolved in 30mL methylene chloride, is down to 0 DEG C, sodium hydride is added
(194mg, 4.95mmol, 60% are dispersed in paraffin) is slowly increased to room temperature reaction 3h, after be down to 0 DEG C, be added water terminate it is anti-
It answers, methylene chloride extraction is concentrated after anhydrous sodium sulfate is dry, and pressurize pillar layer separation, petroleum ether: ethyl acetate=4:1 (v/v)
Elute to obtain 537mg product 191c, yield 84%.[α]D 20-86.0°(c 0.50,CH2Cl2);1H-NMR(500MHz,CDCl3)δ
6.59 (d, J=6.0,1H, H-1), 5.87 (brs, 1H, NH), 4.85-4.88 (m, 2H, H-2/H-4), 4.34 (dd, J=7.5,
4.0Hz, 1H, H-3), 4.04 (dd, J=11.0,3.0Hz, 1H, H-6a), 3.99 (dd, J=11.0,3.60Hz, 1H, H-6b),
3.82-3.84(m,1H,H-5),1.09-1.16(m,3H,((CH3)2CH)3), Si- 1.06 (d, J=6.0Hz, 18H, ((CH 3)2CH)3Si-);13C-NMR(125MHz,CDCl3)δ158.5,147.2,98.5,74.1,71.1,61.8,46.1,17.9×3,
11.9×6;ESIMS m/z 326.1[M–H]–.
Iv) the preparation of compound 191d
Compound 191c (537mg, 1.64mmol) is transferred in two-mouth bottle, the dissolution of 20mL methylene chloride is added, be down to-
It 5 DEG C, is added sodium hydride (197mg, 4.92mmol, 60% are dispersed in paraffin), is warmed to room temperature reaction two hours, sulfuric acid is added afterwards
Dimethyl ester (0.79mL, 8.21mmol) reacts at room temperature 16h, and ice water is added and terminates reaction, methylene chloride extraction, anhydrous sodium sulfate
It is concentrated after drying, pressurize pillar layer separation, petroleum ether: ethyl acetate=6:1 (v/v) elutes to obtain 467mg compound 191d, yield
83%.[α]D 20-77°(c 1.00,CH2Cl2);1H-NMR(500MHz,CDCl3) δ 6.67 (d, J=6.0Hz, 1H, H-1),
4.93 (dd, J=6.0,4.0Hz, 1H, H-2), 4.74 (1H, dd, J=9.0,7.5Hz, H-4), 4.05-4.07 (m, 1H, H-
3), 4.04 (dd, J=12.0,2.5Hz, 1H, H-6a), 4.00 (dd, J=12.0,2.5Hz, 1H, H-6b), 3.60-3.63
(1H,m,H-5),2.84(s,3H,N-CH3)1.08-1.15(m,3H,((CH3)2CH)3Si-), 1.06 (d, J=6.0Hz, 18H,
((CH 3)2CH)3Si-);13C-NMR(125MHz,CDCl3)δ157.3,148.4,96.0,74.5,67.8,61.7,51.0,
28.6,17.9×3,11.9×6;ESIMS m/z 342.2[M+H]+.
V) preparation of compound 191e
Compound 191d (467mg, 1.37mmol) is dissolved in 20mL tetrahydrofuran, is down to 0 DEG C, the dissolution of 20mL water is added
Mercuric acetate (876mg, 2.74mmol), solution becomes yellow, be warmed to room temperature reaction 2h.It is down to 0 DEG C, 60mL water is added, it is rear slow
It is slow that sodium borohydride (416mg, 11.0mmol) is added, carbon dioxide to solution, which is passed through, after 10min is in neutrality.Acetic acid second is used after suction filtration
Ester extraction is concentrated after anhydrous sodium sulfate is dry, and pressurize pillar layer separation, petroleum ether: ethyl acetate=2:1 (v/v) affords
400mg a pair of 1- potential difference to isomer mixture 191e, yield 81%.1H-NMR(500MHz,CDCl3):δ5.30-5.33
(m,1H,H-1),5.15-5.18(m,1H,H-1),4.64-4.68(m,1H,H-4),4.556-4.60(m,1H,H-4),4.04-
3.86(m,6H,H-3,H-6a,H-6b,),3.77-3.82(m,1H,H-5),3.60-3.63(m,1H,H-5),2.87(s,3H,
N-CH3),2.84(s,3H,N-CH3),2.22-2.27(m,1H,H-2a),2.05-2.09(m,1H,H-2a),1.97-2.02(m,
1H,H-2b),1.79-1.85(m,1H,H-2b),1.08-1.15(m,6H,((CH3)2CH)3Si-), 1.07 (d, J=7.2Hz,
36H,((CH 3)2CH)3Si-).13C-NMR(125MHz,CDCl3)δ158.2,157.8,91.6,90.6,74.5,69.0,68.7,
68.1,63.2,63.0,53.7,52.8,31.1,29.9,29.1,28.8,17.9×6,12.0×12;ESIMS m/z360.2
[M+H]+.
Vi) the preparation of compound 191f and 191g
870mg compound 185c (1.59mmol) is placed in tri- mouthfuls of reaction flasks of 250mL, the dry tetrahydro furan of 20mL is added
Mutter dissolution, argon gas protection is cooled to -78 DEG C, be added the dry tetrahydrofuran dissolution of 10mL triphenylphosphine (833mg,
3.18mmol), 0.62mL DIAD (3.18mmol) is dissolved in 10mL tetrahydrofuran after, is added dropwise to reaction solution, it is anti-at -78 DEG C
The compound 191e (380mg, 1.06mmol) that 10mL tetrahydrofuran dissolves is added after answering 1h, rises to room after -78 DEG C of reaction 2h
Warm reaction overnight.The ammonium chloride solution that saturation is added terminates reaction, is concentrated after ethyl acetate extraction, pressurize pillar layer separation, stone
Oily ether: ethyl acetate=4:1 (v/v) affords 226mg compound 191f (yield 24%) and 230mg compound 191g (is received
Rate 25%).
191f:[α]D 20-14.2°(c 1.0,CH2Cl2);1H NMR(500MHz,CDCl3) δ 8.15 (d, J=7.8Hz,
1H,ArH),8.11(s,1H,ArH),7.77(s,1H,ArH),7.36-7.40(m,3H,ArH),7.29-7.32(m,2H,
), ArH 7.23-7.25 (m, 1H, ArH), 7.15-7.18 (m, 1H, ArH), 7.10-7.12 (m, 2H, ArH), 6.86 (t, J=
7.8Hz, 1H, ArH), 6.77-6.81 (m, 2H, ArH), 5.71 (dd, J=10.5,2.0Hz, 1H, H-1'), 5.20-5.25 (m,
2H,PhCH2OCH 2N),4.71(s,2H,PhCH 2OCH2), N 4.69 (dd, J=9.0,7.5Hz, 1H, H-4'), 4.05-4.09
(1H, m, H-3'), 4.00 (dd, J=12.0,2.0Hz, 1H, H-6'a), 3.95 (dd, J=12.0,2.0Hz, 1H, H-6'b),
3.82-3.85(1H,m,H-5'),2.88(s,3H,N-CH3),2.39-2.44(m,1H,H-2'a),2.27-2.30(m,1H,H-
2'b),1.69(s,9H,(CH 3)3CO-),1.05-1.11(m,3H,((CH3)2CH)3Si-), 1.02 (d, J=6.0Hz, 18H,
((CH 3)2CH)3Si-).13C NMR(125MHz,CDCl3)δ171.1,171.0,158.5,149.2,137.7,135.8,
135.2,130.6,129.0,128.6,128.4×2,127.7×2,127.6×2,126.6,125.8,124.6,123.2,
122.5,122.2,121.8,121.6,115.1,110.6,110.5,107.1,84.6,79.5,78.4,71.7,67.4,
67.1,63.0,55.8,29.6,29.4,28.2×3,17.9×3,11.9×6;ESIMS m/z 889.6[M+H]+
191g:[α]D 20+9.3°(c 0.40,CH2Cl2);1H NMR(500MHz,CDCl3) δ 8.15 (d, J=7.2Hz,
1H,ArH),8.13(s,1H,ArH),7.64(s,1H,ArH),7.39-7.42(m,3H,ArH),7.28-7.33(m,3H,
), ArH 7.22-7.25 (m, 1H, ArH), 7.15-7.20 (m, 2H, ArH), 6.95 (t, J=7.0Hz, 1H, ArH), 6.78 (t, J
=8.0Hz, 1H, ArH), 6.72 (d, J=8.0Hz, 1H, ArH), 6.10 (dd, J=10.0,6.0Hz, 1H, H-1'), 5.23
(s,2H,PhCH2OCH 2), N 4.76 (t, J=7.8Hz, 1H, H-4'), 4.72 (s, 2H, PhCH 2OCH2N),3.99-4.04(m,
1H,H-3'),3.85-3.94(m,2H,H-6'),3.80-3.83(m,1H,H-5'),2.87(s,3H,N-CH3),2.39-2.45
(m,1H,H-2'a),2.05-2.13(m,1H,H-2'b),1.69(s,9H,(CH 3)3CO-),1.05-1.10(m,3H,((CH3)2CH)3), Si- 1.02 (d, J=6.0Hz, 18H, ((CH 3)2CH)3Si-).13C NMR(125MHz,CDCl3)δ171.0,170.9,
157.2,149.2,137.8,136.0,135.4,130.8,129.3,128.4×3,127.7,127.6×2,127.3,
126.7,126.0,124.6,123.2,122.4×2,121.9,121.6,115.3,110.5,110.3,107.1,84.7,
78.6,72.4,71.8,68.8,67.4,63.5,53.6,29.7,29.2,28.2×3,17.9×3,11.9×6;ESIMS m/
z 889.6[M+H]+.
Vii) the preparation of compound 191i and 194b
Compound 191f (226mg, 0.254mmol) is dissolved with 40mL toluene, 3.0g silica gel is added, is heated to reflux 5h.
It is cooled to room temperature and is filtered with silica gel, ethyl acetate affords 200mg compound 191h, yield 100%;ESIMS m/z
787.4[M+H]+.With compound 191g (226mg) for raw material, compound 194a (201mg, yield are made in the same way
100%);ESIMS m/z 787.5[M+H]+.Compound 191h (200mg, 0.253mmol) is dissolved with 30mL tetrahydrofuran,
It is down to 0 DEG C, is added tetrabutyl ammonium fluoride (THF solution of 1.0mL, 1.0mmol, 1.0M), 1h, ethyl acetate dilution are reacted at room temperature
After wash, ethyl acetate layer with anhydrous sodium sulfate it is dry after be concentrated, pressurize pillar layer separation, petroleum ether: ethyl acetate=1:2
(v/v) 158mg compound 191i, yield 98% are afforded.With 194a (201mg) for raw material, it is made in the same way
152mg compound 194b, yield 94%.
191i:[α]D 20+11.6°(c 0.55,CH2Cl2);1H NMR(500MHz,CDCl3)δ8.82(brs,1H,NH),
7.69 (d, J=3.0Hz, 1H, ArH), 7.62 (s, 1H, ArH), 7.37-7.38 (m, 2H, ArH), 7.28-7.33 (m, 4H,
), ArH 7.23-7.26 (m, 1H, ArH), 7.15-7.19 (m, 1H, ArH), 7.14 (d, J=7.5Hz, 1H, ArH), 7.07-
7.10 (m, 1H, ArH), 6.-6.92 (m, 2H, ArH), 6.77-6.80 (m, 1H, ArH), 5.71 (dd, J=10.5,2.0Hz,
1H,H-1'),5.17(s,2H,PhCH2OCH2 N),4.68(s,2H,PhCH2 OCH2N), 4.46 (1H, dd, J=9.0,7.0Hz,
H-4'),3.92-3.95(m,1H,H-3'),3.85-3.87(m,1H,H-6'a),3.76-3.79(m,1H,H-5'),3.66-
3.69(m,1H,H-6'b),2.82(s,3H,N-CH3),2.30-2.36(m,1H,H-2'a),2.20-2.23(m,1H,H-2'
b).13C NMR(125MHz,CDCl3)δ171.6,171.5,158.4,137.7,136.1,136.0,129.2,129.0,128.4
×2,127.8,127.7×2,127.6,126.8,126.5,124.8,123.2,122.8,122.7,122.2,121.4,
120.4,111.5,109.8,107.6,106.7,78.8,77.6,71.6,67.2,62.1,60.5,55.7,29.5,28.9;
ESIMS m/z 631.3[M-H]-.
194b:[α]D 20+19.3°(c 0.25,CH2Cl2);1H NMR(500MHz,CDCl3)δ8.90(s,1H,NH),
7.83 (d, J=3.0Hz, 1H, ArH), 7.47 (s, 1H, ArH), 7.45 (d, J=7.5Hz, 1H, ArH), 7.38-7.41 (m,
3H, ArH), 7.36 (d, J=8.0Hz, 1H, ArH), 7.29-7.32 (m, 2H, ArH), 7.20-7.25 (m, 2H, ArH), 7.08-
7.11 (m, 1H, ArH), 7.00-7.03 (t, J=7.2Hz, 1H, ArH), 6.73-6.76 (m, 2H, ArH), 6.06 (dd, J=
10.0,5.0Hz,1H,H-1'),5.20-5.25(m,2H,PhCH2OCH2 N),4.72(s,2H,PhCH2 OCH2N),4.62(t,J
=9.5Hz, 1H, H-4'), 3.94-3.99 (m, 1H, H-3'), 3.71-3.73 (m, 1H, H-6'a), 3.61-3.63 (m, 1H, H-
6'b),3.54-3.57(m,1H,H-5'),2.81(s,3H,N-CH3),2.42-2.47(m,1H,H-2'a),2.01-2.08(m,
1H,H-2'b);13C NMR(125MHz,CDCl3)δ171.5×2,157.0,137.8,136.2,135.8,129.3,129.0,
128.4×2,127.7×3,127.4,127.2,126.8,124.3,123.2,122.8,122.7,122.2,121.5,
120.4,111.6,109.8,107.7,106.7,78.3,71.7,71.3,68.6,67.3,62.1,53.2,29.7,28.9;
ESIMS m/z:631.3[M-H]-.
Viii) the preparation of compound 191j and 194c
10mg compound 191i (0.016mmol) is dissolved in 1000mL acetone, 1mg catalysis of iodine, 125w high-pressure mercury is added
Light irradiation reacts 12h, and solution becomes green fluorescence from red, and saturated sodium thiosulfate solution, ethyl acetate extraction are added after concentration
Take, be concentrated after anhydrous sodium sulfate is dry, pressurize pillar layer separation, petroleum ether: ethyl acetate=1:1 (v/v) elutes to obtain 6.1mg production
Object 191j, yield 61%.With compound 194b (10mg) for raw material, 5.3mg compound 194c, yield are made in the same way
53%.
191j:[α]D 20-51.7°(c 0.07,CH2Cl2);1H NMR(600MHz,CDCl3):δ11.0(s,1H,NH),
9.06 (d, J=7.8Hz, 1H, ArH), 8.64 (d, J=7.8Hz, 1H, ArH), 7.47 (t, J=7.7Hz, 1H, ArH), 7.39
(d, J=7.5Hz, 2H, ArH), 7.38 (d, J=7.7Hz, 1H, ArH), 7.31 (t, J=7.8Hz, 2H, ArH), 7.23-7.26
(m, 3H, ArH), 7.19 (t, J=7.8Hz, 1H, ArH), 6.85 (t, J=8.4Hz, 1H, ArH), 6.11 (d, J=11.0Hz,
1H, H-1'), 5.15 (t, J=7.8Hz, 1H, H-4'), 4.95 (s, 2H, PhCH2OCH2 N),4.70(s,2H,PhCH2 OCH2N),
4.28 (d, J=10.8Hz, 1H, H-3'), 4.04-4.08 (m, 3H, H-5', H-6'), 2.88 (s, 3H, N-CH3),2.21-
2.26(m,1H,H-2'a),1.97-2.00(m,1H,H-2'b);13C NMR(150MHz,CDCl3):δ169.2,168.9,
158.8,140.7,139.6,137.5,129.6,128.5×2,128.1,127.9×3,127.4,126.9,125.9,
124.7,122.4,121.5,121.4,120.4,120.2,119.2,118.1,117.8,111.3,108.6,79.1,78.3,
71.6,66.5,66.3,60.5,56.1,29.6,28.9;ESIMS m/z 629.3[M-H]-.
194c:[α]D 20+32.6°(c 0.11,CH2Cl2);1H NMR(600MHz,CDCl3):δ9.78(s,1H,NH),
8.91-8.94 (m, 2H, ArH), 7.47 (d, J=8.2Hz, 1H, ArH), 7.39-7.41 (m, 3H, ArH), 7.34 (t, J=
7.5Hz, 1H, ArH), 7.31 (t, J=7.8Hz, 2H, ArH), 7.27 (d, J=8.2Hz, 1H, ArH), 7.23-7.26 (m, 1H,
), ArH 7.21 (t, J=7.8Hz, 1H, ArH), 7.16 (t, J=7.8Hz, 1H, ArH), 6.62-6.64 (m, 1H, H-1'),
5.00-5.08(m,2H,PhCH2OCH2 N),4.70(s,2H,PhCH2 OCH2N),4.68(brs,1H,H-4'),4.49-4.50
(m,1H,H-3'),4.31-4.33(m,1H,H-5'),4.04-4.09(m,2H,H-6'),2.59(s,3H,N-CH3),2.07-
2.11(m,1H,H-2'a),1.97-2.03(m,1H,H-2'b);13C NMR(150MHz,CDCl3)δ169.2,169.0,
157.0,140.6,139.7,137.6,129.1,128.6×2,128.1×2,128.0×2,127.7,127.1,125.8,
124.9,122.2,121.6×2,121.0,123.1,118.7,118.3,118.1,111.9,109.0,77.6,75.3,
70.9,66.8,64.6,60.5,54.6,29.8,28.8;ESIMS m/z 629.2[M-H]-.
Ix) the preparation of compound 191l and 194e
242mg triphenylphosphine (0.92mmol) and imidazoles (126mg, 1.85mmol) 20mL methylene chloride are dissolved, drop
It to 0 DEG C, is added iodine (234mg, 1.85mmol), stirs 1h.Compound 191j (97mg, 0.15mmol) is used into 20mL methylene chloride
Dissolution, is slowly added into reaction solution, is warmed to room temperature reaction 6h.After be down to 0 DEG C, water quenching is added, methylene chloride extraction is anhydrous
It is concentrated after sodium sulphate is dry, pressurize pillar layer separation, petroleum ether: ethyl acetate=2:1 (v/v) affords 105mg compound
191k, yield 77%;ESIMSm/z 741.3[M+H]+.With compound 194c (80mg) for raw material, it is made in the same way
Compound 194d (90mg, yield 95%);ESIMS m/z 741.2[M+H]+.By compound 191k (105mg, 0.14mmol)
It is dissolved with 10mL tetrahydrofuran, is down to 0 DEG C, be added DBU (0.4mL, 2.67mmol), 0 DEG C of reaction 1h rises to 40 DEG C of reaction 1h.
Reaction solution is diluted with ethyl acetate, is concentrated after washing, and pressurize pillar layer separation, petroleum ether: ethyl acetate=1:1 (v/v) elution
Obtain 80mg compound 191l, yield 92%.With compound 194d (90mg) for raw material, compound is made in the same way
194e (67mg, yield 90%).
191l:[α]D 20-96.0°(c 0.55,CH2Cl2);1H NMR(600MHz,DMSO-d6)δ12.2(s,1H,NH),
9.22 (d, J=7.8Hz, 1H, ArH), 9.08 (d, J=8.4Hz, 1H, ArH), 7.88 (d, J=8.4Hz, 1H, ArH), 7.75
(d, J=8.4Hz, 1H, ArH), 7.64 (m, 2H, ArH), 7.49 (d, J=7.2Hz, 1H, ArH), 7.34-7.43 (m, 5H,
), ArH 7.29 (m, 1H, ArH), 7.24 (m, 1H, H-1'), 5.46 (d, J=8.5Hz, 1H, H-4'), 5.13 (s, 2H,
PhCH2OCH2 N),5.10(m,2H,H-6'),4.67(s,2H,PhCH2 OCH2N),4.40(m,1H,H-3'),2.77(3H,s,N-
CH3),2.53(m,1H,H-2'a),2.18(m,1H,H-2'b);13C NMR(150MHz,DMSO-d6)δ169.4,169.3,
157.1,152.9,142.1,140.5,138.3,129.6,129.2,128.8×2,128.2,128.1×3,127.9,
125.5,124.8,123.6,122.4,121.7,121.4,120.3,119.2,118.6,118.4,113.6,112.8,
101.2,81.0,71.4,70.9,67.0,53.0,28.8,28.1;ESIMS m/z 611.1[M-H]-.
194e:[α]D 20+12.4°(c 0.20,CH2Cl2);1H NMR(600MHz,CDCl3)δ9.62(s,1H,NH),
9.28 (d, J=8.2Hz, 1H, ArH), 9.10 (d, J=8.2Hz, 1H, ArH), 7.66 (d, J=8.2Hz, 1H, ArH), 7.55-
7.59 (m, 2H, ArH), 7.42-7.47 (m, 4H, ArH), 7.36-7.41 (m, 3H, ArH), 7.30 (t, J=7.8Hz, 1H,
D, J=2.0Hz, 1H, H-6 ' a)), ArH 6.30 (dd, J=11.4,2.4Hz, 1H, H-1 '), 5.52 (5.36 (d, J=
2.0Hz, 1H, H-6 ' b), 5.11 (d, 1H, J=7.2Hz, H-4 '), 5.08-5.18 (m, 2H, PhCH2OCH2 ),4.67(s,2H,
PhCH2 OCH2N),4.18-4.21(m,1H,H-3′),2.83(s,3H,N-CH3),2.51-2.57(m,1H,H-2′a),2.43-
2.47(m,1H,H-2′b);13C NMR(150MHz,CDCl3)δ169.3,169.2,156.7,151.1,140.9,139.9,
138.0,129.4,128.6×2,128.3,128.1×2,128.0,127.9,127.7,126.4,125.4,122.7,
122.4,121.9,121.7,121.0,119.5,119.3,118.9,112.0,108.9,100.2,82.0,71.7,70.3,
66.9,54.6,33.0,29.3;ESIMS m/z 611.4[M-H]-.
X) preparation of compound 191m and 194f
Compound 191l (80mg, 0.13mmol) is dissolved with tetrahydrofuran/methanol 10mL/1mL, 0 DEG C is cooled to, is added
Potassium tert-butoxide (59mg, 0.2mmol), solution become red from yellow, are slowly increased to that 2h is stirred at room temperature, be added iodine (133mg,
0.15mmol), solution colour is deepened, reaction overnight.It is cooled to 0 DEG C, is poured into saturated sodium thiosulfate solution, ethyl acetate
Extraction is concentrated after anhydrous sodium sulfate is dry, and pressurize pillar layer separation, petroleum ether: ethyl acetate=1:2 (v/v) elutes to obtain 60mg
Product 191m, yield 62%.With compound 194e (40mg) for raw material, compound 194f is made in the same way, and (25mg is produced
Rate 52%).
191m:[α]D 20-40.2°(c 0.06,CH2Cl2);1H NMR(600MHz,DMSO-d6) δ 9.22 (d, J=
7.8Hz, 1H, ArH), 9.00 (d, J=7.8Hz, 1H, ArH), 8.10 (d, J=8.4Hz, 1H, ArH), 8.05 (d, J=
8.4Hz, 1H, ArH), 7.63-7.67 (m, 2H, ArH), 7.49-7.54 (m, 1H, ArH), 7.43 (t, J=7.2Hz, 1H,
), ArH 7.37-7.38 (m, 2H, ArH), 7.29-7.32 (m, 2H, ArH), 7.23 (t, J=7.2Hz, 1H, ArH), 7.09 (dd,
J=9.6,7.2Hz, 1H, H-1'), 5.92 (d, J=12.0Hz, 1H, H-4'), 5.20 (s, 2H, PhCH2OCH 2),4.69(s,
2H,PhCH 2OCH2), 1H, d, J=12.6Hz, H-6 ' a), 4.61 (4.51-4.53 (m, 1H, H-3 '), 3.80 (1H, d, J=
12.6Hz,H-6′b),3.01(s,3H,N-CH3),2.86-2.90(m,1H,H-2′a),2.51-2.55(m,1H,H-2′b);13C
NMR(150MHz,DMSO-d6)δ169.4,169.1,156.8,139.8,138.5,138.2,137.4,132.0,129.1,
128.6×2,128.1,127.9×3,125.5,125.0,124.4,122.3,121.5,121.2,120.5,119.2,
117.5,116.8,113.0,110.6,93.3,78.2,70.8,70.3,65.4,52.7,29.3,28.4,11.6;ESIMS m/
z 761.1[M+Na]+.
194f:[α]D 20+51.3°(c 0.12,CH2Cl2);1H NMR(600MHz,DMSO-d6) δ 9.25 (d, J=
8.2Hz, 1H, ArH), 9.03 (d, J=8.2Hz, 1H, ArH), 8.17 (d, J=8.2Hz, 1H, ArH), 7.90 (d, J=
8.2Hz,1H,ArH),7.66(m,1H,ArH),7.65-7.68(m,1H,ArH),7.60-7.63(m,1H,ArH),7.44-
7.50 (m, 2H, ArH), 7.36 (d, J=8.2Hz, 2H, ArH), 7.30 (t, J=7.2Hz, 2H, ArH), 7.23 (t, J=
7.2Hz, 1H, ArH), 7.04-7.07 (m, 1H, H-1 '), 5.49 (d, J=9.0Hz, 1H, H-4 '), 5.13-5.18 (m, 2H,
PhCH2OCH 2), d, J=11.4Hz, 1H, H-6 ' a), 4.93 (4.67 (s, 2H, PhCH 2OCH2),4.34-4.38(m,1H,H-
M, 1H, H-2 ' a), 1H, d, J=11.4Hz, H-6 ' b), 3.96 3 ') (2.99-3.03 (2.65 (s, 3H, N-CH3),2.51-
2.55(m,1H,H-2′b);13C NMR(150MHz,DMSO-d6)δ169.6,169.3,155.9,141.6,138.4,138.3,
132.2×2,132.1,128.9,128.8×2,128.1×4,125.4,125.1,124.4,122.3,121.8,121.5,
120.5,119.2,118.2,116.7,116.1,110.2,92.6,80.1,73.6,71.0,65.6,53.1,30.6,29.0,
14.2;ESIMS m/z 761.1[M+Na]+.
Xi) the preparation of compound 191n and 194g
Compound 191m (60mg, 0.08mmol) is dissolved in 20mL benzene, AIBN (10mg) He Siding is added in argon gas protection
Base stannane (0.2mL), is heated to reflux 1h.It is cooled to room temperature concentration, pressurize pillar layer separation, petroleum ether: ethyl acetate=1:2
(v/v) 42mg product 191n, yield 85% are eluted to obtain.With compound 194f (25mg) for raw material, obtainedization in the same way
It closes object 194g (20mg, yield 96%).
191n:[α]D 20-63.5°(c 0.09,CH2Cl2);1H NMR(600MHz,CDCl3) δ 9.30 (d, J=7.2Hz,
1H, ArH), 9.10 (d, J=7.8Hz, 1H, ArH), 7.68-7.61 (m, 3H, ArH), 7.51-7.43 (m, 4H, ArH), 7.37
(t, J=7.2Hz, 3H, ArH), 7.30 (t, J=7.8Hz, 1H, ArH), 6.55 (dd, J=9.6,7.2Hz, 1H, H-1'),
5.71 (d, J=9.6Hz, 1H, H-4'), 5.20-5.31 (m, 2H, PhCH2OCH 2),4.81(s,2H,PhCH 2OCH2),4.44-
4.46(m,1H,H-3'),3.18(s,3H,N-CH3),2.76-2.81(m,1H,H-2'a),2.46-2.51(m,1H,H-2'b),
1.99(s,3H,6'-CH3);13C NMR(150MHz,CDCl3)δ169.3,169.1,157.3,140.1,138.1,137.7,
130.1,128.9,128.5×2,127.9×2,127.8,127.6,127.4,126.5,126.2,124.6,122.1,
122.0,121.4,120.9,119.4,118.4,117.4,112.3,107.8,94.0,77.2,71.7,71.4,66.8,
52.7,29.6,26.2,24.6;ESIMS m/z 613.5[M+H]+.
194g:[α]D 20+33.1°(c 0.13,CH2Cl2);1H NMR(600MHz,CDCl3) δ 9.38 (d, J=8.0Hz,
1H, ArH), 9.21 (d, J=7.9Hz, 1H, ArH), 8.08 (d, J=8.6Hz, 1H, ArH), 7.57-5.60 (m, 2H, ArH),
7.41-7.46 (m, 5H, ArH), 7.31 (t, J=7.6Hz, 2H, ArH), 7.23 (t, J=7.4Hz, 1H, ArH), 6.58 (dd, J
=10.3,6.4Hz, 1H, H-1'), 5.30-5.35 (m, 2H, PhCH2OCH 2), 5.09 (d, J=8.9Hz, 1H, H-4'), 4.76
(s,2H,PhCH 2OCH2),4.24-4.28(m,1H,H-3'),2.80-2.84(m,1H,H-2'a),2.76(s,3H,3'-
NCH3),2.41-2.47(m,1H,H-2'b),2.07(s,3H,6'-CH3);13C NMR(150MHz,CDCl3)δ169.5,
169.3,155.9,142.2,137.9,137.8,130.7,128.7,128.5×2,128.0×2,127.8,127.6,
127.5,126.5,125.8,124.6,122.3,122.2,121.6,120.9,119.7,119.5,117.3,116.4,
107.6,93.3,79.1,76.2,71.6,67.0,53.1,30.1,29.8,29.7;ESIMS m/z 613.6[M+H]+.
Xii) the preparation of compound 191 and 194
Compound 191n (40mg, 0.065mmol) is dissolved in ethyl acetate/methanol (10mL/10mL) total 20mL, argon gas
The hydroxide palladium carbon of 20mg 20%, rear hydrogen displacement, reaction overnight are added after displacement.It is concentrated after being filtered with silica gel, half prepares
HPLC separation, MeOH:H2O=7:3 (v/v) affords 4 '-O- demethyl of 28mg-(4 '-O, 3 '-N) carbonyl -7- oxygen subunit -
1 ', 5 '-bis- table staurosporines (191), yield 89%.With compound 194g (20mg) for raw material, it is made in the same way
4 '-O- demethyl of 15mg-(4 '-O, 3 '-N) carbonyl -7- oxygen subunit staurosporine (194), yield 96%.
191:[α]D 20-69.5°(c 2.0,CH2Cl2);1H NMR(500MHz,DMSO-d6)δ11.2(s,1H,NH),
9.21 (d, J=7.8Hz, 1H, ArH), 8.98 (d, J=7.8Hz, 1H, ArH), 8.07 (d, J=7.8Hz, 1H, ArH), 7.94
(d, J=8.4Hz, 1H, ArH), 7.61-7.67 (m, 2H, ArH), 7.48 (t, J=7.8Hz, 1H, ArH), 7.41 (t, J=
7.8Hz, 1H, ArH), 6.98-7.01 (m, 1H, H-1'), 5.76 (d, J=10.4Hz, 1H, H-4'), 4.44-4.46 (m, 1H,
H-3'),2.99(s,3H,N-CH3), 2.81 (ddd, J=9.6,6.0,2.4Hz, 1H, H-2'a), 2.18 (ddd, J=9.6,
6.0,2.4Hz,1H,H-2'b),1.80(s,3H,6'-CH3);13C NMR(125MHz,DMSO-d6)δ171.5,171.2,
157.4,140.5,138.6,130.2,129.1,127.8,127.7,125.8,125.3,124.3,122.1,122.0,
121.5,121.4,120.7,117.6,116.5,114.3,110.7,94.1,77.9,71.4,52.4,29.5,25.4,24.9;
ESIMS m/z 491.3[M-H]-.
194:[α]D 20+112.9°(c 0.1,CH2Cl2);1H NMR(500MHz,DMSO-d6)δ11.2(s,1H,NH),
9.23 (d, J=9.0Hz, 1H, ArH), 9.04 (d, J=9.0Hz, 1H, ArH), 8.09 (d, J=9.5Hz, 1H, ArH), 7.88
(d, J=9.5Hz, 1H, ArH), 7.65 (t, J=9.0Hz, 1H, ArH), 7.58 (t, J=9.5Hz, 1H, ArH), 7.43 (t, J
=9.0Hz, 2H, ArH), 7.01 (dd, J=10.0,8.5Hz, 1H, H-1'), 5.33 (d, J=8.5Hz, 1H, H-4'), 4.31-
4.36(m,1H,H-3'),2.93-2.98(m,1H,H-2'a),2.57(s,3H,N-CH3),2.04-2.11(m,1H,H-2'b),
2.05(3H,s,6'-CH3);13C NMR(125MHz,DMSO-d6)δ170.8,170.5,155.5,141.3,137.6,129.8,
128.0,127.0,126.5,124.8,124.5,123.5,121.2,121.0×2,120.8,119.8,117.4,116.5,
115.7,109.3,92.6,79.0,75.3,52.0,29.6,28.2×2;ESIMS m/z 491.1[M-H]-.
The preparation of compound 192,193,195 and 196
Compound 191 (10mg, 0.020mmol) is dissolved in 10mL methanol, be down to 0 DEG C of addition sodium borohydride (7.6mg,
0.2mmol), it is warmed to room temperature reaction two hours, solution is become colorless by yellow, and saturated ammonium chloride is added after being diluted with ethyl acetate
Solution, ethyl acetate extraction are evaporated after anhydrous sodium sulfate is dry.Crude product is dissolved in 5mL glacial acetic acid, addition zinc powder (15mg,
0.23mmol), 40 DEG C are risen to react 1.5 hours, is cooled to room temperature, is diluted with ethyl acetate, saturated sodium bicarbonate solution washing
Afterwards, it is concentrated after anhydrous sodium sulfate is dry.Half preparation HPLC separation, acetonitrile: water=7:13 (v/v) affords 4 '-O- demethyls-
(4 '-O, 3 '-N) carbonyl -1 ', 5 '-bis- table staurosporines (192) (3.2mg, yield 35%), 5- deoxidation -7- oxygen subunit -4 ' -
O- demethyl-(4 '-O, 3 '-N) carbonyl -1 ', 5 '-bis- table staurosporines (193) (3.2mg, yield 35%).With compound
194 (10mg) are raw material, and 5- deoxidation -7- oxygen -4 '-O- of subunit demethyl-(4 '-O, 3 '-N) carbonyl ten is made in the same way
4 '-O- demethyl of word spore alkali (195) (2.7mg, yield 28%) and 2.7mg-(4 '-O, 3 '-N) carbonyl staurosporine (ACT-
007,196), yield 28%.
192:[α]D 20-78.2°(c 0.05,MeOH);1H NMR(600MHz,DMSO-d6) δ 9.19 (d, J=7.8Hz,
1H, ArH), 8.65 (s, 1H, NH), 8.10 (d, J=7.6Hz, 1H, ArH), 7.97 (d, J=8.3Hz, 1H, ArH), 7.91 (d,
J=8.3Hz, 1H, ArH), 7.57 (t, J=7.8Hz, 1H, ArH), 7.48-7.51 (m, 1H, ArH), 7.43 (t, J=7.5Hz,
1H, ArH), 7.29 (t, J=7.5Hz, 1H, ArH), 6.92 (dd, J=9.8,6.8Hz, 1H, H-1'), 5.72 (d, J=
9.7Hz,1H,H-4'),4.94-5.03(m,2H,H-7),4.41-4.44(m,1H,H-3'),2.98(s,3H,N-CH3),
2.71-2.76(m,1H,H-2'a),2.07-2.12(m,1H,H-2'b),1.79(s,3H,6'-CH3).13CNMR(150MHz,
DMSO-d6)δ171.6,156.9,138.8,136.9,133.2,128.4,125.6×2,125.5,124.9,124.8,
122.3,122.0,121.2,120.6,119.6,116.1,115.2,113.6,109.4,93.3,77.4,71.1,52.0,
45.5,28.9,25.0,24.4;HR-ESIMS m/z 479.1710[M+H]+(calcd for C28H23N4O4 +479.1719).
193:[α]D 20-76.5°(c 0.05,MeOH);1H NMR(600MHz,DMSO-d6) δ 9.49 (d, J=7.8Hz,
1H, ArH), 8.61 (s, 1H, NH), 8.09 (d, J=7.8Hz, 1H, ArH), 8.03 (d, J=8.2Hz, 1H, ArH), 7.84 (d,
J=8.4Hz, 1H, ArH), 7.52-7.55 (m, 2H, ArH), 7.36 (t, J=7.5Hz, 2H, ArH), 6.93 (dd, J=9.7,
7.0Hz, 1H, H-1'), 5.76 (d, J=9.5Hz, 1H, H-4'), 4.94-5.02 (m, 2H, H-5), 4.44-4.46 (m, 1H, H-
3'),2.99(s,3H,N-CH3), 2.78 (ddd, J=10.1,6.9,2.4Hz, 1H, H-2'a), 2.14-2.18 (m, 1H, H-2'
b),1.75(s,3H,6'-CH3).13C NMR(150MHz,DMSO-d6)δ171.9,156.9,138.9,137.0,134.5,
127.3,126.4×2,126.2,125.7,125.5,125.2,122.0,120.5,120.4,119.6,117.2,114.5,
113.0,109.9,93.3,77.4,71.1,52.0,45.1,28.9,25.1,24.1;HR-ESIMS m/z 479.1711[M+
H]+(calcd for C28H23N4O4 +479.1719).
195:[α]D 20+66°(c 0.05,MeOH);1H NMR(500MHz,DMSO-d6) δ 9.51 (d, J=7.9Hz, 1H,
), ArH 8.61 (s, 1H, NH), 8.10 (d, J=7.7Hz, 1H, ArH), 8.01 (d, J=8.5Hz, 1H, ArH), 7.85 (d, J=
8.2Hz, 1H, ArH), 7.56 (t, J=7.6Hz, 1H, ArH), 7.46 (t, J=7.6Hz, 1H, ArH), 7.37 (t, J=
7.4Hz, 1H, ArH), 7.30 (t, J=7.4Hz, 1H, ArH), 6.96 (dd, J=9.6,6.2Hz, 1H, H-1'), 5.30 (d, J
=8.7Hz, 1H, H-4'), 4.94-5.02 (m, 2H, H-5), 4.32-4.37 (m, 1H, H-3'), 2.92-2.96 (m, 1H, H-2'
a),2.59(s,3H,N-CH3),2.05-2.10(m,1H,H-2'b),1.99(s,3H,6'-CH3).13C NMR(125MHz,
DMSO-d6)δ171.8,155.6,140.3,136.5,134.2,126.9,126.5,125.6,125.4,125.0×2,
122.0,121.7,120.4,119.9,119.3,117.6,115.9,114.1,109.2,92.4,79.1,75.4,52.0,
44.9,29.4,28.7,28.2;HR-ESIMS m/z 479.1727[M+H]+(calcd for C28H23N4O4 +479.1719).
196:[α]D 20+73.2°(c 0.05,MeOH);1H NMR(500MHz,DMSO-d6) δ 9.23 (d, J=7.9Hz,
1H, ArH), 8.66 (s, 1H, NH), 8.06 (d, J=8.5Hz, 1H, ArH), 8.03 (d, J=7.7Hz, 1H, ArH), 7.79 (d,
J=8.3Hz, 1H, ArH), 7.51 (t, J=8.3Hz, 1H, ArH), 7.53 (t, J=7.7Hz, 1H, ArH), 7.38 (t, J=
7.4Hz, 1H, ArH), 7.30 (t, J=7.5Hz, 1H, ArH), 6.96 (dd, J=9.7,6.3Hz, 1H, H-1'), 5.31 (d, J
=8.7Hz, 1H, H-4'), 4.95-5.03 (m, 2H, H-7), 4.33-4.36 (m, 1H, H-3'), 2.89-2.94 (m, 1H, H-2'
a),2.59(s,3H,N-CH3),2.03(s,3H,6'-CH3),1.97-2.03(m,1H,H-2'b);13C NMR(125MHz,
DMSO-d6)δ171.5,155.6,140.3,136.4,132.9,128.6,125.7,125.4,124.9,124.6×2,
122.4,121.1,120.9,120.2,119.5,116.5,115.8,115.4,108.6,92.4,79.1,75.4,52.0,
45.4,29.5,28.6,28.2;HR-ESIMS m/z 479.1725[M+H]+(calcd for C28H23N4O4 479.1719).
The test of [embodiment 2] anti-tumor activity
1 test method
The preparation of sample solution: test sample is the monomeric compound 1~196 synthesized in above-described embodiment 1.Accurately
Appropriate amount of sample is weighed, the solution of required concentration is configured to DMSO, for active testing.
The squamous subculture of cell line and cell: active testing using people HL-60, A549, HepG2, MCF-7, Jurkat,
MV-4-11, H1975, K562 cell line and its Adriamycin resistant strain K562/A02.Various cells are with the RPMI- containing 10%FBS
1640 culture mediums, the squamous subculture in the incubator that 37 DEG C are passed through 5% carbon dioxide.
This experiment is using the tested sample of mtt assay test evaluation to people HL-60, Jurkat, A549, H1975, HepG2
With the inhibitory activity of MCF-7 cancer cell multiplication.Using the tested sample of CCK8 method test evaluation to people MV-4-11, K562 and
The cell inhibitory effect activity of its Adriamycin resistant strain K562/A02.
Mtt assay: succinate dehydrogenase can be metabolized bromination 3- (the 4,5- dimethyl thiophene of reduction yellow in living cells mitochondria
Azoles) -2,5- diphenyltetrazolium bromide be bluish violet formazan not soluble in water, formazan number can be surveyed by microplate reader
Its fixed trap acquires.Since the amount of formazan is directly proportional to viable count, so living cells can be found out according to trap
Number, to understand the ability of Drug inhibition or killing tumor cell.When active testing, the cell of logarithmic growth phase, with new
It is every milliliter 5 × 10 that fresh RPMI-1640 culture medium, which is configured to density,4The cell suspension of a cell is inoculated in by every hole 100ul
In 96 orifice plates, after cultivating 12 hours at 37 DEG C, culture medium in hole is sopped up, every hole is added to be diluted with the corresponding culture medium of 200 μ L
Various concentration sample, continue culture 72 hours.Then 12 μ LMTT solution (5mg/L) are added, are further cultured for 4 hours, remove training
150 μ L DMSO dissolution formazan is added after nutrient solution, its trap is measured at 570nm or 490nm.It calculates according to the following formula
Cell proliferation inhibition rate (IR%) under each concentration: IR%=(ODBlank control–ODSample)/ODBlank control× 100%.
CCK-8 method: succinate dehydrogenase can be metabolized reduction 3- (2- methoxyl group -4- nitrobenzene in living cells mitochondria
Base) -2- (4- nitrobenzophenone) -5- (2,4- disulfobenzene) -2H- tetrazolium monosodium salt is that yellow formazan with high water soluble produces
The quantity of object (Formazan), generation formazan object is directly proportional to the quantity of living cells.With enzyme-linked immunosorbent assay instrument in 450nm wave
Strong point measures its absorbance value, can reflect living cells quantity indirectly.Since the amount of formazan is directly proportional to viable count, so
The number of living cells can be found out according to trap, to understand the ability of Drug inhibition or killing tumor cell.When active testing,
The cell of logarithmic growth phase, being configured to density with fresh RPMI-1640 culture medium is every milliliter 5 × 104A cell it is thin
Born of the same parents' suspension is inoculated in 96 orifice plates by every 100 μ L of hole, after cultivating 12 hours at 37 DEG C, sops up culture medium in hole, every hole is added
With the sample for the various concentration that the corresponding culture medium of 100 μ L has diluted, continue culture 72 hours.Then it is molten that 10 μ L CCK-8 are added
Liquid is further cultured for 6h, its trap is measured at 450nm.According to formula " IR%=(OD blank control-OD sample)/OD blank pair
The cell proliferation inhibition rate (IR%) under each concentration is calculated according to × 100% ".
Adriamycin (ADM) and Gefitinib are positive controls.
1 be the results are shown in Table to table to table 9.
Inhibitory activity (IC of the table 1 to people's acute promyelocytic leukemic HL-6050,μM)
Compound | IC50 | Compound | IC50 |
46 | 0.99 | 74 | 0.60 |
48 | 0.05 | 84 | 0.37 |
55 | 0.46 | 85 | 0.34 |
57 | 0.87 | 97 | 0.87 |
ADM | 0.02 |
Inhibitory activity (IC of the table 2 to human chronic myeloblastic leukemia K56250,μM)
Compound | IC50 | Compound | IC50 |
55 | 0.053 | 79 | 0.94 |
73 | 0.72 | 84 | 0.25 |
74 | 0.24 | 85 | 0.36 |
78 | 0.43 | ADM | 0.30 |
Inhibitory activity (IC of the table 3 to human T lymphocyte's leukaemia Jurkat50,μM)
Compound | IC50 | Compound | IC50 |
105 | 0.26 | 126 | 0.81 |
115 | 2.13 | 120 | 0.20 |
107 | 0.54 | 122 | 0.39 |
124 | 0.44 | ADM | 0.44 |
Inhibitory activity (IC of the table 4 to infiltration ductal carcinoma of breast MCF-750,μM)
Compound | IC50 |
7 | 0.9 |
55 | 0.3 |
84 | 0.85 |
ADM | 1.00 |
Inhibitory activity (IC of the table 5 to human lung adenocarcinoma A54950,μM)
Compound | IC50 | Compound | IC50 |
8 | 0.64 | 175 | 0.16 |
31 | 0.51 | 176 | 0.15 |
74 | 0.91 | 177 | 0.42 |
167 | 0.02 | 178 | 0.12 |
168 | 0.3 | 179 | 0.49 |
169 | 0.71 | 180 | 0.03 |
170 | 0.41 | 181 | 0.06 |
171 | 0.32 | 183 | 0.02 |
172 | 0.36 | 188 | 0.21 |
174 | 0.68 | ADM | 0.90 |
Inhibitory activity (IC of the table 6 to human liver cancer cell HepG250,μM)
Compound | IC50 | Compound | IC50 |
2 | 2.80 | 83 | 1.80 |
8 | 2.50 | 84 | 1.20 |
12 | 2.30 | 73 | 2.30 |
23 | 3.40 | 75 | 0.43 |
28 | 0.35 | 120 | 1.16 |
43 | 2.10 | 122 | 0.84 |
44 | 2.54 | 105 | 1.34 |
47 | 1.60 | 107 | 2.36 |
56 | 1.90 | 124 | 2.25 |
59 | 1.70 | ADM | 0.60 |
The inhibitory activity of acute double phenotype (B, monokaryon) the myelocytic leukemia MV-4-11 of the people that table 7 is mutated FLT3-ITD
(IC50, μM)
Leukemia K 562/A02 inhibitory activity (IC of the table 8 to Adriamycin resistant50,μM)
Compound | IC50 | Compound | IC50 |
1 | 1.25 | 84 | 1.10 |
2 | 0.75 | 66 | 4.40 |
3 | 1.00 | 73 | 2.10 |
8 | 0.42 | 130 | 1.38 |
45 | 4.50 | 133 | 2.00 |
55 | 3.38 | 135 | 3.91 |
ADM | 19.20 |
The EGFR-T790M/L858R adenocarcinoma of lung medicament-resistant mutation strain H1975 acquired to Gefitinib or Erlotinib of table 9
Inhibitory activity (IC50,μM)
Compound | IC50 | Compound | IC50 |
103 | 6.91 | 113 | 1.32 |
104 | 1.11 | 114 | 5.20 |
105 | 0.89 | 115 | 4.71 |
106 | 1.80 | 119 | 5.60 |
107 | 2.32 | 120 | 2.40 |
108 | 2.10 | 121 | 4.80 |
110 | 4.78 | 122 | 3.30 |
111 | 2.60 | 124 | 5.20 |
112 | 2.92 | 127 | 5.61 |
Gefitinib | 16.82 |
Conclusion: test result show above compound to man―machine systems HL-60, A549, Jurkat, MV-4-11,
H1975, HepG2, MCF-7, K562 and K562/A02 have good inhibitory activity, may serve as preventing and treating above-mentioned swollen
The drug of tumor.
In particular, therapeutic effect of the above compound to drug-resistant tumor, can be realized accurately controlling to specific drug-resistant tumor
It treats.For example, using EGF-R ELISA (EGFR) inhibitor Gefitinib or erlotinib treatment non-small cell lung cancer
(NSCLC), patient but is eventually recurred because of drug resistance in the initial phase good effect for the treatment of.H1975 be exactly to Gefitinib or
The acquired EGFR-T790M/L858R adenocarcinoma of lung medicament-resistant mutation strain of Erlotinib.Compound with H1975 inhibitory effect, it is right
EGFR-T790M/L858R acquired resistance, which is mutated adenocarcinoma of lung, has therapeutic effect, can be used for accurately controlling for such patients with lung cancer
It treats.
Claims (10)
1. following compound of formula I, Formula II compound or their pharmaceutically acceptable salts or prodrug,
Wherein, in Formulas I,
G1~G8It is each independently selected from-H;Halogen;C1~C6Alkyl;C2~C6Alkenyl;C2~C6Alkynyl;
R3Selected from-H;-NR13R14;C1~C6Alkyl, the C1~C6Alkyl is optionally by hydroxyl, cyano, carboxyl, monosaccharide groups, C1~C6
Alkoxy, C6~C10Aryl, 5~10 unit's heteroaryls, 5 or 6 yuan of alicyclic heterocyclic bases ,-NH-CO-C1~C6Alkylidene (NH2)(A1)、-
NR13R14Replace, 5 or 6 yuan of alicyclic heterocyclic bases, 5~10 unit's heteroaryls, C6~C10Aryl is optionally by amino, hydroxyl, halogen, C1
~C6Alkyl, C1~C6Halogenated alkyl replaces;
Wherein A1It is selected from :-H;C1~C6Alkyl, the C1~C6Alkyl is optionally replaced by 5~10 unit's heteroaryls, and described 5~10 yuan
Heteroaryl is optionally by amino, hydroxyl, halogen, C1~C6Alkyl, C1~C6Halogenated alkyl replaces;R13、R14Be each independently selected from :-
H;C1~C6Alkyl;
R1And R2It is each independently selected from :-H;C1~C6Alkyl, the C1~C6Alkyl is optionally by cyano, hydroxyl, carboxyl, C6~
C10Aryl, 5~10 unit's heteroaryls replace, the C6~C10Aryl, 5~10 unit's heteroaryls are optionally by amino, hydroxyl, halogen, C1
~C6Alkyl, C1~C6Halogenated alkyl replaces;
In Formula II,
G1~G8It is each independently selected from-H;Halogen;
R3Selected from-H;C1~C6Alkyl, the C1~C6Alkyl is optionally by hydroxyl, cyano, carboxyl, monosaccharide groups, C1~C6Alkoxy,
C6~C10Aryl, 5~10 unit's heteroaryls, 5 or 6 yuan of alicyclic heterocyclic bases ,-NH-CO-C1~C6Alkylidene (NH2)(A1)、-NR13R14It takes
Generation, 5 or 6 yuan of alicyclic heterocyclic bases, 5~10 unit's heteroaryls, C6~C10Aryl is optionally by amino, hydroxyl, halogen, C1~C6Alkyl,
C1~C6Halogenated alkyl replaces;
Wherein A1It is selected from :-H;C1~C6Alkyl, the C1~C6Alkyl is optionally replaced by 5~10 unit's heteroaryls, and described 5~10 yuan
Heteroaryl is optionally by amino, hydroxyl, halogen, C1~C6Alkyl, C1~C6Halogenated alkyl replaces;R13、R14Be each independently selected from :-
H;C1~C6Alkyl;
R4With R5Composition=O and/or R together6With R7Composition=O together;
Work as R4With R5Or R6With R7Do not constitute=O when, be each independently selected from-H or-OR35, R35For-H or C1~C6Alkyl;
R9、R10It independently is-H or C1~C6Alkyl;R8Selected from-C (=Y1)-Y2,-S (=O)2-Y3;
Wherein, Y1Selected from=O;=S;=NH;
Y2Selected from azanol base;C6~C10Aryl, the C6~C10Aryl is optionally by amino, hydroxyl, halogen, C1~C6Alkoxy, C1
~C6Alkyl, C1~C6Halogenated alkyl replaces;5~10 unit's heteroaryls, 5~10 unit's heteroaryl is optionally by amino, hydroxyl, halogen
Element, C1~C6Alkoxy, C1~C6Alkyl, C1~C6Halogenated alkyl replaces;5 or 6 yuan of alicyclic heterocyclic bases, 5 or 6 yuan of alicyclic heterocyclic bases
Optionally by amino, hydroxyl, halogen, C1~C6Alkoxy, C1~C6Alkyl, C1~C6Halogenated alkyl replaces;5 or 6 yuan of alicyclic heterocyclic bases
Substituted C1~C6Alkyl-substituted 5 or 6 yuan of alicyclic heterocyclic bases, 5 or 6 yuan of alicyclic heterocyclic bases optionally by amino, hydroxyl, halogen,
C1~C6Alkoxy, C1~C6Alkyl, C1~C6Halogenated alkyl replaces;C1~C6Alkylamino, the C1~C6Alkylamino is by oxygen, hydroxyl
Base, 5~10 unit's heteroaryls, C6~C10At least one of aryl replaces, 5~10 unit's heteroaryl, C6~C10Aryl optionally quilt
Amino, hydroxyl, halogen, C1~C6Alkoxy, C1~C6Alkyl, C1~C6Halogenated alkyl replaces;
Y3For optionally by halogen, halogenated C1~C6Alkyl-substituted C6~C10Aryl;
Alternatively, R9With R10Composition-C (=O)-together, R8Selected from-H;C1~C18Alkyl;C1~C6The C that alkoxy replaces1~C18Alkane
Base.
2. compound of formula I according to claim 1, Formula II compound or their pharmaceutically acceptable salts or prodrug,
In:
In Formulas I,
G1~G8Definition in compound of formula I as described in the appended claim 1;
R3Selected from-H;-NR13R14;C1~C6Alkyl, the C1~C6Alkyl is optionally by hydroxyl, cyano, carboxyl, monosaccharide groups, C1~C6
Alkoxy, morpholinyl, piperidyl, piperazinyl, pyridyl group, phenyl or-NH-CO-C1~C6Alkylidene (NH2)(A1)、-NR13R14It takes
In generation, the morpholinyl, piperidyl, piperazinyl, pyridyl group, phenyl are optionally by amino, hydroxyl, halogen, C1~C6Alkyl, C1~C6
Halogenated alkyl replaces;
Wherein A1It is selected from :-H;C1~C6Alkyl, the C1~C6Alkyl is optionally replaced by imidazole radicals, indyl, the imidazole radicals,
Indyl is optionally by amino, hydroxyl, halogen, C1~C6Alkyl, C1~C6Halogenated alkyl replaces;R13、R14Be each independently selected from :-
H;C1~C6Alkyl;
R1And R2It is each independently selected from-H;C1~C6Alkyl, the C1~C6Alkyl optionally by cyano, hydroxyl, carboxyl, phenyl,
Naphthalene, pyridyl group replace, and the phenyl, naphthalene, pyridyl group are optionally by amino, hydroxyl, halogen, C1~C6Alkyl, C1~C6It is halogenated
Alkyl replaces;
In Formula II,
G1~G8Definition in Formula II compound as described in the appended claim 1;
R3Selected from-H;C1~C6Alkyl, the C1~C6Alkyl is optionally by amino, hydroxyl, phenyl, morpholinyl, piperidyl, piperazinyl
Replace, the phenyl, morpholinyl, piperidyl, piperazinyl are optionally by amino, hydroxyl, halogen, C1~C6Alkyl, C1~C6Alkyl halide
Base replaces;
R4With R5Composition=O and/or R together6With R7Composition=O together;
Work as R4With R5Or R6With R7Do not constitute=O when, be each independently selected from-H or-OH;
R9、R10For methyl;
R8Selected from-C (=Y1)-Y2;- S (=O)2-Y3;
Wherein, Y1Selected from=O;=S;=NH;
Y2It is selected from: azanol base;Phenyl, the phenyl is optionally by amino, hydroxyl, halogen, C1~C6Alkoxy, C1~C6Alkyl, C1
~C6Halogenated alkyl replaces;Imidazole radicals;Piperazinyl, the piperazinyl are optionally replaced by morpholinyl;Alkylamino, the alkylamino quilt
At least one of oxygen, hydroxyl, indyl, phenyl replace;
Y3For optionally by halogen, C1~C6The phenyl that halogenated alkyl replaces;
Alternatively, R9With R10Composition-C (=O)-together, R8Selected from-H;C1~C18Alkyl;C1~C6The C that alkoxy replaces1~C18Alkane
Base.
3. compound of formula I according to claim 1 or 2, Formula II compound or their pharmaceutically acceptable salts or prodrug,
Wherein:
In Formulas I,
G1~G8Definition in compound of formula I as described in the appended claim 1;
R3It is selected from: C1~C6Alkyl, the alkyl is by morpholinyl, piperidyl, piperazinyl, pyridyl group, phenyl or-NH-CO-C1~C6
Alkylidene (NH2)(A1) at least one of replace, the morpholinyl, piperidyl, piperazinyl, pyridyl group, phenyl optionally by amino,
Hydroxyl, halogen, C1~C6Alkyl, C1~C6Halogenated alkyl replaces;C2~C6Alkyl, the C2~C6Alkyl is optionally substituted by a hydroxyl group;C3~
C6Alkyl, the C3~C6Alkyl is by-NR13R14Replace;
Wherein A1It is selected from :-H;C1~C6Alkyl, the C1~C6Alkyl is optionally replaced by imidazole radicals, indyl, the imidazole radicals,
Indyl is optionally by amino, hydroxyl, halogen, C1~C6Alkyl, C1~C6Halogenated alkyl replaces;R13、R14Be each independently selected from :-
H;C1~C6Alkyl;
R1And R2It is each independently selected from C1~C6Alkyl, the C1~C6Alkyl is by least one of phenyl, naphthalene, pyridyl group
Replace;
Optionally,
In Formulas I,
G1~G8It is each independently selected from-H, halogen, allyl, isopentene group;
R3Selected from-H;-Me;-(CH2)1~6OH;-(CH2)0~6NH2;-(CH2)1~4NMe2;-(CH2)1~4CN;-(CH2)1~4CO2H;-
(CH2)1~4C6H5OH;-(CH2)1~4C6H5OMe;-(CH2)1~4C6H5NH2;-(CH2)1~4M;Morpholine ethyl;Piperidinoethyl;Piperazine
Ethyl;Methyl piperazine ethyl;Pyridine ethyl;Halophenethyl;-(CH2)1~6-NH-CO-CH(NH2)(A1);Wherein, A1、R13、
R14As described in the appended claim 1, M is monosaccharide groups;
Alternatively, the R3Selected from morpholine ethyl;Piperidinoethyl;Piperazine ethyl;Methyl piperazine ethyl;Pyridine ethyl;Aminobenzoic
Base;Aminophenethyl;Hydroxyphenylmethyl;Halophenethyl;-(CH2)1~6-NH-CO-CH(NH2)(A1);-(CH2)2~4OH;-
(CH2)3~6NH2;-(CH2)1~4NMe2;Wherein, A1Selected from-H;Imidazolmethyl;Indole methyl;
Alternatively, the R3Selected from 2- (4- morpholinyl) ethyl;2- (piperidin-1-yl) ethyl;2- (piperazine -1- base) ethyl;2-(4-
Methylpiperazine-1-yl) ethyl;2- (pyridine -2- base) ethyl;P-aminophenyl methyl;P-aminophenyl ethyl;Para hydroxybenzene methyl;
2- (the chloro- 6- fluorophenyl of 2-) ethyl;-(CH2)1~6-NH-CO-CH(NH2)(A1);-(CH2)2~4OH;-(CH2)3~6NH2;-
(CH2)1~4NMe2;Wherein, A1Selected from-H;(imidazol-4 yl) methyl;(indol-3-yl) methyl;
R1And R2It is each independently selected from-H;-Et;-(CH2)1~4CN;-(CH2)1~4CO2H;-(CH2)1~4OH;Phenethyl;Naphthalene second
Base;Pyridine ethyl;
Alternatively, the R1And R2It is each independently selected from phenethyl;Naphthylethyl;Pyridine ethyl;
In Formula II,
G1~G8It is each independently selected from-H;Halogen;
R3For-H;
R4With R5Composition=O and/or R together6With R7Composition=O together;
Work as R4With R5Or R6With R7Do not constitute=O when, be each independently selected from-H or-OR35, R35For-H or C1~C6Alkyl;
R9、R10It is methyl;
R8Selected from-C (=Y1)-Y2;- S (=O)2-Y3;
Wherein, Y1Selected from=O;=S;=NH;
Y2It is selected from: azanol base;Phenyl, the phenyl is optionally by halogen, C1~C6Halogenated alkyl replaces;Imidazole radicals;Oxindole base
Ethylamino;Oxo phenylethylamino;(morpholine ethyl) piperazinyl;(halogenophenyl) methylamino;(halogenophenyl) ethylamino;(halogen
For aminomethyl phenyl) ethylamino;Phenyl methylamino;(methoxyphenyl) methylamino;Hydroxy propyl amido;4- (N, N- bis- (2- chloroethyls)
Amino) phenyl propyl;
Alternatively, Y2It is selected from: azanol base;Phenyl;Halogenophenyl;The phenyl that trifluoromethyl replaces;2- oxygen subunit -2- (1H- indoles -3-
Base) -1- ethylamino;Imidazoles -1- base;2- oxygen subunit -2- phenyl -1- ethylamino;4- (2 (morpholine -1- base) ethyl) piperazine -1-
Base;(2,6- difluorophenyl) methylamino;(the chloro- 4- fluorophenyl of 3-) methylamino;2- (the chloro- 6- fluorophenyl of 2-) -1- ethylamino;2-
(4- trifluoromethyl) -1- ethylamino;Phenylmethyl amino;(4- methoxyphenyl) methylamino;(S) the third ammonia of -2- hydroxyl -1-
Base;4- (bis- (2- chloroethyl) amino of N, N-) phenyl propyl;
Y3For optionally by halogen, C1~C6The phenyl that halogenated alkyl replaces;
Alternatively, Y3Selected from halogenophenyl;The phenyl that trifluoromethyl replaces;
Alternatively,
R9With R10Composition-C (=O)-together;
R8Selected from-H;C1~C18Alkyl;C1~C6The C that alkoxy replaces1~C18Alkyl;Alternatively, R8For methyl.
4. compound of formula I described in any one of claim 1 to 3, Formula II compound or they are pharmaceutically acceptable
Salt or prodrug are selected from following compounds, its pharmaceutically acceptable salt or prodrug:
5. compound of formula I according to any one of claims 1 to 4, Formula II compound or they are pharmaceutically acceptable
Salt or prodrug, in which:
The pharmaceutically acceptable salt includes the salt of organic or inorganic acid;
Optionally, the pharmaceutically acceptable salt is selected from what the compound of formula I, Formula II compound and following compound were formed
Salt: hydrochloric acid;Sulfuric acid;Phosphoric acid;Formic acid;Acetic acid;Propionic acid;Lactic acid;Citric acid;Tartaric acid;Succinic acid;Fumaric acid;Maleic acid;Almond
Acid;Malic acid;Camphorsulfonic acid;
The pharmaceutically acceptable prodrug includes the phosphate prodrugs or carbamic acid of the compound of formula I, Formula II compound
Ester prodrugs.
Compound of formula I described in any one of claim 1-5, Formula II compound are prepared or they are pharmaceutically acceptable 6. a kind of
The method of salt or prodrug, it is characterised in that: including -1 compound of Formulas I, I-2 compound, II-1 compound or II-2 compound
Preparation step,
In -1 compound of Formulas I, G1~G8、R1、R2As described in any one of claim 1-5, the system of -1 compound of Formulas I
Include: for step
1) preparation step of formula a3 compound is selected from following methods (1) or method (2),
Method (1): formula a3 compound is made by Perkin condensation reaction in formula a1 compound and formula a2 compound;
Method (2): formula a2 compound, formula a6 compound and formula a7 compound are reacted by Grignard, and and iodoethane
It reacts and formula a8 compound is made, then by formula a8 compound by hydrolyzing under alkaline condition, be then acidified and formula a3 compound is made;
With the preparation step of 2) -1 compound of Formulas I,
- 1 compound of Formulas I is made by formula a3 compound;
In -2 compound of Formulas I, G1~G8、R1、R2、R3As described in any one of claim 1-5, but R3It is not H, it is described
The preparation step of -2 compound of Formulas I includes: that -2 compound of Formulas I is made by -1 compound of Formulas I;
Wherein, work as R1、R2Optionally blocking group to be used to be protected when reactive group;
In -1 compound of Formula II, R9、R10For-H or alkyl;G1~G8、R3、R4、R5、R6、R7、R8As appointed in claim 1-5
One Xiang Suoshu, the preparation step of -1 compound of Formula II include: II-1-A class compound, II-1-B class compound, II-1-C
The preparation step of class compound, II-1-D class compound or II-1-E class compound,
The II-1-A class compound is such as undefined -1 compound of Formula II: R in -1 compound of Formula II8For-C (=Y1)-Y2, Y1
Selected from=O or=S;Y2For aryl, the aryl is optionally replaced by amino, hydroxyl, halogen, alkoxy, alkyl, halogenated alkyl;
The II-1-A class compound producing step includes: to be led to by formula b1 compound and aryl formyl reagent or arylsulfonyl reagent
It crosses acylation reaction to be made, the substituent group and Y on aryl in the aryl formyl reagent or arylsulfonyl reagent2Taking on aryl
It is same for base phase;In the formula b1 compound, G1~G8、R3、R4、R5、R6、R7、R9、R10As described in II-1-A class compound;
The II-1-B class compound is such as undefined -1 compound of Formula II: R in -1 compound of Formula II8For-C (=Y1)-Y2, Y1
Selected from=O or=S;Y2For imidazole radicals;The II-1-B class compound producing step includes: by formula b1 compound and 1,1 '-sulphur
It reacts to obtain formula b2 compound with imidazoles for carbonyl dimidazoles or triphosgene;Wherein Y in the formula b2 compound1For=O or
=S;
The II-1-C class compound is such as undefined -1 compound of Formula II: R in -1 compound of Formula II8For-C (=Y1)-Y2, Y1
Selected from=O or=S;Y2Selected from azanol base;-NR13R14;The alkyl-substituted alicyclic heterocyclic base that alicyclic heterocyclic base replaces, the rouge are miscellaneous
Ring group is optionally replaced by amino, hydroxyl, halogen, alkoxy, alkyl, halogenated alkyl;Alkylamino, the alkylamino is by oxygen, hydroxyl
At least one of base, heteroaryl, aryl replace, the heteroaryl, aryl optionally by amino, hydroxyl, halogen, alkoxy, alkyl,
Halogenated alkyl replaces;Wherein, R13、R14As described in the appended claim 1;The preparation step of the II-1-C class compound includes: formula
B2 compound and iodomethane reaction production b3 compound, formula b3 compound is reacted with compound R to be made;Wherein, the chemical combination
Object R is selected from the alkyl-substituted alicyclic heterocyclic that alicyclic heterocyclic base replaces, and the alicyclic heterocyclic base and alicyclic heterocyclic are optionally by amino, hydroxyl
Base, halogen, alkoxy, alkyl, halogenated alkyl replace;Alkane ammonia, the alkane ammonia is by least one of oxygen, hydroxyl, heteroaryl, aryl
Replace, the heteroaryl, aryl are optionally replaced by amino, hydroxyl, halogen, alkoxy, alkyl, halogenated alkyl;
The II-1-D class compound is such as undefined -1 compound of Formula II: R in -1 compound of Formula II8For-C (=NH)-
NHOH;The preparation step of the II-1-D class compound include: by formula b1 compound be made formula b4 compound, formula b4 compound with
Hydroxylamine hydrochloride reaction is made;
The II-1-E class compound is such as undefined -1 compound of Formula II: R in -1 compound of Formula II8For-C (=Y1)-Y2, Y1
For=O, Y2For 4- (bis- (2- chloroethyl) amino of N, N-) phenyl propyl;The preparation step of the II-1-E class compound includes:
Formula b1 compound is reacted with Chlorambucil to be made;
In -2 compound of Formula II, R9With R10Composition-C (=O)-together;G1~G8、R3、R4、R5、R6、R7、R8Such as claim
Described in any one of 1-5;The preparation step of -2 compound of Formula II includes: that formula c1 compound reacts obtained with formula c2 compound
Formula c3 compound, then formula c4 compound is made by reacting, then formula c5 compound is made by reacting, then by reacting the formula of being made
C6 compound, then formula c7 compound is made by reacting, then formula c8 compound is made by reacting, then formula c9 is made by reacting
Compound, then -2 compound of Formula II is made by reacting;
R3To be protected when reactive group optionally with blocking group;
Optionally, the Perkin condensation reaction is in oxalyl chloride, triethylamine (Et3N), carried out in the presence of methylene chloride;
Optionally, the ammonolysis reaction is the presence in hmds gastral cavity (HMDS), n,N-Dimethylformamide and methanol
Lower progress;
Optionally, the formula a6 compound is made by dibromo-maleimide and iodomethane reaction;
Optionally, the formula a8 compound obtains formula a3 compound by hydrolyzing under alkaline condition after acidified;
Optionally, work as R1、R2Or R3When for reactive group, the blocking group is selected from (Boc)2O;
Optionally, R in the II-1-A class compound3For-H;R6With R7Composition=O together;R8For methyl, the II-1-A class
The preparation step for closing object includes: 1. acylation reaction, and staurosporine is dissolved in methylene chloride, triethylamine is added, with halobenzoyl
Change reagent and acylation reaction occurs;2. halogenating reaction, by step 1. products therefrom in methyl alcohol with N-halosuccinimides at room temperature
Halogenating reaction occurs;3. oxidation reaction, by step, 2. products therefrom is obtained containing R with oxidizing4、R5It is independently selected from-H;-OH;
Or R4With R5Composition=O compound together;The acylation reaction, halogenating reaction, oxidation reaction are carried out by optional sequence;It can
Selection of land, the oxidation reaction are carried out using following reagents: O2,DMSO,t-BuOK;
Optionally, the R in the II-1-B class compound, in formula b2 compound3For-H;R4、R5It is independently selected from-H;R6With R7Together
Composition=O;R8For methyl;The preparation of the II-1-B class compound carries out by the following method: method 1.: staurosporine is molten
In methylene chloride, triethylamine is then added, and 1, the reaction of 1 '-thio-carbonyldiimidazole is made;Or method is 2.: by staurosporine
It is dissolved in tetrahydrofuran, diisopropylethylamine and triphosgene reaction is then added, reacting coarse product is dissolved in tetrahydrofuran, is added two
Wopropyl ethyl amine, imidazoles and to dimethylamino naphthyridine be made;
Optionally, R in the II-1-C class compound3For-H;R4、R5It is-H;R6With R7Composition=O together;R8For methyl;Institute
State II-1-C class compound preparation step include: by formula b2 compound in acetonitrile solvent with iodomethane at salt, after be dissolved in two
Chloromethanes, is added triethylamine and compound R carries out substituted in reaction imidazole salts and is made;
Optionally, R in the II-1-D class compound3For-H;R4、R5It is-H;R6With R7Composition=O together;R8For methyl;Institute
The preparation method of classification (4) compound is stated the following steps are included: Fradcarbazole C reacts obtained with hydroxylamine hydrochloride;
Optionally, R in the II-1-E class compound3For-H, R4、R5It is-H;R6With R7Composition=O together;R8For methyl;Institute
The preparation step for stating II-1-E class compound includes: that staurosporine reacts obtained with Chlorambucil;
Optionally, in -2 compound of Formula II, R3For-H;R4With R5Composition=O together;R6With R7Composition=O together;R8For first
Base;The preparation step of -2 compound of Formula II includes: 1. using glucose as raw material, and process is full acetylated, 1- bromos, 1,2-
Position methylates at alkene reaction, deacetylation, the TIPS protection of 6- hydroxyls, 3,4- building oxazole cyclic ketones, oxymercuration hydroboration
Sodium reduction obtains saccharide donor in 1- introducing hydroxyls;2. 3- dibromo-maleimide is raw material with 2, protected by BOM, with
The reaction of indoles Grignard Reagent introduces a molecule indoles, then the nitrogen hydrogen of indoles is protected with Boc, anti-with indoles Grignard Reagent again later
It should obtain parent nucleus;3. utilizing Mitsunobu reaction to carry out glycosylation shape the step 1. saccharide donor and the step 2. parent nucleus
At first glycosidic bond, the isomers of glycosidic bond is separated by silica gel column chromatography, then carries out Boc and TIPS protecting group
Removing, high voltage mercury lamp radiation carry out cyclization, then 6- hydroxyls are replaced with iodine, and 5,6- de- iodine are at double bond, then under catalysis of iodine
Second glycosidic bond is formed, takes off iodine with tetrabutyl stannane, 20% hydroxide palladium carbon removing BOM is made;
Optionally, in -2 compound of Formula II, R3For-H;R8For methyl;R4With R5Composition=O together, R6、R7It is-H;Or
Person, R4、R5It is-H, R6With R7Composition=O together;The preparation step of -2 compound of Formula II includes: by the R3For-H, R4
With R5Composition=O together, R6With R7Composition=O together, R8Pass through sodium borohydride reduction and zinc powder for -2 compound of Formula II of methyl
Acetic acid reduction is made;
Optionally, -2 compound of Formula II, which is used, carries out glycosidic bond and oxazole cyclic ketones configuration not with D-Glucose or L- glucose
The preparation of identical isomers.
7. a kind of antineoplastic pharmaceutical compositions, including the described in any item compound of formula I of Claims 1 to 5, Formula II compound or
At least one of their pharmaceutically acceptable salts or prodrug and pharmaceutically acceptable auxiliary material;Optionally, described antitumor
Drug is overriding resistance tumour medicine;Optionally, the anti-tumor drug is anti-leukemia medicine, anti-breast cancer medicines, anti-lung cancer
Drug or medicines resistant to liver cancer;Optionally, the anti-tumor drug is anti-mutability leukemia medicament or anti-mutability lung-cancer medicament;
Optionally, the anti-tumor drug is that anti-acute promyelocytic leukemic drug, anti-chronic myelogenous leukemia drug, anti-T lymph are thin
Born of the same parents' leukemia medicament, acute double phenotype (B, monokaryon) the myelocytic leukemia drugs of people, the adriamycin of anti-FLT3-ITD mutation are resistance to
Medicine leukemia medicament, anti-infiltration ductal carcinomas of breast drug, Antilung gland cancer medicine, anti-liver cancer and anti-HepG2 drug, anti-K-ras mutation
Type adenocarcinoma of lung drug or the acquired EGFR-T790M/L858R of anti-Gefitinib or Erlotinib are mutated adenocarcinoma of lung drug.
8. a kind of bioprobe for inhibiting cell Proliferation, including the described in any item compound of formula I of Claims 1 to 5, Formula II
Close object or at least one of their pharmaceutically acceptable salts or prodrug and optional solvent.Optionally, the solvent be water,
Methanol, dimethyl sulfoxide or its two or more mixed solvent.
9. compound of formula I described in any one of claim 1-5, Formula II compound or their pharmaceutically acceptable salts or prodrug
Purposes in the preparation of antitumor drugs, optionally, the anti-tumor drug are overriding resistance tumour medicine;Optionally, described anti-
Tumour medicine is anti-leukemia medicine, anti-breast cancer medicines, anti-lung-cancer medicament or medicines resistant to liver cancer;Optionally, described antitumor
Drug is anti-mutability leukemia medicament or anti-mutability lung-cancer medicament;Optionally, the anti-tumor drug is to resist acute early children
Grain leukemia medicament, anti-chronic myelogenous leukemia drug, anti-T lymphocyte leukemia medicament, the people of anti-FLT3-ITD mutation are anxious
Property double phenotype (B, monokaryon) myelocytic leukemia drug, adriamycin drug-resistant leukemia drug, anti-infiltration ductal carcinomas of breast medicine
Object, Antilung gland cancer medicine, anti-liver cancer and anti-HepG2 drug, anti-K-ras saltant type adenocarcinoma of lung drug or anti-Gefitinib or angstrom sieve
Adenocarcinoma of lung drug is mutated for the acquired EGFR-T790M/L858R of Buddhist nun.
10. compound of formula I described in any one of claim 1-5, Formula II compound or their pharmaceutically acceptable salts or preceding
The medicinal purposes as in the bioprobe for inhibiting cell Proliferation.
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