CN109438277A - Oximido naphthoquinone compound and its preparation method and application - Google Patents

Oximido naphthoquinone compound and its preparation method and application Download PDF

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CN109438277A
CN109438277A CN201811227689.6A CN201811227689A CN109438277A CN 109438277 A CN109438277 A CN 109438277A CN 201811227689 A CN201811227689 A CN 201811227689A CN 109438277 A CN109438277 A CN 109438277A
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phenyl
base
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王恒山
经孝腾
黄日镇
贾强
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Puji Biotechnology (taizhou) Co Ltd
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Priority to PCT/CN2019/095516 priority patent/WO2020082817A1/en
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    • C07—ORGANIC CHEMISTRY
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    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/32—Oximes
    • C07C251/34—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C251/44—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atom of at least one of the oxyimino groups being part of a ring other than a six-membered aromatic ring
    • C07C251/46—Quinone oximes
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    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D333/34—Sulfur atoms

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Abstract

The application belongs to medical compounds and technical field of pharmaceuticals, it is related to oximido naphthoquinone compound and its preparation method and application, more particularly to the compound of formula (I), the compound can be used to treat oophoroma, colon cancer and lung cancer etc. as double target spot selective depressants of STAT3 and IDO1.

Description

Oximido naphthoquinone compound and its preparation method and application
Technical field
The application belongs to medical compounds and technical field of pharmaceuticals, in particular to oximido naphthoquinone compound and its Preparation method and purposes.
Background technique
Malignant tumour is by cancer cell escape mankind's natural immune system and caused by being in unlimited proliferation, it has also become existing For the main fatal disease of people.The World Health Organization (WHO) claims in " global cancer report 2014 ", the annual newly-increased cancer in the whole world For disease patient numbers up to 15,000,000 people, many of tumour (especially oophoroma, colon cancer and lung cancer etc.) is common frequently-occurring Cancer.Its treated effect is low, and solid tumor is difficult to treat, and place is high-order in various cancers for recurrence rate.Since these tumours are thin Born of the same parents can make a variation and immune system of escaping, and cause chemotherapeutics not have highly selective, cause conventional medication to fail, be current The significant challenge faced in antineoplastic clinic.It is, thus, sought for the anti-tumor agent of new and effective low side effect, especially Can the dedifferentiation of selective depression tumour cell infinitely expand and the novel formulation of the multiple target point for immunological regulation new mechanism.
Signal transduction and transcription activator (STAT) and dioxygenase (IDO) participate in human body immunological regulation and inflammation and embryo Relevant physiology course is educated and grown to fetal hair, occurs with kinds cancer and malignization is related, be the important target for the treatment of malignant tumor Point.STAT and IDO has key effect to effective identification of tumour cell to regulation immune system as immunologic test point.
Signal transduction and activating transcription factor 3 (STAT3) are immunocyte essence in tumour cell and tumor microenvironment Activity factor, it is the convergence point of many oncogenic signals pathways.Show that STAT3 lacks of proper care for different types of cancer research Growth of cancer cells, proliferation, survival, angiogenesis, transfer and the Primary Actor of invasion, and usually with more pernicious tumour Phenotype is related.STAT3 can transduce the signal from numerous carcinogenic proteins and access, and be many important immunosupress bases Because of vital activator.Moreover, recent studies have shown that, on different molecular levels, the STAT3 of activation is inhibiting place Master in the immunosurveillance of cancer to working, and which also promotes the development of tumour.The IDO that tumour can be mediated by activation STAT3 Catalysis oxidation T cell, which is proliferated required tryptophan transfer, to be become kynurenin and inhibits T cell immune response, and tumour immunity is caused to be escaped Ease.In addition, the receptor signal conduction for maintaining the versatility of glioblastoma stem cell to need to regulate and control by STAT3, inhibits The activation of STAT3 will lead to growth inhibition, differentiation and the apoptosis of cancer stem cell, show that STAT3 is cancer stem cell (CSC) Necessary to survival.It can be seen that STAT3 has become the potential drug targets for the treatment of of cancer, exploitation STAT3 inhibitor is that have Effect alleviates the feasible method of cancer drug resistance and migration.
Currently, inhibiting the active drug design strategies of STAT3 mainly includes two methods.One is inhibit its upstream to swash Enzyme, to prevent the phosphorylation process of STAT3.However, since these kinases target multiple downstream proteins, when under other approach There may be detrimental effects for timing.The other is directly inhibiting the activity of STAT3.Compared with former approach, this strategy The function of normal cell can be minimally interfered, side effect is reduced, thus it is more attractive.So far, have multiple STAT3 suppressions Preparation is in different clinical investigation phases, and wherein STA-21 is first non-peptide small molecule STAT3 inhibitor.STA-21 is four The deoxidation products of angle mycin, the skeleton structure with quinone.And STAT3 inhibitor LLL-3, LLL-12 and the LY-5 being subsequently found are equal Include quinone skeleton.
Indoleamine 2,3-dioxygenase 1 (IDO1) is catalyzed the initial and rate-limiting step of kynurenine pathway, thin by tumour Cellular expression is to escape potential effective immune response, and highly expressed IDO1 is related to the poor prognosis of kinds cancer type (Platten,M.；Wick,W.；Van den Eynde,B.J.Cancer Res.2012,72,5435-5440； Uyttenhove,C.；Pilotte,L.；Théate,I.；Stroobant,V.；Colau,D.；Parmentier,N.；Boon, T.；Van den Eynde,B.J.Nat.Med.2003,9,1269-1274；Théate,I.；van Baren,N.；Pilotte, L.；Moulin,P.；Larrieu,P.；Renauld,J.-C.；Hervé,C.；Gutierrez-Roelens,I.；Marbaix, E.；Sempoux,C.；Van den Eynde,B.J.Cancer Immunol.Res.2015,3,161-172；Godin- Ethier,J.；Hanafi,L.-A.；Piccirillo,C.A.Clin.Cancer Res.2011,17,6985-6991).
Currently, the immunological tolerance that IDO1 is mediated is widely accepted the most important machine developed for tumour to escape immunosurveillance One of system.In fact, in many human tumors, such as breast cancer, prostate cancer, lung cancer, colon cancer and neuroblastoma and The duration height of melanoma, generally existing IDO1 expresses (Munn, D.H.；Mellor,
A.L.Clin.Invest.2007,117,1147-1154.Uyttenhove,C.；Pilotte,L.；Théate, I.；Stroobant,V.；Colau,D.；Parmentier,N.；Boon,T.；Van den Eynde, J.V.Nat.Med.2003,9,1269-1274；Brody,J.R.；Costantino,C.L.；Berger,A.C.；Sato,T.； Lisanti,M.P.；Yeo,C.J.；Emmons,R.V.；Witkiewicz,A.K.Cell Cycle 2009,8,1930- 1934).IDO1 is a kind of hemachrome enzyme, by being catalyzed L-Trp (L- with cracking pyrrole ring substrate in conjunction with molecular oxygen Trp) it is oxidized to N- formylkynurenine (NFK).The crystal structure of people IDO1 has one in terminal heme site (pocket A) A binding pocket, connect with the second pocket of active site inlet (pocket B) (U.F.；Awad,L.； Grosdidier,A.；Larrieu,P.；Stroobant,V.；Colau,D.；Cerundolo,V.；Simpson,A.J.G.； Vogel,P.；Van den Eynde,B.J.；Zoete,V.J.Med.Chem.2010,53,1172-1189).Recent research is Verified IDO1 expression is induced by tumor necrosis factor α (TNF-α) and other inflammatory mediators.Therefore, because initial host is to swollen The inflammatory reaction of tumor may cause IDO1 by chain induction (Dunn, G.P.；Koebel,C.M.；Schreiber, R.D.Nat.Rev.Immunol.2006,6,836-848).In addition, increasing expression and different tumour progression parameters and the contracting of IDO1 The survival period of short patient is positively correlated.All these evidences all show the curative effect for inhibiting IDO1 that may enhance cancer treatment drugs. In fact, the preclinical study based on mouse tumor model shows IDO1 inhibitor and some anticancer drugs such as cyclophosphamide, more It is soft that there is synergistic effect (Hou, D.Y. than star, taxol and cisplatin combined use；Muller,A.J.；Sharma,M.D.；Du Hadaway,J.；Banerjee,T.；Johnson,M.；Mellor,A.L.；Prendergast,G.C.Cancer Res.2007,67,792-801).Inhibit in view of the t cell response that IDO1 enzymatic activity mediates and IDO1 is expressed and several cancers Correlation between the poor prognosis and chemotherapy resistance of indication, IDO1 have become the potential target of cancer immunotherapy.
Existing fraction IDO1 inhibitor enters clinical research, wherein the 1- methyl-developed by NewLink Genetics DL-tryptophan is first IDO1 inhibitor (Cady, S.G.；Sono,M.Cancer Res.1991,291,326-333). The INCB024360 and NLG919 that Incyte Corporation and NewLink Genetics are developed respectively have also been applied to face Bed test (Mautino, M.R.；Jaipuri,F.A.；Waldo,J.；Kumar,S.；Adams,J.；van Allen,C.； Marcinowicz-Flick,A.；Munn,D.Cancer Research Philadelphia,2013,282,355-342； Nayak,A.；Hao,Z.；Sadek,R.；Vahanian,N.；Ramsey,W.；Kennedy,E.；Mautino,M.；Link,C.； Bourbo,P.；Dobbins,R.；Adams,K.；Diamond,A.；Marshall,L.；Munn,D.H.；Janik,J.Cancer 2014,2,250).It is the suppression with high IDO1 enzyme inhibition activity that quinones containing quinone or quinone imine group, which has been reported, Preparation (Bridewell, D.J.；Sperry,J.；Smith,J.R.；Kosim-Satyaputra,P.；Ching,L.-M.； Jamie,J.F.Aust.J.Chem.2013,66,40-49；E.；Larrieu,P.；Meinguet,C.；Colette, D.；Rives,A.；Blanc,S.；Ferain,T.；Pilotte,L.；Stroobant,V.；Wouters, J.Bioorg.Med.Chem.Lett.2013,23,47-54；Pasceri,R.；Siegel,D.；Ross,D.；Moody, C.J.J.Med.Chem.2013,56,3310-3317；Centko,R.M.；A.；Rosell,F.I.；Patrick, B.O.；de Voogd,N.；Mauk,A.G.Org.Lett.2014,16,6480-6483).Quinones can by with enzyme The specificity of active site interacts or by carrying out redox cycle with reduced cofactor or by nucleophilic amino acid The chemical reaction of side chain inhibits IDO1.
Ying Ge, Aibo Li et al. people is in European Journal of Medicinal Chemistry, and 2017,128 (2017) indicate that the anti-tumor activity of 2- amino acid amide naphthoquinones has certain selectivity in 180-191, but its activity is not high, does not have Specific study on mechanism mainly still concentrates on traditional cell toxicant class tumour medicine field in terms of activity.
It clinically there is no the research to the bis- target spot inhibitor of STAT3 and IDO1 at present, therefore, research and development have height special The bis- target spot inhibitor of the STAT3 and IDO1 of one property have important practical significance.
Summary of the invention
According to the one aspect of the application, compound or its pharmaceutically acceptable salt with formula (I) are provided:
Wherein
X is the C being optionally substituted with one or more groups selected from the following6-C10Aryl or 5 yuan are to 10 unit's heteroaryls: Halogen, hydroxyl, sulfydryl, the sulfenyl optionally replaced, the C optionally replaced1-C6Alkyl, the C optionally replaced1-C6Alkenyl optionally takes The C in generation1-C6Alkynyl, the C optionally replaced1-C6Alkoxy, the amino optionally replaced, the hydroxyl C optionally replaced1-C6Alkyl, optionally The halogenated C replaced1-C6Alkyl and the halogenated C optionally replaced1-C6Alkoxy；
Each R1Independently selected from hydrogen, halogen, hydroxyl, sulfydryl, the optionally sulfenyl, the optionally C that replaces that replace1-C6Alkane Base, the C optionally replaced1-C6Alkenyl, the C optionally replaced1-C6Alkynyl, the C optionally replaced1-C6Alkoxy, the ammonia optionally replaced Base, the hydroxyl C optionally replaced1-C6Alkyl, the halogenated C optionally replaced1-C6Alkyl and the halogenated C optionally replaced1-C6Alkoxy；
N is the integer selected from 1,2,3,4 or 5；
Each R2Independently selected from hydrogen, halogen, hydroxyl, sulfydryl, the optionally sulfenyl, the optionally C that replaces that replace1-C6Alkane Base, the C optionally replaced1-C6Alkenyl, the C optionally replaced1-C6Alkynyl, the C optionally replaced1-C6Alkoxy, the ammonia optionally replaced Base, the hydroxyl C optionally replaced1-C6Alkyl, the halogenated C optionally replaced1-C6Alkyl, the halogenated C optionally replaced1-C6Alkoxy, Asia Sulfonyl, sulfonyl, S- sulfonamido, N- sulfonamido, O- carbamoyl, N- carbamoyl, O- thiocarbamoyl Base, N- thiocarbamoyl, C- acylamino- and N- acylamino-；
M is the integer selected from 1,2,3 or 4；With
R3Selected from hydrogen, halogen, hydroxyl, sulfydryl, the optionally sulfenyl, the optionally C that replaces that replace1-C6Alkyl optionally replaces C1-C6Alkenyl, the C optionally replaced1-C6Alkynyl, the C optionally replaced1-C6Alkoxy, optionally replaces the amino that optionally replaces Hydroxyl C1-C6Alkyl, the halogenated C optionally replaced1-C6Alkyl, the halogenated C optionally replaced1-C6Alkoxy, sulfinyl, sulphonyl Base, S- sulfonamido, N- sulfonamido, O- carbamoyl, N- carbamoyl, O- thiocarbamoyl, the thio ammonia of N- Base formoxyl, C- acylamino- and N- acylamino-.
In the embodiment of the application, wherein the C6-C10Aryl is phenyl.
In the embodiment of the application, wherein described 5 yuan to 10 unit's heteroaryls be pyridyl group or thienyl.
In the embodiment of the application, wherein the C6-C10Aryl is optionally replaced by group selected from the following: Halogen, hydroxyl, sulfydryl, the C optionally replaced1-C6Alkyl, the C optionally replaced1-C6Alkoxy, optionally takes the amino optionally replaced The hydroxyl C in generation1-C6Alkyl, the halogenated C optionally replaced1-C6Alkyl and the halogenated C optionally replaced1-C6Alkoxy.
In the embodiment of the application, wherein the C6-C10Aryl is phenyl, optionally selected from the following Group replaces: halogen, the C optionally replaced1-C6Alkyl, the C optionally replaced1-C6Alkoxy and the halogenated C optionally replaced1-C6Alkane Base.
In the embodiment of the application, wherein each R1It is hydrogen.
In the embodiment of the application, wherein each R2It is hydrogen.
In the embodiment of the application, wherein the R3For hydrogen.
According to further aspect of the application, compound selected from the following or its pharmaceutically acceptable salt are provided:
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (4- (trifluoro Methyl) phenyl)-propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (2- fluorobenzene Base)-propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3, N- diphenyl-propionyl Amine；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3- fluorobenzene Base)-propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (2- methoxy Base phenyl)-propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3,5- bis- Aminomethyl phenyl)-propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (4- chlorobenzene Base)-propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (4- bromobenzene Base)-propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (the bromo- 4- of 3- Fluorophenyl)-propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3- (trifluoro Methyl) phenyl)-propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (4- fluorobenzene Base)-propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3- toluene Base)-propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (2- chlorobenzene Base)-propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3- chlorobenzene Base)-propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (2- bromobenzene Base)-propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3- bromobenzene Base)-propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3- methoxy Base phenyl)-propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (4- methoxy Base phenyl)-propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (4- toluene Base)-propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3,5- bis- Methoxyphenyl)-propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (the fluoro- 4- of 3- Bromophenyl)-propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3,5- bis- Fluorophenyl)-propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (the fluoro- 4- of 2- Aminomethyl phenyl)-propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (2,5- bis- Methoxyphenyl)-propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (the chloro- 4- of 3- Aminomethyl phenyl)-propionamide；With
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (2- methyl - 4- bromophenyl)-propionamide.
According to further aspect of the application, compound or its pharmaceutically acceptable salt with formula (II) are provided:
Wherein
X is the C being optionally substituted with one or more groups selected from the following6-C10Aryl or 5 yuan are to 10 unit's heteroaryls: Halogen, hydroxyl, sulfydryl, the sulfenyl optionally replaced, the C optionally replaced1-C6Alkyl, the C optionally replaced1-C6Alkenyl optionally takes The C in generation1-C6Alkynyl, the C optionally replaced1-C6Alkoxy, the amino optionally replaced, the hydroxyl C optionally replaced1-C6Alkyl, optionally The halogenated C replaced1-C6Alkyl and the halogenated C optionally replaced1-C6Alkoxy；
Each R1Independently selected from hydrogen, halogen, hydroxyl, sulfydryl, the optionally sulfenyl, the optionally C that replaces that replace1-C6Alkane Base, the C optionally replaced1-C6Alkenyl, the C optionally replaced1-C6Alkynyl, the C optionally replaced1-C6Alkoxy, the ammonia optionally replaced Base, the hydroxyl C optionally replaced1-C6Alkyl, the halogenated C optionally replaced1-C6Alkyl and the halogenated C optionally replaced1-C6Alkoxy；
N is the integer selected from 1,2,3,4 or 5；
Each R2Independently selected from hydrogen, halogen, hydroxyl, sulfydryl, the optionally sulfenyl, the optionally C that replaces that replace1-C6Alkane Base, the C optionally replaced1-C6Alkenyl, the C optionally replaced1-C6Alkynyl, the C optionally replaced1-C6Alkoxy, the ammonia optionally replaced Base, the hydroxyl C optionally replaced1-C6Alkyl, the halogenated C optionally replaced1-C6Alkyl, the halogenated C optionally replaced1-C6Alkoxy, Asia Sulfonyl, sulfonyl, S- sulfonamido, N- sulfonamido, O- carbamoyl, N- carbamoyl, O- thiocarbamoyl Base, N- thiocarbamoyl, C- acylamino- and N- acylamino-；
M is the integer selected from 1,2,3 or 4；With
R3Selected from hydrogen, halogen, hydroxyl, sulfydryl, the optionally sulfenyl, the optionally C that replaces that replace1-C6Alkyl optionally replaces C1-C6Alkenyl, the C optionally replaced1-C6Alkynyl, the C optionally replaced1-C6Alkoxy, optionally replaces the amino that optionally replaces Hydroxyl C1-C6Alkyl, the halogenated C optionally replaced1-C6Alkyl, the halogenated C optionally replaced1-C6Alkoxy, sulfinyl, sulphonyl Base, S- sulfonamido, N- sulfonamido, O- carbamoyl, N- carbamoyl, O- thiocarbamoyl, the thio ammonia of N- Base formoxyl, C- acylamino- and N- acylamino-.
In the embodiment of the application, wherein the C6-C10Aryl is phenyl.
In the embodiment of the application, wherein described 5 yuan to 10 unit's heteroaryls be pyridyl group or thienyl.
In the embodiment of the application, wherein the C6-C10Aryl is optionally replaced by group selected from the following: Halogen, hydroxyl, sulfydryl, the C optionally replaced1-C6Alkyl, the C optionally replaced1-C6Alkoxy, optionally takes the amino optionally replaced The hydroxyl C in generation1-C6Alkyl, the halogenated C optionally replaced1-C6Alkyl and the halogenated C optionally replaced1-C6Alkoxy.
In the embodiment of the application, wherein the C6-C10Aryl is phenyl, optionally selected from the following Group replaces: halogen, the C optionally replaced1-C6Alkyl, the C optionally replaced1-C6Alkoxy and the halogenated C optionally replaced1-C6Alkane Base.
In the embodiment of the application, wherein each R1It is hydrogen.
In the embodiment of the application, wherein each R2It is hydrogen.
In the embodiment of the application, wherein the R3For hydrogen.
According to further aspect of the application, compound selected from the following or its pharmaceutically acceptable salt are provided:
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (4- (trifluoromethyl) phenyl) - Propionamide；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (2- fluorophenyl)-propionamide；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3, N- diphenyl-propionamide；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3- fluorophenyl)-propionamide；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (2- methoxyphenyl)-propionyl Amine；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3,5- 3,5-dimethylphenyl)-the third Amide；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (4- chlorphenyl)-propionamide；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (4- bromophenyl)-propionamide；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (the bromo- 4- fluorophenyl of 3-)-the third Amide；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3- (trifluoromethyl) phenyl) Propionamide；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (4- fluorophenyl)-propionamide；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3- tolyl)-propionamide；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (2- chlorphenyl)-propionamide；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3- chlorphenyl)-propionamide；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (2- bromophenyl)-propionamide；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3- bromophenyl)-propionamide；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3- methoxyphenyl)-propionyl Amine；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (4- methoxyphenyl)-propionyl Amine；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (4- tolyl)-propionamide；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3,5- dimethoxy benzene；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (the fluoro- 4- bromophenyl of 3-)-the third Amide；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3,5- difluorophenyl)-propionyl Amine；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (the fluoro- 4- aminomethyl phenyl of 2-) - Propionamide；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (2,5- Dimethoxyphenyl) - Propionamide；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (the chloro- 4- aminomethyl phenyl of 3-) - Propionamide；With
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (2- methyl -4- bromophenyl) - Propionamide.
According to further aspect of the application, compound or its pharmaceutically acceptable salt with formula (III) are provided:
Wherein
X is the C being optionally substituted with one or more groups selected from the following6-C10Aryl or 5 yuan are to 10 unit's heteroaryls: Halogen, hydroxyl, sulfydryl, the sulfenyl optionally replaced, the C optionally replaced1-C6Alkyl, the C optionally replaced1-C6Alkenyl optionally takes The C in generation1-C6Alkynyl, the C optionally replaced1-C6Alkoxy, the amino optionally replaced, the hydroxyl C optionally replaced1-C6Alkyl, optionally The halogenated C replaced1-C6Alkyl and the halogenated C optionally replaced1-C6Alkoxy；
Each R1Independently selected from hydrogen, halogen, hydroxyl, sulfydryl, the optionally sulfenyl, the optionally C that replaces that replace1-C6Alkane Base, the C optionally replaced1-C6Alkenyl, the C optionally replaced1-C6Alkynyl, the C optionally replaced1-C6Alkoxy, the ammonia optionally replaced Base, the hydroxyl C optionally replaced1-C6Alkyl, the halogenated C optionally replaced1-C6Alkyl and the halogenated C optionally replaced1-C6Alkoxy；
N is the integer selected from 1,2,3,4 or 5；
Each R2Independently selected from hydrogen, halogen, hydroxyl, sulfydryl, the optionally sulfenyl, the optionally C that replaces that replace1-C6Alkane Base, the C optionally replaced1-C6Alkenyl, the C optionally replaced1-C6Alkynyl, the C optionally replaced1-C6Alkoxy, the ammonia optionally replaced Base, the hydroxyl C optionally replaced1-C6Alkyl, the halogenated C optionally replaced1-C6Alkyl, the halogenated C optionally replaced1-C6Alkoxy, Asia Sulfonyl, sulfonyl, S- sulfonamido, N- sulfonamido, O- carbamoyl, N- carbamoyl, O- thiocarbamoyl Base, N- thiocarbamoyl, C- acylamino- and N- acylamino-；
M is the integer selected from 1,2,3 or 4；
R3Selected from hydrogen, halogen, hydroxyl, sulfydryl, the optionally sulfenyl, the optionally C that replaces that replace1-C6Alkyl optionally replaces C1-C6Alkenyl, the C optionally replaced1-C6Alkynyl, the C optionally replaced1-C6Alkoxy, optionally replaces the amino that optionally replaces Hydroxyl C1-C6Alkyl, the halogenated C optionally replaced1-C6Alkyl, the halogenated C optionally replaced1-C6Alkoxy, sulfinyl, sulphonyl Base, S- sulfonamido, N- sulfonamido, O- carbamoyl, N- carbamoyl, O- thiocarbamoyl, the thio ammonia of N- Base formoxyl, C- acylamino- and N- acylamino-；With
R4For the C being optionally substituted with one or more groups selected from the following6-C10Aryl or 5 yuan are to 10 unit's heteroaryls: Halogen, hydroxyl, sulfydryl, the sulfenyl optionally replaced, the C optionally replaced1-C6Alkyl, the C optionally replaced1-C6Alkenyl optionally takes The C in generation1-C6Alkynyl, the C optionally replaced1-C6Alkoxy, the amino optionally replaced, the hydroxyl C optionally replaced1-C6Alkyl, optionally The halogenated C replaced1-C6Alkyl and the halogenated C optionally replaced1-C6Alkoxy.
In the embodiment of the application, wherein the C6-C10Aryl is phenyl, described 5 yuan to 10 unit's heteroaryls For pyridyl group or thienyl.
In the embodiment of the application, wherein the C6-C10Aryl is phenyl, optionally selected from the following Group replaces: halogen, the C optionally replaced1-C6Alkyl, the C optionally replaced1-C6Alkoxy and the halogenated C optionally replaced1-C6Alkane Base.
In the embodiment of the application, wherein each R1It is hydrogen.
In the embodiment of the application, wherein each R2It is hydrogen.
In the embodiment of the application, wherein the R3For hydrogen.
In the embodiment of the application, wherein the C6-C10Aryl is phenyl, described 5 yuan to 10 unit's heteroaryls For thienyl.
According to further aspect of the application, compound selected from the following or its pharmaceutically acceptable salt are provided:
(R) -2- ((4- ((((4- (tert-butyl) phenyl) sulfonyl) oxygen) imino group) -1- oxo-DHN 1,4 dihydronaphthalene -2- Base) amino) -3- phenyl-N- (3- (trifluoromethyl) phenyl)-propionamide；
(R) -2- ((4- ((((4- (tert-butyl) phenyl) sulfonyl) oxygen) imino group) -1- oxo-DHN 1,4 dihydronaphthalene -2- Base) amino) -3- phenyl-N- (3- bromophenyl)-propionamide；With
(R) -2- ((4- ((((4- (tert-butyl) phenyl) sulfonyl) oxygen) imino group) -1- oxo-DHN 1,4 dihydronaphthalene -2- Base) amino) -3- phenyl-N- (3- methoxyphenyl)-propionamide.
According to further aspect of the application, the method for compound described in preparation formula (II), the method packet are provided Step a) as follows is included to e):
A) react phthalic anhydride and L-phenylalanine, the phenyl in the L-phenylalanine is optionally by 1 to n R1Replace；
B) product and C for obtaining step a)2O2Cl2Reaction；
C) product and X-NH for obtaining step b)2Reaction；
D) product and hydrazine reaction for obtaining step c)；
E) product for obtaining step d) is reacted with 1,4-naphthoquinone, and the phenyl ring in the 1,4-naphthoquinone is optionally by 1 to m R2Replace and 2 carbon are optionally by R3Replace, to obtain the compound of formula (II)；
Wherein X, R1、n、R2, m and R3It is as noted before.
In the embodiment of the application, the reaction condition of step a) be at 55-85 DEG C, preferably at 70 DEG C It flows back in the acid solution of such as acetic acid or glacial acetic acid 10-14 hours, preferably 12 hours；The molar ratio of reactant is about 1:1.
In the embodiment of the application, the reaction condition of step b) is at 0-15 DEG C, preferably at 0 DEG C all As dichloromethane or chloroform halogenated alkane solution in react 10-14 hours, preferably 12 hours；Appropriate dimethyl methyl can be added Amide (DMF) is used as catalyst；The molar ratio of reactant oxalyl chloride and another reactant is 2.5:1 or more.
In the embodiment of the application, the reaction condition of step c) is at 0-15 DEG C, preferably at 0 DEG C all As dichloromethane or chloroform halogenated alkane solution in react 20-40 minutes, preferably 30 minutes, wherein will drop speed control exist 1 drop per second；Triethylamine can be added as acid binding agent；The molar ratio of reactant is about 1:1.
In the embodiment of the application, the reaction condition of step d) is at room temperature in the alcohol of such as dehydrated alcohol It is reacted in class solution, until being precipitated there is no solid, the reaction time is about 2.5-3.5h for reaction；Reactant hydrazine hydrate with it is another The molar ratio of reactant is 2.5:1 or more.
In the embodiment of the application, the reaction condition of step e) is at room temperature in triethylamine, dimethyl methyl It is reacted 18-24 hours in the mixed solution of amide and water；The molar ratio of reactant 1,4- naphthoquinones and another reactant is about 1.5: 1。
According to further aspect of the application, the method for compound described in preparation formula (I) is provided, the method includes Step f) as follows:
The step f) is to react the compound of formula (II) with hydroxylamine hydrochloride, the compound of formula (II) and hydroxylamine hydrochloride Molar ratio is about 1:3；Preferably, the reaction condition of step f) is at 70-80 DEG C in such as dehydrated alcohol or anhydrous methanol 10-14 hours, preferably 12 hours are reacted in alcohol solution, to obtain the compound of formula (I), wherein X, R1、n、R2, m and R3For As described above.
According to further aspect of the application, the method for compound described in preparation formula (III), the method packet are provided Include step g) as follows:
The step g) is by the compound and ClSO of formula (I)2R4Reaction, the compound and ClSO of formula (I)2R4Mole Than for about 1:2；The reaction condition of the preferably described step g) is to exist at 0-15 DEG C, preferably in the inert gas of such as argon gas 20-40 minutes, preferably 30 minutes are reacted at 0 DEG C in methylene chloride, triethylamine is then added dropwise and react 10-20 points Clock；Wherein X, R1、n、R2、m、R3And R4It is as noted before.
According to further aspect of the application, pharmaceutical composition is provided, it includes the active compounds of the application Or its pharmaceutically acceptable salt or according to the obtained compound of method of the compound of preparation formula (I) and formula (III) or its Pharmaceutically acceptable salt and one or more pharmaceutically acceptable carriers, diluent, excipient or combinations thereof.
According to further aspect of the application, provides the active compound of the application or its is pharmaceutically acceptable Salt, according to the obtained compound of method of the compound of preparation formula (I) and formula (III) or its pharmaceutically acceptable salt or The pharmaceutical composition of the application is inhibiting the purposes in STAT3 and/or IDO1.
According to further aspect of the application, the compound or its pharmaceutically acceptable salt, basis of the application are provided The obtained compound of method of the compound of preparation formula (I) and formula (III) or its pharmaceutically acceptable salt or the application's Pharmaceutical composition is preparing the purposes in the drug for inhibiting STAT3 and/or IDO1.
According to further aspect of the application, the compound or its pharmaceutically acceptable salt, basis of the application are provided The compound or its pharmaceutically acceptable salt or this Shen that the method for the compound of preparation formula (I) and formula (III) obtains The purposes of pharmaceutical composition please in the preparation of medicament for cancer treatment.
In the embodiment of the application, the cancer is selected from colon cancer, oophoroma, liver cancer, bladder cancer, cervix Cancer and small cell carcinoma of lung.
Detailed description of the invention
Fig. 1 shows p-STAT3 (Y705), the p- with full cell lysate of the compound Iu processing from SKOV3 cell The Western blotting of STAT3 (S727), total STAT3 and beta-actin.
Fig. 2 shows dynamic with STAT1, STAT5 and β-flesh of full cell lysate of the compound Iu processing from SKOV3 cell The Western blotting of albumen.
Fig. 3 show compound Iu selective depression STAT3, wherein using fluorescein enzyme process detection compound Iu for The active histogram of STAT1, STAT3, STAT4 and STAT5.
Fig. 4 shows the histogram that compound Iu inhibits the DNA of STAT3 to combine (ELISA measurement result).
Fig. 5 shows that compound Iu inhibits pSTAT3 nuclear translocation, SKOV3 cell is stimulated with IL-6, with (0.5 μM) processing p- of Iu Migration of the STAT3 to nucleus.
Fig. 6 is shown in the wound healing assay for carrying out cell migration in SKOV3 cancerous cell line with Iu (0.1 and 0.5 μM).
Fig. 7 shows that compound Iu inhibits the invasion of SKOV3 cancerous cell line.
Fig. 8 show compound Iu and IDO1 combine UV absorption spectrogram, indicate do not have Iu compound (blue) and The UV spectrum of the iron IDO1 of Iu compound (red) with 2mM concentration.There are compound Iu, the peak Soret from 403nm is moved to 413nm.
Fig. 9 show compound Iu and IDO1 interaction surface plasma resonance, measurement hIDO1 and compound Iu it Between combine, it is shown that SPR curve of the IDO1 in conjunction with Iu.Show in the biosensor chip surface for being fixed with IDO-1 albumen The Iu concentration of upper injection.Measure the K generatedDIt is 0.08 μM.
Specific embodiment
In order to better understand the essence of the application, it will illustrate the application with the specific embodiment of the application below Oximido naphthoquinone derivatives, preparation method and pharmacological action as a result, but the technical solution of the application be not limited thereto.
This application provides the double target spot selective depressants for being directed to STAT and IDO, in particular for STAT3's and IDO1 Double target spot selective depressants.Specifically, this application provides oximido naphthoquinone compound, preparation method and such change Object and its pharmaceutical composition are closed in preparing the drug for treating kinds of tumors (especially oophoroma, colon cancer and lung cancer etc.) Purposes.
Specifically, the application designs, synthesis is a series of to be used for tumour immunity for the bis- target spot inhibitor of STAT3 and IDO1 Treatment.By Mechanism Study the effects of ultraviolet-visible spectrum analysis, surface plasmon resonance assay, Enzyme assay, The cytoactive detections such as Western Blot experiment, cell dyeing experiment, SKOV3 cell migration and invasion experiment, it was found that make With double target spot micromolecular inhibitors on STAT3 and IDO1 signal path.Specifically, it can inhibit SKOV3 cancer cell Proliferation, migration and/or invasion.
Definition
Unless specified otherwise herein, all technical and scientific terms used herein have logical with persons skilled in the art The identical meanings understood.Unless specified otherwise herein, all patents, application, published application and other herein cited disclosures are with it It is incorporated herein by reference.Unless specified otherwise herein, in the case where the term of this paper has multiple definition, with determining for this part Subject to justice.
When group is described as " optionally replacing ", then group can be unsubstituted or take shown in one or more Replace for base.Similarly, when group is described as " unsubstituted or substituted ", if it is substituted, then substituent group is optional The substituent group shown in one or more.It is described " optionally replacing " or " substituted " if not pointing out substituent group Group can separately and independently be replaced by one or more groups selected from the following: alkyl, alkenyl, alkynyl, naphthenic base, cyclenes Base, cycloalkynyl radical, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroarylalkyl, (heteroalicyclyl) alkyl, hydroxyl, oxyl, virtue Oxygroup, acyl group, sulfydryl, alkylthio group, arylthio, cyano, halogen, thiocarbonyl, O- carbamoyl, N- carbamoyl, O- Thiocarbamoyl, N- thiocarbamoyl, C- acylamino-, N- acylamino-, S- sulfonamido, N- sulfonamido, C- carboxylic Base, O- carboxyl, isocyanate group, thiocyano-, isothiocyanic acid base, nitro, silicyl, sulfenyl, sulfinyl, sulfonyl, Halogenated alkyl, halogenated oxyl, three halide sulfonyls, three halide sulfonamidos and amino.
“CaTo Cb" refer to alkyl, the carbon atom number in alkenyl or alkynyl or the carbon atom number in aryl, heteroaryl, wherein " a " and " b " is integer.That is, alkyl, alkenyl, alkynyl, aryl, heteroaryl may include " a " to " b " a carbon atom, including " a " and " b " a carbon atom.Thus, for example, " C1To C4Alkyl " group refers to all alkyl with 1 to 4 carbon, i.e. CH3-、 CH3CH2-、CH3CH2CH2-、(CH3)2CH-、CH3CH2CH2CH2-、CH3CH2CH(CH3)-and (CH3)3C-.If not specifying alkane Base, alkenyl, alkynyl, aryl, heteroaryl " a " and " b ", it assumes that these definition described in be widest range.
" alkyl " refers to straight chain hydrocarbon chain or branch hydrocarbon chain comprising fully saturated (without double bond or three key) hydrocarbyl group.Alkyl There can be 1 to 20 carbon atom, whenever occurring herein, the numberical range of such as " 1 to 20 " refers to each in given range A integer；For example, " 1 to 20 carbon atom " refer to may include 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, 10 carbon atoms, 11 carbon atoms, 12 Carbon atom, 13 carbon atoms, 14 carbon atoms, 15 carbon atoms, 16 carbon atoms, 17 carbon atoms, 18 carbon atoms, 19 The alkyl of carbon atom or 20 carbon atoms.Alkyl can also be the median size alkyl with 1 to 10 carbon atom.Alkyl can also be Low alkyl group with 1 to 6 carbon atom.The alkyl of compound can specify as " C1-C6Alkyl " or similar title.For example, “C1-C4Alkyl " indicates to have in alkyl chain one to four carbon atom, that is, alkyl chain is selected from methyl, ethyl, propyl, isopropyl, just Butyl, isobutyl group, sec-butyl and tert-butyl.Typical alkyl includes but is not limited to methyl, ethyl, propyl, isopropyl, fourth Base, isobutyl group, tert-butyl, amyl and hexyl.Alkyl can be substituted or unsubstituted.
" alkenyl " refers to the alkyl comprising one or more double bonds in linear chain or branched chain hydrocarbon chain.Alkenyl can be unsubstituted Or replace.Alkenyl can have 1 to 20 carbon atom, and whenever occurring herein, the numberical range of such as " 1 to 20 " is to show Determine each integer in range；For example, it may include 1 carbon atom, 2 carbon atoms, 3 carbon originals that " 1 to 20 carbon atom ", which refers to, Son, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, 10 carbon atoms, 11 A carbon atom, 12 carbon atoms, 13 carbon atoms, 14 carbon atoms, 15 carbon atoms, 16 carbon atoms, 17 carbon atoms, 18 The alkenyl of a carbon atom, 19 carbon atoms or 20 carbon atoms.
" alkynyl " refers to the alkyl comprising one or more three keys in linear chain or branched chain hydrocarbon chain.Alkynyl can be unsubstituted Or replace.Alkynyl can have 1 to 20 carbon atom, and whenever occurring herein, the numberical range of such as " 1 to 20 " is to show Determine each integer in range；For example, it may include 1 carbon atom, 2 carbon atoms, 3 carbon originals that " 1 to 20 carbon atom ", which refers to, Son, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, 10 carbon atoms, 11 A carbon atom, 12 carbon atoms, 13 carbon atoms, 14 carbon atoms, 15 carbon atoms, 16 carbon atoms, 17 carbon atoms, 18 The alkynyl of a carbon atom, 19 carbon atoms or 20 carbon atoms.
" aryl " refer to throughout all rings complete delocalization π-electron system carbocyclic ring (all carbon) monocycle or Ppolynuclear aromatic ring system (fused ring system that chemical bond is shared including two of them carbocyclic ring).Carbon atom number in aryl is variable Change.For example, aryl can be C6-C14Aryl, C6-C10Aryl or C6Aryl.The example of aryl includes but is not limited to benzene, naphthalene and Azulene. Aryl can be substituted or unsubstituted.
" heteroaryl " refers to (to be removed comprising one or more (for example, 1,2,3,4,5 or 6) hetero atoms Element except carbon includes but is not limited to nitrogen, oxygen and sulphur) monocycle or the Ppolynuclear aromatic ring system (π-with complete delocalization The ring system of electron system).Atomicity in heteroaryl ring is alterable.For example, heteroaryl may include 4 to 14 originals in ring Son may include 5 to 10 atoms in ring or may include 5 to 6 atoms in ring.In addition, term " heteroaryl " includes wherein Two rings, for example, at least an aryl rings and at least one heteroaryl ring or at least two heteroaryl rings, share at least one change Learn the fused ring system of key.The example of heteroaryl ring includes but is not limited to furans, furazan, thiophene, benzothiophene, phthalazines, pyrroles, evil Azoles, benzoxazoles, 1,2,3- oxadiazoles, 1,2,4- oxadiazoles, thiazole, 1,2,3- thiadiazoles, 1,2,4- thiadiazoles, benzo thiophene Azoles, imidazoles, benzimidazole, indoles, indazole, pyrazoles, benzopyrazoles, isoxazole, benzo isoxazole, isothiazole, triazole, benzo three Azoles, thiadiazoles, tetrazolium, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinolin, quinazoline, quinoxaline, cinnolines and Triazine.Heteroaryl can be substituted or unsubstituted.
" alkoxy " refers to formula-OR, and wherein R is alkyl defined herein.Alkoxy it is non-limiting be enumerated as methoxyl group, Ethyoxyl, positive propoxy, 1- methyl ethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy, tert-butoxy.Alkane Oxygroup can be substituted or unsubstituted.
" acyl group " refers to through carbonyl connection as the hydrogen of substituent group, alkyl, alkenyl, alkynyl or aryl.Example includes Formoxyl, acetyl group, propiono, benzoyl and acryloyl group.Acyl group can be substituted or unsubstituted.
" halogenated alkyl " refers to that wherein one or more hydrogen atoms are optionally substituted by halogen (for example, monohaloalkyl alkyl, saturated dihalide Base and tri haloalkyl) alkyl.This kind of group includes but is not limited to chloromethyl, methyl fluoride, difluoromethyl, trifluoromethyl, 1- Chloro- 2- methyl fluoride and 2- fluorine isobutyl group.Halogenated alkyl can be substituted or unsubstituted.
" halogenated oxyl " refers to wherein one or more hydrogen atoms by halogen (for example, monohaloalkyl oxyl, dihalo hydrocarbon Oxygroup and three halogenated oxyls) replace oxyl.This kind of group includes but is not limited to chloromethane epoxide, fluorine methoxyl group, difluoro first The chloro- 2- fluorine methoxyl group of oxygroup, trifluoromethoxy, 1- and 2- fluorine isobutoxy.Halogenated oxyl can be substituted or unsubstituted.
" arylthio " refers to RS-, and wherein R is aryl, such as, but not limited to phenyl.Arylthio can be replacing or unsubstituted 's.
" sulfenyl " group refers to "-SR " group, wherein R can be hydrogen, alkyl (" sulfenyl " at this time is " alkylthio group "), Alkenyl, alkynyl, naphthenic base, cycloalkenyl, cycloalkynyl radical, aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaryl) alkyl or (miscellaneous Alcyl) alkyl.Sulfenyl can be substituted or unsubstituted.
" sulfinyl " group refers to "-S (=O)-R " group, and wherein the R and R in sulfenyl is defined identical.Sulfinyl It can be substituted or unsubstituted.
" sulfonyl " group refers to " SO2R " group, wherein R is identical as the definition of the R in sulfenyl.Sulfonyl can be to take It is generation or unsubstituted.
" O- carboxyl " group refers to " RC (=O) O- " group, and wherein R can be hydrogen as defined herein, alkyl, alkenyl, alkynes Base, naphthenic base, cycloalkenyl, cycloalkynyl radical, aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaryl) alkyl or (heteroalicyclyl) Alkyl.O- carboxyl can be substituted or unsubstituted.
" thiocarbonyl " group refers to "-C (=S) R " group, and wherein R is identical as the definition about the R in O- carboxyl.Sulphur It can be substituted or unsubstituted for carbonyl.
" three halide sulfonyls " group refers to " X3CSO2" group, wherein each X is halogen.
" three halide sulfonamidos " group refers to " X3CS(O)2N(RA)-" group, wherein each X is halogen, and RAFor hydrogen, alkyl, alkenyl, alkynyl, naphthenic base, cycloalkenyl, cycloalkynyl radical, aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaryl Base) alkyl or (heteroalicyclyl) alkyl.
Term " amino " refers to-NH2Group.
Term " hydroxyl " refers to-OH group.
" cyano " group refers to "-CN " group.
" isocyanate group " group refers to "-NCO " group.
" thiocyano- " group refers to "-CNS " group.
" isothiocyanic acid base " group refers to "-NCS " group.
" sulfydryl " group refers to "-SH " group.
" carbonyl " group refers to C=O group.
" S- sulfonamido " group refers to "-SO2N(RARB) " group, wherein RAAnd RBCan independently be hydrogen, alkyl, alkenyl, Alkynyl, naphthenic base, cycloalkenyl, cycloalkynyl radical, aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaryl) alkyl or (heterolipid ring Base) alkyl.S- sulfonamido can be substituted or unsubstituted.
" N- sulfonamido " group refers to " RSO2N(RA)-" group, wherein R and RACan independently be hydrogen, alkyl, alkenyl, Alkynyl, naphthenic base, cycloalkenyl, cycloalkynyl radical, aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaryl) alkyl or (heterolipid ring Base) alkyl.N- sulfonamido can be substituted or unsubstituted.
" O- carbamoyl " group refers to "-OC (=O) N (RARB) " group, wherein RAAnd RBHydrogen, alkane can independently be Base, alkenyl, alkynyl, naphthenic base, cycloalkenyl, cycloalkynyl radical, aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaryl) alkyl or (heteroalicyclyl) alkyl.O- carbamoyl can be substituted or unsubstituted.
" N- carbamoyl " group refers to " ROC (=O) N (RA)-" group, wherein R and RACan independently be hydrogen, alkyl, Alkenyl, alkynyl, naphthenic base, cycloalkenyl, cycloalkynyl radical, aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaryl) alkyl or (miscellaneous Alcyl) alkyl.N- carbamoyl can be substituted or unsubstituted.
" O- thiocarbamoyl " group refers to "-OC (=S)-N (RARB) " group, wherein RAAnd RBIt can independently be Hydrogen, alkyl, alkenyl, alkynyl, naphthenic base, cycloalkenyl, cycloalkynyl radical, aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaryl) alkane Base or (heteroalicyclyl) alkyl.O- thiocarbamoyl can be substituted or unsubstituted.
" N- thiocarbamoyl " group refers to " ROC (=S) N (RA)-" group, wherein R and RACan independently be hydrogen, Alkyl, alkenyl, alkynyl, naphthenic base, cycloalkenyl, cycloalkynyl radical, aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaryl) alkyl Or (heteroalicyclyl) alkyl.N- thiocarbamoyl can be substituted or unsubstituted.
" C- acylamino- " group refers to "-C (=O) N (RARB) " group, wherein RAAnd RBHydrogen, alkyl, alkene can independently be Base, alkynyl, naphthenic base, cycloalkenyl, cycloalkynyl radical, aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaryl) alkyl or (heterolipid Ring group) alkyl.C- acylamino- can be substituted or unsubstituted.
" N- acylamino- " group refers to " RC (=O) N (RA)-" group, wherein R and RACan independently be hydrogen, alkyl, alkenyl, Alkynyl, naphthenic base, cycloalkenyl, cycloalkynyl radical, aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaryl) alkyl or (heterolipid ring Base) alkyl.N- acylamino- can be substituted or unsubstituted.
As used herein, term " halogen atom " or " halogen " refer to the stable original of the radiation that the periodic table of elements the 7th arranges Any of son, such as fluorine, chlorine, bromine and iodine.
Term " pharmaceutically acceptable salt ", which refers to, does not generate significant stimulation and not destruction to the organism applied Close the salt of the bioactivity of object and the compound of property.In some embodiments, the salt is the acid-addition salts of compound.Energy Drug salts are obtained by making compound and inorganic acid reaction, the inorganic acid such as halogen acids (for example, hydrochloric acid or hydrobromic acid), Sulfuric acid, nitric acid and phosphoric acid.It can be by making compound and organic acid reaction obtain drug salts, the organic acids such as aliphatic or virtue The carboxylic acid or sulfonic acid of fragrant race, such as formic acid, acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, cigarette Acid, Loprazolam, ethane sulfonic acid, p-methyl benzenesulfonic acid, salicylic acid or naphthalene sulfonic acids.It can also be by reacting compound to be formed with alkali Salt obtains drug salts, for example, the alkali metal salt of ammonium salt, such as sodium salt or sylvite, such as calcium salt or magnesium salts alkali salt, Such as dicyclohexylamine, N- methyl-D-glucosamine, three (hydroxymethyl) methyl amines, C1-C7Alkylamine, cyclo-hexylamine, three ethyl alcohol Amine, organic alkali salt of ethylenediamine and the salt with the amino acid of such as arginine and lysine.
Unless specified otherwise herein, term used herein and phrase and its modification, especially in the attached claims In should be interpreted it is open and non-limiting.As example above-mentioned, term " includes " be understood to refer to " include without Be limited to " it is synonymous and be include formula or open, and be not excluded for adding, unlisted element or method and step；Term " tool Have " it should be explained " having at least ".
It should be appreciated that in any compound with one or more chiral centres described herein, if unclear Show absolute stereochemistry configuration, then each center can independently be or mixtures thereof R- configuration or S- configuration.Therefore, it mentions herein The compound of confession can for enantiomeric pure, enantiomter enrichment, racemic mixture, diastereisomericallypure pure, Diastereoisomer is enriched with or stereoisomer mixture.In addition, it should be understood that can be defined as in generation described herein In any compound with one or more double bonds of the geometric isomer of E or Z, each double bond can independently be E or Z, its Mixture.
Compound
Some embodiments disclosed herein is related to the compound or its pharmaceutically acceptable salt with formula (I):
Wherein
X is the C being optionally substituted with one or more groups selected from the following6-C10Aryl or 5 yuan are to 10 unit's heteroaryls: Halogen, hydroxyl, sulfydryl, the sulfenyl optionally replaced, the C optionally replaced1-C6Alkyl, the C optionally replaced1-C6Alkenyl optionally takes The C in generation1-C6Alkynyl, the C optionally replaced1-C6Alkoxy, the amino optionally replaced, the hydroxyl C optionally replaced1-C6Alkyl, optionally The halogenated C replaced1-C6Alkyl and the halogenated C optionally replaced1-C6Alkoxy；
Each R1Independently selected from hydrogen, halogen, hydroxyl, sulfydryl, the optionally sulfenyl, the optionally C that replaces that replace1-C6Alkane Base, the C optionally replaced1-C6Alkenyl, the C optionally replaced1-C6Alkynyl, the C optionally replaced1-C6Alkoxy, the ammonia optionally replaced Base, the hydroxyl C optionally replaced1-C6Alkyl, the halogenated C optionally replaced1-C6Alkyl and the halogenated C optionally replaced1-C6Alkoxy；
N is the integer selected from 1,2,3,4 or 5；
Each R2Independently selected from hydrogen, halogen, hydroxyl, sulfydryl, the optionally sulfenyl, the optionally C that replaces that replace1-C6Alkane Base, the C optionally replaced1-C6Alkenyl, the C optionally replaced1-C6Alkynyl, the C optionally replaced1-C6Alkoxy, the ammonia optionally replaced Base, the hydroxyl C optionally replaced1-C6Alkyl, the halogenated C optionally replaced1-C6Alkyl, the halogenated C optionally replaced1-C6Alkoxy, Asia Sulfonyl, sulfonyl, S- sulfonamido, N- sulfonamido, O- carbamoyl, N- carbamoyl, O- thiocarbamoyl Base, N- thiocarbamoyl, C- acylamino- and N- acylamino-；
M is the integer selected from 1,2,3 or 4；With
R3Selected from hydrogen, halogen, hydroxyl, sulfydryl, the optionally sulfenyl, the optionally C that replaces that replace1-C6Alkyl optionally replaces C1-C6Alkenyl, the C optionally replaced1-C6Alkynyl, the C optionally replaced1-C6Alkoxy, optionally replaces the amino that optionally replaces Hydroxyl C1-C6Alkyl, the halogenated C optionally replaced1-C6Alkyl, the halogenated C optionally replaced1-C6Alkoxy, sulfinyl, sulphonyl Base, S- sulfonamido, N- sulfonamido, O- carbamoyl, N- carbamoyl, O- thiocarbamoyl, the thio ammonia of N- Base formoxyl, C- acylamino- and N- acylamino-.
In some embodiments, wherein the C6-C10Aryl is phenyl.
In some embodiments, wherein 5 yuan to 10 unit's heteroaryls be pyridyl group or thienyl.
In some embodiments, wherein the C6-C10Aryl is optionally replaced by group selected from the following: halogen, hydroxyl Base, sulfydryl, the C optionally replaced1-C6Alkyl, the C optionally replaced1-C6Alkoxy, the amino optionally replaced, the hydroxyl optionally replaced Base C1-C6Alkyl, the halogenated C optionally replaced1-C6Alkyl and the halogenated C optionally replaced1-C6Alkoxy.
In some embodiments, wherein the C6-C10Aryl is phenyl, is optionally taken by group selected from the following Generation: halogen, the C optionally replaced1-C6Alkyl, the C optionally replaced1-C6Alkoxy and the halogenated C optionally replaced1-C6Alkyl.
In some embodiments, wherein each R1It is hydrogen.
In some embodiments, wherein each R2It is hydrogen.
In some embodiments, wherein the R3For hydrogen.
Some embodiments disclosed herein is related to the compound or its pharmaceutically acceptable salt with formula (II):
Wherein
X is the C being optionally substituted with one or more groups selected from the following6-C10Aryl or 5 yuan are to 10 unit's heteroaryls: Halogen, hydroxyl, sulfydryl, the sulfenyl optionally replaced, the C optionally replaced1-C6Alkyl, the C optionally replaced1-C6Alkenyl optionally takes The C in generation1-C6Alkynyl, the C optionally replaced1-C6Alkoxy, the amino optionally replaced, the hydroxyl C optionally replaced1-C6Alkyl, optionally The halogenated C replaced1-C6Alkyl and the halogenated C optionally replaced1-C6Alkoxy；
Each R1Independently selected from hydrogen, halogen, hydroxyl, sulfydryl, the optionally sulfenyl, the optionally C that replaces that replace1-C6Alkane Base, the C optionally replaced1-C6Alkenyl, the C optionally replaced1-C6Alkynyl, the C optionally replaced1-C6Alkoxy, the ammonia optionally replaced Base, the hydroxyl C optionally replaced1-C6Alkyl, the halogenated C optionally replaced1-C6Alkyl and the halogenated C optionally replaced1-C6Alkoxy；
N is the integer selected from 1,2,3,4 or 5；
Each R2Independently selected from hydrogen, halogen, hydroxyl, sulfydryl, the optionally sulfenyl, the optionally C that replaces that replace1-C6Alkane Base, the C optionally replaced1-C6Alkenyl, the C optionally replaced1-C6Alkynyl, the C optionally replaced1-C6Alkoxy, the ammonia optionally replaced Base, the hydroxyl C optionally replaced1-C6Alkyl, the halogenated C optionally replaced1-C6Alkyl, the halogenated C optionally replaced1-C6Alkoxy, Asia Sulfonyl, sulfonyl, S- sulfonamido, N- sulfonamido, O- carbamoyl, N- carbamoyl, O- thiocarbamoyl Base, N- thiocarbamoyl, C- acylamino- and N- acylamino-；
M is the integer selected from 1,2,3 or 4；With
R3Selected from hydrogen, halogen, hydroxyl, sulfydryl, the optionally sulfenyl, the optionally C that replaces that replace1-C6Alkyl optionally replaces C1-C6Alkenyl, the C optionally replaced1-C6Alkynyl, the C optionally replaced1-C6Alkoxy, optionally replaces the amino that optionally replaces Hydroxyl C1-C6Alkyl, the halogenated C optionally replaced1-C6Alkyl, the halogenated C optionally replaced1-C6Alkoxy, sulfinyl, sulphonyl Base, S- sulfonamido, N- sulfonamido, O- carbamoyl, N- carbamoyl, O- thiocarbamoyl, the thio ammonia of N- Base formoxyl, C- acylamino- and N- acylamino-.
In some embodiments, wherein the C6-C10Aryl is phenyl.
In some embodiments, wherein 5 yuan to 10 unit's heteroaryls be pyridyl group or thienyl.
In some embodiments, wherein the C6-C10Aryl is optionally replaced by group selected from the following: halogen, hydroxyl Base, sulfydryl, the C optionally replaced1-C6Alkyl, the C optionally replaced1-C6Alkoxy, the amino optionally replaced, the hydroxyl optionally replaced Base C1-C6Alkyl, the halogenated C optionally replaced1-C6Alkyl and the halogenated C optionally replaced1-C6Alkoxy.
In some embodiments, wherein the C6-C10Aryl is phenyl, is optionally taken by group selected from the following Generation: halogen, the C optionally replaced1-C6Alkyl, the C optionally replaced1-C6Alkoxy and the halogenated C optionally replaced1-C6Alkyl.
In some embodiments, wherein each R1It is hydrogen.
In some embodiments, wherein each R2It is hydrogen.
In some embodiments, wherein the R3For hydrogen.
Some embodiments disclosed herein is related to the compound or its pharmaceutically acceptable salt with formula (III):
Wherein
X is the C being optionally substituted with one or more groups selected from the following6-C10Aryl or 5 yuan are to 10 unit's heteroaryls: Halogen, hydroxyl, sulfydryl, the sulfenyl optionally replaced, the C optionally replaced1-C6Alkyl, the C optionally replaced1-C6Alkenyl optionally takes The C in generation1-C6Alkynyl, the C optionally replaced1-C6Alkoxy, the amino optionally replaced, the hydroxyl C optionally replaced1-C6Alkyl, optionally The halogenated C replaced1-C6Alkyl and the halogenated C optionally replaced1-C6Alkoxy；
Each R1Independently selected from hydrogen, halogen, hydroxyl, sulfydryl, the optionally sulfenyl, the optionally C that replaces that replace1-C6Alkane Base, the C optionally replaced1-C6Alkenyl, the C optionally replaced1-C6Alkynyl, the C optionally replaced1-C6Alkoxy, the ammonia optionally replaced Base, the hydroxyl C optionally replaced1-C6Alkyl, the halogenated C optionally replaced1-C6Alkyl and the halogenated C optionally replaced1-C6Alkoxy；
N is the integer selected from 1,2,3,4 or 5；
Each R2Independently selected from hydrogen, halogen, hydroxyl, sulfydryl, the optionally sulfenyl, the optionally C that replaces that replace1-C6Alkane Base, the C optionally replaced1-C6Alkenyl, the C optionally replaced1-C6Alkynyl, the C optionally replaced1-C6Alkoxy, the ammonia optionally replaced Base, the hydroxyl C optionally replaced1-C6Alkyl, the halogenated C optionally replaced1-C6Alkyl, the halogenated C optionally replaced1-C6Alkoxy, Asia Sulfonyl, sulfonyl, S- sulfonamido, N- sulfonamido, O- carbamoyl, N- carbamoyl, O- thiocarbamoyl Base, N- thiocarbamoyl, C- acylamino- and N- acylamino-；
M is the integer selected from 1,2,3 or 4；
R3Selected from hydrogen, halogen, hydroxyl, sulfydryl, the optionally sulfenyl, the optionally C that replaces that replace1-C6Alkyl optionally replaces C1-C6Alkenyl, the C optionally replaced1-C6Alkynyl, the C optionally replaced1-C6Alkoxy, optionally replaces the amino that optionally replaces Hydroxyl C1-C6Alkyl, the halogenated C optionally replaced1-C6Alkyl, the halogenated C optionally replaced1-C6Alkoxy, sulfinyl, sulphonyl Base, S- sulfonamido, N- sulfonamido, O- carbamoyl, N- carbamoyl, O- thiocarbamoyl, the thio ammonia of N- Base formoxyl, C- acylamino- and N- acylamino-；With
R4For the C being optionally substituted with one or more groups selected from the following6-C10Aryl or 5 yuan are to 10 unit's heteroaryls: Halogen, hydroxyl, sulfydryl, the sulfenyl optionally replaced, the C optionally replaced1-C6Alkyl, the C optionally replaced1-C6Alkenyl optionally takes The C in generation1-C6Alkynyl, the C optionally replaced1-C6Alkoxy, the amino optionally replaced, the hydroxyl C optionally replaced1-C6Alkyl, optionally The halogenated C replaced1-C6Alkyl and the halogenated C optionally replaced1-C6Alkoxy.
In some embodiments, wherein the C6-C10Aryl is phenyl, and 5 yuan to 10 unit's heteroaryls are pyridyl group or thiophene Pheno base.
In some embodiments, wherein the C6-C10Aryl is phenyl, is optionally taken by group selected from the following Generation: halogen, the C optionally replaced1-C6Alkyl, the C optionally replaced1-C6Alkoxy and the halogenated C optionally replaced1-C6Alkyl.
In some embodiments, wherein each R1It is hydrogen.
In some embodiments, wherein each R2It is hydrogen.
In some embodiments, wherein the R3For hydrogen.
In some embodiments, wherein the C6-C10Aryl is phenyl, and described 5 yuan to 10 unit's heteroaryls are thienyl.
In above-mentioned embodiment, X is optionally by 1,2,3,4,5,6,7,8,9 or 10 A group replaces.
Synthesis
The specific experiment method of the application synthesizes formula (I), formula based on phthalic anhydride and L-phenylalanine (II) and oximido naphthoquinone derivatives shown in formula (III).
The synthetic route of oximido naphthoquinone derivatives shown in the formula (I) of the application, formula (II) and formula (III) is following (wherein X、R1、n、R2、m、R3And R4As described above):
Wherein
For the compound of formula (II), 2- amino acid amide-naphthoquinone compound (the compound IIa-IIz of the application), It is by step a) to e) preparation:
A) reactant is that (phenyl in L-phenylalanine is optionally by 1 to n R for phthalic anhydride and L-phenylalanine1 Replace), reaction condition: 70 DEG C, flow back 12h in acetic acid；
And C b)2O2Cl2Reaction, reaction condition: DCM (methylene chloride), DMF (dimethylformamide), 0 DEG C, 12h；
And X-NH c)2(X is the C optionally replaced6-C10Aryl or 5 yuan are to 10 unit's heteroaryls, such as aniline) reaction, reaction Condition: triethylamine, DCM, 0 DEG C；Drop speed control is dripped per second 1, the reaction time is about 30min.
D) with hydrazine (NH2NH2) reaction, reaction condition: dehydrated alcohol, room temperature；Reaction time is about 2.5~3.5h.
E) (phenyl ring in 1,4- naphthoquinones is optionally by 1 to m R with 1,4- naphthoquinones2Replace, 2 carbon are by R3Replace) reaction, Reaction condition: DMF, water, triethylamine, room temperature, 18-20h.
For the compound of formula (I), 2- amino acid amide-oximido naphthoquinone compound (compound Ia-Iz), by step It is rapid f) to prepare: the product and hydroxylamine hydrochloride (H of above-mentioned steps e)3NOHCl) react, reaction condition be at 70 DEG C -80 DEG C, Flow back 12h in dehydrated alcohol.
For the compound of formula (III), 2- amino acid amide-hydroxyl oxime ester base naphthoquinone compound (compound IIIk-1, IIIq, IIIr, IIIk-2), it is prepared by step g): the product and ClSO of above-mentioned steps f)2R4(R4It is optionally substituted C6-C10 aryl or 5 yuan are to 10 unit's heteroaryls, such as 4- t-butylbenzenesulfonyl chloride) reaction, reaction condition: DCM, argon gas, three second Amine, water, 0 DEG C, the reaction time: about 40min.
The R of each reactant in the above reaction1-R4, X, n and m it is as described above.
Composition
When the active compound of the application is used as drug, can directly it use, or in the form of pharmaceutical composition It uses.The pharmaceutical composition contains 0.1-99%, the preferably active compound of the application of 0.5-90%, remaining is medicine The upper pharmaceutical carrier acceptable, nontoxic to humans and animals and inert of object.
Optionally, the ratio of the reactive compound contained in the pharmaceutical composition be 1%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 99%.
Pharmaceutically acceptable carrier is one or more solids, semisolid and liquid diluent, filler and drug system Product auxiliary material.The pharmaceutical composition of the application is used in the form of per weight dose.This can be used using the drug of the application The usual dosage form in field, such as: ointment, tablet, pill, suppository emulsion, input liquid and injection etc..These dosage forms are according to many institutes Known method is made using traditional additive and excipients.Thus obtained drug as needed can be by local, non-enteric The approach administration such as road, oral.
The amount of application of the active compound of the application can according to route of administration, the age of patient, weight, treated The variation such as type and severity of disease, daily dose can be 0.01-10mg/kg weight, preferably 0.1-5mg/kg weight. It one or many can apply.
Embodiment
The source of agents useful for same and specification are as follows in the embodiment of the present application.
1,4- naphthoquinones (specification: 25g), hydroxylamine hydrochloride (specification: 25g), 4- t-butylbenzenesulfonyl chloride (specification: 25g), L- benzene Alanine (specification: 500g), phthalic anhydride (specification: 500g), oxalyl chloride (specification: 500ml) are raw purchased from Shanghai Aladdin Change Science and Technology Co., Ltd.；
Triethylamine (specification: 500ml), methylene chloride (specification: 500ml), N,N-dimethylformamide (specification: 500ml), Glacial acetic acid (specification: 500ml), hydrochloric acid (specification: 500ml), anhydrous sodium sulfate (specification: 500g), dehydrated alcohol (specification: 500ml), ethyl acetate (specification: 5L), petroleum ether (specification: 5L) are purchased from Shantou, Guangdong western Gansu Province science limited liability company；
Various aromatic amines (specification: 25g or 25ml), octodrine (specification: 25g), n-propylamine (specification: 250ml) be purchased from All An Naiji reagent Co., Ltd purchases；
SHB-III recirculated water multiplex vavuum pump, rotary evaporator (Zhengzhou Greatwall Scientific Industrial & Trading Co., Ltd.)；Electronic intelligence control Wen Yi, 85-1A type magnetic stirring apparatus (Yuhua Instrument Co., Ltd., Gongyi City)；400 superconduction nuclear magnetic resonance of AVANCE AV Instrument (Switzerland, Brooker company)；EL104 electronic balance (Mei Tele-support benefit Instrument Ltd.)；KQ5200E type ultrasonic wave Washer (Kunshan Ultrasonic Instruments Co., Ltd.)；(the upper macro equipment of Nereid is limited for DHG-9146A type electric heating constant-temperature blowing drying box Company)；RY-1 melting point apparatus (Tianjin natural gift analysis instrument factory, thermometer do not correct)；SHIMADZU QP5050A type mass spectrograph (APCI)；Micro polarimeter (big Chang Hua praises business Co., Ltd)；Ultraviolet device (Agilent Technologies Cary60UV- Vis)。
Hydrazine hydrate (specification: 500ml) is purchased from Sinopharm Chemical Reagent Co., Ltd.；
The above reagent is that analysis is pure.
The synthesis of the compound (compound IIa-IIz) (2- amino acid amide-naphthoquinone compound) of 1 formula of embodiment (II)
Take the round-bottomed flask of a 250mL, pour into the glacial acetic acid of 80mL thereto, add 10g L-phenylalanine and 8.966g phthalic anhydride, the return stirring 12h in 70 DEG C of oil bath pans.To after reaction, allow to cool to room temperature, then 150mL distilled water is slowly added into round-bottomed flask, and stirring, until white crystal is precipitated completely, decompression suction filtration can be obtained white The acicular 2- of color (1,3- dioxo isoindoline -2- base) -3- phenylpropanoic acid crystal, is dried at 55 DEG C.
Above-mentioned product 2- (1,3- dioxo isoindoline -2-) -3- phenylpropionic acid 1g is taken to be added equipped with 25mL dichloromethane In the 100mL round-bottomed flask of alkane, with being stirred under magnetic stirring apparatus under condition of ice bath, all dissolved to the solid in round-bottomed flask Afterwards, 5mL oxalyl chloride is added thereto, adds 1 drop DMF and makees catalyst, put on drying tube, so that it is reacted 12 hours, obtains Chlorizate.
Reaction mixture is depressurized and is rotarily dried, is dissolved with methylene chloride, is transferred to constant pressure buret, and in condition of ice bath Under be added dropwise to equipped with 1mL triethylamine and NH2- X (amount that reactant presses 1:1) is added in round-bottomed flask, controls the drop of a drop per second Speed continues to stir after dripping, after gaseous volatilization is complete, decompression rotary drying.
NH2- X is, for example, 4- (trifluoromethyl) aniline, 2- fluoroaniline, aniline, 3- fluoroaniline, 2- aminoanisole, 3,5- The bromo- 4- fluoroaniline of dimethylaniline, 2- toluidines, 4- chloroaniline, 4- bromaniline, 3-, 3- (trifluoromethyl) aniline, 4- fluorobenzene Amine, 3- toluidines, 2- chloroaniline, 3- chloroaniline, 2- bromaniline, 3- bromaniline, 3- aminoanisole, 4- aminoanisole, 4- The fluoro- 4- bromaniline of toluidines, 3,5- dimethoxyaniline, 3-, 3,5- difluoroaniline, the fluoro- 4- methylaniline of 2-, 2,5- dimethoxy The chloro- 4- methylaniline of base aniline, 3-, 2- methyl -4- bromaniline.
It is dissolved with 25mL dehydrated alcohol, 4mL hydrazine hydrate is added under stirring at normal temperature, reacted until being precipitated there is no solid, Obtain crude product.Decompression rotary drying, is extracted three times (3 × 30mL) with water and methylene chloride, collects the organic liquor of lower layer, discard Water layer, the organic layer dry 2h of anhydrous sodium sulfate, be petroleum ether through eluant, eluent: the silica gel column purification of ethyl acetate (4:1) obtains Following purified product: (R) -2- amino -3- phenyl-N- (4- (trifluoromethyl) phenyl)-propionamide, (R) -2- amino -3- phenyl - N- (2- fluorophenyl)-propionamide, (R) -2- amino -3- phenyl-N- phenylpropionamide, (R) -2- amino -3- phenyl-N- (3- fluorine Phenyl) phenyl)-propionamide, (R) -2- amino -3- phenyl-N- (2- methoxyphenyl)-propionamide, (R) -2- amino -3- benzene Base-N- (3,5- 3,5-dimethylphenyl)-propionamide, (R) -2- amino -3- phenyl-N- (2- tolyl)-propionamide, (R) -2- ammonia Base -3- phenyl-N- (4- chlorphenyl)-propionamide, (R) -2- amino -3- phenyl-N- (4- bromophenyl)-propionamide, (R) -2- ammonia Base -3- phenyl-N- (the bromo- 4- fluorophenyl of 3-)-propionamide, (R) -2- amino -3- phenyl-N- (3- (trifluoromethyl) phenyl)-the third Amide, (R) -2- amino -3- phenyl-N- (4- fluorophenyl)-propionamide, (R) -2- amino -3- phenyl-N- (3- tolyl)-the third Amide, (R) -2- amino -3- phenyl-N- (2- chlorphenyl)-propionamide, (R) -2- amino -3- phenyl-N- (3- chlorphenyl)-the third Amide, (R) -2- amino -3- phenyl-N- (2- bromophenyl)-propionamide, (R) -2- amino -3- phenyl-N- (3- bromophenyl)-the third Amide, (R) -2- amino -3- phenyl-N- (3- methoxyphenyl)-propionamide, (R) -2- amino -3- phenyl-N- (4- methoxyl group Phenyl)-propionamide, (R) -2- amino -3- phenyl-N- (4- tolyl)-propionamide, (R) -2- amino -3- phenyl-N- (3,5- Dimethoxyphenyl)-propionamide, (R) -2- amino -3- phenyl-N- (the fluoro- 4- bromophenyl of 3-)-propionamide, (R) -2- amino -3- Phenyl-N- (3,5- difluorophenyl)-propionamide, (R) -2- amino -3- phenyl-N- (the fluoro- 4- aminomethyl phenyl of 2-)-propionamide, (R) -2- amino -3- phenyl-N- (2,5- Dimethoxyphenyl)-propionamide, (R) -2- amino -3- phenyl-N- (chloro- 4- first of 3- Base phenyl)-propionamide and (R) -2- amino -3- phenyl-N- (2- methyl -4- bromophenyl)-propionamide.
Above-mentioned product and 1,4- naphthoquinones are added with the molar ratio of 1:1.5,0.5mL triethylamine, 15mL DMF and 8- are housed The round-bottomed flask of 10mL distilled water is stirred to react 18-20 hours at normal temperature, and TLC detects reaction process.It uses after the reaction was completed It is 3-4 that 1mol/L hydrochloric acid, which adjusts its pH, is extracted three times (3 × 30mL) with water and methylene chloride, with the dry 2h of anhydrous sodium sulfate, is subtracted Pressure rotary drying, be petroleum ether through eluant, eluent: the silica gel column purification of ethyl acetate (4:1) rotarily dries to obtain yellow solid.Gained Product has following concrete structure formula and parameter characterization.
The concrete structure formula and parameter characterization of the compound of formula (II) are as follows:
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (4- (trifluoromethyl) phenyl) - Propionamide (IIa)
Yield: 45.8%.Yellow solid.210.2~211.0 DEG C of fusing point.01H NMR(400MHz,DMSO):δ10.50 (s, 1H), 7.98 (d, J=6.9Hz, 1H), 7.92-7.86 (m, 1H), 7.80 (ddd, J=8.6,6.7,2.8Hz, 3H), 7.74-7.67 (m, 3H), 7.35-7.24 (m, 5H), 7.18 (t, J=7.1Hz, 1H), 5.70 (s, 1H), 4.49 (q, J= 7.0Hz, 1H), 3.30 (d, J=6.8Hz, 2H).13C NMR(101MHz,DMSO):δ181.84,180.98,169.27, 147.57,141.82,136.83,134.92,132.65,132.50,130.19,129.23,129.23,128.30,128.30, 126.72,126.16,126.12,126.00,125.37,123.75,122.93,119.61,119.61,101.06,57.65, 37.01.HR-MS (m/z) (ESI): it is calculated as C26H19F3N2O3Na[M+Na]+:487.1240；Measured value: 487.1223.
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (2- fluorophenyl)-propionamide (IIb)
Yield: 70.2%.Yellow solid.179.2~179.9 DEG C of fusing point.1H NMR(400MHz,DMSO):δ10.06(s, 1H), 7.97 (d, J=7.4Hz, 1H), 7.90 (d, J=6.9Hz, 1H), 7.83-7.76 (m, 2H), 7.72 (td, J=7.5, 1.1Hz, 1H), 7.34 (d, J=7.2Hz, 2H), 7.27 (dd, J=13.5,6.0Hz, 4H), 7.22-7.15 (m, 3H), 5.73 (s, 1H), 4.63 (dd, J=14.0,8.0Hz, 1H), 3.28 (t, J=6.2Hz, 2H).13C NMR(101MHz,DMSO):δ 181.86,181.03,169.21,155.17,152.73,147.59,136.93,134.96,132.67,132.52,130.21, 129.30,129.30,128.38,128.28,126.69,126.01,125.39,124.53,124.47,115.75,115.56, 101.09,57.17,37.18.HR-MS (m/z) (ESI): it is calculated as C25H20FN2O3[M+H]+:415.1452；Measured value: 415.1437。
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3, N- diphenyl-propionamide (IIc)
Yield: 70.2%.Yellow solid.99.7~100.2 DEG C of fusing point.1H NMR(400MHz,DMSO):δ10.17(s, 1H), 8.00-7.95 (m, 1H), 7.90 (dd, J=7.6,0.7Hz, 1H), 7.79 (td, J=7.5,1.2Hz, 1H), 7.71 (td, J=7.5,1.2Hz, 1H), 7.55 (d, J=7.7Hz, 2H), 7.36-7.29 (m, 4H), 7.26 (t, J=7.4Hz, 2H), 7.19 (d, J=7.6Hz, 2H), 7.08 (t, J=7.4Hz, 1H), 5.70 (s, 1H), 4.45 (q, J=7.0Hz, 1H), 3.27 (d, J=6.8Hz, 2H).13C NMR(101MHz,DMSO):δ181.82,181.00,168.55,147.50,138.24, 136.92,134.91,132.68,132.46,130.19,130.19,129.24,128.80,128.80,128.28,128.28, 126.68,125.98,125.37,123.91,119.74,119.74,100.99,57.55,37.19.HR-MS (m/z) (ESI): It is calculated as C25H21N2O3[M+H]+:397.1547；Measured value: 397.1531.
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3- fluorophenyl)-propionamide (IId)
Yield: 61.4%.Yellow solid.123.5~124.5 DEG C of fusing point.1H NMR(400MHz,DMSO):δ10.42(s, 1H), 7.97 (d, J=7.5Hz, 1H), 7.91-7.85 (m, 1H), 7.85-7.77 (m, 1H), 7.72 (td, J=7.5,1.2Hz, 1H), 7.54 (dd, J=11.5,1.9Hz, 1H), 7.38-7.24 (m, 7H), 7.18 (t, J=7.1Hz, 1H), 6.92 (td, J= 8.4,2.3Hz, 1H), 5.67 (s, 1H), 4.44 (dd, J=14.7,7.0Hz, 1H), 3.27 (d, J=6.8Hz, 2H).13C NMR (101MHz,DMSO):δ181.99,181.08,169.10,163.37,160.97,147.70,140.09,139.99, 136.97,135.08,132.72,132.66,130.70,130.28,129.34,128.42,126.83,126.13,125.49, 115.51,110.63,106.67,101.08,57.69,37.10.HR-MS (m/z) (ESI): it is calculated as C25H20FN2O3[M+H ]+:415.1452；Measured value: 415.1437.
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (2- methoxyphenyl)-propionyl Amine (IIe)
Yield: 72.9%.Yellow solid.133.6~134.6 DEG C of fusing point.1H NMR(400MHz,DMSO):δ9.54(s, 1H), 7.96 (d, J=7.0Hz, 1H), 7.93-7.82 (m, 2H), 7.79 (td, J=7.5,1.0Hz, 1H), 7.70 (td, J= 7.5,1.1Hz, 1H), 7.34 (d, J=7.3Hz, 2H), 7.30-7.17 (m, 4H), 7.09 (dd, J=11.3,4.2Hz, 1H), 7.03 (d, J=7.2Hz, 1H), 6.96-6.88 (m, 1H), 5.79 (s, 1H), 4.73 (dd, J=14.0,8.0Hz, 1H), 3.87-3.67 (m, 3H), 3.25 (t, J=6.1Hz, 2H).13C NMR(101MHz,DMSO):δ181.84,181.07, 168.87,150.05,147.47,137.02,134.91,132.68,132.44,130.16,129.31,129.31,128.22, 128.22,126.60,126.45,125.96,125.36,125.13,122.37,120.27,111.36,101.26,57.16, 55.77,37.31.HR-MS (m/z) (ESI): it is calculated as C26H23N2O4[M+H]+:427.1652；Measured value: 427.1638.
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3,5- 3,5-dimethylphenyl)-the third Amide (IIf)
Yield: 63.7%.Yellow solid.119.9~120.8 DEG C of fusing point.1H NMR(400MHz,DMSO):δ10.03(s, 1H), 7.96 (dd, J=7.6,0.9Hz, 1H), 7.89 (dd, J=7.6,1.0Hz, 1H), 7.79 (td, J=7.5,1.2Hz, 1H), 7.70 (td, J=7.5,1.3Hz, 1H), 7.34-7.30 (m, 2H), 7.27 (t, J=7.5Hz, 2H), 7.20 (q, J= 7.7Hz, 4H), 6.71 (s, 1H), 5.68 (s, 1H), 4.42 (dd, J=14.2,7.6Hz, 1H), 3.30-3.17 (m, 2H), 2.22(s,6H)。13C NMR(101MHz,DMSO):δ181.80,180.99,168.43,147.53,138.14,137.81, 137.81,137.01,134.90,132.67,132.45,130.18,130.18,129.24,129.24,128.29,128.29, 126.66,125.97,125.37,125.37,117.40,100.97,57.66,37.17,21.02,21.02。HR-MS(m/z) (ESI): being calculated as C27H25N2O3[M+H]+:425.1860；Measured value: 425.1843.
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (4- chlorphenyl)-propionamide (IIh)
Yield: 71.3%.Yellow solid.194.3~194.1 DEG C of fusing point.1H NMR(400MHz,DMSO):δ10.29(s, 1H), 7.96 (d, J=7.5Hz, 1H), 7.89 (d, J=6.9Hz, 1H), 7.79 (dd, J=10.8,4.1Hz, 1H), 7.71 (t, J=7.5Hz, 1H), 7.59 (d, J=8.9Hz, 2H), 7.37 (d, J=8.8Hz, 2H), 7.31 (d, J=7.0Hz, 2H), 7.25 (dd, J=12.7,5.0Hz, 3H), 7.18 (t, J=7.1Hz, 1H), 5.69 (s, 1H), 4.44 (q, J=7.0Hz, 1H), 3.27 (d, J=6.8Hz, 2H).13C NMR(101MHz,DMSO):δ181.84,180.98,168.76,147.55,137.20, 136.91,134.91,132.66,132.48,130.19,129.24,129.24,128.74,128.74,128.30,128.30, 127.54,126.71,125.99,125.38,121.28,121.28,101.01,57.59,37.09.HR-MS (m/z) (ESI): It is calculated as C25H19ClN2O3Na[M+Na]+:453.0976；Measured value: 453.0958.
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (4- bromophenyl)-propionamide (IIi)
Yield: 68.5%.Yellow solid.207.2~208.1 DEG C of fusing point.1H NMR(400MHz,DMSO):δ10.27(s, 1H), 7.98 (dd, J=7.6,1.0Hz, 1H), 7.89 (dt, J=8.7,4.4Hz, 1H), 7.81 (td, J=7.5,1.3Hz, 1H), 7.73 (td, J=7.5,1.3Hz, 1H), 7.52 (d, J=2.1Hz, 3H), 7.30 (dd, J=10.4,3.6Hz, 2H), 7.27-7.16 (m, 3H), 5.68 (s, 1H), 4.44 (q, J=7.0Hz, 1H), 3.27 (d, J=6.8Hz, 2H).13C NMR (101MHz,DMSO):δ181.82,180.99,168.75,147.57,137.60,136.89,134.94,132.66, 132.51,131.65,131.65,130.20,129.23,129.23,128.29,128.29,126.69,126.01,125.38, 121.64,121.64,115.56,100.98,57.59,37.05.HR-MS (m/z) (ESI): it is calculated as C25H20BrN2O3[M+H ]+:475.0652；Measured value: 475.0628.
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (the bromo- 4- fluorophenyl of 3-)-the third Amide (IIj)
Yield: 69.9%.Yellow solid.244.2~245.2 DEG C of fusing point.1H NMR(400MHz,DMSO):δ10.45(s, 1H), 7.96 (dd, J=7.6,1.0Hz, 1H), 7.89 (dd, J=7.6,1.0Hz, 1H), 7.79 (td, J=7.5,1.3Hz, 1H), 7.71 (ddd, J=9.4,5.8,1.7Hz, 2H), 7.64 (t, J=8.4Hz, 1H), 7.29 (ddd, J=18.4,11.7, 4.6Hz, 6H), 7.21-7.15 (m, 1H), 5.68 (s, 1H), 4.45 (q, J=7.0Hz, 1H), 3.28 (d, J=6.8Hz, 2H).13C NMR(101MHz,DMSO):δ181.83,180.94,169.15,159.21,156.79,147.57,139.45,136.84, 134.90,133.43,132.62,132.48,130.17,129.21,129.21,128.29,128.29,126.71,125.98, 125.36,116.99,116.96,107.79,101.05,57.63,36.95.HR-MS (m/z) (ESI): it is calculated as C25H17BrFN2O3[M-H]+:491.0412；Measured value: 491.0414.
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3- (trifluoromethyl) phenyl) Propionamide (IIk)
Yield: 46.5%.Yellow solid.160.8~161.5 DEG C of fusing point.1H NMR(400MHz,DMSO):δ10.47(s, 1H), 8.02-7.96 (m, 2H), 7.89 (dd, J=7.6,1.0Hz, 1H), 7.83-7.76 (m, 2H), 7.71 (dd, J=7.5, 1.3Hz, 1H), 7.57 (t, J=8.0Hz, 1H), 7.44 (d, J=7.8Hz, 1H), 7.34-7.29 (m, 2H), 7.26 (dd, J= 8.1,6.7Hz, 3H), 7.19 (ddd, J=7.1,3.8,1.3Hz, 1H), 5.69 (s, 1H), 4.47 (dd, J=14.8,7.1Hz, 1H), 3.30 (d, J=6.9Hz, 2H).13C NMR(101MHz,DMSO):δ181.88,180.99,169.21,147.63, 139.03,136.91,134.94,132.67,132.53,130.21,130.14,129.24,129.24,128.32,128.32, 126.73,126.01,125.39,123.29,120.28,120.25,115.81,115.77,101.07,57.66,37.01。 HR-MS (m/z) (ESI): it is calculated as C26H19F3N2O3Na[M+Na]+:465.1421；Measured value: 465.1401.
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (4- fluorophenyl)-propionamide (IIl)
Yield: 76.6%.Yellow solid.193.2~194.2 DEG C of fusing point.1H NMR(400MHz,DMSO):δ10.22(s, 1H), 7.97 (dd, J=7.6,1.1Hz, 1H), 7.89 (dd, J=7.6,1.1Hz, 1H), 7.80 (td, J=7.5,1.3Hz, 1H),7.74–7.69(m,1H),7.59–7.53(m,2H),7.33–7.22(m,5H),7.21–7.13(m,3H),5.69(s, 1H), 4.43 (dd, J=14.8,7.0Hz, 1H), 3.27 (d, J=6.8Hz, 2H).13C NMR(101MHz,DMSO):δ 181.83,181.00,168.50,159.57,157.18,147.56,136.96,134.93,132.68,132.49,130.20, 129.25,129.25,128.30,128.30,126.69,126.00,125.38,121.64,121.56,115.53,115.31, 100.98,57.53,37.13.HR-MS (m/z) (ESI): it is calculated as C25H20FN2O3[M+H]+:415.1452；Measured value: 415.1436。
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3- tolyl)-propionamide (IIm)
Yield: 60.2%.Yellow solid.145.3~145.0 DEG C of fusing point.1H NMR(400MHz,DMSO):δ10.12(s, 1H), 7.98-7.92 (m, 1H), 7.88 (d, J=7.0Hz, 1H), 7.76 (td, J=7.5,1.1Hz, 1H), 7.67 (td, J= 7.5,1.1Hz, 1H), 7.43-7.36 (m, 2H), 7.33 (d, J=7.2Hz, 2H), 7.30-7.16 (m, 5H), 6.89 (d, J= 7.5Hz, 1H), 5.70 (s, 1H), 4.45 (dd, J=14.4,7.3Hz, 1H), 3.28 (d, J=6.0Hz, 2H), 2.26 (s, 3H)。13C NMR(101MHz,DMSO):δ181.82,180.99,168.53,147.52,138.22,138.06,137.00, 134.87,132.68,132.42,130.17,129.27,129.27,128.66,128.30,128.30,126.69,125.96, 125.37,124.59,120.22,116.88,101.01,57.65,37.21,21.12.HR-MS (m/z) (ESI): it is calculated as C26H23N2O3[M+H]+:411.1703；Measured value: 411.1688.
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (2- chlorphenyl)-propionamide (IIn)
Yield: 71.8%.Yellow solid.185.8~186.6 DEG C of fusing point.1H NMR(400MHz,DMSO):δ9.88(s, 1H), 8.00-7.95 (m, 1H), 7.91 (dd, J=7.6,1.0Hz, 1H), 7.80 (td, J=7.5,1.3Hz, 1H), 7.72 (td, J=7.5,1.3Hz, 1H), 7.59 (dd, J=8.0,1.4Hz, 1H), 7.49 (dd, J=8.0,1.4Hz, 1H), 7.36 (t, J=5.6Hz, 2H), 7.33-7.26 (m, 4H), 7.25-7.18 (m, 2H), 5.81 (s, 1H), 4.64 (dd, J=14.1, 7.9Hz,1H),3.34–3.26(m,2H)。13C NMR(101MHz,DMSO):δ181.86,181.03,169.19,147.57, 136.94,134.92,134.11,132.66,132.50,130.20,129.55,129.32,129.32,128.32,128.32, 127.50,127.11,126.96,126.71,126.53,125.98,125.38,101.41,57.25,37.14。HR-MS(m/ Z) (ESI): it is calculated as C25H20ClN2O3[M+H]+:431.1157；Measured value: 431.1142.
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3- chlorphenyl)-propionamide (IIo)
Yield: 63.3%.Yellow solid.191.6~192.2 DEG C of fusing point.1H NMR(400MHz,DMSO):δ10.33(s, 1H), 7.97 (dd, J=7.6,1.0Hz, 1H), 7.89 (dd, J=7.6,1.0Hz, 1H), 7.80 (td, J=7.5,1.3Hz, 1H), 7.75 (t, J=2.0Hz, 1H), 7.72 (td, J=7.5,1.4Hz, 1H), 7.44 (ddd, J=8.2,1.9,1.0Hz, 1H), 7.38-7.31 (m, 2H), 7.31-7.24 (m, 4H), 7.21-7.12 (m, 2H), 5.69 (s, 1H), 4.44 (q, J= 7.0Hz, 1H), 3.28 (d, J=6.8Hz, 2H).13C NMR(101MHz,DMSO):δ181.85,180.97,168.99, 147.58,139.68,136.88,134.92,133.11,132.65,132.50,130.54,130.20,129.23,129.23, 128.30,128.30,126.71,126.00,125.38,123.62,119.17,118.07,101.04,57.63,37.02。 HR-MS (m/z) (ESI): it is calculated as C25H20ClN2O3[M+H]+:431.1157；Measured value: 431.1143.
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (2- bromophenyl)-propionamide (IIp)
Yield: 75.3%.Yellow solid.178.5~178.6 DEG C of fusing point.1H NMR(400MHz,DMSO):δ9.85(s, 1H), 7.98 (dd, J=7.6,1.1Hz, 1H), 7.91 (dd, J=7.6,1.1Hz, 1H), 7.82 (td, J=7.5,1.3Hz, 1H), 7.76-7.71 (m, 1H), 7.66 (dd, J=8.0,1.3Hz, 1H), 7.51 (dd, J=8.0,1.5Hz, 1H), 7.40- 7.35(m,3H),7.32–7.25(m,3H),7.23–7.19(m,1H),7.20–7.14(m,1H),5.81(s,1H),4.60 (dd, J=14.3,7.7Hz, 1H), 3.31 (s, 1H).13C NMR(101MHz,DMSO):δ181.85,181.02,169.08, 147.58,136.99,135.45,134.94,132.73,132.66,132.52,130.20,129.30,129.30,128.33, 128.33,128.11,127.58,127.23,126.70,125.99,125.38,118.15,101.47,57.28,37.05。 HR-MS (m/z) (ESI): it is calculated as C25H20BrN2O3[M+H]+:475.0652；Measured value: 475.0632.
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3- bromophenyl)-propionamide (IIq)
Yield: 66.9%.Yellow solid.184.0~184.7 DEG C of fusing point.1H NMR(400MHz,DMSO):δ10.31(s, 1H), 7.98 (dd, J=7.6,1.0Hz, 1H), 7.90 (dd, J=8.8,1.3Hz, 2H), 7.81 (td, J=7.5,1.4Hz, 1H), 7.72 (td, J=7.5,1.4Hz, 1H), 7.49 (dt, J=7.1,2.2Hz, 1H), 7.32-7.30 (m, 2H), 7.29- 7.24 (m, 4H), 7.19 (ddd, J=7.1,3.9,1.4Hz, 1H), 5.68 (s, 1H), 4.44 (q, J=7.0Hz, 1H), 3.28 (d, J=6.8Hz, 2H).13C NMR(101MHz,DMSO):δ181.84,180.97,168.95,147.58,139.81, 136.88,134.93,132.65,132.51,130.84,130.19,129.22,129.22,128.30,128.30,126.70, 126.51,126.00,125.38,122.02,121.53,118.45,101.03,57.62,37.00.HR-MS (m/z) (ESI): It is calculated as C25H20BrN2O3[M+H]+:475.0652；Measured value: 475.0632.
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3- methoxyphenyl)-propionyl Amine (IIr)
Yield: 68.9%.Yellow solid.111.9~112.5 DEG C of fusing point.1H NMR(400MHz,DMSO):δ10.17(s, 1H), 7.96 (dd, J=7.7,1.1Hz, 1H), 7.89 (dd, J=7.6,1.0Hz, 1H), 7.78 (td, J=7.5,1.3Hz, 1H), 7.70 (td, J=7.5,1.4Hz, 1H), 7.34-7.30 (m, 2H), 7.29-7.17 (m, 6H), 7.14-7.10 (m, 1H), 6.66 (ddd, J=8.2,2.5,0.7Hz, 1H), 5.69 (s, 1H), 4.44 (dd, J=14.8,7.1Hz, 1H), 3.38 (s, 3H), 3.27 (d, J=6.8Hz, 2H).13C NMR(101MHz,DMSO):δ181.81,180.98,168.61,159.52, 147.50,139.44,136.95,134.89,132.66,132.44,130.17,129.63,129.24,128.28,126.67, 125.97,125.36,111.90,109.36,105.43,100.98,57.61,55.00,37.16。13C NMR(101MHz, DMSO):δ181.81,180.98,168.61,159.52,147.50,139.44,136.95,134.89,132.66,132.44, 130.17,129.63,129.24,129.24,128.28,128.28,126.67,125.97,125.36,111.90,109.36, 105.43,100.98,57.61,55.00,37.16.HR-MS (m/z) (ESI): it is calculated as C26H23N2O4[M+H]+: 427.1652；Measured value: 427.1637.
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (4- methoxyphenyl)-propionyl Amine (IIs)
Yield: 78.9%.Yellow solid.148.3~148.7 DEG C of fusing point.1H NMR(400MHz,DMSO):δ10.06(s, 1H), 7.94 (dd, J=7.6,1.0Hz, 1H), 7.88 (dd, J=7.6,0.9Hz, 1H), 7.76 (td, J=7.5,1.3Hz, 1H), 7.68 (td, J=7.5,1.3Hz, 1H), 7.47-7.42 (m, 2H), 7.30 (dd, J=12.3,5.4Hz, 2H), 7.26 (t, J=7.4Hz, 2H), 7.21-7.15 (m, 2H), 6.92-6.86 (m, 2H), 5.70 (s, 1H), 4.42 (q, J=7.0Hz, 1H), 3.70 (d, J=3.7Hz, 4H), 3.26 (d, J=6.7Hz, 2H).13C NMR(101MHz,DMSO):δ181.88, 181.03,168.11,155.77,147.51,137.00,134.92,132.73,132.47,131.33,130.21,129.31, 129.31,128.33,128.33,126.73,126.01,125.41,121.44,121.44,113.98,113.98,101.00, 57.50,55.21,37.31.HR-MS (m/z) (ESI): it is calculated as C26H23N2O4[M+H]+:427.1652；Measured value: 427.1637。
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (4- tolyl)-propionamide (IIt)
Yield: 70.5%.Yellow solid.97.2~98.1 DEG C of fusing point.1H NMR(400MHz,DMSO):δ10.10(s, 1H), 7.94 (dd, J=7.6,0.9Hz, 1H), 7.88 (dd, J=7.6,0.8Hz, 1H), 7.76 (td, J=7.5,1.3Hz, 1H), 7.67 (td, J=7.5,1.3Hz, 1H), 7.45 (d, J=8.4Hz, 2H), 7.32 (d, J=7.1Hz, 2H), 7.26 (t, J =7.5Hz, 2H), 7.18 (dt, J=9.6,6.5Hz, 2H), 7.11 (d, J=8.3Hz, 2H), 5.70 (s, 1H), 4.44 (dd, J =14.7,7.1Hz, 1H), 3.27 (d, J=6.8Hz, 2H), 2.23 (s, 3H).13C NMR(101MHz,DMSO):δ181.79, 180.96,168.31,147.46,136.97,135.73,134.84,132.90,132.67,132.39,130.16,129.25, 129.25,129.16,129.16,128.27,128.27,126.66,125.94,125.34,119.75,119.75,100.97, 57.54,37.25,20.44.HR-MS (m/z) (ESI): it is calculated as C26H22N2O3Na[M+Na]+:433.1523；Measured value: 433.1505。
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3,5- Dimethoxyphenyl) - Propionamide (IIu)
Yield: 73.0%.Yellow solid.195.3~195.5 DEG C of fusing point.1H NMR(400MHz,DMSO):δ10.04(s, 1H), 7.97 (dd, J=7.6,0.9Hz, 1H), 7.90 (dd, J=7.6,1.0Hz, 1H), 7.81 (td, J=7.5,1.3Hz, 1H), 7.72 (td, J=7.5,1.3Hz, 1H), 7.29 (dt, J=14.9,4.6Hz, 4H), 7.23-7.16 (m, 3H), 7.08 (dd, J=8.7,2.3Hz, 1H), 6.90 (d, J=8.8Hz, 1H), 5.68 (s, 1H), 4.41 (dd, J=14.7,7.0Hz, 1H), 3.72 (d, J=4.7Hz, 6H), 3.26 (d, J=6.8Hz, 2H).13C NMR(101MHz,DMSO):δ179.89, 169.77,160.55,160.55,145.26,140.46,140.12,137.17,133.88,132.95,129.23,129.23, 129.01,128.45,128.35,128.35,126.68,125.86,122.35,97.89,97.89,95.82,91.41, 57.89,55.16,55.16,37.62.HR-MS (m/z) (ESI): it is calculated as C27H25N2O5[M+H]+:457.1758；Measured value: 457.1740。
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (the fluoro- 4- bromophenyl of 3-)-the third Amide (IIv)
Yield: 55.3%.Yellow solid.226.7~227.5 DEG C of fusing point.1H NMR(400MHz,DMSO):δ10.47(s, 1H), 7.96 (dd, J=7.6,1.0Hz, 1H), 7.89 (dd, J=7.6,1.0Hz, 1H), 7.79 (td, J=7.5,1.3Hz, 1H), 7.71 (ddd, J=8.6,4.9,1.9Hz, 2H), 7.63 (t, J=8.4Hz, 1H), 7.34-7.22 (m, 6H), 7.21- 7.14 (m, 1H), 5.68 (s, 1H), 4.45 (q, J=7.0Hz, 1H), 3.28 (d, J=6.8Hz, 2H).13C NMR(101MHz, DMSO):δ181.84,180.95,169.15,159.21,156.80,147.55,139.35,136.81,134.90,133.42, 132.63,132.48,130.17,129.22,129.22,128.30,128.30,126.72,125.98,125.37,116.97, 107.54,101.07,57.62,36.98.HR-MS (m/z) (ESI): it is calculated as C25H19BrFN2O3[M+H]+:493.0558；It is real Measured value: 493.0592.
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3,5- difluorophenyl)-propionyl Amine (IIw)
Yield: 65.8%.Yellow solid.168.4~169.2 DEG C of fusing point.1H NMR(400MHz,DMSO):δ10.50(s, 1H), 7.98-7.94 (m, 1H), 7.89 (dd, J=7.6,1.0Hz, 1H), 7.78 (td, J=7.5,1.3Hz, 1H), 7.70 (td, J=7.5,1.3Hz, 1H), 7.33-7.24 (m, 7H), 7.22-7.16 (m, 1H), 6.96-6.89 (m, 1H), 5.68 (s, 1H), 4.45 (q, J=7.0Hz, 1H), 3.28 (d, J=6.8Hz, 2H).13C NMR(101MHz,DMSO):δ181.88, 180.95,169.34,163.56,161.14,147.57,140.74,136.80,134.91,132.63,132.50,130.18, 129.23,129.23,128.32,128.32,126.74,125.99,125.38,102.69,102.40,101.12,99.05, 57.67,36.94.HR-MS (m/z) (ESI): it is calculated as C25H19F2N2O3[M+H]+:433.1358；Measured value: 433.1345.
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (the fluoro- 4- aminomethyl phenyl of 2-) - Propionamide (IIx)
Yield: 70.5%.Yellow solid.158.5~158.7 DEG C of fusing point.1H NMR(400MHz,DMSO):δ9.95(s, 1H), 7.96 (dd, J=7.7,1.0Hz, 1H), 7.90 (dd, J=7.7,1.0Hz, 1H), 7.79 (td, J=7.5,1.3Hz, 1H), 7.70 (td, J=7.5,1.3Hz, 1H), 7.60 (t, J=8.3Hz, 1H), 7.39-7.32 (m, 2H), 7.27 (t, J= 7.5Hz, 2H), 7.19 (ddd, J=7.2,6.6,3.4Hz, 2H), 7.08 (dd, J=11.8,1.1Hz, 1H), 6.96 (d, J= 8.1Hz, 1H), 5.73 (s, 1H), 4.60 (dt, J=14.0,7.1Hz, 1H), 3.34-3.20 (m, 2H), 2.27 (s, 3H).13C NMR(101MHz,DMSO):δ181.83,181.00,169.03,155.13,152.70,147.51,136.92,134.89, 132.67,132.45,130.18,129.29,129.29,128.25,128.25,126.66,125.96,125.36,124.80, 124.49,122.55,122.43,101.07,57.11,37.22,20.35.HR-MS (m/z) (ESI): it is calculated as C26H22FN2O3Na[M+Na]+:451.1428；Measured value: 451.1410.
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (2,5- Dimethoxyphenyl) - Propionamide (IIy)
Yield: 71.2%.Yellow solid.117.7~117.9 DEG C of fusing point.1H NMR(400MHz,DMSO):δ9.52(s, 1H), 7.97 (dd, J=7.7,1.0Hz, 1H), 7.90 (dd, J=7.6,1.0Hz, 1H), 7.81 (td, J=7.5,1.3Hz, 1H), 7.72 (td, J=7.5,1.4Hz, 1H), 7.59 (d, J=3.1Hz, 1H), 7.33 (d, J=7.1Hz, 2H), 7.25 (dd, J=16.1,8.2Hz, 3H), 7.21-7.16 (m, 1H), 6.96 (d, J=9.0Hz, 1H), 6.65 (dd, J=8.9,3.1Hz, 1H), 5.78 (s, 1H), 4.76 (dt, J=14.0,7.0Hz, 1H), 3.74 (s, 3H), 3.67 (s, 3H), 3.31-3.18 (m, 2H)。13C NMR(101MHz,DMSO):δ181.86,181.08,168.98,152.92,147.49,143.87,137.00, 134.96,132.67,132.49,130.17,129.31,129.31,128.22,128.22,127.35,126.61,125.99, 125.37,112.22,108.84,108.48,101.24,57.13,56.40,55.36,37.28.HR-MS (m/z) (ESI): meter Calculating is C27H24N2O5Na[M+Na]+:479.1577；Measured value: 479.1561.
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (the chloro- 4- aminomethyl phenyl of 3-) - Propionamide (IIz)
Yield: 71.2%.Yellow solid.Fusing point: 178.1~178.6 DEG C.1H NMR(400MHz,DMSO):δ10.22 (s, 1H), 7.97 (dd, J=7.6,0.9Hz, 1H), 7.89 (dd, J=7.6,1.0Hz, 1H), 7.80 (td, J=7.5, 1.3Hz, 1H), 7.72 (ddd, J=8.9,5.6,1.3Hz, 2H), 7.29 (tdd, J=16.3,8.6,3.7Hz, 7H), 7.18 (ddd, J=7.0,3.8,1.4Hz, 1H), 5.68 (s, 1H), 4.43 (q, J=7.0Hz, 1H), 3.27 (d, J=6.8Hz, 2H), 2.26(s,3H)。13C NMR(101MHz,DMSO):δ181.80,180.95,168.70,147.56,137.34,136.91, 134.90,132.99,132.64,132.47,131.24,130.58,130.18,129.22,129.22,128.28,128.28, 126.67,125.97,125.36,119.66,118.30,100.98,57.57,37.03,18.94.HR-MS (m/z) (ESI): It is calculated as C26H22ClN2O3[M+H]+:445.1313；Measured value: 475.1306.
The conjunction of the compound (compound Ia-Iz) (2- amino acid amide-oximido naphthoquinone compound) of 2 formula of embodiment (I) At
It is with mass ratio by the substituted benzene aminated compounds of the 1,4- naphthoquinones -2- aminoacylates as above synthesized and hydroxylamine hydrochloride 1:3 is added in the round-bottomed flask equipped with 25mL dehydrated alcohol, controls temperature back flow reaction 12h at 80 DEG C, and decompression rotarily dries, Three times (3 × 30mL) with water and methylene chloride extraction, with the dry 2h of anhydrous sodium sulfate, decompression rotary drying is stone through eluant, eluent Oily ether: the silica gel column purification of ethyl acetate (5:1), the product rotarily dried are greenish yellow solid.Products therefrom has such as Lower concrete structure formula and parameter characterization.
The concrete structure formula and parameter characterization of the compound of formula (I) are as follows:
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (4- (trifluoro Methyl) phenyl)-propionamide (Ia)
Yield: 48.2%.Greenish yellow solid.194.4~194.7 DEG C of fusing point.1H NMR(400MHz,DMSO):δ12.33 (s, 1H), 10.57 (s, 1H), 8.16 (dd, J=8.0,0.6Hz, 1H), 8.06 (dd, J=7.9,1.0Hz, 1H), 7.78 (d, J =8.6Hz, 2H), 7.67 (dd, J=11.2,5.2Hz, 3H), 7.60-7.54 (m, 1H), 7.35-7.24 (m, 4H), 7.20 (ddd, J=6.7,3.9,1.7Hz, 1H), 6.60 (s, 1H), 6.36 (d, J=8.2Hz, 1H), 4.43 (q, J=7.0Hz, 1H), 3.24 (d, J=6.7Hz, 2H).13C NMR(101MHz,DMSO):δ179.84,170.34,145.21,141.99,140.42, 136.99,133.85,132.93,129.21,129.21,128.99,128.42,128.33,128.33,126.69,126.18, 126.14,125.83,123.94,123.62,122.32,119.49,119.49,91.42,57.88,37.46。HR-MS(m/z) (ESI): being calculated as C26H21F3N3O3[M+H]+:480.1530；Measured value: 480.1521.
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (2- fluorobenzene Base)-propionamide (Ib)
Yield: 55.3%.Greenish yellow solid.226.9~227.2 DEG C of fusing point.1H NMR(400MHz,DMSO):δ12.38 (s, 1H), 10.09 (s, 1H), 8.16 (d, J=7.8Hz, 1H), 8.04 (d, J=7.1Hz, 1H), 7.77 (td, J=7.8, 2.9Hz, 1H), 7.70-7.65 (m, 1H), 7.60-7.53 (m, 1H), 7.28 (dt, J=9.5,4.4Hz, 5H), 7.18 (ddd, J =9.7,8.9,3.2Hz, 3H), 6.64 (s, 1H), 6.33 (d, J=8.3Hz, 1H), 4.57 (dd, J=14.6,7.1Hz, 1H), 3.21 (d, J=6.8Hz, 2H).13C NMR(101MHz,DMSO):δ180.05,170.36,155.27,152.83,145.41, 140.57,137.21,133.99,133.11,129.41,129.41,129.16,128.54,128.45,128.45,126.82, 125.97,125.50,124.59,122.48,115.87,115.68,91.65,57.42,37.71.HR-MS (m/z) (ESI): It is calculated as C25H20FN3O3Na[M+Na]+:452.1381；Measured value: 452.1380.
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3, N- diphenyl-propionamide (Ic)
Yield: 50.6%.Greenish yellow solid.229.6~230.2 DEG C of fusing point.1H NMR(400MHz,DMSO):δ10.27 (s, 1H), 8.12 (d, J=7.9Hz, 1H), 8.05-7.97 (m, 1H), 7.70-7.60 (m, 1H), 7.61-7.52 (m, 1H), 7.50 (d, J=7.7Hz, 2H), 7.34-7.22 (m, 7H), 7.18 (td, J=5.7,2.5Hz, 1H), 7.06 (t, J=7.4Hz, 1H), 6.58 (s, 1H), 6.25 (d, J=8.0Hz, 1H), 4.35 (dd, J=13.6,7.8Hz, 1H), 3.23-3.12 (m, 2H).13C NMR(101MHz,DMSO):δ180.44,170.28,145.80,140.88,138.63,137.39,134.21,133.59, 129.67,129.67,129.63,129.38,129.38,128.89,128.79,128.79,127.28,126.36,124.56, 122.83,120.28,120.28,91.85,58.27,38.02.HR-MS (m/z) (ESI): it is calculated as C25H21N3O3Na[M+Na ]+:434.1475；Measured value: 434.1469.
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3- fluorobenzene Base)-propionamide (Id)
Yield: 49.9%.Greenish yellow solid.202.2~203.1 DEG C of fusing point.1H NMR(400MHz,DMSO):δ12.37 (s, 1H), 10.45 (s, 1H), 8.19-8.14 (m, 1H), 8.05 (dd, J=7.9,0.8Hz, 1H), 7.71-7.63 (m, 1H), 7.60-7.52 (m, 2H), 7.36 (dd, J=11.4,4.7Hz, 1H), 7.33-7.25 (m, 6H), 7.23-7.16 (m, 1H), 6.90 (td, J=8.2,1.8Hz, 1H), 6.60 (s, 1H), 6.35 (d, J=8.2Hz, 1H), 4.40 (q, J=7.0Hz, 1H), 3.22 (d, J=6.7Hz, 2H).13C NMR(101MHz,DMSO):δ179.89,170.13,163.36,160.96,145.27, 140.48,140.23,140.12,137.11,133.89,132.98,130.61,129.26,129.03,128.47,128.39, 126.74,125.89,122.37,115.38,110.42,106.55,91.44,57.90,37.55.HR-MS (m/z) (ESI): It is calculated as C25H20FN3O3Na[M+Na]+:452.1381；Measured value: 452.1377.
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (2- methoxy Base phenyl)-propionamide (Ie)
Yield: 54.8%.Yellow solid.176.9~177.4 DEG C of fusing point.1H NMR(400MHz,DMSO):δ12.35(s, 1H), 9.49 (s, 1H), 8.17 (dd, J=8.0,0.6Hz, 1H), 8.06 (dd, J=7.9,1.0Hz, 1H), 7.88 (dd, J= 8.0,1.5Hz, 1H), 7.71-7.64 (m, 1H), 7.61-7.51 (m, 1H), 7.34-7.31 (m, 2H), 7.26 (t, J= 7.4Hz, 2H), 7.21-7.16 (m, 1H), 7.11-7.05 (m, 1H), 7.02 (dd, J=8.2,1.3Hz, 1H), 6.93-6.88 (m, 1H), 6.65 (s, 1H), 6.41 (d, J=8.3Hz, 1H), 4.63 (dd, J=14.3,7.4Hz, 1H), 3.76 (s, 3H), 3.21 (d, J=6.9Hz, 2H).13C NMR(101MHz,DMSO):δ179.92,169.74,149.85,145.27,140.48, 137.34,133.91,132.92,129.30,129.30,128.98,128.44,128.25,128.25,126.65,126.56, 125.82,124.91,122.35,122.00,120.33,111.38,91.65,57.43,55.80,37.58。HR-MS(m/z) (ESI): being calculated as C26H24N3O4[M+H]+:442.1761；Measured value: 442.1748.
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3,5- bis- Aminomethyl phenyl)-propionamide (If)
Yield: 52.5%.Greenish yellow solid.128.3~129.2 DEG C of fusing point.1H NMR(400MHz,DMSO):δ12.34 (s, 1H), 10.06 (s, 1H), 8.16 (d, J=7.6Hz, 1H), 8.05 (dd, J=7.9,1.0Hz, 1H), 7.72-7.64 (m, 1H), 7.60-7.54 (m, 1H), 7.31-7.25 (m, 4H), 7.21-7.17 (m, 3H), 6.64 (d, J=49.4Hz, 2H), 6.30 (d, J=8.2Hz, 1H), 4.36 (dd, J=14.2,7.4Hz, 1H), 3.20-3.16 (m, 2H), 2.22 (s, 6H).13C NMR (101MHz,DMSO):δ179.94,169.58,145.30,140.50,138.35,137.89,137.89,137.24, 133.91,133.00,129.27,129.27,129.06,128.47,128.39,128.39,126.71,125.89,125.33, 122.39,117.37,117.37,91.40,57.90,37.67,21.11,21.11.HR-MS (m/z) (ESI): it is calculated as C27H25N3O3Na[M+Na]+:462.1788；Measured value: 462.1788.
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (4- chlorobenzene Base)-propionamide (Ih)
Yield: 53.2%.Greenish yellow solid.192.3~193.0 DEG C of fusing point.1H NMR(400MHz,DMSO):δ12.35 (s, 1H), 10.36 (s, 1H), 8.17 (d, J=7.9Hz, 1H), 8.05 (dd, J=7.9,0.9Hz, 1H), 7.70-7.63 (m, 1H), 7.61-7.54 (m, 3H), 7.40-7.34 (m, 2H), 7.32-7.24 (m, 4H), 7.19 (dt, J=9.2,4.2Hz, 1H), 6.61 (s, 1H), 6.33 (d, J=8.1Hz, 1H), 4.40 (dd, J=14.5,7.0Hz, 1H), 3.22 (d, J=6.7Hz, 2H).13C NMR(101MHz,DMSO):δ179.89,169.85,145.27,140.45,137.39,137.09,133.89,132.92, 129.24,129.24,128.98,128.75,128.75,128.46,128.35,128.35,127.43,126.69,125.85, 122.35,121.21,121.21,91.43,57.83,37.60.HR-MS (m/z) (ESI): it is calculated as C25H20ClN3O3Na[M+ Na]+:468.1085；Measured value: 468.1084.
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (4- bromobenzene Base)-propionamide (Ii)
Yield: 54.1%.Greenish yellow solid.179.2~179.4 DEG C of of fusing point1H NMR(400MHz,DMSO):δ12.35 (s, 1H), 10.35 (s, 1H), 8.16 (d, J=7.9Hz, 1H), 8.09-8.01 (m, 1H), 7.73-7.61 (m, 1H), 7.62- 7.47 (m, 5H), 7.28 (t, J=7.3Hz, 4H), 7.19 (dt, J=9.2,4.2Hz, 1H), 6.60 (s, 1H), 6.33 (d, J= 8.1Hz, 1H), 4.39 (q, J=7.0Hz, 1H), 3.22 (d, J=6.7Hz, 2H).13C NMR(101MHz,DMSO):δ 179.91,169.90,145.29,140.46,137.82,137.09,133.90,132.97,131.69,131.69,129.26, 129.26,129.03,128.47,128.38,128.38,126.73,125.89,122.37,121.60,121.60,115.49, 91.43,57.88,37.59.HR-MS (m/z) (ESI): it is calculated as C25H20BrN3O3Na[M+Na]+:512.0580；Measured value: 512.0580。
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (the bromo- 4- of 3- Fluorophenyl)-propionamide (Ij)
Yield: 55.5%.Greenish yellow solid.166.9~170.6 DEG C of fusing point.1H NMR(400MHz,DMSO):δ12.35 (s, 1H), 10.53 (s, 1H), 8.16 (d, J=7.8Hz, 1H), 8.05 (d, J=7.0Hz, 1H), 7.72-7.55 (m, 4H), 7.28 (d, J=6.8Hz, 5H), 7.20 (dd, J=5.9,2.6Hz, 1H), 6.58 (s, 1H), 6.35 (d, J=8.1Hz, 1H), 4.38 (q, J=7.0Hz, 1H), 3.22 (d, J=6.7Hz, 2H).13C NMR(101MHz,DMSO):δ179.82,170.25, 159.24,156.83,145.20,140.42,139.61,136.98,133.83,133.46,132.94,129.21,129.21, 129.00,128.42,128.35,126.71,125.84,122.32,116.92,107.68,101.47,91.41,57.90, 37.44.HR-MS (m/z) (ESI): it is calculated as C25H19BrFN3O3Na[M+Na]+:530.0486；Measured value: 530.0488.
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3- (trifluoro Methyl) phenyl)-propionamide (Ik)
Yield: 38.9%.Greenish yellow solid.118.9~119.5 DEG C of fusing point.1H NMR(400MHz,DMSO):δ12.35 (s, 1H), 10.54 (s, 1H), 8.16 (d, J=7.8Hz, 1H), 8.10-7.98 (m, 2H), 7.78 (d, J=8.3Hz, 1H), 7.71-7.64 (m, 1H), 7.60-7.53 (m, 2H), 7.43 (d, J=8.2Hz, 1H), 7.35-7.25 (m, 4H), 7.20 (t, J =7.0Hz, 1H), 6.60 (s, 1H), 6.36 (d, J=8.1Hz, 1H), 4.40 (dd, J=14.4,7.1Hz, 1H), 3.30 (s, 1H), 3.24 (d, J=6.8Hz, 2H).13C NMR(101MHz,DMSO):δ179.85,170.32,145.23,140.48, 139.19,137.08,133.86,132.95,130.16,129.23,129.23,129.01,128.45,128.37,128.37, 126.72,125.85,125.42,123.18,122.34,120.18,115.69,115.65,91.42,57.95,37.50。HR- MS (m/z) (ESI): it is calculated as C26H20F3N3O3Na[M+Na]+:502.1349；Measured value: 502.1341.
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (4- fluorobenzene Base)-propionamide (Il)
Yield: 56.6%.Greenish yellow solid.175.3~175.9 DEG C of fusing point.1H NMR(400MHz,DMSO):δ12.36 (s, 1H), 10.35 (s, 1H), 8.16 (d, J=7.8Hz, 1H), 8.05 (d, J=7.1Hz, 1H), 7.74-7.64 (m, 1H), 7.61-7.51 (m, 4H), 7.34-7.25 (m, 5H), 7.17 (dt, J=17.7,7.9Hz, 4H), 6.61 (s, 1H), 6.32 (d, J =5.4Hz, 1H), 4.39 (d, J=4.7Hz, 1H), 3.22 (d, J=6.8Hz, 2H).13C NMR(101MHz,DMSO):δ 179.93,169.64,159.56,157.17,145.30,140.48,137.19,134.88,134.85,133.93,132.96, 129.29,129.02,128.49,128.38,126.72,125.89,122.39,121.58,121.50,115.56,115.34, 91.43,57.79,37.66.HR-MS (m/z) (ESI): it is calculated as C25H20FN3O3Na[M+Na]+:452.1381；Measured value: 452.1381。
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3- toluene Base)-propionamide (Im)
Yield: 49.0%.Greenish yellow solid.116.6~117.6 DEG C of fusing point.1H NMR(400MHz,DMSO):δ12.35 (s, 1H), 10.15 (s, 1H), 8.16 (d, J=7.6Hz, 1H), 8.05 (dd, J=7.9,0.9Hz, 1H), 7.73-7.63 (m, 1H), 7.64-7.48 (m, 1H), 7.42-7.25 (m, 6H), 7.24-7.14 (m, 2H), 6.88 (d, J=7.5Hz, 1H), 6.60 (s, 1H), 6.31 (d, J=8.2Hz, 1H), 4.38 (dd, J=14.5,7.2Hz, 1H), 3.20 (d, J=6.9Hz, 2H), 2.26 (s,3H)。13C NMR(101MHz,DMSO):δ179.94,169.64,145.31,140.50,138.42,138.11,137.23, 133.92,133.00,129.28,129.28,129.05,128.73,128.48,128.39,128.39,126.71,125.90, 124.53,122.39,120.19,116.84,91.41,57.86,37.67,21.20.HR-MS (m/z) (ESI): it is calculated as C26H24N3O3[M+H]+:426.1812；Measured value: 426.1810.
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (2- chlorobenzene Base)-propionamide (In)
Yield: 55.9%.Greenish yellow solid.129.7~130.6 DEG C of fusing point.1H NMR(400MHz,DMSO):δ12.36 (s, 1H), 9.86 (s, 1H), 8.17 (d, J=8.0Hz, 1H), 8.05 (dd, J=7.9,0.9Hz, 1H), 7.71-7.65 (m, 1H), 7.62 (dd, J=8.0,1.4Hz, 1H), 7.59-7.54 (m, 1H), 7.48 (dd, J=8.0,1.3Hz, 1H), 7.32 (ddd, J=9.9,7.3,5.4Hz, 5H), 7.20 (ddd, J=9.2,3.5,1.5Hz, 2H), 6.68 (s, 1H), 6.39 (d, J= 8.1Hz, 1H), 4.55 (dd, J=14.5,7.1Hz, 1H), 3.27 (d, J=6.8Hz, 2H).13C NMR(101MHz,DMSO):δ 179.92,170.18,145.28,140.51,137.21,134.30,133.92,132.97,129.57,129.33,129.33, 129.03,128.47,128.39,128.39,127.54,126.96,126.83,126.72,126.29,125.86,122.38, 91.89,57.52,37.54.HR-MS (m/z) (ESI): it is calculated as C25H21ClN3O3Na[M+H]+:446.1266；Measured value: 446.1267.(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3- chlorobenzene Base)-propionamide (Io)
Yield: 48.6%.Greenish yellow solid.159.1~159.9 DEG C of fusing point.1H NMR(400MHz,DMSO):δ12.36 (s, 1H), 10.42 (s, 1H), 8.16 (d, J=7.9Hz, 1H), 8.05 (d, J=7.6Hz, 1H), 7.75 (s, 1H), 7.67 (dd, J=11.2,4.0Hz, 1H), 7.57 (t, J=7.3Hz, 1H), 7.43 (d, J=8.5Hz, 1H), 7.37-7.25 (m, 5H), 7.19 (t, J=6.6Hz, 1H), 7.13 (dd, J=7.9,0.9Hz, 1H), 6.59 (s, 1H), 6.33 (d, J=8.1Hz, 1H), 4.39 (dd, J=14.4,7.0Hz, 1H), 3.22 (d, J=6.7Hz, 2H).13C NMR(101MHz,DMSO):δ 179.87,170.11,145.24,140.45,139.87,137.06,133.87,133.14,132.96,130.59,129.24, 129.24,129.02,128.45,128.37,128.37,126.72,125.86,123.53,122.35,119.10,118.02, 91.44,57.89,37.50.HR-MS (m/z) (ESI): it is calculated as C25H21ClN3O3[M+H]+:446.1266；Measured value: 446.1252。
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (2- bromobenzene Base)-propionamide (Ip)
Yield: 57.2%.Greenish yellow solid.361.2~361.3 DEG C of fusing point.1H NMR(400MHz,DMSO):δ12.30 (s, 1H), 9.75 (s, 1H), 8.11 (dd, J=8.0,0.6Hz, 1H), 7.99 (dd, J=7.9,1.0Hz, 1H), 7.65-7.56 (m, 2H), 7.50 (ddd, J=9.6,7.0,1.4Hz, 2H), 7.32-7.27 (m, 3H), 7.23 (t, J=7.5Hz, 2H), 7.18-7.12 (m, 1H), 7.08 (td, J=7.8,1.6Hz, 1H), 6.61 (s, 1H), 6.33 (d, J=8.1Hz, 1H), 4.44 (dd, J=13.8,7.8Hz, 1H), 3.25-3.19 (m, 2H).13C NMR(101MHz,DMSO):δ179.91,170.10, 145.28,140.55,137.27,135.63,133.92,132.98,132.76,129.32,129.32,129.04,128.47, 128.42,128.42,128.17,127.45,126.94,126.73,125.86,122.39,117.95,91.96,57.60, 37.48.HR-MS (m/z) (ESI): it is calculated as C25H21BrN3O3[M+H]+:490.0761；Measured value: 490.0744.
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3- bromobenzene Base)-propionamide (Iq)
Yield: 51.1%.Greenish yellow solid.129.8~130.3 DEG C of fusing point.1H NMR(400MHz,DMSO):δ12.35 (s, 1H), 10.38 (s, 1H), 8.16 (d, J=7.5Hz, 1H), 8.05 (dd, J=7.9,1.0Hz, 1H), 7.88 (d, J= 1.8Hz, 1H), 7.68 (td, J=7.8,1.4Hz, 1H), 7.62-7.53 (m, 1H), 7.47 (dt, J=7.1,2.1Hz, 1H), 7.34-7.25 (m, 6H), 7.20 (ddt, J=8.5,5.5,2.9Hz, 1H), 6.58 (s, 1H), 6.33 (d, J=8.1Hz, 1H), 4.37 (dd, J=14.5,7.1Hz, 1H), 3.22 (d, J=6.8Hz, 2H).13C NMR(101MHz,DMSO):δ179.88, 170.10,145.25,140.47,140.01,137.06,133.87,132.99,130.91,129.24,129.24,129.05, 128.45,128.39,128.39,126.74,126.45,125.88,122.36,121.96,121.60,118.41,91.44, 57.91,37.51.HR-MS (m/z) (ESI): it is calculated as C25H21BrN3O3[M+H]+:490.0761；Measured value: 490.0760.
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3- methoxy Base phenyl)-propionamide (Ir)
Yield: 50.6%.Greenish yellow solid.112.3~113.2 DEG C of fusing point.1H NMR(400MHz,DMSO):δ12.34 (s, 1H), 10.21 (s, 1H), 8.16 (d, J=7.5Hz, 1H), 8.05 (dd, J=7.9,1.0Hz, 1H), 7.71-7.65 (m, 1H), 7.60-7.54 (m, 1H), 7.32-7.18 (m, 7H), 7.12-7.07 (m, 1H), 6.65 (dd, J=8.2,1.9Hz, 1H), 6.60 (s, 1H), 6.30 (d, J=8.2Hz, 1H), 4.38 (dd, J=14.3,7.3Hz, 1H), 3.72 (s, 3H), 3.20 (d, J =6.8Hz, 2H).13C NMR(101MHz,DMSO):δ179.90,169.71,159.56,145.26,140.45,139.62, 137.17,133.88,132.96,129.67,129.24,129.24,129.02,128.45,128.35,128.35,126.68, 125.86,122.35,111.89,109.29,105.38,91.40,57.83,55.05,37.63.HR-MS (m/z) (ESI): meter Calculating is C26H24N3O4[M+H]+:442.1761；Measured value: 442.1760.
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (4- methoxy Base phenyl)-propionamide (Is)
Yield: 55.7%.Greenish yellow solid.89.9~90.5 DEG C of fusing point.1H NMR(400MHz,DMSO):δ12.33(s, 1H), 10.06 (s, 1H), 8.16 (d, J=7.6Hz, 1H), 8.05 (dd, J=7.9,1.0Hz, 1H), 7.73-7.64 (m, 1H), 7.62-7.53 (m, 1H), 7.51-7.38 (m, 2H), 7.33-7.26 (m, 4H), 7.20 (dd, J=5.8,2.8Hz, 1H), 6.97-6.82 (m, 2H), 6.59 (s, 1H), 6.28 (d, J=8.1Hz, 1H), 4.35 (dd, J=14.4,7.0Hz, 1H), 3.19 (d, J=6.7Hz, 2H).13C NMR(101MHz,DMSO):δ179.91,169.12,155.64,145.28,140.44, 137.22,133.90,132.95,131.50,129.25,129.25,129.01,128.46,128.34,128.34,126.66, 125.86,122.35,121.30,121.30,113.96,113.96,91.35,57.67,55.23,37.69。HR-MS(m/z) (ESI): being calculated as C26H24N3O4[M+H]+:442.1761；Measured value: 442.1761.
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (4- toluene Base)-propionamide (It)
Yield: 50.5%.Greenish yellow solid.137.2~137.4 DEG C of fusing point.1H NMR(400MHz,DMSO):δ12.36 (s, 1H), 10.24 (s, 1H), 8.16 (d, J=7.6Hz, 1H), 8.05 (dd, J=7.9,0.9Hz, 1H), 7.70-7.64 (m, 1H), 7.59-7.53 (m, 1H), 7.44 (d, J=8.4Hz, 2H), 7.33-7.23 (m, 5H), 7.21-7.16 (m, 1H), 7.10 (d, J=8.3Hz, 2H), 6.60 (s, 1H), 6.29 (d, J=8.2Hz, 1H), 4.40 (dd, J=14.1,7.4Hz, 1H), 3.29–3.12(m,3H),2.24(s,4H)。13C NMR(101MHz,DMSO):δ179.90,169.39,145.24,140.41, 137.22,135.98,133.91,132.92,132.74,129.26,129.26,129.17,129.17,128.97,128.44, 128.31,128.31,126.63,125.84,122.35,119.67,119.67,91.36,57.68,37.67,20.50。HR- MS (m/z) (ESI): it is calculated as C26H23N3O3Na[M+Na]+:448.1632；Measured value: 448.1619.
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3,5- bis- Methoxyphenyl)-propionamide (Iu)
Yield: 50.5%.Greenish yellow solid.114.1~114.6 DEG C of fusing point.1H NMR(400MHz,DMSO):δ12.35 (s, 1H), 10.19 (s, 1H), 8.16 (d, J=7.9Hz, 1H), 8.10-8.02 (m, 1H), 7.72-7.63 (m, 1H), 7.56 (dd, J=11.1,4.0Hz, 1H), 7.38-7.25 (m, 4H), 7.20 (dt, J=9.1,4.2Hz, 1H), 6.81 (d, J= 2.2Hz, 2H), 6.59 (s, 1H), 6.30 (d, J=8.2Hz, 1H), 6.24 (t, J=2.2Hz, 1H), 4.37 (dd, J=14.1, 7.5Hz,1H),3.71(s,6H),3.26–3.14(m,2H)。13C NMR(101MHz,DMSO):δ179.89,169.77, 160.55,160.55,145.26,140.46,140.12,137.17,133.88,132.95,129.23,129.23,129.01, 128.45,128.35,128.35,126.68,125.86,122.35,97.89,97.89,95.82,91.41,57.89, 55.16,55.16,37.62.HR-MS (m/z) (ESI): it is calculated as C27H26N3O5[M+H]+:472.1867；Measured value: 472.1851。
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (the fluoro- 4- of 3- Bromophenyl)-propionamide (Iv)
Yield: 49.2%.Greenish yellow solid.121.2~122.2 DEG C of fusing point.1H NMR(400MHz,DMSO):δ10.47 (s, 1H), 7.99 (dd, J=7.6,0.9Hz, 1H), 7.90 (dd, J=7.6,1.0Hz, 1H), 7.82 (td, J=7.5, 1.3Hz, 1H), 7.76-7.62 (m, 3H), 7.36-7.15 (m, 7H), 5.67 (s, 1H), 4.44 (q, J=7.0Hz, 1H), 3.27 (d, J=6.8Hz, 2H).13C NMR(101MHz,DMSO):δ181.89,181.00,169.19,147.63,139.47, 139.37,136.85,135.01,133.50,132.66,132.59,130.22,129.25,128.34,126.75,126.06, 125.42,117.05,107.82,107.55,101.64,101.44,101.06,57.64,36.96.HR-MS (m/z) (ESI): It is calculated as C25H19BrFN3O3Na[M+Na]+:530.0486；Measured value: 530.0471.
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3,5- bis- Fluorophenyl)-propionamide (Iw)
Yield: 43.5%.Greenish yellow solid.163.3~163.6 DEG C of fusing point.1H NMR(400MHz,DMSO):δ12.35 (s, 1H), 10.57 (s, 1H), 8.20-8.15 (m, 1H), 8.05 (dd, J=7.9,1.0Hz, 1H), 7.68 (td, J=7.8, 1.4Hz, 1H), 7.61-7.53 (m, 1H), 7.37-7.26 (m, 6H), 7.21 (dd, J=5.9,2.8Hz, 1H), 6.93 (tt, J =9.3,2.3Hz, 1H), 6.57 (s, 1H), 6.34 (d, J=8.1Hz, 1H), 4.38 (dd, J=14.5,7.0Hz, 1H).13C NMR(101MHz,DMSO):δ179.82,170.43,163.72,161.30,145.21,140.87,140.43,136.93, 133.83,132.95,129.20,129.20,129.01,128.42,128.36,128.36,126.73,125.84,122.32, 102.59,102.30,98.96,91.46,57.95,37.40.HR-MS (m/z) (ESI): it is calculated as C25H19F2N3O3Na[M+ Na]+:470.1287；Measured value: 470.1270.
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (the fluoro- 4- of 2- Aminomethyl phenyl)-propionamide (Ix)
Yield: 60.2%.Greenish yellow solid.218.5~219.4 DEG C of fusing point.1H NMR(400MHz,DMSO):δ9.96 (s, 1H), 8.16 (dd, J=8.0,0.6Hz, 1H), 8.05 (dd, J=7.9,1.0Hz, 1H), 7.72-7.65 (m, 1H), 7.58 (dt, J=8.3,4.7Hz, 2H), 7.30 (dt, J=14.9,4.6Hz, 4H), 7.23-7.17 (m, 1H), 7.08 (dd, J= 11.8,1.1Hz, 1H), 6.96 (d, J=8.2Hz, 1H), 6.63 (s, 1H), 6.32 (d, J=8.3Hz, 1H), 4.55 (q, J= 6.9Hz, 1H), 3.21 (d, J=6.7Hz, 2H), 2.27 (s, 3H).13C NMR(101MHz,DMSO):δ179.91,170.03, 155.08,152.64,145.27,140.44,137.15,136.01,133.91,132.94,129.30,128.99,128.45, 128.30,126.65,125.84,124.83,124.80,124.38,122.63,116.05,115.86,91.49,57.24, 37.63,20.41.HR-MS (m/z) (ESI): it is calculated as C26H23FN3O3[M+H]+:444.1718；Measured value: 444.1704.
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (2,5- bis- Methoxyphenyl)-propionamide (Iy)
Yield: 49.3%.Greenish yellow solid.121.1~121.6 DEG C of fusing point.1H NMR(400MHz,DMSO):δ12.35 (s, 1H), 9.48 (s, 1H), 8.17 (d, J=7.6Hz, 1H), 8.06 (dd, J=7.9,0.8Hz, 1H), 7.72-7.61 (m, 2H), 7.61-7.54 (m, 1H), 7.32 (d, J=7.1Hz, 2H), 7.26 (t, J=7.4Hz, 2H), 7.18 (t, J=7.2Hz, 1H), 6.94 (d, J=9.0Hz, 1H), 6.63 (dd, J=8.3,3.7Hz, 2H), 6.43 (d, J=8.3Hz, 1H), 4.65 (dd, J=14.5,7.1Hz, 1H), 3.70 (s, 3H), 3.67 (s, 3H), 3.21 (d, J=6.7Hz, 2H).13C NMR(101MHz, DMSO):δ179.90,169.86,152.99,145.24,143.70,140.47,137.32,133.89,132.92,129.28, 129.28,128.97,128.42,128.24,128.24,126.55,125.82,122.34,112.28,108.62,108.14, 91.64,57.42,56.44,55.37,37.52.HR-MS (m/z) (ESI): it is calculated as C27H26N3O5[M+H]+:472.1867； Measured value: 472.1851.
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (the chloro- 4- of 3- Aminomethyl phenyl)-propionamide (Iz)
Yield: 51.2%.Greenish yellow solid.169.1~169.5 DEG C of fusing point.1H NMR(400MHz,DMSO):δ12.28 (s, 1H), 10.30 (s, 1H), 8.16 (d, J=7.5Hz, 1H), 8.05 (dd, J=7.9,1.0Hz, 1H), 7.72 (d, J= 2.0Hz, 1H), 7.70-7.65 (m, 1H), 7.60-7.54 (m, 1H), 7.33 (dd, J=8.3,2.1Hz, 1H), 7.30-7.26 (m, 4H), 7.20 (td, J=5.7,2.6Hz, 1H), 6.65-6.64 (m, 1H), 6.58 (s, 1H), 6.31 (d, J=8.1Hz, 1H), 4.36 (dd, J=14.5,7.0Hz, 1H), 3.21 (d, J=6.7Hz, 3H), 2.26 (s, 3H).13C NMR(101MHz, DMSO):δ179.85,169.80,145.22,140.42,137.52,137.06,133.86,133.02,132.94,131.27, 130.49,129.21,129.21,129.00,128.43,128.34,128.34,126.69,125.84,122.33,119.59, 118.25,91.40,57.81,37.52,18.96.HR-MS (m/z) (ESI): it is calculated as C26H23ClN3O3[M+H]+: 460.1422；Measured value: 460.1405.
The synthesis of the compound (2- amino acid amide-hydroxyl oxime ester base naphthoquinone compound) of 3 formula of embodiment (III)
Under protection of argon gas, take compound Ik, compound Iq, each 0.5g of compound Ir respectively with 4- t-butylbenzenesulfonyl chloride It is dissolved in the methylene chloride of 10mL in the ratio of the amount 1:1.5 of substance, 30min is stirred under condition of ice bath, is then added dropwise The amount of substance is 2 times of oxime compound of triethylamine, is subsequently agitated for 10min, then the ice water quenching reaction with 20mL.With 10mL's Methylene chloride extracts three times, merges organic layer solution, and with the dry 2h of anhydrous sodium sulfate, decompression rotary drying, is stone with eluant, eluent Oily ether: the silica gel column purification of ethyl acetate (8:1), the final products rotarily dried are yellow solid.Products therefrom (chemical combination Object IIIk-1, IIIq and IIIr) concrete structure formula and parameter characterization it is as follows.
Under protection of argon gas, 0.5g compound Ik and 2- thiophene-benzene sulfonyl chloride is taken to be dissolved in 10ml's according to the ratio of 1:1.5 In methylene chloride, 30min is stirred under condition of ice bath, the amount that substance is then added dropwise is 2 times of oxime compound of triethylamine, 10min, then the ice water quenching reaction with 20mL are stirred after dripping off.It is extracted three times with the methylene chloride of 10ml, it is molten to merge organic layer Liquid, with the dry 2h of anhydrous sodium sulfate, decompression rotary drying, be petroleum ether with eluant, eluent: the silicagel column of ethyl acetate (8:1) is pure Change, the final products rotarily dried are yellow solid.The concrete structure formula and parameter of products therefrom (compound IIIk-2) It is characterized as below.
The concrete structure formula and parameter characterization of the compound of formula (III) are as follows:
(R) -2- ((4- ((((4- (tert-butyl) phenyl) sulfonyl) oxygen) imino group) -1- oxo-DHN 1,4 dihydronaphthalene -2- Base) amino) -3- phenyl-N- (3- (trifluoromethyl) phenyl)-propionamide (IIIk-1)
Yield: 80.1%.Yellow solid.118.5~119.2 DEG C of fusing point.1H NMR(400MHz,DMSO):δ10.71(s, 1H), 8.07 (s, 1H), 7.98 (dd, J=7.7,1.3Hz, 1H), 7.95-7.92 (m, 1H), 7.84 (dd, J=15.3, 8.5Hz, 3H), 7.66-7.53 (m, 5H), 7.46 (d, J=7.8Hz, 1H), 7.34 (d, J=7.0Hz, 2H), 7.25 (t, J= 7.5Hz, 2H), 7.16 (t, J=7.3Hz, 2H), 6.12 (s, 1H), 4.56 (dd, J=13.8,7.7Hz, 1H), 3.32-3.18 (m, 2H), 1.22 (d, J=11.2Hz, 9H).13C NMR(101MHz,DMSO):δ179.14,169.46,157.86,151.72, 143.46,139.06,136.92,134.02,131.98,131.12,130.19,129.30,129.30,129.00,128.33, 128.33,128.28,128.28,126.73,126.32,126.32,125.34,124.34,123.16,122.69,120.30, 115.72,88.16,57.85,37.45,34.97,31.04,30.52,30.52,30.52,26.32。HR-MS(m/z)(ESI): It is calculated as C36H33N3O5S[M+H]+:676.2088；Measured value: 676.2062.
(R) -2- ((4- ((((4- (tert-butyl) phenyl) sulfonyl) oxygen) imino group) -1- oxo-DHN 1,4 dihydronaphthalene -2- Base) amino) -3- phenyl-N- (3- bromophenyl)-propionamide (IIIq)
Yield: 85.2%.Yellow solid.125.3~125.6 DEG C of fusing point.1H NMR(400MHz,DMSO):δ10.54(s, 1H), 8.01 (dd, J=7.7,1.3Hz, 1H), 7.96-7.92 (m, 2H), 7.88-7.80 (m, 2H), 7.69 (td, J=7.6, 1.5Hz, 1H), 7.63 (td, J=7.6,1.2Hz, 1H), 7.60-7.56 (m, 2H), 7.49 (dt, J=7.2,2.0Hz, 1H), 7.35-7.30 (m, 4H), 7.25 (t, J=7.5Hz, 2H), 7.15 (dd, J=17.3,7.7Hz, 2H), 6.09 (s, 1H), 4.51 (dd, J=14.0,7.5Hz, 1H), 3.32-3.15 (m, 2H), 1.23 (s, 10H).13C NMR(101MHz,DMSO):δ 179.21,169.27,157.98,151.80,143.49,139.86,136.90,134.18,131.98,131.28,131.17, 130.98,129.34,129.34,129.07,128.40,128.40,128.33,126.80,126.66,126.44,126.44, 125.36,124.39,123.23,122.04,121.70,118.51,88.20,57.85,37.47,35.09,30.65, 30.65,30.65.HR-MS (m/z) (ESI): it is calculated as C35H32BrN3O5S[M+Na]+:708.1138；Measured value: 708.1109.(R) -2- ((4- ((((4- (tert-butyl) phenyl) sulfonyl) oxygen) imino group) -1- oxo-DHN 1,4 dihydronaphthalene -2- Base) amino) -3- phenyl-N- (3- methoxyphenyl)-propionamide (IIIr)
Yield: 85.5%.Yellow solid.104.2~104.9 DEG C of fusing point.1H NMR(400MHz,DMSO):δ10.41(s, 1H), 7.95 (dd, J=7.6,1.4Hz, 1H), 7.89 (dd, J=13.0,5.0Hz, 3H), 7.61-7.52 (m, 4H), 7.36- 7.30 (m, 4H), 7.26 (dt, J=7.7,6.1Hz, 4H), 7.17 (d, J=7.6Hz, 2H), 7.09 (d, J=8.1Hz, 1H), 6.70 (dd, J=8.2,1.8Hz, 1H), 6.11 (s, 1H), 4.54 (dd, J=14.0,7.5Hz, 1H), 3.74 (s, 4H), 3.30-3.21 (m, 2H), 1.22 (d, J=11.7Hz, 12H).13C NMR(101MHz,DMSO):δ179.15,168.88, 159.60,157.85,151.76,143.39,139.53,137.00,133.99,132.00,131.13,131.09,129.73, 129.32,129.32,128.96,128.31,128.31,126.69,126.62,126.37,126.37,125.35,124.38, 123.15,111.88,109.36,105.39,88.10,57.76,55.01,34.99,31.05,30.56,30.56,30.56。 HR-MS (m/z) (ESI): it is calculated as C36H36N3O6S[M+H]+:638.2319；Measured value: 638.2294.
(R) -2- ((4- (((thiophene -2- base sulfonyl) oxygen) imino group) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) - 3- phenyl-N- (3- (trifluoromethyl) phenyl)-propionamide (IIIk-2)
Yield: 80.2%.Yellow solid.163.4~164.8 DEG C of fusing point.1H NMR(400MHz,MeOD):δ8.03– 7.95 (m, 1H), 7.93 (s, 1H), 7.89 (dd, J=5.0,1.3Hz, 1H), 7.80 (dd, J=3.8,1.3Hz, 1H), 7.72 (d, J=8.2Hz, 1H), 7.54 (td, J=7.7,1.4Hz, 1H), 7.51-7.45 (m, 1H), 7.40 (d, J=7.8Hz, 1H), 7.30-7.23 (m, 2H), 7.20-7.13 (m, 1H), 6.12 (s, 1H), 4.44 (t, J=7.0Hz, 1H), 3.33 (td, J= 3.3,1.7Hz, 1H), 3.19 (dd, J=13.5,7.7Hz, 1H).13C NMR(101MHz,MeOD):δ180.54,171.36, 153.45,144.45,139.78,137.43,136.64,136.64,136.52,136.52,135.86,134.72,132.92, 131.91,130.79,130.59,130.46,130.46,129.76,129.76,128.56,128.24,127.79,124.83, 124.66,122.00,118.03,89.80,59.41,39.74.HR-MS (m/z) (ESI): it is calculated as C30H21F3N3O5S2[M-H] +:624.0880；Measured value: 624.0905.
Embodiment 4 targets the anti tumor activity in vitro research of STAT3
The preparation of 4.1 reagents
The preparation of PBS buffer solution: taking PBS powder, first with 800mL deionized water by its all dissolve, then plus 200mL go from Sub- water constant volume is to 1L (10mmol/L).In experiment using preceding by its high pressure sterilization, by the PBS buffer solution after sterilizing in 4 DEG C of conditions Lower preservation.
The preparation and use of MTT coloring agent: weigh 0.25g MTT (methyl thiazolyl tetrazolium, again Referred to as thiazolyl blue), with without phenol red culture medium or phosphate buffer (PBS) dissolution, constant volume to 50mL.It is filtered out in liquid with filter membrane Bacterium, be then placed in brown bottle, storage be protected from light at 4 DEG C.
The screening of 4.2 mtt assay
This experiment be study oximido naphthaquinone derivatives anti tumor activity in vitro, choose human colon cancer cell Hct-116, Ovarian cancer cell SKOV3 and small cell carcinoma of lung cell A549 resist the compound that the application synthesizes using MTT method in vitro Cancer active testing, steps are as follows for experiment.
(1) culture of cell: human cervical carcinoma cell HeLa is placed in the DMEM dual anti-containing 10% fetal calf serum and 1% (Dulbecco ' s modified eagle medium) culture medium, and in 37 DEG C of temperature, 5%CO2And 95% air CO2 It is cultivated in constant incubator.After cell is adherent cover with after, passed on, frozen.
(2) plant plate: during the logarithmic growth of cell, after washing 2 times with PBS, then use 0.25% trypsin digestion, addition Culture medium terminates digestion, and carefully blows and beats, and obtains single cell suspension.By counting, by suitable 10% training of cell suspension It supports base to dilute and be inoculated in 96 orifice plates, every 180 μ L of hole, every hole cell number is 2 × 104To 4 × 104。
(3) be loaded product: in 96 orifice plates that kind has different cancer cells, 20 μ L of sample to be tested is added in every hole, and (sample concentration is 200 μM), final sample concentration is 20 μM, is screened for the first time.By screening, it is different dense to select the preferable sample progress of result Degree gradient is sieved again, calculates IC50, each group is all 9 multiple holes.The each hole of control group is put into 20 cultures of the μ L containing 10%DMSO Base is incubated for 48h.After adding sample effect 48h, the MTT liquid that 10 μ L concentration are 5mg/mL is put in each hole into, in CO2In incubator It is further cultured for 4h.
(4) it tests: the culture medium in hole being inhaled and is abandoned, and 100 μ L DMSO are added in every hole, and 10min is shaken on shaking table, is made The crystallization of first a ceremonial jade-ladle, used in libation is completely dissolved.Then the absorbance value in every hole is measured with microplate reader (TECAN infinite M1000) (490nm). Cancer inhibition rate is calculated by following formula: inhibiting rate (%)=1-ASample/AControl× 100%.It is dense according to the difference of same sample Degree charts to growth of cancer cells inhibiting rate, obtains dose response line, calculates IC according to linear regression curves50, i.e., under cell survival rate Sample concentration when dropping 50%.
Adriamycin (DOX) is wherein used as positive control, specific test result is shown in Table 1.
Cytotoxic activity of the compound of 1. the application of table for tumor cell line Hct-116, SKOV-3 and A549
* (R) -2- (Isosorbide-5-Nitrae-dihydro-Isosorbide-5-Nitrae-dioxo naphthalene -3- base amino) -3- phenylpropionic acid, is the Isosorbide-5-Nitrae-to form amide The amino acid that naphthoquinones replaces, structure are as follows:
* adriamycin (DOX) structure is as follows:
As known from Table 1, the compound of the application shows tumor cell line Hct-116, SKOV-3 and the A549 tested Significant anti tumor activity in vitro out.Different substituents on terminal aryl group can produce certain influence to anti-tumor activity.
There are one or more electron-withdrawing groups anti tumor activity in vitro can be improved on terminal aryl group.For example, having one Space electronic characteristic is determined to enhance lipophilic substituent group, and the ability of penetrating cell film is stronger, can cause anti-proliferative effect Enhancing.
Show that compound Iu is to Hct-116, SKOV-3 and A549 according to the screening active ingredients data above to tumor cell line Anti-tumor activity be respectively 0.037 ± 0.01 μM, 0.028 ± 0.01 μM and 0.033 ± 0.01 μM, (respectively than adriamycin 0.27 ± 0.08 μM, 0.16 ± 0.17 μM and 0.074 ± 0.05 μM) it is good, in particular for human colon cancer cell Hct-116 and Ovarian cancer cell SKOV3.
4.3 Western Blot protein blot experiments
4.3.1 the preparation of protein sample
1. preparing protein lysate: being put into 1mL lysate in 10 μ l PMSF (100mM), rock and be homogeneously disposed on ice (PMSF need to rock can mix when there is not crystal with lysate).
2. the culture solution that will be loaded after product (sample concentration is 0.1 μM and 0.5 μM respectively) is centrifuged down in 15mL centrifuge tube Time is 10min, is centrifuged with the speed of 2000r/min.
3. discarding supernatant liquid, 3mL PBS is added and gently blows and beats, washes twice repeatedly, centrifugation time 10min, with The speed of 2000r/min blots supernatant with rifle and is placed on ice.
4. culture bottle is placed in face on ice after washing cell 3 times repeatedly with the buffer of pre-cooling.
5. lysate is added 100 μ L into centrifuge tube, to culture bottle plus 400 μ L, being placed on constantly to shake on ice together makes carefully Born of the same parents are completely severed, time about 30min.
6. having cracked, cell is scraped off with clean pipette tips, lysate is thinning again by dilute retrogradation.In 4 DEG C of conditions Under, cell fragment and all lysates are poured in 15mL centrifuge tube, centrifugation time 5min, speed 12000r/min. Supernatant is put into 0.5mL EP pipe on ice, is saved at -20 DEG C.
4.3.2 SDS-PAGE electrophoresis
1. illustratively electrophoresis apparatus is installed, guarantee horizontal not leak adhesive.
2. a separation gel prepares, encapsulating after TEMED is mixed is added, does not occur bubble as far as possible in this process.It is added to big Stop when about 3/4, and uses water seal upper layer at once.
3. obviously there is a line in water and glue, then be gelled completion.The water on upper layer is sucked, then blots water with filter paper.It puts Enter the 6% concentration glue made in advance, inserts comb at once, should not occur bubble in this process.
4. it is solid wait be gelled, slowly extract comb.Protein sample, which is put into boiling water, to boil 15 minutes causes to be denaturalized.It is put into 5 × SDS buffer make ultimate density 1 ×, be loaded as 10 μ l, do not spill over hole as far as possible.Control group is Marker.
5. running glue: (running concentration glue) after carrying out half an hour at 50V, increase to 100V and run 1.5 hours, electrophoresis is set Marker is all separated, and can be stopped when indicator is moved to electrophoresis trench bottom.
4.3.3 transferring film
1. preparing: first thick filter paper 1 is opened, it is middle it is thick filter paper 1 is opened, thin filter paper 2 is opened and is soaked in transferring film buffer, and by NC film Taking-up is soaked in secondary water.
2. be put into suitable transferring film buffer in flat box, first put middle thick filter paper, then put thin filter paper, then put NC film in In transferring film buffer.Glue is removed, cutting glue makes its size and filter paper sizableness, is placed horizontally on NC film, paying attention to cannot Generate bubble.Again toward thin filter paper is put on glue, top layer is thick filter paper, pays attention to driving bubble.With tweezers by the thick filter paper of top layer It is separated with undermost middle thick filter paper, avoids burning NC film.Gently the filter paper handled well is put into the transferring film instrument of half dry type, is turned Film 1.5 hours.
3. transferring film terminates, with 1 × Ponceaux dye liquor vacuolar membrane five minutes, there is band after secondary washing, according to Marker's Glue is cut in instruction.
4.3.4 immune response
1. closing.It by the Membrane cleaning cut and is transferred in the ware containing skim milk, by ware in room temperature item on shaking table Closing is rocked 1.5 hours under part.Then film is cleaned with TBST, i.e., shakes cleaning on shaking table.
2. the method for the back-off of use is incubated for primary antibody according to the dilution proportion primary antibody of 1:500, shaken using shaking table in being incubated for Ginseng.Primary antibody incubation is placed in 4 DEG C overnight.
3. after being incubated overnight primary antibody, washing primary antibody with TBST.It washs 5 times, every time 30 minutes repeatedly.According to the ratio of 1:1000 Example dilution secondary antibody, the method for the back-off also used are incubated for secondary antibody, are shaken using shaking table and be incubated for internal reference.Secondary antibody is incubated for 1.5 hours. After the completion of secondary antibody is incubated for, secondary antibody is done the wash with TBST.Repetition is washed 5 times, every time 10 minutes.
4.3.5 shining
1. transparent preservative film is pasted onto luminous clip, film is placed in two preservative films.Luminescent solution is added dropwise on film, Fluorescence intensity is observed under the conditions of being protected from light to be convenient for determining fluorescent lifetime.
2. film is put into luminous clip, covers and give out light after a certain period of time, takes out film and be immediately placed into developer solution.Note The meaning control time for exposure, be exposed to purpose band occur then can, in order to avoid over-exposed and too black.It takes out and is put into after exposure Several minutes in fixing solution, taking-up is washed in clear water, is dried and then may be used.Luminescence imaging, the result is shown in Figure 1 and figure are carried out after immune incubation 2.Experimental result parsing is as follows.
Inhibit STAT3 phosphorylation
The phosphorylation of Tyr705 leads to the dimerization of STAT3, specifically binds to nuclear transfer, with DNA in STAT3, and raises Various downstream target genes, as Bcl-xl, Bcl-2, Survivin, c-Myc, cyclin D1 (Bikash Debnath, Shili Xu,and Nouri Neamati.J.Med.Chem.2012,55,6645-6668).As shown in Figure 1, through various concentration Compound Iu processing after, the expression of p-STAT3 (Y705) is substantially reduced in cell, and the expression in the site S727 and total STAT3 No change has taken place (Y705 and S727 respectively represent number in STAT3 albumen be respectively 705 and 727 two amino acid it is residual Base).This illustrates that compound Iu inhibits the activation of STAT3 by the phosphorylation in the inhibition site Y705, and not due to reducing The expression of total STAT3 and inhibit.
Compound Iu selective depression STAT3
STAT family includes the different subtype proteins such as STAT1, STAT2, STAT3, STAT4, STAT5 and STAT6, swollen STAT3 is often active in oncocyte.In order to verify compound Iu to the selectivity of STAT3, we are printed by protein Notation has detected the expression of other subtype proteins.Fig. 2 is not the result shows that compound Iu influences the expression of STAT1 and STAT5. In order to further verify compound Iu to the selectivity of STAT3, we using fluorescein enzyme process have detected STAT1, STAT3, The activity of STAT4 and STAT5.
Luciferase assay: by cell inoculation in 24 orifice plates, and with STAT3 reporter plasmid 4 × M67 pTATA TK- Luc and Rluc control reporter plasmid transiently transfect together.Then cell and complete medium one are reinstated into chemical combination After object Iu is incubated for processing in 24 hours, simultaneously supernatant is collected by centrifugation in each 100 μ L cell lysis buffer solution lytic cell of Kong Zhongyong.It takes 25 μ L supernatants measure the uciferase activity of STAT3 by microplate reader using Dual-Luciferase assay kit.As a result see Fig. 3.
As the result is shown through compound Iu handle cell after uciferase activity reduction, and almost without observe STAT1, The variation of STAT4 and STAT5 transcriptional activity.These results show that compound Iu can selective depression STAT3.Selective depression STAT3 can be inferred that the inhibitory activity to cancer.
Inhibit STAT3 in conjunction with DNA
We are detected using enzyme linked immunosorbent assay (ELISA).
Enzyme linked immunosorbent assay (ELISA): it is separately added into 30 μ L into each hole and is completely combined buffer and 20 μ L STAT3 recombinant protein, by plate gentle agitation 1 hour at room temperature.Complete cracking using 20 μ L without STAT3 recombinant protein is slow Fliud flushing is as control wells.After being incubated for 1 hour, washed 3 times with 200 μ L 1X washing buffers, it is then anti-with 100 μ L 1X STAT3 Body (1:1000 dilution) is incubated for 1 hour, without stirring.3 times, and and 100uL are washed into the 1X washing buffer of 200 μ L in hole The antibody (1:1000 dilution) of the HRP conjugation of 1X is incubated for 1 hour, without stirring.Finally, being washed with the 1X washing buffer of 200 μ L It washs 4 times, is then developed the color at room temperature 15 minutes using developing solution.Stop bath is added, is existed immediately using microplate reader Absorbance value is read at 450/655nm.
Compound Iu through various concentration handles cell, and sample is carried out ELISA measurement.As shown in figure 4, with without change The sample for closing object processing is compared, and it is in concentration dependent that compound Iu, which inhibits STAT3-DNA to combine activity, hence it is demonstrated that compound Iu It is to inhibit the activation of STAT3 by hindering STAT3 and DNA.
The imaging of 4.4 immunofluorescences
By SKOV3 cell inoculation on sterilized slide glass and grow 24 hours.Cell compound Iu was handled in second day 24 hours.Core transposition is tested, after serum-free is stayed overnight, is pre-processed SKOV3 cell 2 hours with compound Iu, is then added again Enter IL-6 (interleukin-6, interleukin-6) 30 minutes.After processing, buffered with cold phosphate buffered saline (PBS) (PBS) Liquid washs cell, and fixes 15 minutes with cold methanol at room temperature.After being washed twice with the PBS buffer solution of pre-cooling, in room temperature The lower X-100 permeabilization cell containing 0.3%Triton is closed at least 1 hour with the PBS buffer solution of 5% Normal Goat Serum. Then it is stayed overnight with STAT3 the or STAT3 multi-clone rabbit antibody incubation cell of phosphorylation and at 4 DEG C.After being incubated overnight, with containing The PBS buffer solution of 0.1%Tween-20 washs cell.Cell and FITC fluorescence anti-rabbit secondary antibody are incubated for 1 hour at room temperature.It washes It is carried out after washing cell with DAPI, imaging analysis is then carried out by fluorescence microscope.As a result see Fig. 5, experimental result parsing is as follows.
Inhibit the nuclear transfer of STAT3
It is transferred in nucleus in order to which whether detection compound Iu is able to suppress STAT3, we are imaged using immunofluorescence It is analyzed.As shown in figure 5, STAT3 is phosphorylated and indexing is into nucleus in IL-6 processing SKOV3 cell.So And in the cell handled with (0.5 μM) of compound Iu, most of STAT3 is retained in cytoplasm.Therefore, should the result shows that Compound Iu can inhibit STAT3 in conjunction with DNA and phosphorylation, and the functional transcription for damaging STAT3 in SKOV3 cell mainly leads to It crosses and blocks its nuclear transfer.
4.5 scratch experiments and invasion experiment
Scratch experiment
With the DMEM culture medium culture SKOV3 cell containing 10%FBS and cell inoculation is cultivated in 6 orifice plates.Cell After covering with, 1 time is washed to remove non-adherent cell using 10uL pipettor tip scratch, and with PBS.Culture plate is placed in inversion Microscopically observation is simultaneously imaged, and is as a result used as not processed negative control.Fresh culture is replaced, is handled with compound Iu thin Cell is placed in incubator and is incubated for 24 hours by born of the same parents.Cell migration situation is observed and recorded after incubation under the microscope.Experimental result See Fig. 6, experimental result parsing sees below.
Invasion experiment
Migration test carries out in 24 holes of 8.0 μm of polycarbonate membranes invasion cell (transwell).Firstly, by 600 μ L Room under invasion cell is added in complete medium or treatment factors.Secondly, 200 μ L are contained 2 × 105/ ml SKOV3 cell is without FBS's DMEM inoculation of suspension liquid is inserted into bottom compartment into invasion cell upper chamber, and by cell migration filter.24 are incubated at 37 DEG C Hour.Then, the SKOV3 cell on the upside of filter is removed, fixes migrating cell 20 minutes with 500 μ L, 4% paraformaldehyde, and With hematoxylin by fixed cell dyeing 3 minutes.It counts migrating cell quantity and takes pictures under fluorescence microscope.Experimental result is shown in Fig. 7, experimental result parsing are as follows.
Inhibit SKOV3 cell migration and invasion
The transfer of tumour and tissue invasion be lead to one of the principal element of tumor patient death and treatment failure, and The activation of STAT3 and proliferation, differentiation, survival, transfer and the invasion of tumour have close ties.Compound Iu can block STAT3 And the combination of DNA is to inhibit the transcriptional activity of STAT3, therefore we are detected using scratch experiment and cell compartments staining analysis Can compound Iu inhibit the migration and invasion of SKOV3 cell.As shown in fig. 6, the migration of compound Iu inhibition SKOV3 cell is in Concentration dependent.Fig. 7 show it is similar as a result, with concentration increase, the cell quantity of migration gradually decreases.These data The migration and invasion of SKOV3 cell can be inhibited by showing compound Iu.
Embodiment 5IDO1 inhibitory activity research
5.1 IDO1 Enzyme assays
Illustrate to carry out the test of people IDO1 enzymatic activity (Tojo, S. according to what reagent quotient provided；Kohno,T.；Tanaka,T.； Kamioka,S.；Ota,Y.；Ishii,T.；Kamimoto,K.；Asano,S.Med.Chem.Lett.2014,5,1119- 1123).Using IDO inhibitor IDO5L as positive control.By people IDO1,10 μ L comprising 50 μ L reaction premixed liquids, 10 μ L purifying Compound to be detected, IDO1 detection buffer mixed liquor (90 μ L) be incubated for 10 minutes at room temperature, 10 μ L are then added The substrate solution of the L-Trp containing 1mM makes 100 μ L of its final volume, is protected from light incubation 45 minutes at 37 DEG C.50 μ L fluorescence are added Developing agents are protected from light incubation 3 hours at 45 DEG C.Fluorescence intensity (Ex/Em=402/488nm) after room temperature is 1 hour cooling. Suppression percentage is calculated according to formula [100- (A/B) 100]/100, wherein A is the fluorescence intensity of addition test compound, and B is Do not add the fluorescence intensity of test compound.Experimental result is shown in Table 2, and experimental result parsing sees below.
Inhibitory activity of the compound of 2. the application of table for IDO1
* (R) -2- (1,4- dihydro -1,4- dioxo naphthalene -3- base amino) -3- phenylpropionic acid
* IDO5L is IDO inhibitor, and chemical structure is as follows:
HIDO1 inhibitory activity
We test compound synthesized by the application to people IDO1's (hIDO1) (people's indole amine 2,3-dioxygenase 1) Inhibitory activity, wherein using IDO1 inhibitor IDO5L as positive control.As shown in table 2, test result shows the oximido of the application Naphthaquinone derivatives have good selectivity inhibitory activity, IC to hIDO150With every liter of micromole of concentration calculation, partization The activity for closing object approaches or is slightly better than positive drug IDO5L (IC50=0.073 μM).
The structure-activity relationship that oximido naphthaquinone derivatives inhibit hIDO1 can be tentatively inferred to from the data in table 2.To peptide end Hold the R for being located at meta position on aryl1The impact analysis of substituent group is shown, compared with methyl or methoxy substitution group, halogen Or trifluoromethyl atomic radical can enhance derivative to the inhibitory activity of hIDO1 to a certain extent.For example, working as compound Im When meta position methyl is replaced by trifluoromethyl on terminal aryl group (compound Ik), hIDO1 inhibitory activity is significantly increased, inhibitory activity phase 16.8 times are improved for compound Im.With the contraposition of fluorine atom or chlorine atom substituted aryl respectively obtain compound Il and Ih produces obviously inhibitory activity, and the substituent group with electron rich characteristic can play centainly the inhibitory activity of hIDO1 Effect.Form oxime ester when the oxime in quinone ring is substituted, activity decrease (compound IIIk-1, IIIq, IIIr) illustrate oxime Structure has a certain effect hIDO1 inhibitory activity, and reason may be that oxime can be with the iron atom of combination ferroheme.
5.2 ultraviolet (UV)-visible spectrums
Ultraviolet-visible absorption spectroscopy measures on the spectrophotometer of Cary 1E UV-Visible, scanning range 200- 700nm.In order to keep the temperature of each sample to measure at 25 DEG C, Haake F3 water bath heating device and spectrophotometer are joined With.Measurement uses sample phosphate buffer solution (PBS) aqueous solution of 1mL, wherein IDO1 and 25 μM containing 10 μM of purifying Compound Iu.Experimental result is shown in Fig. 8, as a result parse as follows.
Ultraviolet spectra detection compound Iu and IDO1 interacts
Since compound Iu has preferable inhibitory activity to IDO1, compound will be studied by UV- visible spectrum The binding pattern of Iu and IDO1.IDO1 has ferroheme co-factor activities site, makes it possible to characterize between inhibitor and IDO Interaction.Compound can cause light absorbing change in conjunction with heme iron, therefore can directly be inferred to and the bound site Point combines.Porphyrin ring with iron coordination centered on ferroheme, according to the oxidation of its iron and co-ordination state, uv-vis spectra Absorption maximum optical wavelength is about 400nm.Inhibitor will change its absorption maximum optical wavelength in conjunction with the iron of ferroheme.Ferroheme The absorption spectrum of group is sensitive to polar change in elevation around ferroheme after ligand/Binding Capacity, this changes ferroheme Spectral characteristic.Therefore, the variation of ultraviolet-visible spectrum caused by being interacted by IDO1 and ligand can be used for assessing compound with The combination of IDO1.Herein, we are interacted using ultraviolet-visible spectrum detection compound Iu and IDO1.Do not changing In the case where closing object Iu, there is the peak Soret in 403nm in the absorption spectrum of IDO1 iron, this (Yi- consistent with document report before Hui Peng,Shau-Hua Ueng,Chen-Tso Tseng,et al,J.Med.Chem.2016,59,282-293).Changing It in the presence of closing object Iu, absorbs light and is transferred to 413nm, this proves that compound Iu is chelated in conjunction with IDO1 and with ferroheme (referring to Fig. 8).
The analysis of 5.3 surface plasma body resonant vibrations
Use the interaction between surface plasma body resonant vibration (SPR) verifying compound Iu and IDO1 albumen.It will purification People IDO1 proteopexy sensor chip CM5 (GE) and at 25 DEG C in Biacore T200 (GE, model Biacore T200 it) is analyzed on instrument.By HBS-EP buffer (0.01M HEPES, 0.15M NaCl, 3mM EDTA, 0.05%v/v Surfactant P20 (pH7.4)) it is used as running buffer.Ratio association and dissociation rate constant are confirmed as binding affinity (KD).Experimental result is shown in Fig. 9, as a result parse as follows.
Surface plasma resonance detection compound Iu and IDO1 interaction
It is raw using GE Biacore T200 optics in order to further verify the interaction between compound Iu and IDO1 Object sensor measures surface plasma resonance (SPR).As shown in figure 9, in selected concentration range, response units value (RU) with The concentration of compound is directly proportional.Instrument carries software and calculates after tested, the equilibrium dissociation constant between compound Iu and IDO1 It (KD) is 0.02 μM, this sufficiently demonstrates the binding affinity of compound Iu Yu target IDO1 albumen.

Claims (31)

1. the compound of formula (I):
Wherein
X is the C being optionally substituted with one or more groups selected from the following6-C10Aryl or 5 yuan are to 10 unit's heteroaryls: halogen, Hydroxyl, sulfydryl, the sulfenyl optionally replaced, the C optionally replaced1-C6Alkyl, the C optionally replaced1-C6Alkenyl optionally replaces C1-C6Alkynyl, the C optionally replaced1-C6Alkoxy, the amino optionally replaced, the hydroxyl C optionally replaced1-C6Alkyl optionally replaces Halogenated C1-C6Alkyl and the halogenated C optionally replaced1-C6Alkoxy；
Each R1Independently selected from hydrogen, halogen, hydroxyl, sulfydryl, the optionally sulfenyl, the optionally C that replaces that replace1-C6Alkyl is appointed Choose the C in generation1-C6Alkenyl, the C optionally replaced1-C6Alkynyl, the C optionally replaced1-C6Alkoxy, the amino optionally replaced, optionally Substituted hydroxyl C1-C6Alkyl, the halogenated C optionally replaced1-C6Alkyl and the halogenated C optionally replaced1-C6Alkoxy；
N is the integer selected from 1,2,3,4 or 5；
Each R2Independently selected from hydrogen, halogen, hydroxyl, sulfydryl, the optionally sulfenyl, the optionally C that replaces that replace1-C6Alkyl is appointed Choose the C in generation1-C6Alkenyl, the C optionally replaced1-C6Alkynyl, the C optionally replaced1-C6Alkoxy, the amino optionally replaced, optionally Substituted hydroxyl C1-C6Alkyl, the halogenated C optionally replaced1-C6Alkyl, the halogenated C optionally replaced1-C6Alkoxy, sulfinyl, Sulfonyl, S- sulfonamido, N- sulfonamido, O- carbamoyl, N- carbamoyl, O- thiocarbamoyl, N- sulphur For carbamoyl, C- acylamino- and N- acylamino-；
M is the integer selected from 1,2,3 or 4；With
R3Selected from hydrogen, halogen, hydroxyl, sulfydryl, the optionally sulfenyl, the optionally C that replaces that replace1-C6Alkyl, the C optionally replaced1- C6Alkenyl, the C optionally replaced1-C6Alkynyl, the C optionally replaced1-C6Alkoxy, the amino optionally replaced, the hydroxyl optionally replaced C1-C6Alkyl, the halogenated C optionally replaced1-C6Alkyl, the halogenated C optionally replaced1-C6Alkoxy, sulfinyl, sulfonyl, S- Sulfonamido, N- sulfonamido, O- carbamoyl, N- carbamoyl, O- thiocarbamoyl, N- thiocarbamoyl Base, C- acylamino- and N- acylamino-；
Or its pharmaceutically acceptable salt.
2. compound as described in claim 1, wherein the C6-C10Aryl is phenyl.
3. compound as described in claim 1, wherein described 5 yuan to 10 unit's heteroaryls be pyridyl group or thienyl.
4. compound as described in claim 1, wherein the C6-C10Aryl is optionally replaced by group selected from the following: halogen Element, hydroxyl, sulfydryl, the C optionally replaced1-C6Alkyl, the C optionally replaced1-C6Alkoxy, optionally replaces the amino optionally replaced Hydroxyl C1-C6Alkyl, the halogenated C optionally replaced1-C6Alkyl and the halogenated C optionally replaced1-C6Alkoxy.
5. compound as described in claim 1, wherein the C6-C10Aryl is phenyl, optionally by base selected from the following Group replaces: halogen, the C optionally replaced1-C6Alkyl, the C optionally replaced1-C6Alkoxy and the halogenated C optionally replaced1-C6Alkane Base.
6. compound as described in claim 1, wherein each R1It is hydrogen.
7. compound as described in claim 1, wherein each R2It is hydrogen.
8. compound as described in claim 1, wherein the R3For hydrogen.
9. compound selected from the following:
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (4- (fluoroform Base) phenyl)-propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (2- fluorophenyl) - Propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3, N- diphenyl-propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3- fluorophenyl) - Propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (2- methoxybenzene Base)-propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3,5- dimethyl Phenyl)-propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (4- chlorphenyl) - Propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (4- bromophenyl) - Propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (the bromo- 4- fluorobenzene of 3- Base)-propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3- (fluoroform Base) phenyl)-propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (4- fluorophenyl) - Propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3- tolyl) - Propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (2- chlorphenyl) - Propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3- chlorphenyl) - Propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (2- bromophenyl) - Propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3- bromophenyl) - Propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3- methoxybenzene Base)-propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (4- methoxybenzene Base)-propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (4- tolyl) - Propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3,5- dimethoxy Base phenyl)-propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (the fluoro- 4- bromobenzene of 3- Base)-propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3,5- difluorobenzene Base)-propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (the fluoro- 4- methyl of 2- Phenyl)-propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (2,5- dimethoxy Base phenyl)-propionamide；
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (the chloro- 4- methyl of 3- Phenyl)-propionamide；With
(R) -2- ((4- (oxyimino) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (2- methyl -4- bromine Phenyl)-propionamide；
Or its pharmaceutically acceptable salt.
10. the compound of formula (II):
Wherein
X is the C being optionally substituted with one or more groups selected from the following6-C10Aryl or 5 yuan are to 10 unit's heteroaryls: halogen, Hydroxyl, sulfydryl, the sulfenyl optionally replaced, the C optionally replaced1-C6Alkyl, the C optionally replaced1-C6Alkenyl optionally replaces C1-C6Alkynyl, the C optionally replaced1-C6Alkoxy, the amino optionally replaced, the hydroxyl C optionally replaced1-C6Alkyl optionally replaces Halogenated C1-C6Alkyl and the halogenated C optionally replaced1-C6Alkoxy；
Each R1Independently selected from hydrogen, halogen, hydroxyl, sulfydryl, the optionally sulfenyl, the optionally C that replaces that replace1-C6Alkyl is appointed Choose the C in generation1-C6Alkenyl, the C optionally replaced1-C6Alkynyl, the C optionally replaced1-C6Alkoxy, the amino optionally replaced, optionally Substituted hydroxyl C1-C6Alkyl, the halogenated C optionally replaced1-C6Alkyl and the halogenated C optionally replaced1-C6Alkoxy；
N is the integer selected from 1,2,3,4 or 5；
Each R2Independently selected from hydrogen, halogen, hydroxyl, sulfydryl, the optionally sulfenyl, the optionally C that replaces that replace1-C6Alkyl is appointed Choose the C in generation1-C6Alkenyl, the C optionally replaced1-C6Alkynyl, the C optionally replaced1-C6Alkoxy, the amino optionally replaced, optionally Substituted hydroxyl C1-C6Alkyl, the halogenated C optionally replaced1-C6Alkyl, the halogenated C optionally replaced1-C6Alkoxy, sulfinyl, Sulfonyl, S- sulfonamido, N- sulfonamido, O- carbamoyl, N- carbamoyl, O- thiocarbamoyl, N- sulphur For carbamoyl, C- acylamino- and N- acylamino-；
M is the integer selected from 1,2,3 or 4；With
R3Selected from hydrogen, halogen, hydroxyl, sulfydryl, the optionally sulfenyl, the optionally C that replaces that replace1-C6Alkyl, the C optionally replaced1- C6Alkenyl, the C optionally replaced1-C6Alkynyl, the C optionally replaced1-C6Alkoxy, the amino optionally replaced, the hydroxyl optionally replaced C1-C6Alkyl, the halogenated C optionally replaced1-C6Alkyl, the halogenated C optionally replaced1-C6Alkoxy, sulfinyl, sulfonyl, S- Sulfonamido, N- sulfonamido, O- carbamoyl, N- carbamoyl, O- thiocarbamoyl, N- thiocarbamoyl Base, C- acylamino- and N- acylamino-；
Or its pharmaceutically acceptable salt.
11. compound as claimed in claim 10, wherein the C6-C10Aryl is phenyl.
12. compound as claimed in claim 10, wherein described 5 yuan to 10 unit's heteroaryls be pyridyl group or thienyl.
13. compound as claimed in claim 10, wherein the C6-C10Aryl is optionally replaced by group selected from the following: Halogen, hydroxyl, sulfydryl, the C optionally replaced1-C6Alkyl, the C optionally replaced1-C6Alkoxy, optionally takes the amino optionally replaced The hydroxyl C in generation1-C6Alkyl, the halogenated C optionally replaced1-C6Alkyl and the halogenated C optionally replaced1-C6Alkoxy.
14. compound as claimed in claim 10, wherein the C6-C10Aryl is phenyl, optionally selected from the following Group replaces: halogen, the C optionally replaced1-C6Alkyl, the C optionally replaced1-C6Alkoxy and the halogenated C optionally replaced1-C6Alkane Base.
15. compound as claimed in claim 10, wherein each R1、R2It is hydrogen, R3For hydrogen.
16. compound selected from the following:
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (4- (trifluoromethyl) phenyl)-propionyl Amine；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (2- fluorophenyl)-propionamide；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3, N- diphenyl-propionamide；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3- fluorophenyl)-propionamide；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (2- methoxyphenyl)-propionamide；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3,5- 3,5-dimethylphenyl)-propionyl Amine；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (4- chlorphenyl)-propionamide；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (4- bromophenyl)-propionamide；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (the bromo- 4- fluorophenyl of 3-)-propionamide；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3- (trifluoromethyl) phenyl) propionyl Amine；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (4- fluorophenyl)-propionamide；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3- tolyl)-propionamide；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (2- chlorphenyl)-propionamide；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3- chlorphenyl)-propionamide；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (2- bromophenyl)-propionamide；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3- bromophenyl)-propionamide；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3- methoxyphenyl)-propionamide；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (4- methoxyphenyl)-propionamide；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (4- tolyl)-propionamide；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3,5- dimethoxy benzene；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (the fluoro- 4- bromophenyl of 3-)-propionamide；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (3,5- difluorophenyl)-propionamide；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (the fluoro- 4- aminomethyl phenyl of 2-)-propionyl Amine；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (2,5- Dimethoxyphenyl)-propionyl Amine；
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (the chloro- 4- aminomethyl phenyl of 3-)-propionyl Amine；With
(R) -2- ((1,4- dioxo-DHN 1,4 dihydronaphthalene -2- base) amino) -3- phenyl-N- (2- methyl -4- bromophenyl)-propionyl Amine；
Or its pharmaceutically acceptable salt.
17. the compound of formula (III):
Wherein
X is the C being optionally substituted with one or more groups selected from the following6-C10Aryl or 5 yuan are to 10 unit's heteroaryls: halogen, Hydroxyl, sulfydryl, the sulfenyl optionally replaced, the C optionally replaced1-C6Alkyl, the C optionally replaced1-C6Alkenyl optionally replaces C1-C6Alkynyl, the C optionally replaced1-C6Alkoxy, the amino optionally replaced, the hydroxyl C optionally replaced1-C6Alkyl optionally replaces Halogenated C1-C6Alkyl and the halogenated C optionally replaced1-C6Alkoxy；
Each R1Independently selected from hydrogen, halogen, hydroxyl, sulfydryl, the optionally sulfenyl, the optionally C that replaces that replace1-C6Alkyl is appointed Choose the C in generation1-C6Alkenyl, the C optionally replaced1-C6Alkynyl, the C optionally replaced1-C6Alkoxy, the amino optionally replaced, optionally Substituted hydroxyl C1-C6Alkyl, the halogenated C optionally replaced1-C6Alkyl and the halogenated C optionally replaced1-C6Alkoxy；
N is the integer selected from 1,2,3,4 or 5；
Each R2Independently selected from hydrogen, halogen, hydroxyl, sulfydryl, the optionally sulfenyl, the optionally C that replaces that replace1-C6Alkyl is appointed Choose the C in generation1-C6Alkenyl, the C optionally replaced1-C6Alkynyl, the C optionally replaced1-C6Alkoxy, the amino optionally replaced, optionally Substituted hydroxyl C1-C6Alkyl, the halogenated C optionally replaced1-C6Alkyl, the halogenated C optionally replaced1-C6Alkoxy, sulfinyl, Sulfonyl, S- sulfonamido, N- sulfonamido, O- carbamoyl, N- carbamoyl, O- thiocarbamoyl, N- sulphur For carbamoyl, C- acylamino- and N- acylamino-；
M is the integer selected from 1,2,3 or 4；
R3Selected from hydrogen, halogen, hydroxyl, sulfydryl, the optionally sulfenyl, the optionally C that replaces that replace1-C6Alkyl, the C optionally replaced1- C6Alkenyl, the C optionally replaced1-C6Alkynyl, the C optionally replaced1-C6Alkoxy, the amino optionally replaced, the hydroxyl optionally replaced C1-C6Alkyl, the halogenated C optionally replaced1-C6Alkyl, the halogenated C optionally replaced1-C6Alkoxy, sulfinyl, sulfonyl, S- Sulfonamido, N- sulfonamido, O- carbamoyl, N- carbamoyl, O- thiocarbamoyl, N- thiocarbamoyl Base, C- acylamino- and N- acylamino-；With
R4For the C being optionally substituted with one or more groups selected from the following6-C10Aryl or 5 yuan are to 10 unit's heteroaryls: halogen, Hydroxyl, sulfydryl, the sulfenyl optionally replaced, the C optionally replaced1-C6Alkyl, the C optionally replaced1-C6Alkenyl optionally replaces C1-C6Alkynyl, the C optionally replaced1-C6Alkoxy, the amino optionally replaced, the hydroxyl C optionally replaced1-C6Alkyl optionally replaces Halogenated C1-C6Alkyl and the halogenated C optionally replaced1-C6Alkoxy；
Or its pharmaceutically acceptable salt.
18. compound as claimed in claim 17, wherein the C6-C10Aryl is phenyl, and described 5 yuan to 10 unit's heteroaryls are Pyridyl group or thienyl.
19. compound as claimed in claim 17, wherein the C6-C10Aryl is phenyl, optionally selected from the following Group replaces: halogen, the C optionally replaced1-C6Alkyl, the C optionally replaced1-C6Alkoxy and the halogenated C optionally replaced1-C6Alkane Base.
20. compound as claimed in claim 17, wherein the R1、R2It is hydrogen, R3For hydrogen.
21. compound as claimed in claim 17, wherein the C6-C10Aryl is phenyl, and described 5 yuan to 10 unit's heteroaryls are Thienyl.
22. compound selected from the following:
(R) -2- ((4- ((((4- (tert-butyl) phenyl) sulfonyl) oxygen) imino group) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) ammonia Base) -3- phenyl-N- (3- (trifluoromethyl) phenyl)-propionamide；
(R) -2- ((4- ((((4- (tert-butyl) phenyl) sulfonyl) oxygen) imino group) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) ammonia Base) -3- phenyl-N- (3- bromophenyl)-propionamide；With
(R) -2- ((4- ((((4- (tert-butyl) phenyl) sulfonyl) oxygen) imino group) -1- oxo-DHN 1,4 dihydronaphthalene -2- base) ammonia Base) -3- phenyl-N- (3- methoxyphenyl)-propionamide；
Or its pharmaceutically acceptable salt.
23. the method for preparing compound described in any one of claim 10-16, the method includes steps as follows A) to e):
A) react phthalic anhydride and L-phenylalanine, the phenyl in the L-phenylalanine is optionally by 1 to n R1It takes Generation；
B) product and C for obtaining step a)2O2Cl2Reaction；
C) product and X-NH for obtaining step b)2Reaction；
D) product and hydrazine reaction for obtaining step c)；
E) product for obtaining step d) is reacted with 1,4-naphthoquinone, and the phenyl ring in the 1,4-naphthoquinone is optionally by 1 to m R2It takes Generation and 2 carbon optionally by R3Replace, to obtain the compound of formula (II)；
Wherein X, R1、n、R2, m and R3As claimed in claim 10.
24. method as claimed in claim 23, in which:
The reaction condition of step a) is at 55-85 DEG C, preferably reacts 10-14 hours in an acidic solution at 70 DEG C, preferably 12 hours；
The reaction condition of step b) is to react 10-14 hours in halogenated alkane solution at 0-15 DEG C, preferably at 0 DEG C, excellent It selects 12 hours；
The reaction condition of step c) is to react 20-40 minutes in halogenated alkane solution at 0-15 DEG C, preferably at 0 DEG C, excellent It selects 30 minutes；
The reaction condition of step d) is to react 2.5 to 3.5 hours in alcohol solution at room temperature；
The reaction condition of step e) is to react in the mixed solution of triethylamine, N,N-dimethylformamide and water at room temperature 18-24 hours.
25. the method for preparing compound of any of claims 1-9, the method includes steps as follows F):
The step f) is to react the compound of formula (II) with hydroxylamine hydrochloride, it is preferable that the reaction condition of the step f) is 10-14 hours, preferably 12 hours are reacted in alcohol solution at 70-80 DEG C, to obtain the compound of formula (I), wherein X, R1、n、R2, m and R3For as described in the appended claim 1.
26. the method for preparing compound described in any one of claim 17-22, the method includes steps as follows G):
The step g) is by the compound and ClSO of formula (I)2R4Reaction, the reaction condition of the preferably described step g) are lazy Property gas in reacted in methylene chloride at 0-15 DEG C, preferably at 0 DEG C 20-40 minutes, preferably 30 minutes, then dropwise plus Enter triethylamine and reacts 10-20 minutes；Wherein X, R1、n、R2、m、R3And R4For as described in claim 17.
27. pharmaceutical composition, it includes as described in any one of claim 1-9 or 17-22 compound or its pharmaceutically may be used The compound or its pharmaceutically acceptable salt and one kind of the preparation of method described in the salt or claim 25 or 26 of receiving Or a variety of pharmaceutically acceptable carriers, diluent, excipient or combinations thereof.
28. compound or its pharmaceutically acceptable salt, claim 25 described in any one of claim 1-9 or 17-22 Or pharmaceutical composition described in the compound or its pharmaceutically acceptable salt or claim 27 of the preparation of method described in 26 Inhibiting the purposes in STAT3 and/or IDO1.
29. compound or its pharmaceutically acceptable salt, claim 25 described in any one of claim 1-9 or 17-22 Or pharmaceutical composition described in the compound or its pharmaceutically acceptable salt or claim 27 of the preparation of method described in 26 Preparing the purposes in the drug for inhibiting STAT3 and/or IDO1.
30. compound or its pharmaceutically acceptable salt, claim 25 described in any one of claim 1-9 or 17-22 Or pharmaceutical composition described in the compound or its pharmaceutically acceptable salt or claim 27 of the preparation of method described in 26 Purposes in the preparation of medicament for cancer treatment.
31. purposes as claimed in claim 30, wherein the cancer is selected from colon cancer, oophoroma, liver cancer, bladder cancer, uterus Neck cancer and small cell carcinoma of lung.
CN201811227689.6A 2018-10-22 2018-10-22 Oximido naphthoquinone compound and its preparation method and application Withdrawn CN109438277A (en)

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WO2020082817A1 (en) * 2018-10-22 2020-04-30 普济生物科技（台州）有限公司 Naphthoquinone oxime compound, preparation method therefor, and uses thereof
CN115124541A (en) * 2021-03-24 2022-09-30 中国医学科学院药物研究所 Preparation and application of IDO1 inhibitor

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CN109438277A (en) * 2018-10-22 2019-03-08 普济生物科技（台州）有限公司 Oximido naphthoquinone compound and its preparation method and application

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WO2020082817A1 (en) * 2018-10-22 2020-04-30 普济生物科技（台州）有限公司 Naphthoquinone oxime compound, preparation method therefor, and uses thereof
CN115124541A (en) * 2021-03-24 2022-09-30 中国医学科学院药物研究所 Preparation and application of IDO1 inhibitor
CN115124541B (en) * 2021-03-24 2023-09-26 中国医学科学院药物研究所 Preparation and application of IDO1 inhibitor

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