CN103588697B - Disubstituted benzenes sulfamide compound of one class 2,5 and its production and use - Google Patents
Disubstituted benzenes sulfamide compound of one class 2,5 and its production and use Download PDFInfo
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- CN103588697B CN103588697B CN201210289517.8A CN201210289517A CN103588697B CN 103588697 B CN103588697 B CN 103588697B CN 201210289517 A CN201210289517 A CN 201210289517A CN 103588697 B CN103588697 B CN 103588697B
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- 0 COc(ccc(CN(C(c1ccccc11)=O)C1=O)c1)c1*(NCc(cc1)ccc1F)=O Chemical compound COc(ccc(CN(C(c1ccccc11)=O)C1=O)c1)c1*(NCc(cc1)ccc1F)=O 0.000 description 5
- TXHDHVNCAYRPBN-UHFFFAOYSA-N CC(C1C(c2c3cccc2)=O)C1C3=O Chemical compound CC(C1C(c2c3cccc2)=O)C1C3=O TXHDHVNCAYRPBN-UHFFFAOYSA-N 0.000 description 1
- MYHXLUDLPUJNKU-UHFFFAOYSA-N CCc(cc1S(NCc(cc2)ccc2F)(=O)=O)ccc1OC Chemical compound CCc(cc1S(NCc(cc2)ccc2F)(=O)=O)ccc1OC MYHXLUDLPUJNKU-UHFFFAOYSA-N 0.000 description 1
- MHVYSAHPBFITLO-UHFFFAOYSA-N COc(ccc(CN(C(c1ccccc11)=O)C1=O)c1)c1S(NC(CCC1)c2c1cccc2)(=O)=O Chemical compound COc(ccc(CN(C(c1ccccc11)=O)C1=O)c1)c1S(NC(CCC1)c2c1cccc2)(=O)=O MHVYSAHPBFITLO-UHFFFAOYSA-N 0.000 description 1
- KBSAUETWMISGCC-UHFFFAOYSA-N COc1ccc(CN(C(c2ccccc22)=O)C2=O)cc1 Chemical compound COc1ccc(CN(C(c2ccccc22)=O)C2=O)cc1 KBSAUETWMISGCC-UHFFFAOYSA-N 0.000 description 1
- BDYAXTMPCZPROI-UHFFFAOYSA-N COc1ccc(CN(C2OC2c2ccccc22)C2=O)cc1S(Cl)(=O)=O Chemical compound COc1ccc(CN(C2OC2c2ccccc22)C2=O)cc1S(Cl)(=O)=O BDYAXTMPCZPROI-UHFFFAOYSA-N 0.000 description 1
- IDPURXSQCKYKIJ-UHFFFAOYSA-N COc1ccc(CN)cc1 Chemical compound COc1ccc(CN)cc1 IDPURXSQCKYKIJ-UHFFFAOYSA-N 0.000 description 1
- LGRFSURHDFAFJT-UHFFFAOYSA-N O=C(c1c2cccc1)OC2=O Chemical compound O=C(c1c2cccc1)OC2=O LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members 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
- C07D207/36—Oxygen or sulfur atoms
- C07D207/40—2,5-Pyrrolidine-diones
- C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
- C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
- C07D207/448—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide
- C07D207/452—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide with hydrocarbon radicals, substituted by hetero atoms, directly attached to the ring nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The present invention relates to disubstituted benzenes sulfamide compound of a class 2,5 and its production and use.Specifically, treatment is being prepared by the application in the medicine of the CCR6 diseases mediated as CCR6 antagonists the present invention relates to compound, its preparation method, its pharmaceutical composition and such compound as shown in following formula I, wherein, the disease mediated by CCR6 can be autoimmune disease, inflammation, psoriasis, multiple sclerosis or cancer etc..
Description
Technical field
The present invention relates to a class 2,5- disubstituted benzenes sulfamide compound, its pharmaceutical composition and preparation method thereof and use
On the way, such compound can be as CCR6 antagonists, for preparing medicine of the treatment by the CCR6 diseases mediated.
Background technology
Chemokine receptors CCR6 is the g protein coupled receptor of seven cross-film, is mainly expressed in T cell, B cell sub-
Group and dendritic cells etc., CCL20 is its only part.CCL20 is the (macrophage of macrophage inflammatory protein 3
Inflammatory protein 3, MIP-3 α), mainly it is expressed in liver, embryo, lung, skin, lymph node and periphery blood strangury
Bar cell.Due to the popularity of its expression, therefore it take part in the generating process of numerous diseases, such as enteritis, psoriasis, rheumatoid
The autoimmune disease such as arthritis and multiple sclerosis.
Interaction between CCL20 and CCR6 plays a significant role in the formation of intestinal inflammatory.Enterocyte upper table
The CCL20 reached can be combined activation, chemotactic T cell with the CCR6 on T cell surface and be migrated to intestines, promote inflammatory cytokine and inflammation
Disease medium discharges.And inflammatory cytokine further raises chemotactic factor (CF) and its expression of receptor, inflammation is aggravated, is produced pernicious
Circulation.Activation, chemotaxis of the chemotactic factor (CF) that areas of inflammation is produced to lymphocyte are the bases for causing Histopathological lesions.
Therefore, CCL20/CCR6 signal pathways are blocked mucosal inflammation may to be enable to mitigate.Varona etc.（Varona R, Cadenas
V, Flores J, et al.CCR6 has a nonredundant role in the development of
inflammatory bowel disease.Eur J Immunol,2003,33(10):2937-2946.）It was found that, CCR6 missings
The leucocyte homeostasis and cytokine environment of intestinal mucosa can be changed, the mouse colitis for inducing TNB (TNBS)
Disease mitigates promptings CCL20/CCR6 and played a crucial role in vivo during intestine immunity reacts.Katchar etc.（Katchar K,Kelly
C P, Keates S, et al.MIP-3alpha neutralizing monocloual antibody protects
against TNBS induced colonic injury and inflammation in mice.Am J Physiol
Gastrointest Liver Physicl,2007,292(5):G1263-G1271.）Studies have shown that TNBS induce it is small
In mouse colitis, colon's CCL20 protein levels are substantially raised, and with mucosa lamina propria CCR6 positives CD4+T cell and
CD8+T cell ratio rises；And CCL20 biological activity is blocked with CCL20 monoclonal antibodies (1mg/kg), it can significantly mitigate TNBS and lure
The Traumatic Colon and T cell led are raised.These results are pointed out by blocking CCL20/CCR6 signal path effectively to treat small
Mouse experimental colitis.
During inflammation, T-lymphocyte activation, the T cell of activation is just obtained to inflammation portion after expressing CCR6
The ability of position migration.Under MIP-3a/CCR6 interactions, the T lymphocytes of these activation are migrated into liver, mediate liver
Local immunity, participates in virus sweep, may also bring immunopathogenesis reaction simultaneously.Research discovery, patients with chronic HCV infection CCR6
Expression it is significantly raised compared with normal person, dysfunction of liver person CCR6 expression is less than the normal person of liver function.Point out chronic HCV infection
Person's periphery lymphocyte is activated, and the T effector cell of part activation is migrated to liver under CCR6 mediations, causes local exempt from
Epidemic disease.
In skin histology, CCL20 is primarily present in keratinocyte (KC), skin fibroblasts, the micro- blood of skin
Endothelial cell and BMDC（Rossi D L, Vicari A P, Franz-Bacon K, et
al.Identification through bioinformatics of two new macrophage
preinflammatory human chemokines：MIP-3alpha and MIP-3beta.J Immunol, 1997,158
(3):1033-1036.Tanaka Y, Imai T, Baba M, et al.Selective expression of liver and
activation-regulated chemokine(LARC)in intestinal epithelium in mice and
Humans.Eur J Immunol, 1999,29 (2):633-642.）.Research discovery, memory/effector T cell and prematurity tree
Prominent shape cell surface has CCR6 expression.Thus, CCL20 is this strong chemoattractant of two classes cell, and is considered current
The most strong attraction Langerhan's cells understood（LC）The chemotactic factor (CF) of precursor（Dieu-Nosjean M C,
Massacrier C,Homey B,et al.Macrophage inflammatory protein 3alpha is
expressed at inflamed epithelial surfaces and is the most potent chemokine
Known in attracting Langerhans cell precursors.J Exp Med, 2000,192 (5):705-
718）.A large amount of evidences show that T cell and BMDC especially LC play work in the inflammation generation mechanism of psoriasis
With, and CCL20 and CCR6 promote T then possibly through the attraction to memory/effector T cell and immature dendritic cell
Cell and BMDC are in localized clusters, so as to participate in the generation of psoriasis, this point has been demonstrate,proved in testing in vitro
It is real（Uyemura K, Yamamura M, Fivenson D F, et al.The cytokine network in lesional
and lesion-free psoriatic skin is characterized by a T-helper type 1 cell-
mediated response.J Invest Dermatol,1993,101(5):701-705.Sehon M P.Animal
models of psoriasis-what can we learn from them?J Invest Dermatol,1999,112
(4):405-410.Homey B,Dieu-Nosjean M C,Wiesenborn A,et al.Up-regulation of
macrophage infl ammatory protein-3 alpha/CCL20 and CC chemokine receptor 6 in
Psoriasis.J Immunol, 2000,164 (12):6621-6632.）.Result of study shows, in normal human skin tissues and
There are the chemotactic factor (CF) and acceptor in CCL20 and CCR6 mRNA expression, Psoriasis in Psoriasis
MRNA expression is substantially increased compared with normal human skin tissues, and difference has conspicuousness (P<0.001).CCL20 by pro-inflammatory cells because
Sub- IL-1 β, IFN-γ, IL-17 etc. regulation and control, under the induction of these cell factors, CCL20 expression is substantially raised；CCL20
Promote memory/effector T cell and immature dendritic cell in localized clusters by CCR6, and memory/effector T cell is then
The main source cell of the cytokine profiles such as IL-1 β, IFN-γ, IL-17, and these cell factors are in the morbidity of psoriasis
In play certain effect（Chabaud M,Page G, Miossec P.Enhancing effect of IL-1,IL-
17,and TNF-alpha on macrophage inflammatory protein-3alpha production in
rheumatoid arthritis:regulation by soluble receptors and Th2 cytokines.J
Immunol,2001,167(10):6015-6020.Albanesi C,Scarponi C,Cavani A,et
al.Interleukin-17 is produeed by both Thl and Th2 lymphoeytes,and modulates
interferon-gamma- and interleukin-4-induced activation of human
keratinocytes.J Invest Dermatol,2000,115(1):81-87）.It is therefore contemplated that CCL20 and CCR6 and
These cell factors are mutually promoted, mutual induction, form vicious circle, the generation of psoriasis is take part in jointly.
Recent studies have shown that CCL20 is also relevant and CCL20 with the morbidity of rheumatoid arthritis and synovitis
Expression is also treated by anti-tumor necrosis factor to be influenceed.In fact, CCL20 level is bright in patient with rheumatoid arthritis synovia
It is aobvious higher than degenerative joint disease Human Osteoarthritis（Matsui T, Akahoshi T, Namai R, et
al.Selective recruitment of CCR6-expressing cells by increased production of
MIP-3 in rheumatoid arthritis.Clin Exp Immunol 2001;125:155-61）.Rheumatoid joint
Scorching synovial tissue is transplanted in vitro culture can discharge more CCL20 than Osteoarthritic Synovium tissue（Chabaud M,Page
G, Miossec P.Enhancing effect of IL-1, IL-17, and TNF-alpha on macrophage
inflammatory protein-3alpha production in rheumatoid arthritis:regulation by
soluble receptors and Th2 cytokines.J Immunol,2001,167(10):6015-6020）.In addition,
Give TNF in vitro, after the stimulation of interleukin 1 and Interleukin-17, separation synovia into fiber finer
CCL20 mRNA and protein expression is raised in born of the same parents and rheumatoid arthritis synovial（Chabaud M, Page G, Miossec
P.Enhancing effect of IL-1,IL-17,and TNF-alpha on macrophage inflammatory
protein-3alpha production in rheumatoid arthritis:regulation by soluble
receptors and Th2 cytokines.J Immunol,2001,167(10):6015-6020.Matsui T,
Akahoshi T,Namai R,et al.Selective recruitment of CCR6-expressing cells by
increased production of MIP-3 in rheumatoid arthritis.Clin Exp Immunol 2001;
125:(IL1) and of 155-61.Chevrel G, Garnero P, Miossec P.Addition ofinterleukin 1
IL17soluble receptors to a tumour necrosis factor α soluble receptor more
effectively reduces the production of IL6 and macrophage inhibitory protein-3
αand increases that of collagen in an in vitro model of rheumatoid
synoviocyte activation.Ann Rheum Dis 2002;61:730-3.）.CCL20 transcript is also in rheumatoid
It is detected in property arthritis synovial fluid cell（Matsui T,Akahoshi T,Namai R,et al.Selective
recruitment of CCR6-expressing cells by increased production of MIP-3 in
rheumatoid arthritis.Clin Exp Immunol 2001;125:155-61）.
Northern hybridization analysis shows, is organized compared to normal human pancreas, and CCL20 transcription is anxious in Pancreatic Adenocarcinoma
Play up-regulation（Kleeff J,Kusama T,Rossi DL,et al.Detection and localization of MIP-3α/
LARC/Exodus,a macrophage proinflammatory chemokine,and its CCR6 receptor in
human pancreatic cancer.Int J Cancer 1999;81:650-7）.In situ hybridization shows that glandular tube sample tumour is thin
Born of the same parents and tumor-associated macrophage are internal CCL20 mRNA sources.In addition, pancreatic carcinoma not only expresses turning for CCL20
Record thing also expresses its acceptor CCR6 transcript.In vitro, CCL20 stimulates the migration and growth of these cell lines（Kleeff J,
Kusama T,Rossi DL,et al.Detection and localization of MIP-3α/LARC/Exodus,a
macrophage proinflammatory chemokine,and its CCR6 receptor in human
pancreatic cancer.Int J Cancer 1999;81:650-7）.Therefore, CCL20 swells except that can collect effect/memory
, can also be by autocrine and paracrine mechanism come to pancreas outside knurl infiltrating lymphocytes prematurity dendritic cells related to tumour
Other aspects of gland oncobiology are acted, such as growth and invasion and attack of tumour cell.RT -PCR is analyzed
Show with immunohistochemical analysis in breast cancer sample tumour cell, CCL20 transcript and albumen are all high expression（Bell
D, Chomarat P, Broyles D, et al.In breast carcinoma tissue, immature dendritic
cells reside within the tumor,whereas mature dendritic cells are located in
peritumoral areas.J Exp Med 1999;190:1417-26.）.However, in normal galactophore epithelial cell not
CCL20 can be expressed and seldom there is BMDC.
Multiple sclerosis is a kind of inflammatory disorderses of generation in central nervous system, such as brain and spinal cord.Mankind's brain
The height expression of choroid epithelium cell CCL20, antigentic specificity CCR6+Th17 cells pass through with expressing on choroid epithelium cell
CCL20 interaction, hence into central nervous system, starts the generation of disease（Reboldi A,Coisne C,
Baumjohann D,Benvenuto F,Bottinelli D,Lira S,Uccelli A,Lanzavecchia A,
Engelhardt B,Sallusto F.C-C chemokine receptor 6-regulated entry of TH-
17cells into the CNS through the choroid plexus is required for the
initiation of EAE.Nat Immunol,2009,10:514–523.）.Liston A etc. are also considered as CCR6 gene knockouts
Afterwards, the state of an illness of multiple sclerosis can be alleviated（ListonA,Kohler RE,Townley S,Haylock-Jacobs S,
Comerford I,Caon AC,Webster J,Harrison JM,Swann J,Clark-Lewis I,Korner H,
McColl SR.Inhibition of CCR6 function reduces the severity of experimental
autoimmune encephalomyelitis via effects on the priming phase of the immune
response.J Immunol,2009,182:3121-3130.）.Therefore, generations of the CCL20/CCR6 in multiple sclerosis
Important function has been played in journey.
So, the fact that be related to many autoimmune diseases for CCR6 acceptors, develop effective CCR6 acceptors short of money
Anti-agent seems particularly significant.
The content of the invention
It is an object of the invention to provide a class 2,5- disubstituted benzenes sulfamide compound, its medicine as CCR6 antagonists
Acceptable salt, ester, prodrug or hydrate on.
It is a further object of the present invention to provide above-claimed cpd or its pharmaceutically acceptable salt, ester, prodrug or hydrate
Preparation method.
It is yet another object of the invention to provide a kind of one or more above-claimed cpds or its medicine comprising therapeutically effective amount
Acceptable salt on, ester, the pharmaceutical composition of prodrug or hydrate.
The a further object of the present invention is to provide such compound as the application of CCR6 antagonists, and it is preparing treatment
Application in the medicine of the CCR6 diseases mediated.
The first aspect of the present invention there is provided 2, the 5- disubstituted benzenes sulfamide compound shown in a kind of formula I or its
Pharmaceutically acceptable salt, ester, prodrug or hydrate,
In Formulas I,
A rings are 3-8 members cycloaliphatic ring, aliphatic heterocycle, aromatic ring or heteroaromatic, and described aliphatic heterocycle or heteroaromatic include 1-3
The individual hetero atom in N, O and S；
It is preferred thatFor
More preferablyFor
R2For H, C1-C6Alkyl, C1-C6Alkoxy, C1-C6Alkylamino radical, halogen, amino, nitro, hydroxyl, CN and CF3；It is preferred that
For H, C1-C4Alkyl or C1-C4Alkoxy；
R3For H, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C8Cycloalkyl, benzyl orPreferably H,
C1-C4Alkyl, C3-C6Cycloalkyl, benzyl or
R4For H, C that is unsubstituted or being replaced by 1-3 substituent5-C12Aryl or it is unsubstituted or by 1-3 substitution
Heteroatomic 5 to the 12 circle heterocycles base containing 1-2 in N, O and S of base substitution, described substituent is selected from following atom
Or group：C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Alkoxy, C1-C6Alkylamino radical, C3-C8Cycloalkyl, C5-C12Virtue
Base, C5-C12Heteroaryl, halogen, hydroxyl, amino, CF3, CN and NO2；It is preferably H, unsubstituted or replaced by 1-3 substituent
C5-C12Aryl or heteroatomic 5 arriving in N, O and S containing 1-2 that be unsubstituted or being replaced by 1-3 substituent
12 circle heterocycles bases, described substituent is selected from following atom or group：C1-C4Alkyl, C1-C4Alkoxy, C1-C4Alkylamino radical, C3-
C8Cycloalkyl, C5-C12It is aryl, unsubstituted or by C1-C3Alkyl-substituted C5-C12Heterocyclic radical, halogen, hydroxyl, amino, CF3With
NO2；
L is not present or is C1-C6Alkylidene, C1-C6Alkylenecarbonyl, it is preferable that L is not present or is C1-C3Alkylidene,
C1-C3Alkylenecarbonyl；
Or, when L is not present, five are formed together with the nitrogen-atoms that R3 and R4 can be adjacent with them and arrives heptatomic ring；
C described above5-C12Aryl can be more preferably phenyl or naphthyl；It is described individual in N, O and S containing 1-2
Heteroatomic 5 to 12 circle heterocycles base can be more preferably thiophene, furans, pyridine or piperazine group etc..
The halogen is fluorine, chlorine, bromine or iodine.
The present invention preferred embodiment in, compound of the present invention is preferably selected from following compounds：
N- benzyls -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxybenzenesulphoismides,
2- (3- ((the 1H)-base sulfonyl of 3,4- dihydro-isoquinoline -2) -4- methoxy-benzyls) isoindoline -1,3- diketone,
5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxyl groups-N- (1,2,3,4- naphthane -1- bases) benzene
Sulfonamide,
5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxyl group-N- phenethyl benzsulfamides,
5- ((1,3- dioxoisoindolin -2- bases) methyl)-N- (4- luorobenzyls) -2- methoxybenzenesulphoismides,
N- (3,4- dichloro benzyl) -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxybenzenesulphoismides,
N- (2,4- dichloro benzyl) -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxybenzenesulphoismides,
N- (3,5- bis- (trifluoromethyl) benzyl) -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxybenzenes
Sulfonamide,
5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxyl groups-N- (thiophene -2- ylmethyls) benzsulfamide,
5- ((1,3- dioxoisoindolin -2- bases) methyl)-N- (4- iodine benzyl) -2- methoxybenzenesulphoismides,
N- (2- chloro- 5- (trifluoromethyl) benzyl) -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxyl groups
Benzsulfamide,
5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxyl groups-N- (4- nitrobenzyls) benzsulfamide,
5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxyl groups-N- (4- (thiophene -2- bases) benzyl) benzene sulphur
Acid amides,
N- (4- chlorobenzyls) -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxybenzenesulphoismides,
5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxyl groups-N- (4- methyl-benzyls) benzsulfamide,
5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxyl groups-N- (4- (trifluoromethyl) benzyl) benzene sulfonyl
Amine,
N- (3,4- dimethyl benzyl) -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxybenzene sulphonyl
Amine,
N- (4- bromobenzyls) -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxybenzenesulphoismides,
N- benzyls -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxy-. N-methyl benzsulfamides,
N- benzyls -5- ((1,3- dioxoisoindolin -2- bases) methyl)-N- ethyl -2- methoxybenzenesulphoismides,
N- benzyls -5- ((1,3- dioxoisoindolin -2- bases) methyl)-N- isopropyl -2- methoxybenzenesulphoismides,
N- benzyl-N- butyl -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxybenzenesulphoismides,
N- benzyls -5- ((1,3- dioxoisoindolin -2- bases) methyl)-N- isobutyl group -2- methoxybenzenesulphoismides,
N- benzyls -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxyl group-N- propylbenzenesulfonamides,
N- benzyls -5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -2-
Methoxy-. N-methyl benzsulfamide,
N- benzyls -5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl)-N-
Isopropyl -2- methoxybenzenesulphoismides,
N- benzyls -5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl)-N-
Ethyl -2- methoxybenzenesulphoismides,
N- benzyl-N- butyl -5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2)
Methyl) -2- methoxybenzenesulphoismides,
N- benzyls -5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -2-
Methoxybenzenesulphoismide,
N- benzyls -5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl)-N-
Isobutyl group -2- methoxybenzenesulphoismides,
N- benzyls -5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -2-
Methoxyl group-N- propylbenzenesulfonamides,
2- (3- ((the 1H)-base sulfonyl of 3,4- dihydro-isoquinoline -2) -4- methoxy-benzyls) hexahydro -1H- iso-indoles -1,3
(2H)-diketone,
5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -2- methoxyl groups -
N- phenethyl benzsulfamides,
5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -2- methoxyl groups -
N- (1,2,3,4- naphthane -1- bases) benzsulfamide,
5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl)-N- (4- fluorine benzyls
Base) -2- methoxybenzenesulphoismides,
5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -2- methoxyl groups -
N- (thiophene -2- ylmethyls) benzsulfamide,
5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl)-N- (4- iodine benzyls
Base) -2- methoxybenzenesulphoismides,
N- (3,4- dichloro benzyl) -5- ((1,3- dioxo -1H- iso-indoles -2 (3H, 3aH, 4H, 5H, 6H, 7H, 7aH) -
Base) methyl) -2- methoxybenzenesulphoismides,
N- (3,5- bis- (trifluoromethyl) benzyl) -5- ((1,3- dioxo -1H- iso-indoles -2 (3H, 3aH, 4H, 5H, 6H,
7H, 7aH)-yl) methyl) -2- methoxybenzenesulphoismides,
N- (3,4- dichloro benzyl) -5- ((1,3- dioxo -1H- iso-indoles -2 (3H, 3aH, 4H, 5H, 6H, 7H, 7aH) -
Base) methyl) -2- methoxybenzenesulphoismides,
N- (4- chlorobenzyls) -5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) first
Base) -2- methoxybenzene cyclic amides,
5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -2- methoxyl groups -
N- (4- methyl-benzyls) benzsulfamide,
5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -2- methoxyl groups -
N- (4- nitrobenzyls) benzsulfamide,
N- (the chloro- 4- luorobenzyls of 3-) -5- ((1,3- dioxo -1H- iso-indoles -2 (3H, 3aH, 4H, 5H, 6H, 7H, 7aH) -
Base) methyl) -2- methoxybenzenesulphoismides,
5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -2- methoxyl groups -
N- (3- (trifluoromethyl) benzyl) benzsulfamide,
N- (2- chloro- 5- (trifluoromethyl) benzyl) -5- ((1,3- dioxo -1H- iso-indoles -2 (3H, 3aH, 4H, 5H, 6H,
7H, 7aH)-yl) methyl) -2- methoxybenzenesulphoismides,
5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -2- methoxyl groups -
N- (4- (trifluoromethyl) benzyl) benzsulfamide,
N- (3,4- dimethyl benzyl) -5- ((1,3- dioxo -1H- iso-indoles -2 (3H, 3aH, 4H, 5H, 6H, 7H,
7aH)-yl) methyl) -2- methoxybenzenesulphoismides,
N- (4- bromobenzyls) -5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) first
Base) -2- methoxybenzenesulphoismides,
5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -2- methoxyl groups -
N- (4- (thiophene -2- bases) benzyl) benzsulfamide,
N- (4- chlorobenzyls) -5- ((2,5- dioxotetrahydro pyrroles -1- bases) methyl) -2- methoxybenzenesulphoismides,
N- (4- chlorobenzyls) -5- ((2,5- dioxo -2,5- dihydro -1H- pyrroles -1- bases) methyl) -2- methoxybenzene sulphurs
Acid amides,
N- (3- (N- (4- chlorobenzyls) sulfonamides) -4- methoxy-benzyls) Cyclohexamide,
N- (3- (N- (4- chlorobenzyls) sulfonamides) -4- methoxy-benzyls) ring pentanamide,
N- (4- chlorobenzyls) -5- ((dimethylamino) methyl) -2- methoxybenzenesulphoismides,
N- ((S) -1- (4- chlorphenyls) ethyl) -5- ((1,3- dioxo -1H- iso-indoles -2 (3H, 3aH, 4H, 5H, 6H,
7H, 7aH)-yl) methyl) -2- methoxybenzenesulphoismides,
N- ((R) -1- (4- chlorphenyls) ethyl) -5- ((1,3- dioxo -1H- iso-indoles -2 (3H, 3aH, 4H, 5H, 6H,
7H, 7aH)-yl) methyl) -2- methoxybenzenesulphoismides,
5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -2- methoxyl groups -
N- (4- (4- methylpiperazine-1-yls) benzyl) benzsulfamide,
5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -2- methoxyl groups -
N- (naphthalene -1- ylmethyls) benzsulfamide,
N, N- dibenzyl -5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) first
Base) -2- methoxybenzenesulphoismides,
N- (4- aminobenzyls) -5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2)
Methyl) -2- methoxybenzenesulphoismides,
5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -2- methoxyl groups
Benzsulfamide,
The chloro- N- of 4- (5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -
2- MethOxybenzenesulfonyls) benzamide.
In the second aspect of the present invention there is provided the preparation method of compound of the present invention, this method can use following institute
Show prepared by flow：
Generalized flowsheet
Wherein, A rings, R2、R4It is defined as described above with L, R3It is defined as described above in addition to for H；
Step a)：By phthalic anhydride andBackflow obtains compound II in acetic acid；
Step b)：Compound II is obtained into compound III under chlorosulfonic acid effect；Specifically, the reaction is in room temperature, stirring
Under the conditions of carry out；
Step c)：By compound III and amineIt is condensed to yield compound IV；Specifically, in the reaction, in alkali
Property under the conditions of carry out（Alkali is such as made with triethylamine）, and solvent is made with dichloromethane；
Step d)：By compound IV and iodo thing R3- I carries out alkyl under the effect of sodium hydrogen in DMF
Change obtains compound V；
Step e)：By compound V, deprotection obtains compound VI under hydrazine hydrate effect；Specifically, in the reaction, with
Ethanol as solvent, is reacted under reflux；
Step f)：By compound VI in acetic acid withEffect obtains compound shown in Formulas I；Specifically, this is anti-
It should carry out under reflux.
In the third aspect of the present invention there is provided a kind of pharmaceutical composition, it includes the one or more of therapeutically effective amount
Compound shown in formula I or its pharmaceutically acceptable salt, ester, prodrug and/or its hydrate, and can further include and pharmaceutically may be used
The carrier of receiving.The pharmaceutically acceptable carrier includes cyclodextrin, Arabic gum, aspartame, the third two without limitation
Alcohol dilaurate, poloxamer, microcrystalline cellulose, starch, polysorbate, carbomer, lactose, hydroxypropylcellulose etc..
The fourth aspect of the present invention there is provided compound shown in a kind of formula I or pharmaceutically acceptable salt,
Ester, prodrug and/or its hydrate as CCR6 antagonist application, and its prepare treatment by the CCR6 diseases mediated
Application in medicine.Specifically, the disease mediated by CCR6 is immune correlated disease（For example, autoimmune disease,
Such as rheumatoid arthritis）, inflammation（Such as colitis, pancreatitis, gastritis）, psoriasis, multiple sclerosis or cancer（Such as,
Colon cancer, liver cancer, cancer of pancreas etc.）.
Embodiment
With reference to specific embodiment, the invention will be further described.It should be understood that these embodiments are merely to illustrate this
Invent and do not limit the scope of the invention.
Agents useful for same is purchased from：Chemical Reagent Co., Ltd., Sinopharm Group, Adama this limited public affairs of beta Solution on Chemical Reagents in Shanghai
Department, Alfa Aesar Tianjin Chemical Co., Ltd., lark waffle Science and Technology Ltd..
Prepare embodiment
Embodiment 1
Compound 1：N- benzyls -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxybenzenesulphoismides
Step a：2- (4- methoxybenzyls) isoindoline -1,3- diketone
Under stirring, (4- methoxybenzenes are added into phthalic anhydride (2.96g, 20mmol) acetic acid (30ml) solution
Base) methylamine (2.62ml, 20mmol), mixture return stirring 18 hours.It is evaporated off solvent, residue dchloromethane, according to
Secondary to be washed with 1M hydrochloric acid, saturated sodium bicarbonate solution and saturated common salt, anhydrous sodium sulfate drying, filtering and concentrating, residue is direct
For next step reaction (faint yellow solid, 5.24g, yield 98%).
Step b：5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxybenzene -1- sulfonic acid chlorides
In the case where 0 DEG C is stirred, 2- (4- methoxy-benzyls) isoindoline -1,3- diketone is added portionwise into chlorosulfonic acid (30ml)
(5.45g,20.4mmol).Finish, mixture is stirred for 2 hours at room temperature, then, reaction solution is poured into mixture of ice and water,
Extracted three times with ethyl acetate, merge organic phase.Organic phase washed with water and saturated common salt washing, anhydrous sodium sulfate drying, mistake
Filter concentration, residue (brown solid, 6.7g, yield 90%) is directly used in next step reaction.
Step c：N- benzyls -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxybenzenesulphoismides
Under stirring, to 5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxybenzene -1- sulfonic acid chlorides (1.75g,
4.79mmol, 1eq) dichloromethane (10ml) solution in add triethylamine (1.33ml, 9.58mmol, 2eq) and benzylamine
(785ul, 7.19mmol, 1.5eq), mixture is stirred at room temperature 2 hours.Solvent is evaporated off, residue column chromatography obtains title
Compound, is white solid (yield 81%).
1H-NMR(CDCl3):δ7.94(s,1H),7.87-7.84(m,2H),7.74-7.71(m,2H),7.56(d,1H,J
=8.4Hz), 7.14-7.07 (m, 5H), 6.83 (d, 1H, J=8.7Hz), 5.22 (t, 1H, J=6.3Hz), 4.81 (s, 2H),
4.07 (d, 2H, J=6.6Hz), 3.79 (s, 3H) EI-MS:436(M+).
Embodiment 2
Compound 2：2- (3- (3,4- dihydro-isoquinolines -2 (1H)-base sulfonyl) -4- methoxy-benzyls) isoindoline -1,
3- diketone
Course of reaction is same as Example 1, replaces benzylamine with 1,2,3,4- tetrahydroisoquinoline only in step c, obtains white
Color solid (yield 61%).
1H-NMR(CDCl3):δ8.04(d,1H,J=2.1Hz),7.87-7.84(m,2H),7.74-7.71(m,2H),7.56
(dd,1H,J1=8.4Hz,J2=2.1Hz),7.14-7.11(m,2H),7.05-7.03(m,2H),6.86(d,1H,J=8.7Hz),
4.83(s,2H),4.52(s,2H),3.66(s,3H),3.59(t,2H,J=6.0Hz),2.74(t,2H,J=6.0Hz);EI-MS:
462(M+).
Embodiment 3
Compound 3：
5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxyl groups-N- (1,2,3,4- naphthane -1- bases) benzene
Sulfonamide
Course of reaction is same as Example 1, replaces benzylamine with 1,2,3,4- naphthane -1- amine only in step c, obtains white
Color jelly (yield 94%).
1H-NMR(CDCl3):δ8.03(d,1H,J=2.4Hz),7.83-7.80(m,2H),7.71-7.68(m,2H),7.63
(dd,1H,J1=8.7Hz,J2=1.8Hz),7.11-6.91(m,5H),5.15(d,1H,J=7.2Hz),4.82(s,2H),4.39
(m,1H),3.83(s,3H),2.81-2.57(m,2H),1.94-1.62(m,4H);EI-MS:476(M+).
Embodiment 4
Compound 4：5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxyl group-N- phenethyl benzsulfamides
Course of reaction is same as Example 1, only replaces benzylamine in step c with 2- phenyl ethylamines, obtains white size foam-like
Solid (yield 87%).
1H-NMR(CDCl3):δ7.93(d,1H,J=2.1Hz),7.84-7.82(m,2H),7.72-7.69(m,2H),7.58
(dd,1H,J1=8.7Hz,J2=2.1Hz),7.26-7.19(m,3H),7.05(d,2H,J=6.6Hz),6.86(d,2H,J=
8.4Hz),4.89(t,1H,J=6.0Hz),4.81(s,2H),3.61(s,3H),3.12(q,2H,J=6.6Hz),2.76(t,2H,
J=6.6Hz);EI-MS:450(M+).
Embodiment 5
Compound 5：5- ((1,3- dioxoisoindolin -2- bases) methyl)-N- (4- luorobenzyls) -2- methoxybenzene sulphonyl
Amine
Course of reaction is same as Example 1, only replaces benzylamine in step c with 4- fluorin benzyl amines, obtains white powder and consolidates
Body (yield 67%).
1H-NMR(CDCl3):δ7.93(s,1H),7.88-7.85(m,2H),7.74-7.72(m,2H),7.58(d,1H,J=
7.2Hz),7.10-7.06(m,2H),6.84(t,3H,J=8.7Hz),5.18(t,1H,J=6.3Hz),4.82(s,2H),4.06
(d,2H,J=6.6Hz),3.83(s,3H);EI-MS:454(M+).
Embodiment 6
Compound 6：N- (3,4- dichloro benzyls) -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxybenzenes
Sulfonamide
Course of reaction is same as Example 1, only replaces benzylamine with 3,4- dichloro-benzylamines in step c, obtains white solid
(yield 64%).
1H-NMR(CDCl3):δ7.89-7.84(m,3H),7.73-7.70(m,2H),7.58(dd,1H,J1=8.7Hz,J2=
2.4Hz),7.20-7.15(m,2H),6.97(dd,1H,J1=8.1Hz,J2=1.8Hz),6.85(d,1H,J=8.4Hz),5.41
(t,1H,J=6.9Hz),4.80(s,2H),4.06(d,2H,J=6.9Hz),3.85(s,3H);EI-MS:504(M+).
Embodiment 7
Compound 7：N- (2,4- dichloro benzyl) -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxybenzenes
Sulfonamide
Course of reaction is same as Example 1, only replaces benzylamine with 2,4- dichloro-benzylamines in step c, obtains colorless gum
Thing (yield 25%).
1H-NMR(CDCl3):δ7.88-7.86(m,2H),7.77-7.72(m,3H),7.48(dd,1H,J1=8.4Hz,J2=
1.8Hz),7.13(s,1H),6.96(d,1H,J=8.4Hz),6.82(d,1H,J=8.4Hz),6.69(d,1H,J=8.7Hz),
5.63(t,1H,J=6.6Hz),4.77(s 2H),4.23(d,2H,J=6.6Hz),3.79(s,3H);EI-MS:504(M+).
Embodiment 8
Compound 8：N- (3,5- bis- (trifluoromethyl) benzyl) -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2-
Methoxybenzenesulphoismide
Course of reaction is same as Example 1, replaces benzylamine with the trifluoromethyl benzylamines of 3,5- bis- only in step c, obtains nothing
Color jelly (yield 88%).
1H-NMR(CDCl3):δ7.92-7.55(m,9H),6.88-6.83(m,1H),5.93(t,1H,J=6.6Hz),4.77
(s,2H),4.25(d,2H,J=6.6Hz),3.83(s,3H);EI-MS:572(M+).
Embodiment 9
Compound 9：5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxyl groups-N- (thiophene -2- ylmethyls)
Benzsulfamide
Course of reaction is same as Example 1, replaces benzylamine with thiophene -2- methylamines only in step c, obtains white foam
Solid (yield 97%).
1H-NMR(CDCl3):δ7.91(d,1H,J=2.4Hz),7.86-7.81(m,2H),7.74-7.69(m,2H),7.55
(dd,1H,J1=8.7Hz,J2=1.8Hz),7.04-7.02(m,1H),6.85(d,1H,J=8.4Hz),6.68-6.66(m,2H),
5.33(t,1H,J=6.0Hz),4.80(s,2H),4.28(d,2H,J=6.3Hz),3.81(s,3H);EI-MS:442(M+).
Embodiment 10
Compound 10：5- ((1,3- dioxoisoindolin -2- bases) methyl)-N- (4- iodine benzyl) -2- methoxybenzene sulphurs
Acid amides
Course of reaction is same as Example 1, and benzylamine is replaced with 4- iodine benzylamines only in step c, obtains white powder and consolidates
Body (yield 33%).
1H-NMR(CDCl3):δ7.93-7.86(m,3H),7.76-7.73(m,2H),7.58(d,1H,J=8.4Hz),7.47
(d,2H,J=7.5Hz),6.90-6.83(m,3H),5.23(t,1H,J=6.6Hz),4.81(s,2H),4.03(d,2H,J=
6.3Hz),3.83(s,3H);EI-MS:562(M+).
Embodiment 11
Compound 11：N- (2- chloro- 5- (trifluoromethyl) benzyl) -5- ((1,3- dioxoisoindolin -2- bases) methyl) -
2- methoxybenzenesulphoismides
Course of reaction is same as Example 1, replaces benzylamine with the chloro- 5- trifluoromethyl benzylamines of 2- only in step c, obtains light
Yellow solid (yield 99%).
1H-NMR(CDCl3):δ7.88(s,1H),7.86-7.83(m,2H),7.73-7.70(m,2H),7.50-7.45(m,
2H),7.34(s,1H),7.30(s,1H),6.66(d,1H,J=8.4Hz),5.66(t,1H,J=6.6Hz),4.76(s,2H),
4.33(d,2H,J=6.9Hz),3.76(s,3H);EI-MS:538(M+).
Embodiment 12
Compound 12：5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxyl groups-N- (4- nitrobenzyls) benzene
Sulfonamide
Course of reaction is same as Example 1, only replaces benzylamine with 4- nitro-benzylamines in step c, obtains faint yellow solid
(yield 95%).
1H-NMR(CDCl3):δ8.04(d,2H,J=8.1Hz),7.92-7.86(m,3H),7.75(brs,2H),7.58(d,
1H,J=8.4Hz),7.36(d,2H,J=7.8Hz),6.89(d,1H,J=8.4Hz),5.47(t,1H,J=6.3Hz),4.81(s,
2H),4.21(d,2H,J=6.3Hz),3.88(s,3H);EI-MS:481(M+).
Embodiment 13
Compound 13：5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxyl groups-N- (4- (thiophene -2- bases)
Benzyl) benzsulfamide
Course of reaction is same as Example 1, replaces benzylamine with (4- (thiophene -2- bases) phenyl) methylamine only in step c, obtains
To white gum thing (yield 66%).
1H-NMR(CDCl3):δ7.93(d,1H,J=2.1Hz),7.86-7.83(m,2H),7.72-7.69(m,2H),7.52
(dd,1H,J1=5.4Hz,J2=3.3Hz),7.33(d,2H,J=7.8Hz),7.22(d,1H,J=5.1Hz),7.16(d,1H,J=
3.3Hz),7.08-7.01(m,3H),6.78(d,1H,J=8.4Hz),5.34(t,1H,J=6.3Hz),4.79(s,2H),4.08
(d,2H,J=6.0Hz),3.78(s,3H);EI-MS:518(M+).
Embodiment 14
Compound 14：N- (4- chlorobenzyls) -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxybenzene sulphurs
Acid amides
Course of reaction is same as Example 1, only replaces benzylamine in step c with 4- chlorobenzylamines, obtains white solid (yield
32%)。
1H-NMR(CDCl3):δ7.91(d,1H,J=2.4Hz),7.88-7.85(m,2H),7.74-7.71(m,2H),7.58
(dd,1H,J1=8.4Hz,J2=2.1Hz),7.13(d,2H,J=8.4Hz),7.05(d,1H,J=8.7Hz),6.86(d,1H,J=
8.4Hz),5.20(t,1H,J=6.3Hz),4.82(s,2H),4.06(d,2H,J=6.6Hz),3.83(s,3H);EI-MS:470
(M+).
Embodiment 15
Compound 15：5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxyl groups-N- (4- methyl-benzyls) benzene
Sulfonamide
Course of reaction is same as Example 1, only replaces benzylamine with 4- methylbenzylamines in step c, obtains white powder
Solid (yield 86%).
Embodiment 16
Compound 16：5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxyl groups-N- (4- (trifluoromethyl) benzyls
Base) benzsulfamide
Course of reaction is same as Example 1, only replaces benzylamine in step c with 4- trifluoromethyl benzylamines, obtains white solid
Body (yield 99%).
1H-NMR(CDCl3):δ7.89(d,1H,J=2.1Hz),7.86-7.83(m,2H),7.73-7.70(m,2H),7.71
(dd,1H,J1=8.7Hz,J2=2.1Hz),7.36(d,2H,J=7.8Hz),7.26-7.22(m,2H),6.80(d,1H,J=
8.4Hz),5.54(t,1H,J=6.9Hz),4.78(s,2H),4.14(d,2H,J=6.6Hz),3.80(s,3H);EI-MS:504
(M+).
Embodiment 17
Compound 17：N- (3,4- dimethyl benzyl) -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxies
Base benzsulfamide
Course of reaction is same as Example 1, only replaces benzylamine in step c with 3,4- dimethyl benzylamines, obtains white bubble
Foam shape solid (yield 99%).
1H-NMR(CDCl3):δ7.94(s,1H),7.83-7.80(m,2H),7.71-7.68(m,2H),7.56(d,1H,J=
8.1Hz),6.89-6.78(m,4H),5.28(t,1H,J=6.0Hz),4.79(s,2H),3.98(d,2H,J=6.0Hz),3.78
(s,3H),2.11(s,3H),2.08(s,3H);EI-MS:464(M+).
Embodiment 18
Compound 18：N- (4- bromobenzyls) -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxybenzene sulphurs
Acid amides
Course of reaction is same as Example 1, only replaces benzylamine in step c with 4- bretylium tosylates, obtains white powder and consolidates
Body (yield 97%).
1H-NMR(CDCl3):δ7.83-7.80(m,3H),7.70-7.67(m,2H),7.52(d,1H,J=8.4Hz),7.21
(d,2H,J=7.8Hz),6.96(d,2H,J=8.1Hz),6.80(d,1H,J=8.7Hz),5.57(t,1H,J=6.3Hz),4.75
(s,2H),3.99(d,2H,J=6.9Hz),3.78(s,3H);EI-MS:514(M+).
Embodiment 19
Compound 19：N- benzyls -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxy-. N-methyl benzene sulphurs
Acid amides
Under stirring, to N- benzyls -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxybenzenes of embodiment 1
In DMF (2ml) solution of sulfonamide (107mg, 0.24mmol, 1eq) add sodium hydride (15mg,
0.36mmol, 1.5eq), mixture is stirred at room temperature 0.5 hour.Then, add iodomethane (19ul, 0.29mmol,
1.2eq), mixture is stirred at room temperature overnight.Solvent evaporated, residue is diluted with dichloromethane and water, the anhydrous sulphur of organic phase
Sour sodium is dried, and filtering and concentrating, residue column chromatography obtains title compound, is white solid (yield 80%).
1H-NMR(CDCl3):δ 8.01 (d, 1H, J=1.5Hz), 7.86-7.84 (m, 2H), 7.73-7.70 (m, 2H),
7.60(dd,1H,J1=8.7Hz,J2=1.8Hz), 7.29-7.26 (m, 5H), 6.96 (d, 1H, J=8.7Hz), 4.83 (s, 2H),
4.33(s,2H),3.90(s,3H),2.71(s,3H);EI-MS:450(M+).
Embodiment 20
Compound 20：N- benzyls -5- ((1,3- dioxoisoindolin -2- bases) methyl)-N- ethyl -2- methoxybenzene sulphurs
Acid amides
Course of reaction be the same as Example 19, only replaces iodomethane with iodoethane, obtains white solid (yield 78%).
1H-NMR(CDCl3):δ8.00(s,1H),7.83-7.80(m,2H),7.71-7.67(m,2H),7.56(d,1H,J
=8.7Hz), 7.25-7.21 (m, 5H), 6.93 (d, 1H, J=8.7Hz), 4.80 (s, 2H), 4.46 (s, 2H), 3.86 (s,
3H), 3.23 (q, 2H, J=6.9Hz), 0.88 (t, 3H, J=6.9Hz);EI-MS:464(M+).
Embodiment 21
Compound 21：N- benzyls -5- ((1,3- dioxoisoindolin -2- bases) methyl)-N- isopropyl -2- methoxybenzenes
Sulfonamide
Course of reaction be the same as Example 19, only replaces iodomethane with Iso-Propyl iodide, obtains white solid (yield 58%).
1H-NMR(CDCl3):δ 7.94 (d, 1H, J=2.1Hz), 7.87-7.84 (m, 2H), 7.74-7.71 (m, 2H),
7.56(dd,1H,J1=8.7Hz, J2=1.8Hz), 7.40-7.16 (m, 5H), 6.93 (d, 1H, J=8.4Hz), 4.79 (s, 2H),
4.50(s,2H),4.11(m,1H),3.93(s,3H),0.96(d,6H,J=6.9Hz);EI-MS:478(M+).
Embodiment 22
Compound 22：N- benzyl-N- butyl -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxybenzene sulphurs
Acid amides
Course of reaction be the same as Example 19, only replaces iodomethane with iodo-n-butane, obtains white solid (yield 72%).
1H-NMR(CDCl3):δ8.00(d,1H,J=1.8Hz),7.83-7.80(m,2H),7.70-7.68(m,2H),7.57
(dd,1H,J1=8.7Hz,J2=2.1Hz),7.22(brs,5H),6.92(d,1H,J=8.4Hz),4.80(s,2H),4.45(s,
2H),3.85(s,3H),3.14(t,2H,J=7.8Hz),1.31-1.21(m,2H),1.12-1.00(m,2H),0.66(t,3H,J
=7.2Hz);EI-MS:492(M+).
Embodiment 23
Compound 23：N- benzyls -5- ((1,3- dioxoisoindolin -2- bases) methyl)-N- isobutyl group -2- methoxybenzenes
Sulfonamide
Course of reaction be the same as Example 19, only replaces iodomethane with iodo isobutane, obtains colorless gum (yield 33%).
1H-NMR(CDCl3):δ8.02(s,1H),7.86-7.83(m,2H),7.73-7.70(m,2H),7.58(d,1H,J
=8.4Hz), 7.21-7.17 (m, 5H), 6.91 (d, 1H, J=8.7Hz), 4.82 (s, 2H), 4.44 (s, 2H), 3.84 (s, 3H),
3.00(d,2H,J=7.8Hz),1.68(m,1H),0.71(d,6H,J=6.6Hz);EI-MS:492(M+).
Embodiment 24
Compound 24：N- benzyls -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxyl group-N- propylbenzene sulphurs
Acid amides
Course of reaction be the same as Example 19, only replaces iodomethane with propyl iodide, obtains white powdery solids (yield
77%)。
1H-NMR(CDCl3):δ7.90(d,1H,J=1.5Hz),7.51(d,1H,J=8.7Hz),7.30-7.22(m,5H),
6.92(d,1H,J=8.7Hz),4.60(s,2H),4.44(s,2H),3.86(s,3H),3.14(t,2H,J=7.8Hz),2.85
(t,2H,J=4.2Hz),1.84-1.65(m,4H),1.44-1.23(m,6H),1.15-1.03(m,2H),0.71(t,3H,J=
7.2Hz);EI-MS:478(M+).
Embodiment 25
Compound 25：N- benzyls -5- ((1,3- dioxo -1H- iso-indoles -2 (3H, 3aH, 4H, 5H, 6H, 7H, 7aH) -
Base) methyl) -2- methoxy-. N-methyl benzsulfamides
By N- benzyls -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxy-. N-methyls of embodiment 19
Benzsulfamide (35mg, 0.077mmol, 1eq) is dissolved in ethanol (2ml), adds hydrazine hydrate (50ul, 0.62mmol, 8eq), mixing
Thing return stirring reacts 2 hours, lets cool, and filters, filtrate concentration, the amine that residue column chromatography is deprotected.This is deprotected
Amine (16mg, 0.05mmol, 1eq) is dissolved in acetic acid (5ml), adds cyclohexyldicarboxylic acids acid anhydride (8mg, 0.05mmol, 1eq), mixing
The reaction of thing return stirring is stayed overnight.Solvent is evaporated off, residue column chromatography obtains title compound, is white oil thing (yield 77%).
1H-NMR(CDCl3):δ7.90(d,1H,J=2.1Hz),7.53(dd,1H,J1=8.4Hz,J2=2.4Hz),7.31-
7.26(m,5H),6.96(d,1H,J=8.4Hz),4.62(s,2H),4.32(s,2H),3.90(s,3H),2.86(t,2H,J=
4.2Hz),2.70(s,3H),1.84-1.67(m,4H),1.47-1.31(m,4H);EI-MS:456(M+);HRMS(EI):
C24H28N2O5S(M)+:Calculated value：456.1719;Measured value：456.1723.
Embodiment 26
Compound 26：N- benzyls -5- ((1,3- dioxo -1H- iso-indoles -2 (3H, 3aH, 4H, 5H, 6H, 7H, 7aH) -
Base) methyl)-N- isopropyl -2- methoxybenzenesulphoismides
Course of reaction be the same as Example 25, only replaces with initiation material N- benzyls -5- ((1, the 3- dioxos of embodiment 21
Isoindoline -2- bases) methyl)-N- isopropyl -2- methoxybenzenesulphoismides, obtain colorless gum (yield 67%).
1H-NMR(CDCl3):δ7.85(s,1H),7.48(d,1H,J=8.7Hz),7.39(d,2H,J=7.5Hz),7.30-
7.20(m,3H),6.92(d,1H,J=8.4Hz),4.58(s,2H),4.50(s,2H),4.15-4.03(m,1H),3.92(s,
3H),2.86(brs,2H),1.84-1.66(m,4H),1.46-1.32(m,4H),0.93(d,6H,J=6.9Hz);EI-MS:484
(M+);HRMS(EI):C26H32N2O5S(M)+:Calculated value：484.2032;Measured value：484.2039.
Embodiment 27
Compound 27：N- benzyls -5- ((1,3- dioxo -1H- iso-indoles -2 (3H, 3aH, 4H, 5H, 6H, 7H, 7aH) -
Base) methyl)-N- ethyl -2- methoxybenzenesulphoismides
Course of reaction be the same as Example 25, only replaces with initiation material N- benzyls -5- ((1, the 3- dioxos of embodiment 20
Isoindoline -2- bases) methyl)-N- ethyl -2- methoxybenzenesulphoismides, obtain colorless gum (yield 66%).
1H-NMR(CDCl3):δ7.90(d,1H,J=1.2Hz),7.50(d,1H,J=9.0Hz),7.25(brs,5H),6.92
(d,1H,J=8.7Hz),4.60(s,2H),4.46(s,2H),3.87(s,3H),3.22(q,2H,J=7.2Hz),2.85(t,2H,
J=4.2Hz),1.81-1.64(m,4H),1.44-1.21(m,4H),0.88(t,3H,J=7.2Hz);EI-MS:470(M+);
HRMS(EI):C25H30N2O5S(M)+:Calculated value：470.1875;Measured value：470.1874.
Embodiment 28
Compound 28：N- benzyl-N- butyl -5- ((1,3- dioxo -1H- iso-indoles -2 (3H, 3aH, 4H, 5H, 6H, 7H,
7aH)-yl) methyl) -2- methoxybenzenesulphoismides
Course of reaction be the same as Example 25, only replaces with initiation material the N- benzyl-N- butyl -5- ((1,3- of embodiment 22
Dioxoisoindolin -2- bases) methyl) -2- methoxybenzenesulphoismides, obtain colorless gum (yield 74%).
1H-NMR(CDCl3):δ7.90(d,1H,J=1.5Hz),7.51(d,1H,J=8.7Hz),7.30-7.22(m,5H),
6.92(d,1H,J=8.7Hz),4.60(s,2H),4.44(s,2H),3.86(s,3H),3.14(t,2H,J=7.8Hz),2.85
(t,2H,J=4.2Hz),1.84-1.65(m,4H),1.44-1.23(m,6H),1.15-1.03(m,2H),0.71(t,3H,J=
7.2Hz);EI-MS:498(M+);HRMS(EI):C27H34N2O5S(M)+:Calculated value：498.2188;Measured value：498.2190.
Embodiment 29
Compound 29：N- benzyls -5- ((1,3- dioxo -1H- iso-indoles -2 (3H, 3aH, 4H, 5H, 6H, 7H, 7aH) -
Base) methyl) -2- methoxybenzenesulphoismides
Course of reaction be the same as Example 25, only by N- benzyls -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- first
Epoxide benzsulfamide replaces with N- benzyls -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxyl groups of embodiment 1
Benzsulfamide, obtains colorless gum (yield 70%).
1H-NMR(CDCl3):δ7.85(d,1H,J=1.8Hz),7.49(dd,1H,J1=8.4Hz,J2=2.4Hz),7.20-
7.18(m,3H),7.10-7.07(m,2H),6.83(d,1H,J=9.0Hz),5.19(t,1H,J=6.0Hz),4.61(s,2H),
4.05(d,2H,J=6.3Hz),3.78(s,3H),2.87(t,2H,J=4.2Hz),1.91-1.63(m,4H),1.50-1.34(m,
4H);EI-MS:442(M+);HRMS(EI):C23H26N2O5S(M)+:Calculated value：442.1562;Measured value：442.1556.
Embodiment 30
Compound 30：N- benzyls -5- ((1,3- dioxo -1H- iso-indoles -2 (3H, 3aH, 4H, 5H, 6H, 7H, 7aH) -
Base) methyl)-N- isobutyl group -2- methoxybenzenesulphoismides
Course of reaction be the same as Example 25, only by N- benzyls -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- first
Epoxide benzsulfamide replaces with N- benzyls -5- ((1,3- dioxoisoindolin -2- bases) methyl)-N- isobutyls of embodiment 23
Base -2- methoxybenzenesulphoismides, obtain colorless gum (yield 82%).
1H-NMR(CDCl3):δ7.91(d,1H,J=1.8Hz),7.50(dd,1H,J1=8.4Hz,J2=2.1Hz),7.17-
7.14(m,2H),7.10-7.07(m,2H),6.90(d,1H,J=8.4Hz),4.61(s,2H),4.43(s,2H),3.83(s,
3H),2.96(d,2H,J=7.8Hz),2.85(t,2H,J=4.2Hz),1.84-1.60(m,4H),1.49-1.25(m,4H),
0.70(d,6H,J=6.6Hz);EI-MS:498(M+);HRMS(EI):C27H34N2O5S(M)+:Calculated value：498.2188;Actual measurement
Value：498.2188.
Embodiment 31
Compound 31：N- benzyls -5- ((1,3- dioxo -1H- iso-indoles -2 (3H, 3aH, 4H, 5H, 6H, 7H, 7aH) -
Base) methyl) -2- methoxyl group-N- propylbenzenesulfonamides
Course of reaction be the same as Example 25, only by initiation material N- benzyls -5- ((1,3- dioxoisoindolin -2- bases) first
Base)-2- methoxybenzenesulphoismides replace with the N- benzyls-5- ((1,3- dioxoisoindolin-2- bases) methyl) of embodiment 24-
2- methoxyl group-N- propylbenzenesulfonamides, obtain colorless gum (yield 84%).
1H-NMR(CDCl3):δ8.40(d,1H,J=1.5Hz),8.00(dd,1H,J1=8.7Hz,J2=1.5Hz),7.78-
7.72(m,5H),7.41(d,2H,J=8.7Hz),5.10(s,2H),4.94(s,2H),4.36(s,3H),3.60(t,2H,J=
7.8Hz),3.33(brs,2H),2.32-2.19(m,4H),1.94-1.74(m,6H),1.16(t,3H,J=7.2Hz);EI-MS:
484(M+);HRMS(EI):C26H32N2O5S(M)+:Calculated value：484.2032;Measured value：484.2034.
Embodiment 32
Compound 32：2- (3- ((the 1H)-base sulfonyl of 3,4- dihydro-isoquinoline -2) -4- methoxy-benzyls) hexahydro -1H- is different
Indoles -1,3 (2H)-diketone
Course of reaction be the same as Example 25, only by initiation material N- benzyls -5- ((1,3- dioxoisoindolin -2- bases) first
Base) -2- methoxybenzenesulphoismides replace with 2- (3- (3,4- dihydro-isoquinolines -2 (1H)-base sulfonyl) -4- first of embodiment 2
Oxy-benzyl) isoindoline -1,3- diketone, obtain yellow oil (yield 83%).
1H-NMR(CDCl3):δ7.92(d,1H,J=2.1Hz),7.48(dd,1H,J1=8.7Hz,J2=1.8Hz),7.17-
7.08(m,2H),7.05-7.02(m,2H),6.84(d,1H,J=8.7Hz),4.61(s,2H),4.50(s,2H),3.66(s,
3H),3.57(t,2H,J=5.7Hz),2.87(t,2H,J=4.2Hz),2.72(t,2H,J=5.7Hz),1.87-1.63(m,4H),
1.50-1.32(m,4H);EI-MS:468(M+);HRMS(EI):Calculated value：C25H28N2O5S(M)+:468.1719;Measured value：
468.1723.
Embodiment 33
Compound 33：5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -
2- methoxyl group-N- phenethyl benzsulfamides
Course of reaction be the same as Example 25, only by initiation material N- benzyls -5- ((1,3- dioxoisoindolin -2- bases) first
Base) -2- methoxybenzenesulphoismides replace with 5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxies of embodiment 4
Base-N- phenethyl benzsulfamides, obtain colorless gum (yield 91%).
1H-NMR(CDCl3):δ7.83(s,1H),7.51(d,1H,J=8.7Hz),7.28-7.18(m,3H),7.06(d,
2H,J=7.5Hz),6.85(d,1H,J=8.4Hz),4.85(t,1H,J=5.7Hz),4.60(s,2H),3.61(s,3H),3.10
(q,2H,J=6.3Hz),2.86(brs,2H),2.75(t,2H,J=6.3Hz),1.83-1.66(m,4H),1.45-1.31(m,
4H);EI-MS:456(M+);HRMS(EI):C24H28N2O5S(M)+:Calculated value：456.1719;Measured value：456.1717.
Embodiment 34
Compound 34：5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -
2- methoxyl groups-N- (1,2,3,4- naphthane -1- bases) benzsulfamide
Course of reaction be the same as Example 25, only by initiation material N- benzyls -5- ((1,3- dioxoisoindolin -2- bases) first
Base) -2- methoxybenzenesulphoismides replace with 5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxies of embodiment 3
Base-N- (1,2,3,4- naphthane -1- bases) benzsulfamide, obtains white foam solid (yield 70%).
1H-NMR(CDCl3):δ7.94(d,1H,J=2.1Hz),7.58(dd,1H,J1=8.7Hz,J2=2.1Hz),7.12
(t,1H,J=7.5Hz),7.04-6.96(m,3H),6.88(d,1H,J=7.5Hz),5.09(d,1H,J=7.2Hz),4.64(s,
2H),4.40-4.35(m,1H),3.84(s,3H),2.88-2.59(m,4H),1.90-1.66(m,8H),1.48-1.28(m,
4H);EI-MS:481(M-1)+;HRMS(EI):C26H29N2O5S(M-1)+:Calculated value：481.1797;Measured value：481.1798.
Embodiment 35
Compound 35：5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -
N- (4- luorobenzyls) -2- methoxybenzenesulphoismides
Course of reaction be the same as Example 25, only by initiation material N- benzyls -5- ((1,3- dioxoisoindolin -2- bases) first
Base) -2- methoxybenzenesulphoismides replace with 5- ((1,3- dioxoisoindolin -2- bases) methyl)-N- (4- fluorine of embodiment 5
Benzyl) -2- methoxybenzenesulphoismides, obtain colorless gum (yield 57%).
1H-NMR(CDCl3):δ7.82(d,1H,J=2.1Hz),7.49(dd,1H,J1=8.7Hz,J2=2.1Hz),7.10-
7.05(m,2H),6.90-6.84(m,3H),5.21(t,1H,J=6.3Hz),4.61(s,2H),4.04(d,2H,J=6.3Hz),
3.82(s,3H),2.88(t,2H,J=4.5Hz),1.88-1.69(m,4H),1.51-1.35(m,4H);EI-MS:460(M+);
HRMS(EI):C23H25FN2O5S(M)+:Calculated value：460.1468;Measured value：460.1467.
Embodiment 36
Compound 36：5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -
2- methoxyl groups-N- (thiophene -2- ylmethyls) benzsulfamide
Course of reaction be the same as Example 25, only by initiation material N- benzyls -5- ((1,3- dioxoisoindolin -2- bases) first
Base) -2- methoxybenzenesulphoismides replace with 5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxies of embodiment 9
Base-N- (thiophene -2- ylmethyls) benzsulfamide, obtains colorless gum (yield 70%).
1H-NMR(CDCl3):δ7.83(s,1H),7.50(d,1H,J=8.7Hz),7.10(d,1H,J=4.8Hz),6.85
(d,1H,J=8.4Hz),6.78-6.75(m,1H),6.68(brs,1H),5.26(t,1H,J=6.0Hz),4.60(s,2H),
4.27(d,2H,J=6.3Hz),3.81(s,3H),2.87(brs,2H),1.84-1.67(m,4H),1.46-1.33(m,4H);
EI-MS:448(M+);HRMS(EI):C21H24N2O5S2(M)+:Calculated value：448.1127;Measured value：448.1132.
Embodiment 37
Compound 37：5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -
N- (4- iodine benzyl) -2- methoxybenzenesulphoismides
Course of reaction be the same as Example 25, only by initiation material N- benzyls -5- ((1,3- dioxoisoindolin -2- bases) first
Base) -2- methoxybenzenesulphoismides replace with 5- ((1,3- dioxoisoindolin -2- bases) methyl)-N- (4- iodine of embodiment 10
Benzyl) -2- methoxybenzenesulphoismides, obtain colorless gum (yield 37%).
1H-NMR(CDCl3):δ7.80(d,1H,J=1.8Hz),7.53-7.50(m,3H),6.88-6.83(m,3H),5.18
(t,1H,J=6.3Hz),4.62(s,2H),4.02(d,2H,J=6.6Hz),3.83(s,3H),2.89(t,2H,J=5.2Hz),
1.87-1.67(m,4H),1.50-1.32(m,4H);EI-MS:568(M+);HRMS(EI):C23H25IN2O5S(M)+:Calculated value：
568.0529;Measured value：568.0535.
Embodiment 38
Compound 38：N- (3,4- dichloro benzyl) -5- ((1,3- dioxo -1H- iso-indoles -2 (3H, 3aH, 4H, 5H, 6H,
7H, 7aH)-yl) methyl) -2- methoxybenzenesulphoismides
Course of reaction be the same as Example 25, only by initiation material replace with embodiment 7 N- (2,4- dichloro benzyl) -5- ((1,
3- dioxoisoindolin -2- bases) methyl) -2- methoxybenzenesulphoismides, obtain colorless gum (yield 40%).
1H-NMR(CDCl3):δ7.67(s,1H),7.38(d,1H,J=8.1Hz),7.18(s,1H),6.98-6.91(m,
2H),6.68(d,1H,J=8.4Hz),5.59(t,1H,J=6.6Hz),4.57(s,2H),4.23(d,2H,J=6.6Hz),3.80
(s,3H),2.90(brs,2H),1.95-1.63(m,4H),1.50-1.34(m,4H);EI-MS:510(M+);HRMS(EI):
C23H24Cl2N2O5S(M)+:Calculated value：510.0783;Measured value：510.0782.
Embodiment 39
Compound 39：N- (3,5- bis- (trifluoromethyl) benzyl) -5- ((1,3- dioxo -1H- iso-indoles -2 (3H, 3aH,
4H, 5H, 6H, 7H, 7aH)-yl) methyl) -2- methoxybenzenesulphoismides
Course of reaction be the same as Example 25, only by N- benzyls -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- first
Epoxide benzsulfamide replaces with N- (3,5- bis- (trifluoromethyl) benzyl) -5- ((1,3- dioxoisoindolin -2- of embodiment 8
Base) methyl) -2- methoxybenzenesulphoismides, obtain white powdery solids (yield 88%).
1H-NMR(CDCl3):δ7.82(s,1H),7.69(s,1H),7.18(s,1H),7.63(s,2H),7.51(d,1H,J
=8.1Hz),6.86(d,1H,J=8.4Hz),5.61(t,1H,J=5.7Hz),4.58(s,2H),4.24(d,2H,J=6.3Hz),
3.86(s,3H),2.86(brs,2H),1.81(brs,2H),1.70(brs,2H),1.46-1.32(m,4H);EI-MS:578(M+);HRMS(EI):C25H24F6N2O5S(M)+:Calculated value：578.1310;Measured value：578.1314.
Embodiment 40
Compound 40：N- (3,4- dichloro benzyl) -5- ((1,3- dioxo -1H- iso-indoles -2 (3H, 3aH, 4H, 5H, 6H,
7H, 7aH)-yl) methyl) -2- methoxybenzenesulphoismides
Course of reaction be the same as Example 25, only by initiation material N- benzyls -5- ((1,3- dioxoisoindolin -2- bases) first
Base) -2- methoxybenzenesulphoismides replace with N- (3,4- dichloro benzyls)-the 5- ((1,3- dioxoisoindolins -2- of embodiment 6
Base) methyl) -2- methoxybenzenesulphoismides, obtain white powdery solids (yield 77%).
1H-NMR(CDCl3):δ7.77(s,1H),7.49(d,1H,J=8.7Hz),7.24(d,1H,J=10.2Hz),7.18
(s,1H),6.97(d,1H,J=8.4Hz),6.84(d,1H,J=8.4Hz),5.45(t,1H,J=6.0Hz),4.59(s,2H),
4.04(d,2H,J=5.7Hz),3.85(s,3H),2.87(brs,2H),1.85-1.67(m,4H),1.47-1.34(m,4H);
EI-MS:510(M+);HRMS(EI):C23H24Cl2N2O5S(M)+:Calculated value：510.0783;Measured value：510.0783.
Embodiment 41
Compound 41：N- (4- chlorobenzyls) -5- ((1,3- dioxo -1H- iso-indoles -2 (3H, 3aH, 4H, 5H, 6H, 7H,
7aH)-yl) methyl) -2- methoxybenzene cyclic amides
Course of reaction be the same as Example 25, only by initiation material N- benzyls -5- ((1,3- dioxoisoindolin -2- bases) first
Base) -2- methoxybenzenesulphoismides replace with N- (4- chlorobenzyls) -5- ((1,3- dioxoisoindolin -2- bases) of embodiment 14
Methyl) -2- methoxybenzenesulphoismides, obtain white powdery solids (yield 78%).
1H-NMR(CDCl3):δ7.67(d,1H,J=1.5Hz),7.37(dd,1H,J1=6.3Hz,J2=1.5Hz),7.01
(d,2H,J=6.3Hz),6.95(d,2H,J=6.3Hz),6.74(d,1H,J=6.6Hz),5.75(t,1H,J=4.8Hz),4.50
(s,2H),3.94(d,2H,J=4.8Hz),3.70(s,3H),2.80(t,2H,J=3.3Hz),1.75-1.58(m,4H),1.37-
1.25(m,4H);EI-MS:476(M+);HRMS(EI):C23H25ClN2O5S(M)+:Calculated value：476.1173;Measured value：
476.1182.
Embodiment 42
Compound 42：5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -
2- methoxyl groups-N- (4- methyl-benzyls) benzsulfamide
Course of reaction be the same as Example 25, only by initiation material N- benzyls -5- ((1,3- dioxoisoindolin -2- bases) first
Base) -2- methoxybenzenesulphoismides replace with 5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxies of embodiment 15
Base-N- (4- methyl-benzyls) benzsulfamide, obtains colorless gum (yield 73%).
1H-NMR(CDCl3):δ7.85(d,1H,J=2.1Hz),7.51(dd,1H,J1=8.7Hz,J2=2.1Hz),7.03-
6.96(m,4H),6.85(d,1H,J=8.4Hz),5.10(t 1H,J=6.3Hz),4.62(s,2H),4.00(d,2H,J=
6.0Hz),3.80(s,3H),2.88(t,2H,J=4.2Hz),2.27(s,3H),1.87-1.70(m,4H),1.50-1.30(m,
4H);EI-MS:456(M+);HRMS(EI):C24H28N2O5S(M)+:Calculated value：456.1719;Measured value：456.1721.
Embodiment 43
Compound 43：5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -
2- methoxyl groups-N- (4- nitrobenzyls) benzsulfamide
Course of reaction be the same as Example 25, only by initiation material N- benzyls -5- ((1,3- dioxoisoindolin -2- bases) first
Base) -2- methoxybenzenesulphoismides replace with 5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxies of embodiment 12
Base-N- (4- nitrobenzyls) benzsulfamide, obtains faint yellow solid (yield 29%).
Pale yellow solid(29%).1H-NMR(CDCl3):δ8.09(d,2H,J=8.1Hz),7.83(s,1H),
7.50(d,1H,J=8.4Hz),7.38(d,2H,J=8.4Hz),6.88(d,1H,J=8.4Hz),5.34(t,1H,J=6.6Hz),
4.62(s,2H),4.21(d,2H,J=6.6Hz),3.89(s,3H),2.91(t,2H,J=4.2Hz),1.88-1.70(m,4H),
1.50-1.36(m,4H);EI-MS:487(M+);HRMS(EI):C23H25N3O7S(M)+:Calculated value：487.1413;Measured value：
487.1405.
Embodiment 44
Compound 44：N- (the chloro- 4- luorobenzyls of 3-) -5- ((1,3- dioxo -1H- iso-indoles -2 (3H, 3aH, 4H, 5H,
6H, 7H, 7aH)-yl) methyl) -2- methoxybenzenesulphoismides
Step a：N- (the chloro- 4- luorobenzyls of 3-) -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxybenzenes
The preparation of sulfonamide
Course of reaction be the same as Example 1, replaces benzylamine with the chloro- 4- fluorin benzyl amines of 3- only in step c, obtains white solid, (receives
Rate：86%).
Step b：N- (the chloro- 4- luorobenzyls of 3-) -5- ((1,3- dioxo -1H- iso-indoles -2 (3H, 3aH, 4H, 5H, 6H,
7H, 7aH)-yl) methyl) and -2- methoxybenzenesulphoismides preparation
Course of reaction be the same as Example 25, only by initiation material replace with step a N- (the chloro- 4- luorobenzyls of 3-) -5- ((1,
3- dioxoisoindolin -2- bases) methyl) -2- methoxybenzenesulphoismides, obtain colorless gum (yield 66%).
1H-NMR(CDCl3):δ7.78(d,1H,J=2.1Hz),7.48(dd,1H,J1=),7.50(d,1H,J1=8.4Hz,
J2=2.1Hz),7.12(dd,1H,J1=7.2Hz,J2=2.1Hz),7.02-6.90(m,2H),6.84(d,1H,J=8.7Hz),
5.45(t,1H,J=6.6Hz),4.59(s,2H),4.03(d,2H,J=6.9Hz),3.84(s,3H),2.87(t,2H,J=
4.5Hz),1.91-1.67(m,4H),1.50-1.32(m,4H);EI-MS:494(M+);HRMS(EI):C23H24ClFN2O5S(M
)+:Calculated value：494.1078;Measured value：494.1076.
Embodiment 45
Compound 45：5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -
2- methoxyl groups-N- (3- (trifluoromethyl) benzyl) benzsulfamide
Step a：5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxyl groups-N- (3- (trifluoromethyl) benzyl)
The preparation of benzsulfamide
Benzylamine in step c in embodiment 1, is only replaced with 3- trifluoromethyl benzylamines, obtained by course of reaction be the same as Example 1
White solid, (yield：75%)
Step b：5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -2-
The preparation of methoxyl group-N- (3- (trifluoromethyl) benzyl) benzsulfamide
Course of reaction be the same as Example 25, only replaces with initiation material step a 5- ((1,3- dioxoisoindolin -2-
Base) methyl) -2- methoxyl groups-N- (3- (trifluoromethyl) benzyl) benzsulfamide, obtain white foam solid (yield 85%).
1H-NMR(CDCl3):δ7.81(d,1H,J=2.1Hz),7.50-7.42(m,2H),7.34(brs,3H),6.83(d,
1H,J=8.4Hz),5.42(t,1H,J=6.3Hz),4.59(s,2H),4.15(d,2H,J=6.6Hz),3.81(s,3H),2.87
(t,2H,J=4.5Hz),1.86-1.66(m,4H),1.49-1.31(m,4H);EI-MS:510(M+);HRMS(EI):
C24H25F3N2O5S(M)+:Calculated value：510.1436;Measured value：510.1438.
Embodiment 46
Compound 46：N- (2- chloro- 5- (trifluoromethyl) benzyl) -5- ((1,3- dioxo -1H- iso-indoles -2 (3H, 3aH,
4H, 5H, 6H, 7H, 7aH)-yl) methyl) -2- methoxybenzenesulphoismides
Course of reaction be the same as Example 25, only replaces with initiation material N- (2- chloro- 5- (trifluoromethyl) benzyls of embodiment 11
Base) -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxybenzenesulphoismides, obtain white foam solid (receipts
Rate 83%).
1H-NMR(CDCl3):δ7.77(s,1H),7.42-7.26(m,4H),6.66(d,1H,J=8.4Hz),5.72(t1H,
J=6.6Hz),4.54(s,2H),4.30(d,2H,J=6.6Hz),3.77(s,3H),2.84(brs,2H),1.80(brs,2H),
1.68(brs,2H),1.44-1.31(m,4H);EI-MS:544(M+);HRMS(EI):C24H24ClF3N2O5S(M)+:Calculated value：
544.1047;Measured value：544.1042.
Embodiment 47
Compound 47：5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -
2- methoxyl groups-N- (4- (trifluoromethyl) benzyl) benzsulfamide
Course of reaction be the same as Example 25, only replaces with initiation material 5- ((1, the 3- dioxoisoindoles of embodiment 16
Quinoline -2- bases) methyl) -2- methoxyl groups-N- (4- (trifluoromethyl) benzyl) benzsulfamide, obtain white solid (yield 85%).
1H-NMR(CDCl3):δ7.79(s,1H),7.47-7.42(m,3H),7.24(d,1H,J=8.1Hz),6.81(d,
1H,J=8.7Hz),5.46(t,1H,J=6.3Hz),4.60(s,2H),4.14(d,2H,J=6.3Hz),3.81(s,3H),2.88
(brs,2H),1.85-1.68(m,4H),1.47-1.34(m,4H);EI-MS:510(M+);HRMS(EI):C24H25F3N2O5S(M
)+:Calculated value：510.1436;Measured value：510.1434.
Embodiment 48
Compound 48：N- (3,4- dimethyl benzyl) -5- ((1,3- dioxo -1H- iso-indoles -2 (3H, 3aH, 4H, 5H,
6H, 7H, 7aH)-yl) methyl) -2- methoxybenzenesulphoismides
Course of reaction be the same as Example 25, only by N- (the chloro- 4- luorobenzyls of 3-) -5- ((1,3- dioxoisoindolin -2- bases)
Methyl) -2- methoxybenzenesulphoismides replace with N- (3,4- dimethyl benzyl) -5- ((1,3- dioxoisoindoles of embodiment 17
Quinoline -2- bases) methyl) -2- methoxybenzenesulphoismides, obtain white foam solid (yield 87%).
1H-NMR(CDCl3):δ7.84(d,1H,J=2.1Hz),7.50(dd,1H,J1=8.7Hz,J2=2.1Hz),6.96
(d,1H,J=7.5Hz),6.86-6.80(m,3H),5.15(t,1H,J=6.0Hz),4.61(s,2H),3.96(d,2H,J=
6.0Hz),3.78(s,3H),2.86(t,2H,J=4.2Hz),2.17(s,3H),2.13(s,3H),1.83-1.67(m,4H),
1.49-1.31(m,4H);EI-MS:470(M+).;HRMS(EI):C25H30N2O5S(M)+:Calculated value：470.1875;Measured value：
470.1871.
Embodiment 49
Compound 49：N- (4- bromobenzyls) -5- ((1,3- dioxo -1H- iso-indoles -2 (3H, 3aH, 4H, 5H, 6H, 7H,
7aH)-yl) methyl) -2- methoxybenzenesulphoismides
Course of reaction be the same as Example 25, only by initiation material N- (the chloro- 4- luorobenzyls of 3-) -5- ((1,3- dioxoisoindoles
Quinoline -2- bases) methyl) -2- methoxybenzenesulphoismides replace with N- (4- bromobenzyls) -5- ((the different Yin of 1,3- dioxo of embodiment 18
Diindyl quinoline -2- bases) methyl) -2- methoxybenzenesulphoismides, obtain white solid (yield 75%).
1H-NMR(CDCl3):δ7.77(s,1H),7.47(d,1H,J=8.4Hz),7.27(d,2H,J=7.8Hz),6.96
(d,2H,J=8.4Hz),6.82(d,1H,J=8.4Hz),5.41(t,1H,J=6.3Hz),4.58(s,2H),4.00(d,2H,J=
6.6Hz),3.79(s,3H),2.87(brs,2H),1.85-1.66(m,4H),1.46-1.33(m,4H);EI-MS:520(M+);
HRMS(EI):C23H25BrN2O5S(M)+:Calculated value：520.0668;Measured value：520.0664.
Embodiment 50
Compound 50：5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -
2- methoxyl groups-N- (4- (thiophene -2- bases) benzyl) benzsulfamide
Course of reaction be the same as Example 25, only by N- (the chloro- 4- luorobenzyls of 3-) -5- ((1,3- dioxoisoindolin -2- bases)
Methyl) -2- methoxybenzenesulphoismides replace with 5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- first of embodiment 13
Epoxide-N- (4- (thiophene -2- bases) benzyl) benzsulfamide, obtains white gum thing (yield 48%).
1H-NMR(CDCl3):δ7.83(s,1H),7.48(d,1H,J=8.4Hz),7.42(d,2H,J=8.1Hz),7.28-
7.25(m,2H),7.10-7.05(m,3H),6.82(d,1H,J=8.4Hz),5.24(t,1H,J=6.3Hz),4.61(s,2H),
4.08(d,2H,J=6.3Hz),3.80(s,3H),2.87(t,2H,J=4.2Hz),1.86-1.68(m,4H),1.48-1.35(m,
4H);EI-MS:524(M+);HRMS(EI):C27H28N2O5S2(M)+:Calculated value：524.1440;Measured value：524.1433.
Embodiment 51
Compound 51：N- (4- chlorobenzyls) -5- ((2,5- dioxotetrahydro pyrroles -1- bases) methyl) -2- methoxybenzene sulphurs
Acid amides
By N- (4- chlorobenzyls) -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxybenzenes of embodiment 14
Sulfonamide (850mg, 1.81mmol, 1eq) is dissolved in ethanol (2ml), adds hydrazine hydrate (827ul, 14.5mmol, 8eq), mixture
Return stirring reacts 2 hours, lets cool, and filters, filtrate concentration, the amine that residue column chromatography is deprotected.By the deprotection amine
(27mg, 0.079mmol, 1eq) is dissolved in acetic acid (5ml), adds dihydrofuran -2,5- diketone (10mg, 0.079mmol, 1eq),
The reaction of mixture return stirring is stayed overnight.Solvent is evaporated off, residue column chromatography obtains title compound, be colorless gum (33mg,
Yield 82%).
1H-NMR(CDCl3):δ7.83(s,1H),7.54(d,1H,J=8.7Hz),7.15(d,2H,J=7.8Hz),7.06
(d,2H,J=8.1Hz),6.85(d,1H,J=8.7Hz),5.31(t,1H,J=6.3Hz),4.62(s,2H),4.06(d,2H,J=
6.3Hz),3.84(s,3H),2.73(s,4H);EI-MS:422(M+);HRMS(EI):C19H19ClN2O5S(M)+:Calculated value：
422.0703;Measured value：422.0702.
Embodiment 52
Compound 52：N- (4- chlorobenzyls) -5- ((2,5- dioxo -2,5- dihydro -1H- pyrroles -1- bases) methyl) -2- first
Epoxide benzsulfamide
Course of reaction be the same as Example 51, only replaces dihydrofuran -2,5- diketone with furans -2,5- diketone, obtains no coloring agent
Shape thing (yield 72%).
1H-NMR(CDCl3):δ7.81(s,1H),7.49(d,1H,J=8.4Hz),7.15(d,2H,J=8.1Hz),7.05
(d,2H,J=7.8Hz),6.86(d,1H,J=8.7Hz),6.74(s,2H),5.26(t,1H,J=4.0Hz),4.64(s,2H),
4.06(d,2H,J=6.0Hz),3.84(s,3H);EI-MS:420(M+);HRMS(EI):C19H17ClN2O5S(M)+:Calculated value：
420.0547;Measured value：420.0554.
Embodiment 53
Compound 53：N- (3- (N- (4- chlorobenzyls) sulfonamides) -4- methoxy-benzyls) Cyclohexamide
Under stirring, to embodiment 51 5- (aminomethyl)-N- (4- chlorobenzyls) -2- methoxybenzenesulphoismides (31mg,
In DMF (2ml) solution 0.09mmol), cyclohexanecarboxylic acid (12.8mg, 10mmol) is sequentially added, BTA-N, N, N',
N'- tetramethylureas hexafluorophosphate (36mg, 0.094mmol) and DIPEA (21ul, 0.126mmol).Mixing
Thing is stirred at room temperature overnight, and solvent is evaporated off, residue is with water and dichloromethane point liquid.Organic phase anhydrous sodium sulfate drying, mistake
Filter concentration, residue column chromatography obtains title compound, is white solid (33mg, yield 82%).
1H-NMR(CDCl3):δ7.71(s,1H),7.44(d,1H,J=8.1Hz),7.16(d,2H,J=8.7Hz),7.06
(d,2H,J=8.4Hz),6.86(d,1H,J=8.4Hz),6.15(brs,1H),5.37(t,1H,J=6.3Hz),4.36(d,2H,J
=6.0Hz),4.02(d,2H,J=6.3Hz),3.82(s,3H),2.16-1.16(m,11H);EI-MS:450(M+);HRMS
(EI):C22H27ClN2O4S(M)+:Calculated value：450.1380;Measured value：450.1380.
Embodiment 54
Compound 54：N- (3- (N- (4- chlorobenzyls) sulfonamides) -4- methoxy-benzyls) ring pentanamide
Course of reaction be the same as Example 53, only replaces cyclohexanecarboxylic acid with cyclopentanecarboxylic acid, obtains white solid (30mg, yield
83%)。
1H-NMR(CDCl3):δ7.98(s,1H),7.71(d,1H,J=8.4Hz),7.42(d,2H,J=8.4Hz),7.32
(d,2H,J=8.4Hz),7.13(d,1H,J=8.4Hz),6.37(brs,1H),5.59(t,1H,J=6.3Hz),4.63(d,2H,J
=6.0Hz),4.28(d,2H,J=6.6Hz),4.09(s,3H),2.87-2.74(m,1H),2.17-1.80(m,8H);EI-MS:
436(M+);HRMS(EI):C21H25ClN2O4S(M)+:Calculated value：436.1224;Measured value：436.1217.
Embodiment 55
Compound 55：N- (4- chlorobenzyls) -5- ((dimethylamino) methyl) -2- methoxybenzenesulphoismides
Under stirring, to 5- (amino methyl)-N- (4- rates benzyl) -2- methoxybenzenesulphoismides (46mg, 0.135mmol)
In ethanol-acetic acid (3ml-2ml) solution, formaldehyde (107ul) and palladium carbon (9mg) are added.Mixture is stirred in room temperature under a hydrogen atmosphere
Mix 9 hours.Cross and filter out catalyst, filtrate concentration, residue column chromatography obtains title compound, and for colorless gum, (31mg is received
Rate 63%).
1H-NMR(CDCl3):δ7.78(s,1H),7.48(d,1H,J=8.1Hz),7.18-7.06(m,4H),6.89(d,
1H,J=8.1Hz),5.35(t,1H,J=6.3Hz),4.05(d,2H,J=6.3Hz),3.85(s,3H),3.38(s,2H),2.22
(s,6H);EI-MS:368(M+);HRMS(EI):C17H21ClN2O3S(M)+:Calculated value：368.0961;Measured value：368.0965.
Embodiment 56
Compound 56：N- ((S) -1- (4- chlorphenyls) ethyl) -5- ((1,3- dioxo -1H- iso-indoles -2 (3H, 3aH,
4H, 5H, 6H, 7H, 7aH)-yl) methyl) -2- methoxybenzenesulphoismides
Step a：The preparation of 2- (4- methoxy-benzyls) hexahydro -1H- iso-indoles -1,3 (2H)-diketone
Under stirring, added into acetic acid (30ml) solution of hexahydro isobenzofuran -1,3- diketone (3.08g, 20mmol)
(4- methoxyphenyls) methylamine (2.62ml, 20mmol), mixture return stirring reacts 18 hours.Solvent is evaporated off, residue is used
Dchloromethane, successively with 1M hydrochloric acid, saturated sodium bicarbonate solution and saturated common salt washing, anhydrous sodium sulfate drying, filtering
Concentration, residue is directly used in next step reaction (faint yellow solid, 5.46g, yield 100%).
Step b：5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -2-
The preparation of methoxybenzene -1- sulfonic acid chlorides
In the case where 0 DEG C is stirred, 2- (4- methoxy-benzyls) hexahydro -1H- iso-indoles -1 is added portionwise into chlorosulfonic acid (30ml),
3 (2H)-diketone (5.46g, 20.40mmol).Finish, mixture is stirred for 2 hours at room temperature, and then, reaction solution is poured into
Mixture of ice and water, is extracted three times with ethyl acetate, merges organic phase.Organic phase washed with water and saturated common salt washing, anhydrous sulphur
Sour sodium is dried, filtering and concentrating, and residue (brown solid, 7.18g, yield 91%) is directly used in next step reaction.
Step c：N- ((S) -1- (4- chlorphenyls) ethyl) -5- ((1,3- dioxo -1H- iso-indoles -2 (3H, 3aH, 4H,
5H, 6H, 7H, 7aH)-yl) methyl) and -2- methoxybenzenesulphoismides preparation
Under stirring, to 5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxybenzene -1- sulfonic acid chlorides (56mg,
0.15mmol, 1eq) dichloromethane (5ml) solution in add triethylamine (32ul, 0.23mmol, 1.5eq) and (S) -1- (4-
Chlorphenyl) ethamine (24ul, 0.18mmol, 1.2eq), mixture is stirred at room temperature 2 hours.Solvent, residue post layer is evaporated off
Analysis obtains title compound for colorless gum (yield 81%).
1H-NMR(CDCl3):δ7.68(s,1H),7.40(d,1H,J=8.7Hz),7.03(d,2H,J=7.5Hz),6.93
(d,2H,J=8.1Hz),6.70(d,1H,J=8.4Hz),5.40(d,1H,J=8.1Hz),4.63-4.51(m,2H),4.36-
4.27(m,1H),3.72(s,3H),2.88(brs,2H),1.83-1.72(m,4H),1.40(brs,4H),1.38(s,3H);
EI-MS:490(M+);HRMS(EI):C24H27ClN2O5S(M)+:Calculated value：490.1329;Measured value：490.1322.
Embodiment 57
Compound 57：N- ((R) -1- (4- chlorphenyls) ethyl) -5- ((1,3- dioxo -1H- iso-indoles -2 (3H, 3aH,
4H, 5H, 6H, 7H, 7aH)-yl) methyl) -2- methoxybenzenesulphoismides
Course of reaction be the same as Example 56, only replaces (S) -1- (4- chlorphenyls) ethamine with (R) -1- (4- chlorphenyls) ethamine,
Obtain colorless gum (yield 81%).
1H-NMR(CDCl3):δ7.68(s,1H),7.40(dd,1H,J1=8.7Hz,J2=1.8Hz),7.03(d,2H,J=
8.4Hz),6.92(d,2H,J=8.7Hz),6.69(d,1H,J=8.7Hz),5.45(d,1H,J=8.1Hz),4.62-4.50(m,
2H),4.36-4.26(m,1H),3.71(s,3H),2.88(t,2H,J=4.2Hz),1.88-1.67(m,4H),1.47-1.37
(m,7H);EI-MS:490(M+);HRMS(EI):C24H27ClN2O5S(M)+:Calculated value：490.1329;Measured value：490.1322.
Embodiment 58
Compound 58：5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -
2- methoxyl groups-N- (4- (4- methylpiperazine-1-yls) benzyl) benzsulfamide
Course of reaction be the same as Example 56, only replaces (S) -1- (4- chlorobenzenes with (4- (4- methylpiperazine-1-yls) phenyl) methylamine
Base) ethamine, obtain faint yellow jelly (yield 70%).
1H-NMR(CDCl3):δ7.84(s,1H),7.49(d,1H,J=9.0Hz),6.96(d,2H,J=8.7Hz),6.84
(d,1H,J=9.0Hz),6.74(d,2H,J=8.1Hz),5.08(t,1H,J=6.0Hz),4.61(s,2H),3.95(d,2H,J=
6.0Hz),3.79(s,3H),3.14(brs,4H),2.87(brs,2H),2.54(brs,4H),2.33(s,3H),1.92-1.63
(m,4H),1.46-1.31(m,4H);EI-MS:540(M+);HRMS(EI):C28H36N4O5S(M)+:Calculated value：540.2406;It is real
Measured value：540.2397.
Embodiment 59
Compound 59：5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -
2- methoxyl groups-N- (naphthalene -1- ylmethyls) benzsulfamide
Course of reaction be the same as Example 56, (S) -1- (4- chlorphenyls) ethamine is only replaced with naphthalene -1- base methylamines, no coloring agent is obtained
Shape thing (yield 63%).
1H-NMR(CDCl3):δ7.91(d,1H,J=8.1Hz),7.81(d,2H,J=7.2Hz),7.66(d,1H,J=
8.1Hz),7.54-7.45(m,2H),7.38(dd,1H,J1=8.7Hz,J2=2.1Hz),7.15(t,1H,J=8.1Hz),7.04
(d,1H,J=6.9Hz),6.56(d,1H,J=8.4Hz),5.34(t,1H,J=6.3Hz),4.60(s,2H),4.54(d,2H,J=
6.3Hz),3.34(s,3H),2.92-2.84(m,2H),1.86-1.70(m,4H),1.49-1.35(m,4H);EI-MS:492(M+);HRMS(EI):C27H28N2O5S(M)+:Calculated value：492.1719;Measured value：492.1718.
Embodiment 60
Compound 60：N, N- dibenzyl -5- ((1,3- dioxo -1H- iso-indoles -2 (3H, 3aH, 4H, 5H, 6H, 7H,
7aH)-yl) methyl) -2- methoxybenzenesulphoismides
Course of reaction be the same as Example 56, only replaces (S) -1- (4- chlorphenyls) ethamine with dibenzylamine, obtains white solid (receipts
Rate 86%).
1H-NMR(CDCl3):δ7.97(d,1H,J=1.5Hz),7.54(dd,1H,J1=8.4Hz,J2=1.8Hz),7.21-
7.19(m,6H),7.01-6.99(m,4H),6.89(d,1H,J=8.7Hz),4.62(s,2H),4.37(s,4H),3.74(s,
3H),2.89-2.81(m,2H),1.81-1.65(m,4H),1.42-1.23(m,4H);EI-MS:532(M+);HRMS(EI):
C30H32N2O5S(M)+:Calculated value：532.2032;Measured value：532.2046.
Embodiment 61
Compound 61：N- (4- aminobenzyls) -5- ((1,3- dioxo -1H- iso-indoles -2 (3H, 3aH, 4H, 5H, 6H,
7H, 7aH)-yl) methyl) -2- methoxybenzenesulphoismides
Course of reaction be the same as Example 56, (S) -1- (4- chlorphenyls) ethamine is only replaced with 4- (amino methyl) aniline, is obtained
White gum thing (yield 75%).
1H-NMR(CDCl3):δ7.83(d,1H,J=1.5Hz),7.50(dd,1H,J1=8.4Hz,J2=1.5Hz),6.84
(t,3H,J=8.4Hz),6.49(d,2H,J=8.1Hz),5.02(t,1H,J=5.7Hz),4.62(s,2H),3.92(d,2H,J=
6.0Hz),3.80(s,3H),3.66(brs,2H),2.92-2.84(m,2H),1.86-1.69(m,4H),1.48-1.32(m,
4H);EI-MS:457(M+);HRMS(EI):C23H27N3O5S(M)+:Calculated value：457.1671;Measured value：457.1671.
Embodiment 62
Compound 62：5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -
2- methoxybenzenesulphoismides
By 5- ((1,3- dioxo -1H- iso-indoles -2 (3H, 3aH, 4H, 5H, 6H, 7H, 7aH)-Ji Jia of embodiment 56
Base) -2- methoxybenzene -1- sulfonic acid chlorides (371mg, 1mmol) are dissolved in NH3/CH3OH solution (10ml), mixture is stirred at room temperature
1 hour.Solvent evaporated, residue column chromatography obtains title compound (273mg, yield 78%), is faint yellow solid.
1H-NMR(CDCl3):δ7.73(s,1H),7.47(d,1H,J=8.7Hz),6.94(d,1H,J=8.7Hz),5.46
(brs,2H),4.51(s,2H),3.93(s,3H),2.82(brs,2H),1.78-1.59(m,4H),1.41-1.24(m,4H);
EI-MS:352(M+);HRMS(EI):C16H20N2O5S(M)+:Calculated value：352.1093;Measured value：352.1102.
Embodiment 63
Compound 63：The chloro- N- of 4- (5- ((1,3- dioxo -1H- iso-indoles -2 (3H, 3aH, 4H, 5H, 6H, 7H, 7aH) -
Base) methyl) -2- MethOxybenzenesulfonyls) benzamide
Under stirring, 1- second is added in (5mL) into the anhydrous methylene chloride solution of 4- chlorobenzoic acids (78mg, 0.5mmol)
Base -3- (3- dimethylaminopropyls) phosphinylidyne diimine (96mg, 0.5mmol), triethylamine (76uL, 0.55mmol), 4- diformazans
Aminopyridine (10mg) and 5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -
2- methoxybenzenesulphoismides (175mg, 0.5mmol).Mixture is stirred at room temperature 6 hours.Add saturated sodium bicarbonate solution,
Divide liquid, aqueous phase is extracted twice again with dichloromethane, merge organic phase, anhydrous sodium sulfate drying, filtering and concentrating, residue column chromatography
Title compound is obtained, is colorless gum (173mg, yield 71%).
1H-NMR(CDCl3):δ9.80(brs,1H),8.13(s,1H),7.78(d,2H,J=8.4Hz),7.60(d,1H,J=
8.1Hz),7.33(d,1H,J=7.8Hz),6.93(d,1H,J=8.4Hz),4.67(s,2H),3.89(s,3H),2.89(brs,
2H),1.84-1.71(m,4H),1.48-1.42(m,4H);EI-MS:490(M+);HRMS(EI):C23H23ClN2O6S(M)+:Meter
Calculation value：490.0965;Measured value：490.0972.
The test of the biological activity of embodiment 64
Experimental method：
CCR6 and G is expressed by stableα16HEK293 cells be inoculated in 96 hole plates（Costar）In, after culture 24h, go
Except culture medium, Hank balanced salt solutions of the 40 μ L containing 2 μm of ol/LFluo-4AM is added per hole（HBSS:Include 5.4mmol/L
KCl,0.3mmol/L Na2HPO4,0.4mmol/L KH2PO4,4.2mmol/L NaHCO3,1.3mmol/L CaCl2,
0.5mmol/LMgCl2,0.6mmol/L MgSO4, 137mmol/L NaCl, 5.6mmol/L D-Glucoses, and 250 μm of o/L sulphurs
Pyrrone（sulfinpyrazone）,pH 7.4）45min is incubated in incubator.Dyestuff is abandoned in suction, is added 50 μ L and is contained testing compound
Or 1%DMSO HBSS, 10min is incubated at room temperature, then with Flex Station3 micropore board detector readings.Detector is referring to
Fix time a little, can be automatically by 25 μ L activators CCL20（Final concentration 10nmol/L）It is added in reaction system, while using 485nm
Light excite and detect the change of dye fluorescence intensity caused by intracellular calcium concentration change in 525nm wave bands.
Data analysis：
After different pharmaceutical is incubated, cell is calculated by below equation CCR6 activators CCL20 reactivity：
Reactivity %=(D-B)/(S-B) * 100%;
Wherein D is the calcium current signal peak that CCL20 evokes with after drug incubation to be measured；B is incubated for the HBSS containing 1%DMSO
Afterwards, the calcium current signal peak that HBSS evokes；After S is incubated for the HBSS containing 1%DMSO, the calcium current signal peak that CCL20 evokes.
The reactivity of same medicine various dose does nonlinear regression analysis with GraphPad Prism softwares, obtains dosage
Response curve simultaneously measures IC50 values.Data are stated with Mean ± SEM, are three independent experiment results, and experiment every time is three multiple
Hole.
By inhibitory activity of the calcium current experiment test above-claimed cpd to CCR6, acquired results are listed in the table below 1：
Table 1
"-" represents undetermined.
As can be seen from the above table, 11 compound activities in the present invention are in micromolar levels, wherein best compound is lived
Property is 2.81uM.Therefore, the compounds of this invention is good CCR6 antagonists, available for controlling for the CCR6 relevant diseases mediated
Treat.
Claims (10)
1. 2,5- disubstituted benzenes sulfamide compound or its pharmaceutically acceptable salt shown in a kind of formula I,
In Formulas I,
For
R2For H, C1-C4Alkyl or C1-C4Alkoxy；
R3For H, C1-C4Alkyl, C3-C6Cycloalkyl, benzyl or
R4For H, C that is unsubstituted or being replaced by 1-3 substituent5-C12Aryl is unsubstituted or replaced by 1-3 substituent
Heteroatomic 5 to the 12 circle heterocycles base containing 1-2 in N, O and S, described substituent is selected from following atom or base
Group：C1-C4Alkyl, C1-C4Alkoxy, C1-C4Alkylamino radical, C3-C8Cycloalkyl, C5-C12It is aryl, unsubstituted or by C1-C3Alkyl takes
The C in generation5-C12Heterocyclic radical, halogen, hydroxyl, amino, CF3And NO2；
L is not present or is C1-C3Alkylidene, C1-C3Alkylenecarbonyl；
Or, when L is not present, R3With R4Nitrogen-atoms that can be adjacent with them forms five to heptatomic ring together.
2. compound according to claim 1 or its pharmaceutically acceptable salt, wherein,For
R2For H, C1-C4Alkyl or C1-C4Alkoxy；
R3For H, C1-C4Alkyl, C3-C6Cycloalkyl, benzyl or
R4For H, phenyl or naphthyl that is unsubstituted or being replaced by 1-3 substituent or unsubstituted or taken by 1-3 substituent
Thiophene, furans, pyridine or the piperazine group in generation, described substituent are selected from following atom or group：C1-C4Alkyl, C1-C4Alkane
Epoxide, C1-C4Alkylamino radical, C3-C8Cycloalkyl, C5-C12It is aryl, unsubstituted or by C1-C3Alkyl-substituted C5-C12Heterocyclic radical, halogen
Element, hydroxyl, amino, CF3And NO2；
L is not present or is C1-C3Alkylidene, C1-C3Alkylenecarbonyl；
Or, when L is not present, R3With R4Nitrogen-atoms that can be adjacent with them forms five to heptatomic ring together.
3. a class 2,5- disubstituted benzenes sulfamide compound or its pharmaceutically acceptable salt, wherein, the compound is：
N- benzyls -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxybenzenesulphoismides,
2- (3- ((the 1H)-base sulfonyl of 3,4- dihydro-isoquinoline -2) -4- methoxy-benzyls) isoindoline -1,3- diketone,
5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxyl groups-N- (1,2,3,4- naphthane -1- bases) benzene sulfonyl
Amine,
5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxyl group-N- phenethyl benzsulfamides,
5- ((1,3- dioxoisoindolin -2- bases) methyl)-N- (4- luorobenzyls) -2- methoxybenzenesulphoismides,
N- (3,4- dichloro benzyl) -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxybenzenesulphoismides,
N- (2,4- dichloro benzyl) -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxybenzenesulphoismides,
N- (3,5- bis- (trifluoromethyl) benzyl) -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxybenzene sulphonyl
Amine,
5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxyl groups-N- (thiophene -2- ylmethyls) benzsulfamide,
5- ((1,3- dioxoisoindolin -2- bases) methyl)-N- (4- iodine benzyl) -2- methoxybenzenesulphoismides,
N- (2- chloro- 5- (trifluoromethyl) benzyl) -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxybenzene sulphurs
Acid amides,
5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxyl groups-N- (4- nitrobenzyls) benzsulfamide,
5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxyl groups-N- (4- (thiophene -2- bases) benzyl) benzsulfamide,
N- (4- chlorobenzyls) -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxybenzenesulphoismides,
5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxyl groups-N- (4- methyl-benzyls) benzsulfamide,
5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxyl groups-N- (4- (trifluoromethyl) benzyl) benzsulfamide,
N- (3,4- dimethyl benzyl) -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxybenzenesulphoismides,
N- (4- bromobenzyls) -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxybenzenesulphoismides,
N- benzyls -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxy-. N-methyl benzsulfamides,
N- benzyls -5- ((1,3- dioxoisoindolin -2- bases) methyl)-N- ethyl -2- methoxybenzenesulphoismides,
N- benzyls -5- ((1,3- dioxoisoindolin -2- bases) methyl)-N- isopropyl -2- methoxybenzenesulphoismides,
N- benzyl-N- butyl -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxybenzenesulphoismides,
N- benzyls -5- ((1,3- dioxoisoindolin -2- bases) methyl)-N- isobutyl group -2- methoxybenzenesulphoismides,
N- benzyls -5- ((1,3- dioxoisoindolin -2- bases) methyl) -2- methoxyl group-N- propylbenzenesulfonamides,
N- benzyls -5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -2- methoxies
Base-N- methyl benzenesulfonamides,
N- benzyls -5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl)-N- isopropyls
Base -2- methoxybenzenesulphoismides,
N- benzyls -5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl)-N- second
Base -2- methoxybenzenesulphoismides,
N- benzyl-N- butyl -5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) first
Base) -2- methoxybenzenesulphoismides,
N- benzyls -5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -2- methoxies
Base benzsulfamide,
N- benzyls -5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl)-N- isobutyls
Base -2- methoxybenzenesulphoismides,
N- benzyls -5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -2- methoxies
Base-N- propylbenzenesulfonamides,
2- (3- ((the 1H)-base sulfonyl of 3,4- dihydro-isoquinoline -2) -4- methoxy-benzyls) hexahydro -1H- iso-indoles -1,3 (2H) -
Diketone,
5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -2- methoxyl group-N- benzene
Ethyl beneznesulfonamide,
5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -2- methoxyl groups-N-
(1,2,3,4- naphthane -1- bases) benzsulfamide,
5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl)-N- (4- luorobenzyls) -
2- methoxybenzenesulphoismides,
5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -2- methoxyl groups-N-
(thiophene -2- ylmethyls) benzsulfamide,
5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl)-N- (4- iodine benzyl) -
2- methoxybenzenesulphoismides,
N- (3,4- dichloro benzyl) -5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) first
Base) -2- methoxybenzenesulphoismides,
N- (3,5- bis- (trifluoromethyl) benzyl) -5- ((1,3- dioxo -1H- iso-indoles -2 (3H, 3aH, 4H, 5H, 6H, 7H,
7aH)-yl) methyl) -2- methoxybenzenesulphoismides,
N- (3,4- dichloro benzyl) -5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) first
Base) -2- methoxybenzenesulphoismides,
N- (4- chlorobenzyls) -5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -
2- methoxybenzene cyclic amides,
5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -2- methoxyl groups-N-
(4- methyl-benzyls) benzsulfamide,
5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -2- methoxyl groups-N-
(4- nitrobenzyls) benzsulfamide,
N- (the chloro- 4- luorobenzyls of 3-) -5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2)
Methyl) -2- methoxybenzenesulphoismides,
5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -2- methoxyl groups-N-
(3- (trifluoromethyl) benzyl) benzsulfamide,
N- (2- chloro- 5- (trifluoromethyl) benzyl) -5- ((1,3- dioxo -1H- iso-indoles -2 (3H, 3aH, 4H, 5H, 6H, 7H,
7aH)-yl) methyl) -2- methoxybenzenesulphoismides,
5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -2- methoxyl groups-N-
(4- (trifluoromethyl) benzyl) benzsulfamide,
N- (3,4- dimethyl benzyl) -5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2)
Methyl) -2- methoxybenzenesulphoismides,
N- (4- bromobenzyls) -5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -
2- methoxybenzenesulphoismides,
5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -2- methoxyl groups-N-
(4- (thiophene -2- bases) benzyl) benzsulfamide,
N- (4- chlorobenzyls) -5- ((2,5- dioxotetrahydro pyrroles -1- bases) methyl) -2- methoxybenzenesulphoismides,
N- (4- chlorobenzyls) -5- ((2,5- dioxo -2,5- dihydro -1H- pyrroles -1- bases) methyl) -2- methoxybenzenesulphoismides,
N- (3- (N- (4- chlorobenzyls) sulfonamides) -4- methoxy-benzyls) Cyclohexamide,
N- (3- (N- (4- chlorobenzyls) sulfonamides) -4- methoxy-benzyls) ring pentanamide,
N- (4- chlorobenzyls) -5- ((dimethylamino) methyl) -2- methoxybenzenesulphoismides,
N- ((S) -1- (4- chlorphenyls) ethyl) -5- ((1,3- dioxo -1H- iso-indoles -2 (3H, 3aH, 4H, 5H, 6H, 7H,
7aH)-yl) methyl) -2- methoxybenzenesulphoismides,
N- ((R) -1- (4- chlorphenyls) ethyl) -5- ((1,3- dioxo -1H- iso-indoles -2 (3H, 3aH, 4H, 5H, 6H, 7H,
7aH)-yl) methyl) -2- methoxybenzenesulphoismides,
5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -2- methoxyl groups-N-
(4- (4- methylpiperazine-1-yls) benzyl) benzsulfamide,
5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -2- methoxyl groups-N-
(naphthalene -1- ylmethyls) benzsulfamide,
N, N- dibenzyl -5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -2-
Methoxybenzenesulphoismide,
N- (4- aminobenzyls) -5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) first
Base) -2- methoxybenzenesulphoismides,
5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -2- methoxybenzene sulphurs
Acid amides,
The chloro- N- of 4- (5- (((3H, 3aH, 4H, 5H, 6H, 7H, the 7aH)-yl of 1,3- dioxo -1H- iso-indoles -2) methyl) -2- first
Epoxide benzenesulfonyl) benzamide.
4. a kind of 2,5- disubstituted benzenes sulfamide compound shown in formula according to claim 1 I or its pharmaceutically may be used
The preparation method of the salt of receiving, this method comprises the following steps：
Step a)：By phthalic anhydride andBackflow obtains compound II in acetic acid；
Step b)：Compound II is obtained into compound III under chlorosulfonic acid effect；
Step c)：By compound III and amineIt is condensed to yield compound IV；
Step d)：By compound IV and iodo thing R3- I is alkylated under the effect of sodium hydrogen in DMF
To compound V；
Step e)：By compound V, deprotection obtains compound VI under hydrazine hydrate effect；With
Step f)：By compound VI in acetic acid withEffect obtains compound shown in Formulas I；
Wherein, A rings, R2、R4Definition such as claim 1 with L, R3For C1-C4Alkyl, C3-C6Cycloalkyl, benzyl or
5. a kind of pharmaceutical composition, one or more of the said composition comprising therapeutically effective amount are selected from the Formulas I described in claim 1
Shown compound or its pharmaceutically acceptable salt and one or more pharmaceutic adjuvants.
6. compound shown in the Formulas I described in a kind of claim 1 or its pharmaceutically acceptable salt are used as CCR6 antagonisms in preparation
Application in the medicine of agent.
7. compound shown in the Formulas I described in a kind of claim 1 or its pharmaceutically acceptable salt are situated between in preparation treatment by CCR6
Application in the medicine for the disease led.
8. compound shown in the Formulas I described in a kind of claim 1 or its pharmaceutically acceptable salt are preparing treatment autoimmunity
Application in property disease, inflammation, psoriasis, the medicine of multiple sclerosis or cancer.
9. compound shown in the Formulas I described in a kind of claim 1 or its pharmaceutically acceptable salt are preparing treatment rheumatoid
Applied in arthritis, colitis, pancreatitis, gastritis, psoriasis, the medicine of multiple sclerosis or cancer.
10. compound shown in the Formulas I described in a kind of claim 1 or its pharmaceutically acceptable salt prepare treatment colon cancer,
Applied in the medicine of liver cancer or cancer of pancreas.
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| CN109020924B (en) * | 2018-10-24 | 2022-05-13 | 湖南农业大学 | Method for synthesizing benzene sulfonamide compound from benzene sulfonyl chloride compound and secondary amine through metal-free catalysis |
| CN117018202A (en) * | 2019-07-08 | 2023-11-10 | 上海交通大学医学院附属瑞金医院 | Novel use of chemokine receptor CCR6 inhibitors for preventing psoriasis recurrence |
| CN113527153B (en) * | 2020-04-20 | 2023-01-06 | 中国科学院上海药物研究所 | Active compound for inhibiting intestinal inflammatory reaction |
| KR20230005938A (en) | 2020-04-30 | 2023-01-10 | 이도르시아 파마슈티컬스 리미티드 | Azetidin-3-ylmethanol derivatives as CCR6 receptor modulators |
| WO2023057548A1 (en) | 2021-10-07 | 2023-04-13 | Idorsia Pharmaceuticals Ltd | Ccr6 receptor modulators |
| CN118215662A (en) | 2021-10-26 | 2024-06-18 | 爱杜西亚药品有限公司 | Modulators of CCR6 receptors |
| CN118139854A (en) | 2021-10-28 | 2024-06-04 | 爱杜西亚药品有限公司 | Modulators of CCR6 receptors |
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| WO2009093026A1 (en) * | 2008-01-22 | 2009-07-30 | Oxagen Limited | Compounds having crth2 antagonist activity |
| GB2457040A (en) * | 2008-01-30 | 2009-08-05 | Oxagen Ltd | 1-Acetic acid indole derivatives with PGD2 activity |
| CN101712679A (en) * | 2008-10-08 | 2010-05-26 | 中国科学院上海药物研究所 | Acylamide class compound, medicine composition, preparation method and application thereof |
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