CN109734677A - The small molecule compound and its application of inhibition of histone lysine methyltransferase NSD2 - Google Patents
The small molecule compound and its application of inhibition of histone lysine methyltransferase NSD2 Download PDFInfo
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Abstract
The invention belongs to chemical medicines, and in particular to the small molecule compound of inhibition of histone lysine methyltransferase NSD2, general formula are as follows:It is confirmed by some embodiments of the small molecule compound, the small molecule compound has good inhibiting effect to histone-lysine methyltransferase NSD2, simultaneously to tumour cell have good inhibiting effect, inhibitor can be made into, can as preparation treating cancer drug carry out using；The chemical combination microbic activity that the present invention is prepared is higher, strong to the selectivity of tumour cell, and quasi-medicated property is significant, has a vast market foreground.
Description
Technical field
The present invention relates to chemical synthetic drug technical field, in particular to a kind of inhibition of histone lysine methyltransferases
The small molecule compound and its application of NSD2.
Background technique
The methylation modification of histone is mediated by histone methyltransferase (PMTs), and such transferase can be catalyzed first
Base is from the transfer on co-factor S-5 '-adenosyl-L-methione (SAM) to istone lysine or arginine residues.According to generation
The difference of the amino acid residue of methylation, histone methyltransferase can be divided into two classes: histone arginine methyltransferase
(PRMTs) and histone-lysine methyltransferase (PKMTs).The methylation modification occurred on lysine or arginine residues
The charge of residue will not be changed, but the size and hydrophobicity of protein can be changed, to influence mutual between protein
Effect.
Nuclear receptor combination SET domain protein NSD family be belong to one group of SET2 family occur with tumour it is closely related
Lysine methyltransferase, the family include three members: NSD1, NSD2 (MMSET/WHSC1) and NSD3 (WHSC1L1).
The structure of NSD protein family member is closely similar, all contains SET, PWWP and PHD structural domain.NSD2, that is, nuclear receptor combination SET knot
Structure domain albumen 2, be it is a kind of to the generation of many human tumors, the relevant histone-lysine methyltransferase of development.It is a series of
Experimental result confirms that NSD2 can specifically be catalyzed H3K36me and H3K36me2 during participating in gene transcriptional activation, and
H3K36me2 is the primary product that NSD2 plays its physiological function.The overexpression of NSD2 then with many human diseases especially tumour
Generation, development it is related.Since NSD2 is the main attemperator of chromatin Structure and transcription, overexpression will lead to genome
H3K36me2 horizontal abnormality increases, while being remarkably decreased with H3K37 methylation level, to influence turning for lots of genes
Record is horizontal.
Simultaneously research shows that the overexpression of NSD2 can accelerate the proliferation of tumour cell, inhibit the apoptosis of tumour cell, simultaneously
It can promote the transfer of tumour cell.The discovery such as Min, NSD2 can stimulate the expression of c-MYC, so that it is thin to promote Huppert's disease
The proliferative capacity of born of the same parents.In prostate gland cancer cell, the expression of NSD2 is apparently higher than normal prostate cell.NSD2 can lead to
Activation TWIST1 is crossed, the generation of EMT is promoted, increases the invasive ability of prostate gland cancer cell.NSD2 can also be with androgen receptor
(AR) it combines, promotes the expression of related gene, to increase the generation of prostate specific antigen (PSA), promote prostate cancer
Occur.In addition, can also detect that NSD2's crosses table in the tumours such as glioma, Small Cell Lung Cancer, oophoroma, breast cancer
It reaches.Therefore nuclear receptor combination SET domain protein NSD2 is considered as a kind of important histone-lysine methyltransferase, it
Include the generation of Huppert's disease, prostate cancer, breast cancer, glioma, lung cancer etc., play in development in many tumours
Important role.It is now also extremely limited to the research of histone-lysine methyltransferase NSD2 at present, yet there are no about
Histone-lysine methyltransferase NSD2 is directed to the relevant report in terms of disease treatment, and there are no the suppressions of the NSD2 small molecule of high activity
Preparation.
Summary of the invention
The purpose of the present invention is to provide a kind of small molecules for being able to suppress histone-lysine methyltransferase NSD2
Close object.
It is another object of the present invention to provide the inhibitor of histone-lysine methyltransferase NSD2 a kind of.
It is also an object of the present invention to provide a kind of activity is higher, selectivity is strong, the significant treating cancer of quasi-medicated property
Drug.
The present invention provides the small molecule compound of inhibition of histone lysine methyltransferase NSD2, and general formula is as follows:
Wherein,
A is independent containing an at most nitrogen-atoms, an oxygen atom, five-ring heterocycles of sulphur atom or containing at most
The aromatic ring of one nitrogen-atoms or hexa-member heterocycle containing an oxygen atom, nitrogen-atoms；
B is independent containing most three nitrogen-atoms, an oxygen atom, five-ring heterocycles of sulphur atom or containing at most
The aromatic ring of two nitrogen-atoms or hexa-member heterocycle containing a nitrogen-atoms；
R1Be independent H, methyl, new butyl, nitro, carboxyl, ehter bond, peptide bond, ester bond, halogen,
R2Be independent H, methyl, new butyl, nitro, carboxyl, ehter bond, peptide bond, ester bond, halogen,
R3It is independent H, O, methyl or is not present；
R4It is independent H, O, methyl or is not present；
R5It is independent H, O, methyl or is not present.
In view of the NSD2 micromolecular inhibitor that there is no high activity at present, the present invention to existing transmethylase by pressing down
After preparation carries out structural analysis, in conjunction with high flux screening, it has been found that this compound: 1- (1- methyl-1 H- benzo [d] [1,2,
3] triazole -5-) -3- (3- nitrobenzophenone) urea, to the IC of NSD250Respectively 8.3 μM.The structure of this compound is divided
Analysis, we, which have designed and synthesized, comes to carry out structure optimization to them comprising benzo-heterocycle twin nuclei series compound.It obtains
Higher active NSD2 inhibitor small molecule structure.
It specifically includes with flowering structure:
Above-mentioned small molecule compound has the effect of inhibition of histone lysine methyltransferase NSD2, thus can be with this
The inhibitor for inhibiting protein lysine transmethylase NSD2 is prepared as main active for serial small molecule compound
In, and NSD2 can specifically be catalyzed H3K36me and H3K36me2 during participating in gene transcriptional activation, H3K36me2 is
NSD2 plays the primary product of its physiological function.NSD2 overexpression then with the generation of many human diseases especially tumour, hair
Exhibition is related.Since NSD2 is the main attemperator of chromatin Structure and transcription, overexpression will lead to genome H3K36me2 water
Flat exception increases, while being remarkably decreased with H3K37 methylation level, to influence the transcriptional level of lots of genes.Together
When NSD2 overexpression can accelerate tumour cell proliferation, inhibit tumour cell apoptosis, while can promote tumour cell turn
It moves.The discovery such as Min, NSD2 can stimulate the expression of c-MYC, to promote the proliferative capacity of multiple myeloma cells.Preceding
In column adenocarcinoma cell, the expression of NSD2 is apparently higher than normal prostate cell.NSD2 can be promoted by activating TWIST1
The generation of EMT increases the invasive ability of prostate gland cancer cell.NSD2 can also be combined with androgen receptor (AR), promote dependency basis
The expression of cause promotes the generation of prostate cancer to increase the generation of prostate specific antigen (PSA).In addition, in neuroglia
Also the overexpression of NSD2 can be detected in the tumours such as tumor, Small Cell Lung Cancer, oophoroma, breast cancer.Therefore nuclear receptor combination SET knot
Structure domain albumen NSD2 is considered as a kind of important histone-lysine methyltransferase, it includes multiple bone in many tumours
It plays an important role in the generation of myeloma, prostate cancer, breast cancer, glioma, lung cancer etc., development.Therefore this is small
Molecular compound can be used directly as the main active of preparation treating cancer drug, can also be prepared into inhibiting
Agent, the inhibitor can be used directly by the drug as treating cancer, or as treating cancer drug chief active at
Divide to use, the cancer that emphasis is directed to has including prostate cancer, lung cancer, breast cancer, oophoroma.
Compared with prior art, the present invention have the following advantages that and the utility model has the advantages that
The present invention has synthesized a kind of new small point of compound for being able to suppress histone-lysine methyltransferase NSD2, and
In some embodiments for confirming the small point of compound, histone-lysine methyltransferase NSD2 can be generated preferable
Inhibiting effect, while there is good inhibiting effect to tumour cell, there is good pharmaceutical potential, provided for clinical application
A kind of new potential selection；Meanwhile the preparation method of noval chemical compound provided by the invention is easy, reaction condition is mild, convenient for behaviour
To make and controls, energy consumption is small, and yield is high, and it is at low cost, industrialization production can be suitble to, the chemical combination microbic activity being prepared is higher,
Strong to the selectivity of tumour cell, quasi-medicated property is significant, has a vast market foreground.
Detailed description of the invention
Upon reading the detailed description of non-limiting embodiments with reference to the following drawings, other features of the invention,
Objects and advantages will become apparent:
Fig. 1 is the Proliferation Ability line chart that compound 22 inhibits prostate gland cancer cell 22Rv-1 in the present invention；
Fig. 2 is compound 22 in the present invention in the methylation effect picture for inhibiting H3K36 into the cell in 22Rv-1.
Specific embodiment
The present invention is described in further detail below with reference to embodiment, embodiments of the present invention are not limited thereto,
Without departing from the idea case in the present invention described above, according to ordinary skill knowledge and customary means, various replace is made
It changes and changes, should all be included within the scope of the invention.
For the purpose of the present invention, process conditions and advantage effect is more clearly understood, in conjunction with following embodiment, to this
Invention is described in further detail, and specific implementation example described herein only to explain the present invention, is not used to limit this
Invention.
Embodiment 1:
Compound 1: compound N-cyclopropyl -3- (3- (1- methyl-1 H- benzo [d] [1,2,3] triazole -5) urea groups) benzene
Sulfonamide
Synthetic route is as follows:
Specific synthesis step is as follows:
Under the conditions of 0 DEG C, disperse N- methyl -4- nitrobenzene -1,2- diamines (A01a) (1.13g, 6.76mmol) in
In 22ml water, then be added 5.6ml concentrated hydrochloric acid formed highly acid mixture after instill be dissolved in 10ml sodium nitrite (568mg,
8.23mmol) aqueous solution.It is slowly warmed to room temperature after keeping 0 DEG C of condition to stir 4 hours, filters and washs filter cake with cold water, obtained
Linen compound is 5- nitro benzo (1- methyl) triazole (A01b).
Then about 50ml EtOH:H is dispersed by A01b (950mg, 5.3mmol)2In the dicyandiamide solution of O=2:1, it is added
Ammonium chloride (570mg, 10.6mmol) heats up afterwards, iron powder (1190mg, 21.2mmol) is added when temperature rises to 60 DEG C, after of continuing rising
Temperature is to 80 DEG C of back flow reactions.Stop reaction after 2h, reaction solution is cooled to room temperature, is washed after suction filtration with dehydrated alcohol, gained is filtered
After liquid vacuum distillation removes solvent, with saturated sodium bicarbonate solution (200ml) and methylene chloride (200ml × 2) extraction, then with pure
Water (200ml) washing, vacuum distillation removes solvent and obtains intermediate (A01c) after organic layer anhydrous magnesium sulfate drying.
3- amino-N-cyclopropyl benzsulfamide (A01d) (180mg, 0.85mmol) and 1 drop triethylamine are dissolved in about
In 30ml toluene, it is slowly dropped under the conditions of -5 DEG C in the triphosgene (A01e) (252mg, 0.85mmol) by 10ml dissolution, drop
After complete, reaction solution was moved to after stirring at normal temperature half an hour and is warming up to 110 DEG C of back flow reactions, fully reacting after 3 hours will be anti-
Liquid vacuum distillation is answered to remove solvent, obtained solid is suspended in ethyl acetate, solvent is distilled off in filtrate decompression after suction filtration and is obtained
To inter-mediate isocyanate, by the intermediate and synthesized intermediate 5- amino benzo (1- methyl) triazole (A01c)
(63mg, 0.42mmol) is dissolved in 30ml Isosorbide-5-Nitrae-dioxane, is warming up to 100 DEG C of reactions.End of reaction after 2 hours, will
To the turbid solution filter cake that directly filters, and washed with methylene chloride, obtain pale solid (compound 1,95mg).Yield is
58.0%.
MS (ESI) data of compound 1 are as follows:
MS(ESI)387.2[M+H]+；1H NMR(400MHz,DMSO-d6)δ9.15(s,1H),8.97(s,1H),8.20
(d, J=1.2Hz, 1H), 8.12 (s, 1H), 7.93 (d, J=2.4Hz, 1H), 7.78 (d, J=8.8Hz, 1H), 7.63 (d, J=
9.2Hz, 1H), 7.57-7.48 (m, 2H), 7.41 (d, J=7.6Hz, 1H), 4.28 (s, 3H), 2.15-2.11 (m, 1H),
0.50-0.47(m,2H),0.45–0.37(m,2H).
Embodiment 2:
Compound 2:N- cyclopropyl -3- (3- (1- methyl-1 H- benzo [d] [1,2,3] triazole -5) urea groups) benzamide
Synthetic route is as follows:
Other specific same above-described embodiments of synthesis step, are prepared compound 2, yield 61.2%.
MS (ESI) data of compound 2 are as follows:
MS(ESI)351.3[M+H]+；1H NMR(400MHz,DMSO-d6)δ8.91(s,1H),8.89(s,1H),8.41
(d, J=3.6Hz, 1H), 8.20 (s, 1H), 7.86 (s, 1H), 7.77 (d, J=8.8Hz, 1H), 7.64 (d, J=8.0Hz,
1H), 7.51 (d, J=7.6Hz, 1H), 7.40 (d, J=7.6Hz, 1H), 7.35 (t, J=7.6Hz, 1H), 4.28 (s, 3H),
2.91–2.79(m,1H),0.73–0.66(m,2H),0.58-0.57(m,2H).
Embodiment 3:
Compound 3:1- (1- methyl-1 H- benzo [d] [1,2,3] triazole -5) -3- (3- (morpholine -4- carbonyl) phenyl)
Urea
Synthetic route is as follows:
Other specific same above-described embodiments of synthesis step, are prepared compound 3, yield 68.3%.
MS (ESI) data of compound 3 are as follows:
MS(ESI)381.1[M+H]+；1H NMR(400MHz,DMSO-d6)δ8.96(s,1H),8.90(s,1H),8.19
(d, J=1.2Hz, 1H), 7.77 (d, J=8.8Hz, 1H), 7.60 (s, 1H), 7.54-7.43 (m, 2H), 7.36 (t, J=
7.6Hz, 1H), 7.01 (d, J=7.6Hz, 1H), 4.27 (s, 3H), 3.61 (s, 8H)
Embodiment 4:
Compound 4:1- (the fluoro- 5- nitrobenzophenone of 3-) -3- (1- methyl-1 H- benzo [d] [1,2,3] triazole -5) urea
Synthetic route is as follows:
Other specific same above-described embodiments of synthesis step, are prepared compound 4, yield 70.5%.
MS (ESI) data of compound 4 are as follows:
MS(ESI)331.0[M+H]+；1H NMR(400MHz,DMSO-d6)δ9.48(s,1H),9.18(s,1H),8.29
(s, 1H), 8.18 (d, J=1.2Hz, 1H), 7.83-7.75 (m, 2H), 7.72-7.65 (m, 1H), 7.56 (dd, J=8.8,
1.6Hz,1H),4.28(s,3H).
Embodiment 5:
Compound 5:1- (benzo [d] thiazole -6-) -3- (3- nitrobenzophenone) urea
Synthetic route is as follows:
Other specific same above-described embodiments of synthesis step, are prepared compound 5, yield 53.1%.
MS (ESI) data of compound 5 are as follows:
MS(ESI)315.0[M+H]+1HNMR(400MHz,DMSO-d6)δAo9.33(s,1H),9.24(s,1H),9.15
(s, 1H), 8.61 (s, 1H), 8.41 (s, 1H), 8.01 (d, J=8.4Hz, 1H), 7.85 (d, J=8.0Hz, 1H), 7.73 (d, J
=7.6Hz, 1H), 7.59 (t, J=8.0Hz, 1H), 7.52 (d, J=8.8Hz, 1H)
Embodiment 6:
Compound 6:1- (benzo [d] thiazole -5-) -3- (3- nitrobenzophenone) urea
Synthetic route is as follows:
Other specific same above-described embodiments of synthesis step, are prepared compound 6, yield 56.5%.
MS (ESI) data of compound 6 are as follows:
MS(ESI)315.0[M+H]+；1H NMR(400MHz,DMSO-d6)δ9.37(s,1H),9.32(s,1H),9.11
(s, 1H), 8.59 (s, 1H), 8.34 (d, J=1.6Hz, 1H), 8.07 (d, J=8.4Hz, 1H), 7.85 (dd, J=8.0,
1.6Hz, 1H), 7.76 (d, J=8.0Hz, 1H), 7.59 (t, J=8.0Hz, 1H), 7.52 (dd, J=8.8,1.6Hz, 1H)
Embodiment 7:
Compound 7:1- (1H- indoles -6-) -3- (3- nitrobenzophenone) urea
Synthetic route is as follows:
Other specific same above-described embodiments of synthesis step, are prepared compound 7, yield 61.6%.
MS (ESI) data of compound 7 are as follows:
MS(ESI)297.1[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.99(s,1H),9.12(s,1H),8.59
(d, J=6.8Hz, 2H), 7.80 (d, J=8.4Hz, 1H), 7.71 (d, J=7.2Hz, 2H), 7.56 (t, J=8.0Hz, 1H),
7.33 (s, 1H), 7.31 (s, 1H), 7.10 (d, J=8.4Hz, 1H), 6.37 (s, 1H)
Embodiment 8:
Compound 8:1- (benzo [d] [1,2,3] thiadiazoles -6-) -3- (3- nitrobenzophenone) urea
Synthetic route is as follows:
Specific synthesis step is as follows:
Using synthesized intermediate 6- amino [1,2,3] diazosulfide (B) and 3- nitroaniline (A05b), synthesis is eventually
Product 1- (benzo [d] [1,2,3] thiadiazoles -6-) -3- (3- nitrobenzophenone) urea (A08).The synthetic method of intermediate B are as follows: will
6- nitrobenzene thiazole (A08a) (15g, 83mmol) is suspended in 200ml dehydrated alcohol, is heated back after 20ml hydrazine hydrate is added
Stream reaction.After 2h, reaction solution becomes red tan solution from yellow muddiness shape, and 18ml is added when reaction solution is cooled to 30 DEG C
30% hydrogen peroxide, and so that temperature is remained unchanged with ice-water bath, yellow mercury oxide is formed in reaction solution, stirring is taken out after one hour
Filter, it is dry after being washed with water and ether, obtain compound (2- amino -5- nitrobenzophenone) disulphide (A08b).Then will change
It closes object A08b (10g, 29mmol) to be scattered in the 70ml concentrated sulfuric acid, at 0 DEG C, sodium nitrite (5.1g, 74mmol) is added by several times,
Reaction temperature is set to be maintained at 10 DEG C or less simultaneously.After adding sodium nitrite, it is warmed to room temperature reaction temperature, is stirred to react 15 small
When after end of reaction, reaction solution is poured into 400ml ice water, stirring 1 as a child after, yellow solid is filtered to obtain, with water and ether
Compound 6- nitro [1,2,3] diazosulfide (A08c) is obtained after washing.Compound A-40 8c (9g, 50mmol) and ammonium chloride
(5.3g, 99mmol) is scattered in the dicyandiamide solution of EtOH:H2O=2:1, when temperature rises to 60 DEG C be added iron powder (11.1g,
199mmol), 80 DEG C of back flow reactions are continuously heating to.Stop reaction after 2h, reaction solution is cooled to room temperature, and filters and with anhydrous second
Alcohol washing, after solvent is distilled off in gained filtrate decompression, with saturated sodium bicarbonate solution (200ml) and methylene chloride (200ml
× 2) it extracts, then is washed with pure water (200ml), vacuum distillation removes solvent and obtains centre after organic layer anhydrous magnesium sulfate drying
Body B (7.8g, yield 86.7%).Compound 8, yield is prepared referring to the synthetic method of final product A01 in subsequent specific steps
For 57.8%.
MS (ESI) data of compound 8 are as follows:
MS(ESI)316.3[M+H]+；1H NMR(400MHz,DMSO-d6)δ9.54(s,1H),9.46(s,1H),8.66
(s, 1H), 8.62 (s, 1H), 8.59 (s, 1H), 7.87 (d, J=7.2Hz, 1H), 7.75 (d, J=8.0Hz, 1H), 7.70 (d, J
=8.4Hz, 1H), 7.61 (t, J=8.0Hz, 1H)；13CNMR(100MHz,DMSO-d6)δ153.79,152.24,148.10,
142.16,140.76,140.54,130.10,124.55,123.57,119.74,116.72,112.41,106.80.
Embodiment 9:
Compound 9:1- (3- nitrobenzophenone) -3- (quinoline -7-) urea
Synthetic route is as follows:
Other specific same above-described embodiments of synthesis step, are prepared compound 9, yield 68.2%.
MS (ESI) data of compound 9 are as follows:
MS(ESI)309.1[M+H]+；1HNMR(400MHz,DMSO-d6)δ10.02(s,1H),9.90(s,1H),9.00
(dd, J=4.8,1.2Hz, 1H), 8.67 (d, J=8.0Hz, 1H), 8.61 (t, J=2.0Hz, 1H), 8.49 (d, J=1.2Hz,
1H), 8.11 (d, J=8.8Hz, 1H), 7.88 (dd, J=8.0,2.0Hz, 1H), 7.78 (dd, J=8.0,2.0Hz, 1H),
7.74 (dd, J=9.2,2.0Hz, 1H), 7.66-7.59 (m, 2H)；13C NMR(100MHz,DMSO-d6)δ152.35,
148.13,147.60,144.02,142.64,140.56,130.17,129.39,124.34,124.20,121.22,119.43,
116.70,112.18,109.33。
Embodiment 10:
Compound 10:1- (benzo [d] [1,2,3] thiadiazoles -6-) -3- (3- chlorphenyl) urea
Synthetic route is as follows:
Other specific same above-described embodiments of synthesis step, are prepared compound 10, yield 57.1%.
MS (ESI) data of compound 10 are as follows:
MS(ESI)305.1[M+H]+；1H NMR(600MHz,DMSO-d6)δ9.42(s,1H),9.10(s,1H),8.60
(d, J=1.8Hz, 1H), 8.58 (d, J=9.0Hz, 1H), 7.74 (s, 1H), 7.68 (dd, J=9.0,1.8Hz, 1H) 7.35-
7.30(m,2H),7.11–6.96(m,1H).MS(ESI)305.1[M+H]+.
Embodiment 11:
Compound 11:1- (benzo [d] [1,2,3] thiadiazoles -6-) -3- (3- methoxyphenyl) urea
Synthetic route is as follows:
Other specific same above-described embodiments of synthesis step, are prepared compound 11, yield 59.6%.
MS (ESI) data of compound 11 are as follows:
MS(ESI)301.0[M+H]+；1H NMR(600MHz,DMSO-d6)δ9.32(s,1H),8.90(s,1H),8.61
(d, J=1.8Hz, 1H), 8.57 (d, J=9.0Hz, 1H), 7.66 (dd, J=9.0,1.8Hz, 1H), 7.23 (dd, J=4.2,
2.4Hz, 1H), 7.20 (d, J=8.4Hz, 1H), 6.97 (d, J=7.8Hz, 1H), 6.60 (dd, J=7.8,2.4Hz, 1H),
3.74(s,3H).
Embodiment 12:
Compound 12:1- (benzo [d] [1,2,3] thiadiazoles -6-) -3- (3- cyano-phenyl) urea
Synthetic route is as follows:
Other specific same above-described embodiments of synthesis step, are prepared compound 12, yield 62.3%.
MS (ESI) data of compound 12 are as follows:
MS(ESI)318.3[M+H]+；1HNMR(400MHz,DMSO-d6)δ9.52(s,1H),9.25(s,1H),8.60(d,
J=8.8Hz, 2H), 8.01 (s, 1H), 7.72 (t, J=8.8Hz, 2H), 7.52 (d, J=8.0Hz, 1H), 7.47 (d, J=
7.2Hz,1H).
Embodiment 13:
Compound 13:N- (3- (3- (benzo [d] [1,2,3] thiadiazoles -6-) urea groups) phenyl) acetamide
Synthetic route is as follows:
Other specific same above-described embodiments of synthesis step, are prepared compound 13, yield 50.1%.
MS (ESI) data of compound 13 are as follows:
MS(ESI)350.2[M+Na]+；1H NMR(400MHz,DMSO-d6)δ9.94(s,1H),9.24(s,1H),8.94
(s, 1H), 8.58 (d, J=2.4Hz, 1H), 8.57 (s, 1H), 7.82 (s, 1H), 7.67 (dd, J=9.2,2.0Hz, 1H),
7.22 (d, J=7.6Hz, 1H), 7.19 (s, 1H), 2.04 (s, 3H)
Embodiment 14:
Compound 14:1- (benzo [d] [1,2,3] thiadiazoles -6-) -3- (3- (morpholine -4- carbonyl) phenyl) urea
Synthetic route is as follows:
Other specific same above-described embodiments of synthesis step, are prepared compound 14, yield 70.1%.
MS (ESI) data of compound 14 are as follows:
MS(ESI)406.0[M+Na]+；1H NMR(400MHz,DMSO-d6)δ9.40(s,1H),9.05(s,1H),8.60
(s, 1H), 8.57 (s, 1H), 7.69 (dd, J=9.2,2.0Hz, 1H), 7.61 (s, 1H), 7.50 (d, J=9.2Hz, 1H),
7.39 (t, J=8.0Hz, 1H), 7.04 (d, J=7.6Hz, 1H), 3.61 (s, 8H)
Embodiment 15:
Compound 15:3- (3- (benzo [d] [1,2,3] thiadiazoles -6-) urea groups)-N- cyclopropyl-phenyl sulfonamide
Synthetic route is as follows:
Other specific same above-described embodiments of synthesis step, are prepared compound 15, yield 69.5%.
MS (ESI) data of compound 15 are as follows:
MS(ESI)412.2[M+Na]+；1H NMR(400MHz,DMSO-d6)δ9.41(s,1H),9.28(s,1H),8.63
(d, J=1.6Hz, 1H), 8.59 (d, J=8.8Hz, 1H), 8.15 (s, 1H), 7.93 (d, J=2.0Hz, 1H), 7.70 (dd, J
=9.2,2.0Hz, 1H), 7.63 (d, J=8.8Hz, 1H), 7.54 (t, J=8.0Hz, 1H), 7.44 (d, J=8.0Hz, 1H),
2.13 (td, J=6.8,3.2Hz, 1H), 0.53-0.45 (m, 2H), 0.45-0.37 (m, 2H)
Embodiment 16:
Compound 16:3- (3- (benzo [d] [1,2,3] thiadiazoles -6-) urea groups)-N- cyclopropyl-phenyl formamide
Synthetic route is as follows:
Other specific same above-described embodiments of synthesis step, are prepared compound 16, yield 67.3%.
MS (ESI) data of compound 16 are as follows:
MS(ESI)376.2[M+Na]+；1H NMR(400MHz,DMSO-d6)δ9.37(s,1H),9.05(s,1H),8.62
(d, J=1.6Hz, 1H), 8.59 (d, J=9.2Hz, 1H), 8.43 (d, J=4.0Hz, 1H), 7.90 (s, 1H), 7.69 (dd, J
=9.2,1.6Hz, 1H), 7.64 (d, J=8.0Hz, 1H), 7.44 (d, J=8.0Hz, 1H), 7.38 (d, J=8.0Hz, 1H),
2.85 (td, J=7.2,4.0Hz, 1H), 0.74-0.64 (m, 2H), 0.62-0.51 (m, 2H)
Embodiment 17:
Compound 17:1- (benzo [d] [1,2,3] thiadiazoles -6-) -3- (bis- (trifluoromethyl) phenyl of 3,5-) urea
Synthetic route is as follows:
Other specific same above-described embodiments of synthesis step, are prepared compound 17, yield 47.8%.
MS (ESI) data of compound 17 are as follows:
MS(ESI)407.2[M+H]+；1H NMR(400MHz,DMSO-d6)δ9.69(s,1H),9.61(s,1H),8.67
(s, 1H), 8.61 (d, J=9.2Hz, 1H), 8.19 (s, 2H), 7.73 (s, 1H), 7.71 (s, 1H)
Embodiment 18:
Compound 18:1- (benzo [d] [1,2,3] thiadiazoles -6-) -3- (3- bromo- 5- (trifluoromethyl) phenyl) urea
Synthetic route is as follows:
Other specific same above-described embodiments of synthesis step, are prepared compound 18, yield 57.6%.
MS (ESI) data of compound 18 are as follows:
MS(ESI)417.3[M+H]+；1H NMR(400MHz,DMSO-d6)δ9.61(s,1H),9.41(s,1H),8.64
(s, 1H), 8.60 (d, J=8.8Hz, 1H), 7.99 (s, 1H), 7.94 (s, 1H), 7.70 (d, J=9.2Hz, 1H), 7.57 (s,
1H).
Embodiment 19:
Compound 19:1- (benzo [d] [1,2,3] thiadiazoles -6-) -3- (the fluoro- 5- nitrobenzophenone of 3-) urea
Synthetic route is as follows:
Other specific same above-described embodiments of synthesis step, are prepared compound 19, yield 56.6%.
MS (ESI) data of compound 19 are as follows:
MS(ESI)356.1[M+Na]+；1H NMR(400MHz,DMSO-d6)δ9.64(s,1H),9.62(s,1H),8.64
(d, J=1.6Hz, 1H), 8.60 (d, J=8.8Hz, 1H), 8.33 (s, 1H), 7.77 (d, J=10.8Hz, 1H), 7.72 (d, J
=8.4Hz, 2H)
Embodiment 20:
Compound 20:3- (3- (benzo [d] [1,2,3] thiadiazoles -6-) urea groups) -5- nitrobenzene methyl
Synthetic route is as follows:
Other specific same above-described embodiments of synthesis step, are prepared compound 20, yield 58.8%.
MS (ESI) data of compound 20 are as follows:
MS(ESI)396.2[M+Na]+；1HNMR(400MHz,DMSO-d6)δ9.71(s,1H),9.60(s,1H),8.71
(t, J=2.0Hz, 1H), 8.67 (d, J=2.0Hz, 1H), 8.60 (d, J=8.8Hz, 1H), 8.46 (s, 1H), 8.26 (d, J=
1.2Hz, 1H) 7.72 (dd, J=9.2,2.0Hz, 1H), 3.94 (s, 3H)
Embodiment 21:
Compound 21:3- (3- (benzo [d] [1,2,3] thiadiazoles -6-) urea groups) -5- fluorophenyl carbamate
Synthetic route is as follows:
Other specific same above-described embodiments of synthesis step, are prepared compound 21, yield 53.9%.
MS (ESI) data of compound 21 are as follows:
MS(ESI)369.1[M+Na]+；1HNMR(400MHz,DMSO-d6)δ9.47(s,1H),9.39(s,1H),8.63
(d, J=1.6Hz, 1H), 8.60 (d, J=9.2Hz, 1H), 7.97 (s, 1H), 7.73-7.65 (m, 2H), 7.33 (d, J=
9.2Hz,1H),3.88(s,3H).
Embodiment 22:
Dibenzoic acid dimethyl ester between compound 22:5- (3- (benzo [d] [1,2,3] thiadiazoles -6-) urea groups)
Synthetic route is as follows:
Other specific same above-described embodiments of synthesis step, are prepared compound 22, yield 51.3%.
MS (ESI) data of compound 22 are as follows:
MS(ESI)387.2[M+H]+；1HNMR(400MHz,DMSO-d6) δ 9.48 (d, J=3.2Hz, 2H), 8.67 (s,
1H), 8.60 (d, J=9.2Hz, 1H), 8.39 (s, 2H), 8.13 (s, 1H), 7.71 (dd, J=8.8,1.6Hz, 1H), 3.91
(s,6H)；13CNMR(100MHz,DMSO-d6)δ170.55,159.02,157.52,147.40,146.07,146.02,
145.61,135.93,128.75,128.16,125.04,112.15,112.06,57.75.
Embodiment 23:
Compound 23:3- (3- (benzo [d] [1,2,3] thiadiazoles -6-) urea groups) -5- methyl-bromobenzoate
Synthetic route is as follows:
Other specific same above-described embodiments of synthesis step, are prepared compound 23, yield 59.4%.
MS (ESI) data of compound 23 are as follows:
MS(ESI)429.3[M+Na]+；1H NMR(400MHz,DMSO-d6)δ9.49(s,1H),9.35(s,1H),8.63
(d, J=1.6Hz, 1H), 8.59 (d, J=9.2Hz, 1H), 8.12 (s, 1H), 8.01 (t, J=1.6Hz, 1H), 7.71 (d, J=
2.0Hz,1H),7.70–7.67(m,1H),3.88(s,3H).
Embodiment 24:
Compound 24:1- (benzo [d] [1,2,3] thiadiazoles -6-) -3- (the bromo- 5- nitrobenzophenone of 2-) urea
Synthetic route is as follows:
Other specific same above-described embodiments of synthesis step, are prepared compound 24, yield 57.7%.
MS (ESI) data of compound 24 are as follows:
MS(ESI)394.0[M+H]+；1H NMR(400MHz,DMSO-d6) δ 10.31 (s, 1H), 9.11 (d, J=2.8Hz,
1H), 8.73 (s, 1H), 8.71 (d, J=1.6Hz, 1H), 8.63 (d, J=8.8Hz, 1H), 7.97 (d, J=8.8Hz, 1H),
7.83 (dd, J=8.8,2.8Hz, 1H), 7.69 (dd, J=9.2,2.0Hz, 1H)
Embodiment 25:
Compound 25:1- (benzo [d] [1,2,3] thiadiazoles -6-) -3- (4- methyl-3-nitro phenyl) urea
Synthetic route is as follows:
Other specific same above-described embodiments of synthesis step, are prepared compound 25, yield 67.7%.
MS (ESI) data of compound 25 are as follows:
MS(ESI)330.4[M+H]+；1H NMR(400MHz,DMSO-d6)δ9.49(s,1H),9.29(s,1H),8.64
(d, J=2.0Hz, 1H), 8.60 (d, J=9.2Hz, 1H), 8.35 (d, J=2.4Hz, 1H), 7.70 (dd, J=9.2,2.0Hz,
1H), 7.60 (dd, J=8.4,2.0Hz, 1H), 7.44 (d, J=8.4Hz, 1H), 2.48 (s, 3H)
Embodiment 26:
Compound 26:1- (benzo [d] [1,2,3] thiadiazoles -6-) -3- (5- (tert-butyl) isoxazole -3-) urea
Synthetic route is as follows:
Other specific same above-described embodiments of synthesis step, are prepared compound 26, yield 68.1%.
MS (ESI) data of compound 26 are as follows:
MS(ESI)340.1[M+Na]+；1H NMR(400MHz,DMSO-d6)δ9.73(s,1H),9.42(s,1H),8.60
(s, 1H), 8.61 (d, J=8.8Hz, 1H), 7.69 (d, J=9.2Hz, 1H), 6.54 (s, 1H), 1.31 (s, 9H)
Embodiment 27:
Compound 27:2- (3- (benzo [d] [1,2,3] thiadiazoles -6-) urea groups) 4-thiazolecarboxylic acid ethyl ester
Synthetic route is as follows:
Other specific same above-described embodiments of synthesis step, are prepared compound 27, yield 48.2%.
MS (ESI) data of compound 27 are as follows:
MS(ESI)350.6[M+H]+；1H NMR(400MHz,DMSO-d6)δ11.19(s,1H),9.61(s,1H),8.67
(s, 1H), 8.63 (d, J=8.8Hz, 1H), 8.03 (s, 1H), 7.73 (d, J=8.8Hz, 1H), 4.28 (q, J=6.4Hz,
2H), 1.30 (t, J=6.4Hz, 3H)
Embodiment 28:
Compound 28:2- (3- (benzo [d] [1,2,3] thiadiazoles -6-) urea groups) thiophene -3- carboxylate methyl ester
Synthetic route is as follows:
Other specific same above-described embodiments of synthesis step, are prepared compound 28, yield 57.1%.
MS (ESI) data of compound 28 are as follows:
MS(ESI)335.7[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.90(s,1H),10.63(s,1H),8.71
(d, J=2.0Hz, 1H), 8.62 (d, J=9.2Hz, 1H), 7.69 (dd, J=9.2,2.0Hz, 1H), 7.17 (d, J=5.6Hz,
1H), 6.97 (d, J=6.0Hz, 1H), 3.87 (s, 3H)
Embodiment 29:
Compound 29:3- (3- (benzo [d] [1,2,3] thiadiazoles -6-) urea groups) -4- methylthiophene -2- methyl formate
Synthetic route is as follows:
Other specific same above-described embodiments of synthesis step, are prepared compound 29, yield 51.9%.
MS (ESI) data of compound 29 are as follows:
MS(ESI)371.1[M+Na]+；1H NMR(400MHz,DMSO-d6)δ10.02(s,1H),8.75(s,1H),8.60
(d, J=2.8Hz, 1H), 8.58 (s, 1H), 7.68 (dd, J=9.2,1.6Hz, 1H), 7.57 (s, 1H), 3.80 (s, 3H),
2.15(s,3H).
Embodiment 30:
Compound 30:1- (benzo [d] [1,2,3] thiadiazoles -6-) -3- (6- chloropyridine -3-) urea
Synthetic route is as follows:
Other specific same above-described embodiments of synthesis step, are prepared compound 30, yield 61.6%.
MS (ESI) data of compound 30 are as follows:
MS(ESI)306.3[M+H]+；1HNMR(400MHz,DMSO-d6)δ9.55(s,1H),9.23(s,1H),8.60(d,
J=2.4Hz, 1H), 8.59 (s, 1H), 8.53 (d, J=2.8Hz, 1H), 8.02 (dd, J=8.8,2.8Hz, 1H), 7.70 (dd,
J=9.2,1.6Hz, 1H), 7.47 (d, J=8.4Hz, 1H)；13CNMR(100MHz,DMSO-d6)δ153.79,152.25,
142.70,142.16,140.80,139.83,135.64,129.24,124.11,123.60,119.70,106.74
Embodiment 31:
Compound 31:1- (benzo [d] [1,2,3] thiadiazoles -6-) -3- (6- bromopyridine -3-) urea
Synthetic route is as follows:
Other specific same above-described embodiments of synthesis step, are prepared compound 31, yield 60.1%.
MS (ESI) data of compound 31 are as follows:
MS(ESI)351.1[M+H]+；1H NMR(400MHz,DMSO-d6)δ9.56(s,1H),9.23(s,1H),8.60
(d, J=8.0Hz, 2H), 8.52 (s, 1H), 7.93 (d, J=8.8Hz, 1H), 7.70 (d, J=9.6Hz, 1H), 7.59 (d, J=
8.4Hz,1H).
Embodiment 32:
Compound 32:1- (3- (5- acetyl thiophene -2-) -5- trifluoromethyl) -3- (benzo [d] [1,2,3] thiophene two
Azoles -6-) urea
Synthetic route is as follows:
Specific synthesis step is as follows:
By synthesized compound 1- (benzo [d] [1,2,3] thiadiazoles -6-) -3- (3- bromo- 5- (trifluoromethyl) phenyl)
Urea (B16) (85mg, 0.20mmol), 5- acetyl group -2- thienyl boric acid (B31f) (52mg, 0.30mmol), K2CO3 (84mg,
It 0.60mmol) is suspended in 3ml DMF and 1ml H2O with Pd (PPh3) 4 (24mg, 0.02mmol), reaction system is set with N2
It changes and is placed on 80 DEG C of reactions three times, the color of reaction solution becomes black from yellow after 5 hours, and vacuum distillation removes in reaction solution
After solvent, the mixture containing a large amount of salt is obtained, gained mixture is purified into (eluent gradient: methylene chloride/first through column chromatography
Alcohol=50/1) milky final product (compound 32,32mg) is recrystallized to obtain through ethyl acetate and petroleum ether again.Yield are as follows:
34.7%.
MS (ESI) data of compound 32 are as follows:
MS(ESI)463.5[M+H]+；1H NMR(400MHz,DMSO-d6)δ9.59(s,1H),9.42(s,1H),8.69
(d, J=1.6Hz, 1H), 8.60 (d, J=9.2Hz, 1H), 8.10 (s, 1H), 8.01 (d, J=4.0Hz, 1H), 7.97 (s,
1H), 7.82 (d, J=4.0Hz, 1H), 7.77 (s, 1H), 7.71 (dd, J=8.8,2.0Hz, 1H), 2.58 (s, 3H)
Embodiment 33:
Compound 33:1- (benzo [d] [1,2,3] thiadiazoles -6-) -3- (3- (pyridine -3-) -5- (trifluoromethyl) phenyl)
Urea
Synthetic route is as follows:
Other specific same above-described embodiments of synthesis step, are prepared compound 33, yield 42.2%.
MS (ESI) data of compound 33 are as follows:
MS(ESI)416.1[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.13(s,1H),9.93(s,1H),8.95
(d, J=13.2Hz, 1H), 8.70-8.58 (m, 2H), 8.16-8.00 (m, 2H), 8.01 (s, 1H), 7.75-7.51 (m, 4H)
Embodiment 34:
Compound 34:3- acrylamido -5- (3- (benzo [d] [1,2,3] thiadiazoles -6-) urea groups) methyl benzoate
Synthetic route is as follows:
Specific synthesis step is as follows:
By synthesized compound 3- (3- (benzo [d] [1,2,3] thiadiazoles -6-) urea groups) -5- nitrobenzene methyl
(B18) (50mg, 0.13mmol) and NH4Cl (14mg, 0.26mmol) are scattered in the dicyandiamide solution of EtOH:H2O=2:1,
Iron powder (30mg, 0.52mmol) is added when rising to 60 DEG C in temperature, is continuously heating to 80 DEG C of back flow reactions.Stop reaction after 2h, instead
It answers liquid to be cooled to room temperature, filter and is washed with dehydrated alcohol, after solvent is distilled off in gained filtrate decompression, with unsaturated carbonate hydrogen
Sodium solution (30ml) and methylene chloride (30ml × 2) extraction, then washed with pure water (50ml), organic layer is dry with anhydrous magnesium sulfate
Vacuum distillation removes solvent and obtains corresponding amino intermediate afterwards, which is dissolved in 10ml tetrahydrofuran (THF), often
Temperature is lower to be added n,N-diisopropylethylamine (DIEA, 33mg, 0.26mmol), and acryloyl chloride (B07f) is added after dissolving completely
(12mg, 0.13mmol) after normal-temperature reaction 1 hour, is added 2ml saturated sodium bicarbonate aqueous solution and extra acryloyl chloride is quenched,
Vacuum distillation removes the tetrahydrofuran in reaction solution, and water (20ml) and methylene chloride (2 × 20ml) extraction, organic layer nothing is added
Vacuum distillation removes solvent after water magnesium sulfate is dry, obtains brown crude product, purifies (eluent gradient: dichloro by column chromatography
Methane/methanol=50/1) white final product (compound 34,18mg) is recrystallized to obtain through ethyl acetate and petroleum ether again.Yield are as follows:
35.3%.
MS (ESI) data of compound 34 are as follows:
MS(ESI)420.5[M+Na]+；1H NMR(400MHz,DMSO-d6)δ10.38(s,1H),9.31(s,1H),9.26
(s, 1H), 8.63 (s, 1H), 8.59 (d, J=9.2Hz, 1H), 8.15 (s, 1H), 7.98 (s, 1H), 7.95 (s, 1H), 7.70
(d, J=8.8Hz, 1H), 6.45 (dd, J=16.9,10.1Hz, 1H), 6.30 (d, J=17.0Hz, 1H), 6.18 (dd, J=
17.2,10.0Hz,1H),3.87(s,3H).
Embodiment 35:
Compound 35:5- (3- (quinoline -5- base) urea groups) dimethyl isophthalate
Synthetic route is as follows:
Other specific synthesis steps are as follows
5- amino isophthalic acid dimethyl ester (D01a) (0.85mmol) and 1 drop triethylamine are dissolved in about 30ml toluene
In, it is slowly dropped under the conditions of -5 DEG C in the triphosgene (0.85mmol) by 10ml dissolution, after dripping off, reaction solution is moved to often
Temperature is warming up to 110 DEG C of back flow reactions after stirring half an hour, reaction solution is evaporated under reduced pressure and removes solvent by fully reacting after 3 hours,
Obtained solid is suspended in ethyl acetate, and solvent is distilled off in filtrate decompression after suction filtration and obtains intermediate 3, the bis- (methoxyl groups of 5-
Carbonyl) phenyl isocyanate (D01b), the intermediate and 5- aminoquinoline (D01c) (0.42mmol) are dissolved in 30ml Isosorbide-5-Nitrae-two
In six ring of oxygen, it is warming up to 100 DEG C of reactions.Obtained turbid solution is directly filtered, and uses dichloromethane by end of reaction after 2 hours
The filter cake that alkane is washed obtains pale solid (compound 35,81mg).
Compound 35, yield 52% is prepared.
Compound 351H NMR data is as follows:
1H NMR (400MHz, DMSO) δ 9.58 (s, 1H), 9.33 (s, 1H), 8.94 (s, 1H), 8.60 (d, J=6.0Hz,
1H), 8.38 (d, J=1.4Hz, 2H), 8.23 (d, J=7.1Hz, 1H), 8.12 (d, J=1.4Hz, 1H), 7.94 (d, J=
6.1Hz, 1H), 7.88 (d, J=8.2Hz, 1H), 7.68 (t, J=7.9Hz, 1H), 3.91 (s, 6H)
Embodiment 36:
Compound 36:5- (3- (quinoxalin-6-yl) urea groups) dimethyl isophthalate
Synthetic route is as follows:
Other specific same above-described embodiments of synthesis step, are prepared compound 36, yield 55%.
Compound 371H NMR data is as follows:
1H NMR (400MHz, DMSO) δ 9.47 (s, 1H), 9.38 (s, 1H), 8.87 (d, J=1.8Hz, 1H), 8.79 (d,
J=1.9Hz, 1H), 8.39 (d, J=1.5Hz, 2H), 8.33 (d, J=2.3Hz, 1H), 8.13 (t, J=1.5Hz, 1H), 8.03
(d, J=9.1Hz, 1H), 7.88 (dd, J=9.1,2.4Hz, 1H), 3.91 (s, 6H)
Embodiment 37:
Compound 37:5- (3- (quinoline-8-yl) urea groups) dimethyl isophthalate
Synthetic route is as follows:
Other specific same above-described embodiments of synthesis step, are prepared compound 37, yield 57%.
Compound 371H NMR data is as follows:
1H NMR (400MHz, DMSO) δ 9.60 (s, 1H), 9.53 (s, 1H), 9.20 (s, 1H), 8.54 (d, J=5.7Hz,
1H), 8.39 (d, J=1.4Hz, 2H), 8.12 (d, J=1.4Hz, 1H), 8.09 (d, J=7.0Hz, 1H), 7.84 (d, J=
5.6Hz, 1H), 7.75 (t, J=7.8Hz, 1H), 7.70 (d, J=8.0Hz, 1H), 3.91 (s, 6H)
Embodiment 38:
Compound 38:5- (3- (2- oxo -2,3,3a, 7a- tetrahydro -1H- indoles -6- base) urea groups) M-phthalic acid diformazan
Ester
Synthetic route is as follows:
Other specific same above-described embodiments of synthesis step, are prepared compound 38, yield 50%.
Compound 381H NMR data is as follows:
1H NMR (400MHz, DMSO) δ 10.25 (s, 1H), 9.15 (s, 1H), 8.54 (s, 1H), 8.33 (d, J=
1.4Hz, 2H), 8.07 (t, J=1.4Hz, 1H), 7.40 (s, 1H), 7.21 (dd, J=8.3,1.8Hz, 1H), 6.74 (d, J=
8.3Hz, 1H), 3.90 (d, J=5.6Hz, 6H), 3.46 (s, 2H)
Embodiment 39:
Compound 39:5- (3- (2- oxo -1,2,3,4- tetrahydroquinoline -7- base) urea groups) dimethyl isophthalate
Synthetic route is as follows:
Other specific same above-described embodiments of synthesis step, are prepared compound 39, yield 58%.
Compound 391H NMR data is as follows:
1H NMR (400MHz, DMSO) δ 9.97 (s, 1H), 9.16 (s, 1H), 8.56 (s, 1H), 8.33 (d, J=1.5Hz,
2H), 8.08 (t, J=1.5Hz, 1H), 7.34 (d, J=1.9Hz, 1H), 7.18 (dd, J=8.5,2.3Hz, 1H), 6.78 (d, J
=8.5Hz, 1H), 3.89 (s, 6H), 2.86 (t, J=7.5Hz, 2H), 2.43 (t, J=7.5Hz, 2H)
Embodiment 40:
Compound 40:5- (3- (2- methyl-1,3-dioxy is for isoindoline -5- base) urea groups) dimethyl isophthalate
Synthetic route is as follows:
Other specific same above-described embodiments of synthesis step, are prepared compound 40, yield 56%.
Compound 401H NMR data is as follows:
1H NMR (400MHz, DMSO) δ 9.50 (s, 1H), 9.48 (s, 1H), 8.37 (d, J=1.5Hz, 2H), 8.13 (t,
J=1.5Hz, 1H), 8.10 (d, J=1.8Hz, 1H), 7.78 (d, J=8.2Hz, 1H), 7.72 (dd, J=8.2,1.9Hz,
1H),3.90(s,6H),3.02(s,3H).
Embodiment 41:
Compound 41:5- (3- (isoquinolin -7- base) urea groups) dimethyl isophthalate
Synthetic route is as follows:
Other specific same above-described embodiments of synthesis step, are prepared compound 41, yield 68%.
Compound 411H NMR data is as follows:
1H NMR (400MHz, DMSO) δ 9.43 (s, 1H), 9.23 (s, 1H), 9.21 (s, 1H), 8.40 (d, J=1.5Hz,
2H), 8.38 (d, J=5.7Hz, 1H), 8.36 (d, J=1.7Hz, 1H), 8.12 (t, J=1.4Hz, 1H), 7.92 (d, J=
8.9Hz, 1H), 7.75 (dd, J=11.7,3.9Hz, 2H), 3.91 (s, 6H).
Embodiment 42:
The synthesis of compound 42:5- (3- (quinoline -7- base) urea groups) dimethyl isophthalate (43)
Synthetic route is as follows:
Other specific same above-described embodiments of synthesis step, are prepared compound 42, yield 67%.
Compound 421H NMR data is as follows:
1H NMR (400MHz, DMSO) δ 9.40 (s, 1H), 9.16 (s, 1H), 8.76 (d, J=2.8Hz, 1H), 8.39 (s,
2H), 8.29 (d, J=8.2Hz, 1H), 8.23 (s, 1H), 8.12 (s, 1H), 7.96 (d, J=9.0Hz, 1H), 7.73 (d, J=
9.1Hz, 1H), 7.47 (dd, J=8.3,4.1Hz, 1H), 3.91 (s, 6H).
Embodiment 43:
The present embodiment is based on the particular chemical for the small molecule compound that above-mentioned 42 embodiments provide, using same
The plain mark test in position carries out external enzyme inhibition activity test.In the experiment, the AdoMet of [3H]-label is to generate radioactive bottom
Object, the natural products chaetocin with wide spectrum transmethylase inhibitory activity are positive control.
Test method is as follows:
(1) experimental material:
NSD2(Active Motif,Cat.No.31476)
SAM(Sigma,Cat.No.A7007-100MG)
Chaetocin(BPS,Cat No.27221)
GF/B Plate(Millipore,Cat.No.MSFBN6B50)
[3H]-SAM(PerkinElmer,Cat No.NET155V001MC)。
(2) experimental method:
Prepare 1 times of buffer solution (Tris buffer)；The compound diluted is transferred in experimental plate with Echo；Match
The enzyme buffer liquid of 1 times of system；Substrate is added in 1 times of buffer, is made into substrate buffer solution；Add [3H]-SAM to 1 times of buffering
[3H]-SAM solution is made into liquid；The SAM solution with ice making in SAM to 1 times of buffer is added；10ul is shifted into experimental plate
Enzyme solutions are substituted by enzyme solutions with 1 times of reaction buffer of 10 μ l, is incubated at room temperature 15 minutes for no enzyme activity control wells；
To the substrate solution of each Kong Zhongjia 10ul；[3H]-SAM solution of each Kong Zhongjia 10ul starts to react.It is incubated at room temperature
240min；The SAM solution that 15ul ice is added to each hole terminates reaction；The reaction mixture of 44ul is shifted into GF/B plate
(pre-processing 15min with 0.5% PEI), then passes through vacuum filtration cleaning 3 times with the distilled water of ice；It is read with Microbate
Number；Inhibiting rate is calculated by the following formula with excel:
Inh%=(Max-Signal)/(Max-Min) * 100
IC50 is calculated by the following formula with GraphPad
Y=Bottom+ (Top-Bottom)/(1+10^ ((LogIC50-X) * Hill Slope))
(3) experimental result:
By the above experimental method, the suppression that the compounds of this invention is directed to histone-lysine methyltransferase NSD2 is tested
System activity, it is specific as shown in Table 1.
Inhibitory activity (Inh%) of one the compounds of this invention of table to histone-lysine methyltransferase NSD2
42 kinds provided by the invention specific suppressions of the chemical combination to histone-lysine methyltransferase NSD2 as shown in Table 1
System activity, wherein it shows the inhibitory activity to NSD296% to compound 8 when 50 μM, further measures its IC50For
4.8μM.Compound 9, in 50 μM of the inhibitory activity for having 92% to NSD2, IC50It is 11.5 μM.Compound 12, at 50 μM
When be 92%, IC to the inhibitory activity of NSD250It is 7.5 μM.Compound 19 is 67% to the inhibitory activity of NSD2 at 50 μM,
IC50It is 17.0 μM.Compound 22 is 95%, IC to the inhibiting rate of NSD2 at 50 μM50It is 3.7 μM.Compound 34 is in chemical combination
Object is 92%, IC to the inhibiting rate of NSD2 at 50 μM50It is 8.1 μM.Compound 30 and 31 all shows inhibitory activity to NSD2.
Its IC50Respectively 20.0 μM and 19.0 μM.Compound 32 is 99%, IC to the inhibiting rate of NSD2 at 50 μM50It is 7.3 μM.Change
Close its inhibitory activity for having 93% to NSD2 at 50 μM of object 42.
Except above compound, it is substantially better than the natural chaetocin in positive controls to the inhibitory activity that NSD2 is shown
Outside, other compounds are not much different compared with positive controls, but have one to histone-lysine methyltransferase NSD2
Determine inhibitory effect.Thus provable small molecule compound provided by the invention has histone-lysine methyltransferase NSD2
Obvious inhibitory effect, part chemical structure are far superior to the inhibitory activity of positive controls, therefore small point synthesized in the present invention
Sub- compound inhibits field to have significant progress in histone-lysine methyltransferase NSD2.
Embodiment 44:
According to compound each in above-described embodiment to the inhibition sister-in-law of histone-lysine methyltransferase NSD2, especially select
It selects the best compound 22 of inhibitory activity and is used as primary study object.According to the prior art it is found that knocking out istone lysine first
Based transferase NSD2 can induce the apoptosis of prostate gland cancer cell, therefore using 22Rv-1 cell come the external of detection compound 22
Cell growth inhibiting activity.As a result as shown in Figure 1, compound 22 is able to suppress the proliferation of 22Rv-1 cell, and there is dosage
And time dependence.After drug effect 12 days, the inhibitory rate of cell growth under 10 μM of concentration of the compound is 66%.
Embodiment 45:
The present embodiment is analyzed to confirm compound 22 in 22Rv-1 cell to the inhibition of NSD2 using Western blot
Effect.The methylation procedure of histone K36 needs the participation of NSD2, thus with the monomethylation of istone lysine H3K36 and
Di-methylation (H3K36me and H3K36me2) is horizontal to be changed to detect the activity of NSD2, and result is as shown in Figure 2.Compound 22
When acting on 22Rv-1 cell, the methylation level of H3K36 can be dose-dependently reduced, while to the protein expression of NSD2
Level does not have an impact.Show that compound 22 can inhibit the activity of NSD2 in the cell.
Above data explanation, compound 22 can reduce istone lysine residue by making NSD2 inactivation in the cell
Methylation level, to inhibit the proliferation of 22Rv-1 cell.
Embodiment 46:
The present embodiment carries out the test of the inhibition selectivity of transmethylase for compound 22, tests it to MLL-1,
Inhibiting rate of the six kinds of transmethylases such as PRMTs, SETDB1, SMYD3 at 10 μM, the results are shown in Table 2:
Inhibitory activity of the compound 22 to other histone methyltransferase in two present invention of table
Compound 22 is 97% to the inhibiting rate of NSD2 at 10 μM, there is certain inhibitory activity to MLL-1 and SETDB1,
And to PRDM9, PRMT5, PRMT7 and SMYD3 almost without inhibitory activity.Illustrate that compound 22 has the inhibition of transmethylase
There is significant selectivity.
Embodiment 47:
The present embodiment is right respectively to it based on the particular chemical of small molecule compound provided by the above embodiment
Various tumor cell strains proliferation carries out Inhibition test, verifies its inhibitory effect to tumour cell.
(1) experimental material:
Main agents: RPMI-1640, fetal calf serum, pancreatin etc. are purchased from GibcoBRL company
(InvitrogenCorporation, USA), IMDM culture medium are purchased from ATCC
(AmericanTypeCultureCollection).Tetramethyl azo azoles salt (MTT), dimethyl sulfoxide (DMSO) are Sigma public
Take charge of (USA) product.Human prostate cancer cell line (PC-3), human lung cancer cell line (H2228), human lung cancer cell line (NCI-
H1975), human lung cancer cell line (PC-9), people's triple negative breast cancer cell line (MDA-MB-231), people's triple negative breast cancer cell
It is (MDA-MB-435), abortion syndrome (SK-OV-3), abortion syndrome (OVCAR-3), abortion syndrome
(HO8910), abortion syndrome (A2780S), abortion syndrome (A2780/T) etc. are purchased from U.S. ATCC
(Americantypeculturecollection), it is saved by this laboratory.
(2) experimental method:
The cell suspension for being 1~2 × 104/mL with complete cell culture fluid adjustment cell concentration, is inoculated in 96 orifice plates,
Every 200 μ l cell suspension of hole, overnight incubation.Next day inhales and abandons supernatant (drawing supernatant after suspension cell centrifugation), then respectively with ladder
The test-compound for spending concentration handles cell.The not negative control group of drug containing and isometric solvent control group are set simultaneously,
DMSO concentration is 0.1%, and each dosage group sets 3 multiple holes, at 37 DEG C, 5%CO2Under the conditions of cultivate.After 72 hours, every hole is added
Concentration is the 20 μ l of MTT reagent of 5mg/mL, after being further cultured for 2-4h, abandons supernatant, every hole adds DMSO150 μ L, and oscillation mixes
15min measures absorbance (A) value (A value is directly proportional to viable count) with microplate reader (λ=570nm), takes its average value.Relatively
Cell proliferation inhibition rate=(negative control group A570- experimental group A570)/negative control group A570 × 100%.Experiment is at least heavy
It is 3 times multiple.Experimental data indicates that data statistics data is examined using t with mean, and P < 0.05 is that difference is statistically significant.Below
Each compound on intracellular inhibited proliferation uses IC50It indicates.
(3) experimental result:
Using above method, choose to the relatively significant compound of histone-lysine methyltransferase NSD2 inhibitory effect
22 are used as test object, have carried out respectively to it human prostate cancer cell line (PC-3), human lung cancer cell line (H2228), people's lung
Cancerous cell line (NCI-H1975), human lung cancer cell line (PC-9), people's triple negative breast cancer cell line (MDA-MB-231), people three
Negative breast cancer cells system (MDA-MB-435), abortion syndrome (SK-OV-3), abortion syndrome (OVCAR-3),
Abortion syndrome (HO8910), abortion syndrome (A2780S), the suppression of the proliferation such as abortion syndrome (A2780/T)
Active testing processed, specific inhibitory effect are shown in Table three:
Proliferation inhibition activity (IC of three the compounds of this invention of table to different tumor cell lines50)
By two content of table it is found that compound 22 is to the IC of each tumour cell50(μM) quantity is respectively less than 10, and inhibitory effect is aobvious
Write, for tumour cell it is more polynary, the outer mutation of non-amount incurred has good pharmaceutical potential.Can be used for preparing treatment and/
Or the drug of pre- preventing tumor.
Although an embodiment of the present invention has been shown and described, it will be understood by those skilled in the art that: not
A variety of change, modification, replacement and modification can be carried out to these embodiments by being detached under the principle of the present invention and objective, of the invention
Range is defined by the claims and their equivalents.
Claims (17)
1. the small molecule compound of inhibition of histone lysine methyltransferase NSD2, general formula are as follows:
Wherein,
A be independent containing an at most nitrogen-atoms, an oxygen atom, sulphur atom five-ring heterocycles or contain at most one
The aromatic ring of nitrogen-atoms or hexa-member heterocycle containing an oxygen atom, nitrogen-atoms；
B be independent containing most three nitrogen-atoms, an oxygen atom, sulphur atom five-ring heterocycles or contain at most two
The aromatic ring of nitrogen-atoms or hexa-member heterocycle containing a nitrogen-atoms；
R1It is independent H, methyl, new butyl, nitro, ehter bond, peptide bond, ester bond, halogen ,-CF3、
R2It is independent H, methyl, new butyl, nitro, ehter bond, peptide bond, ester bond, halogen ,-CF3、
R3It is independent H, O, methyl or is not present；
R4It is independent H, O, methyl or is not present；
R5It is independent H, O, methyl or is not present.
2. the small molecule compound of inhibition of histone lysine methyltransferase NSD2 according to claim 1, feature
Be, when A be containing an at most nitrogen-atoms, an oxygen atom, sulphur atom five-ring heterocycles when,
B is containing there are two the five-ring heterocycles of nitrogen-atoms and a sulphur atom；
R1Be independent H, methyl, new butyl, ester bond,
R2Be independent H, methyl, new butyl, ester bond,
3. the small molecule compound of inhibition of histone lysine methyltransferase NSD2 according to claim 2, feature
It is, when A only contains a nitrogen-atoms and an oxygen atom,
B is containing there are two the five-ring heterocycles of nitrogen-atoms and a sulphur atom；
R1It is independent H, new butyl；
R2It is independent H, new butyl.
4. the small molecule compound of inhibition of histone lysine methyltransferase NSD2 according to claim 2, feature
It is, when A only contains a nitrogen-atoms and a sulphur atom,
B is containing there are two the five-ring heterocycles of nitrogen-atoms and a sulphur atom；
R1 be independent H,
R2 be independent H,
5. the small molecule compound of inhibition of histone lysine methyltransferase NSD2 according to claim 2, feature
It is, when A only contains a sulphur atom,
B is containing there are two the five-ring heterocycles of nitrogen-atoms and a sulphur atom；
R1It is independent H, methyl, ester bond；
R2It is independent H, methyl, ester bond.
6. the small molecule compound of inhibition of histone lysine methyltransferase NSD2 according to claim 1, feature
Be, when A be containing an oxygen atom, nitrogen-atoms hexa-member heterocycle when,
B is containing there are two the five-ring heterocycles of nitrogen-atoms and a sulphur atom；
R1 is independent H；
R2 is independent H.
7. the small molecule compound of inhibition of histone lysine methyltransferase NSD2 according to claim 1, feature
It is, when A is the aromatic ring containing a nitrogen-atoms,
B is containing there are two the five-ring heterocycles of nitrogen-atoms and a sulphur atom；
R1 is independent H, halogen；
R2 is independent H, halogen.
8. the small molecule compound of inhibition of histone lysine methyltransferase NSD2 according to claim 1, feature
Be, when A is aromatic ring, B be containing most three nitrogen-atoms, an oxygen atom, sulphur atom five-ring heterocycles when；
R1It is independent H, methyl, nitro, ehter bond, peptide bond, ester bond, halogen ,-CF3、
R2It is independent H, methyl, nitro, ehter bond, peptide bond, ester bond, halogen ,-CF3、
R3It is independent H, O, methyl or is not present；
R4It is independent H, O, methyl or is not present；
R5It is independent H, O, methyl or is not present.
9. the small molecule compound of inhibition of histone lysine methyltransferase NSD2 according to claim 1, feature
It is, when A is aromatic ring, and B is the aromatic ring containing at most two nitrogen-atoms,
R1It is independent H, nitro, ester bond；
R2It is independent H, nitro, ester bond；
R3It is independent H；
R4It is independent H；
R5It is independent H.
10. the small molecule compound of inhibition of histone lysine methyltransferase NSD2 according to claim 9, feature
Be, when A is aromatic ring, B be containing there are two when the aromatic ring of nitrogen-atoms,
R1It is independent ester bond；
R2It is independent ester bond；
R3It is independent H；
R4It is independent H；
R5It is independent H.
11. the small molecule compound of inhibition of histone lysine methyltransferase NSD2 according to claim 9, feature
It is, when A is aromatic ring, and B is the aromatic ring containing a nitrogen-atoms,
R1It is independent H, nitro, ester bond；
R2It is independent H, nitro, ester bond；
R3It is independent H；
R4It is independent H；
R5It is independent H.
12. the small molecule compound of inhibition of histone lysine methyltransferase NSD2 according to claim 1, feature
It is, when A is aromatic ring, and B is the hexa-member heterocycle containing a nitrogen-atoms,
R1It is independent ester bond；
R2It is independent ester bond；
R3It is independent H, O；
R4It is independent H, O；
R5It is independent H, O.
13. the small molecule of described in any item inhibition of histone lysine methyltransferase NSD2 according to claim 1~12
It closes object and its salt, hydrate or pharmaceutical composition is preparing the targeted drug of inhibition of histone lysine methyltransferase NSD2
Purposes.
14. the small molecule of described in any item inhibition of histone lysine methyltransferase NSD2 according to claim 1~12
The purposes of object and its salt, hydrate or pharmaceutical composition in preparation oral or intravenous preparation is closed, it is described oral or intravenous
Ejection preparation includes the described in any item inhibition of histone lysine methyltransferase NSD2's of at least one claim 1~12
Small molecule compound and its salt, hydrate or pharmaceutical composition and arbitrary excipient and/or adjuvant.
15. a kind of inhibitor of histone-lysine methyltransferase NSD2, which is characterized in that any with claim 1~12
Acceptable salt, crystal form, solvate on the biopharmacy of active constituent are wanted based on the item acrylamide analog derivative.
16. a kind of drug for the treatment of cancer, which is characterized in that with the histone-lysine methyltransferase described in claim 15
NSD2 inhibitor is main component, adds acceptable complementary ingredient on biopharmacy and is prepared.
17. the drug of 6 treating cancers according to claim 1, which is characterized in that the cancer for the treatment of includes prostate cancer, ovum
Nest cancer, breast cancer, lung cancer.
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