CN114349735A - O-GlcNAc transferase inhibitors and preparation method and application thereof - Google Patents

O-GlcNAc transferase inhibitors and preparation method and application thereof Download PDF

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CN114349735A
CN114349735A CN202210021882.4A CN202210021882A CN114349735A CN 114349735 A CN114349735 A CN 114349735A CN 202210021882 A CN202210021882 A CN 202210021882A CN 114349735 A CN114349735 A CN 114349735A
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ylmethyl
sulfonyl
thien
glcnac transferase
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CN114349735B (en
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曲玮
姜洪丽
张宁
冯锋
廖淸宏
朱嘉新
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China Pharmaceutical University
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Abstract

The invention belongs to the technical field of drug synthesis, and discloses an O-GlcNAc transferase inhibitor, and a preparation method and application thereof. The O-GlcNAc transferase inhibitor has a structure shown in formula I, and the preparation method has the advantages of easily obtained raw materials, simple steps and higher yield; the O-GlcNAc transferase inhibitor is synthesized by fusing natural product fragments, has good in vitro activity and specificity, and can be widely applied to preparation of drugs for inhibiting the activity of OGT.

Description

O-GlcNAc transferase inhibitors and preparation method and application thereof
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to an O-GlcNAc transferase inhibitor.
Background
O-linked N-acetylglucosamine (O-GlcNAc) glycosylation, similar to protein phosphorylation, is a post-translational modification (PTM) of proteins widely present in organisms, and was first discovered in 1984. During the glycosylation modification of protein O-GlcNAc, GlcNAc dynamically and reversibly attaches to serine and threonine hydroxyl groups of intracellular proteins in a beta configuration with O-glycosidic bonds, thereby influencing the function of the proteins and participating in the regulation of various intracellular signaling pathways. To date, 4000 more proteins capable of being modified by O-GlcNAc glycosylation, including signal proteins, transcription factors, metabolic enzymes, histones, and the like, have been reported to be involved in the regulation of key cellular processes such as signal transduction, transcription, translation, and protein degradation. As a potential nutrient receptor, O-GlcNAcylation is involved in a complex series of cellular activities such as signal transduction, gene transcription, protein translation, cellular responses and protein degradation. More and more studies have demonstrated that abnormal levels of O-glcnacalation are closely associated with certain complex diseases that severely threaten human health, such as cancer, neurodegenerative diseases, diabetes and other chronic diseases.
In contrast to phosphorylation modifications controlled by hundreds of kinases and phosphatases, O-GlcNAc glycosylation of proteins regulates the level of intracellular O-GlcNAc glycosylation by two enzymes in an organism catalyzed only by a pair of opposing enzymes, O-GlcNAc glycosyltransferase (OGT) covalently attaching GlcNAc to proteins from the glycosyl donor uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) and O-GlcNAc glycosidase (OGA) hydrolyzing GlcNAc from proteins. The OGT plays a key role in the O-GlcNAc glycosylation process of nuclear and cytoplasmic proteins, and the design and synthesis of a compound capable of regulating the OGT intervenes the glycosylation process of the proteins, thereby having important significance for the research of the function and action mechanism of the O-GlcNAc glycosylation and the development of related drugs. However, the use of gene knockout of the gene encoding OGT or RNA interference methods to regulate OGT activity has limitations such as intracellular instability, poor cell permeability, and influence on normal cell function, and is not suitable for wide application. The method has the advantages of good cell permeability, controllable dosage, concise action passage and the like by inhibiting the activity of OGT in vitro by using small molecular compounds. Recent studies have designed the synthesis of several OGT inhibitors and have made significant scientific progress in the field of O-GlcNAc, however, the lack of specificity, potential off-target effects and/or limited cellular permeability remain major drawbacks of current small-molecule OGT inhibitors.
Disclosure of Invention
The purpose of the invention is as follows: the object of the present invention is to provide a class of O-GlcNAc transferase inhibitors having good in vitro activity; another object of the present invention is to provide a process for producing the O-GlcNAc transferase inhibitor; another object of the present invention is to provide the use of the O-GlcNAc transferase inhibitor for the preparation of a medicament for inhibiting OGT activity.
The technical scheme is as follows: the O-GlcNAc transferase inhibitor of the invention is characterized by comprising a compound represented by formula I or a pharmaceutically acceptable salt thereof:
Figure BDA0003462723350000021
wherein R is1Selected from five-membered or six-membered heterocycles, R2Is selected from the group consisting of1～C4Alkyl, halogen substituted C1～C4Alkyl radical, C1～C4Alkoxy radical,C1～C4Alkoxycarbonyl, C1～C4Acyl, phenyl, optionally substituted phenyl, benzyl or optionally substituted benzyl.
Further, R1Is selected from
Figure BDA0003462723350000022
R2Selected from isopropyl, phenyl, benzyl or p-methylphenol.
Further, the inhibitor is selected from any one of the following compounds:
Figure BDA0003462723350000023
Figure BDA0003462723350000031
。
further, the pharmaceutically acceptable salt is selected from hydrochloride, maleate or citrate.
In another aspect, the process for the preparation of an inhibitor of O-GlcNAc transferase of the present invention comprises the steps of:
Figure BDA0003462723350000041
(1) to be provided with
Figure BDA0003462723350000042
The intermediate is obtained by reacting chlorosulfonic acid as the starting material
Figure BDA0003462723350000043
(2) 2-thiophenecarboxaldehyde is obtained by three-step reaction of glycine ethyl ester hydrochloride, amino acid and deamination protection
Figure BDA0003462723350000044
Then and intermediates
Figure BDA0003462723350000045
And (3) preparing the O-GlcNAc transferase inhibitor by reaction.
In another aspect, the pharmaceutical composition of the invention comprises an O-GlcNAc transferase inhibitor described above and a pharmaceutically acceptable carrier or excipient, and optionally a therapeutic agent.
Wherein the excipient is tablet, capsule, powder, syrup, liquid, suspending agent or injection; flavoring agent, sweetener, liquid or solid filler or diluent, and other common pharmaceutical adjuvants can be added.
In a further aspect, the use of an inhibitor of O-GlcNAc transferase of the present invention in the manufacture of a medicament for inhibiting the activity of OGT.
In a further aspect, the use of an inhibitor of O-GlcNAc transferase of the invention in the manufacture of a medicament for the treatment or prevention of a condition associated with OGT activity.
Has the advantages that: compared with the prior art, the invention has the following remarkable advantages: the O-GlcNAc transferase inhibitor is synthesized by fusing natural product fragments, has good in vitro activity and specificity, and can be widely applied to preparation of drugs for inhibiting the activity of OGT.
Detailed Description
Example 1
Figure BDA0003462723350000046
Synthesis of ethyl (R) -N- (2- (((2-oxo-1, 2-dihydroquinolin) -6-yl) sulfonyl) -2-phenylacetyl) -N- (thien-2-ylmethyl) glycine
(1) Synthesis of 2-oxo-1, 2-dihydroquinoline-6-sulfonyl chloride (intermediate 1)
2-hydroxyquinoline (300mg,2.04mmol) was weighed into a reaction flask, chlorosulfonic acid (1ml, 15.2mmol) was added thereto, and the mixture was stirred in an oil bath at 80 ℃ for reaction. After about 4h the reaction mixture was allowed to cool to room temperature and then carefully poured into 20mL of crushed ice to form a precipitate. Vacuum filtering with Buchner funnel, washing with small amount of cold water, and drying to obtain light brown2-oxo-1, 2-dihydroquinoline-6-sulfonyl chloride as a colored solid powder (330mg, 66.44% yield).1H NMR(400MHz,DMSO-d6)δ:11.94(s,1H),8.00(t,J＝9.0Hz,1H),7.94(td,J＝5.2,4.0,1.9Hz,1H),7.74(d,J＝7.8Hz,1H),7.30(d,J＝8.6Hz,1H),6.57(dd,J＝20.6,9.4Hz,1H).
(2) Synthesis of (thien-2-ylmethyl) glycine ethyl ester
A50 mL round bottom flask was charged with glycine methyl ester hydrochloride (500mg, 3.58mmol) and a stir bar. Anhydrous MeOH (20mL) and Et were added dropwise in that order3N (1mL, 7mmol) followed by thiophene 2-carbaldehyde (300. mu.L, 3.25mmol) was added. The reaction was stirred at room temperature for 2h and the presence of imine was confirmed using ESI/MS. The solution was cooled to 0-5 ℃ in an ice bath, and then sodium borohydride (262.5mg, 7mmol) was slowly added to the reaction mixture in portions. The ice bath was removed and the reaction was allowed to warm to room temperature. After stirring at room temperature for 2-4H, TLC checked for completion, quenched by addition of ice water, solvent removed by rotary drying under reduced pressure, and the reaction mixture was washed with EtOAc (10mL) and H2Partition between O (10 mL). The aqueous layer was discarded, and the combined organic layers were washed with saturated brine (10 mL). The organic layer was treated with anhydrous n.a.2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with PE/EtOAc ═ 50:1(V/V) to give (thiophen-2-ylmethyl) glycine ethyl ester (123mg, 22.79% yield) as a pale yellow clear oil.1H NMR(300MHz,Chloroform-d)δ:7.25(dd,J＝4.7,1.6Hz,1H),6.98(d,J＝3.4Hz,1H),6.96(s,1H),4.21(q,J＝7.1Hz,2H),4.04(s,2H),3.46(s,2H),1.96(s,1H),1.30(t,J＝7.2Hz,3H).
(3) Synthesis of (R) -ethyl N- (2- ((tert-butoxycarbonyl) amino) -2-phenylacetyl) -N- (thien-2-ylmethyl) glycine (intermediate 2)
In a 25mL round bottom flask was added (R) -2- ((tert-butoxycarbonyl) amino) -2-phenylacetic acid (442mg, 1.76mmol), dissolved with DMF with stirring, and dissolved completely by addition of DIPEA (320. mu.L, 1.93 mmol). HATU (734mg, 1.93mmol) was added and stirred at room temperature for 2.5 h. Subsequently, the glass piston was opened, the compound (thien-2-ylmethyl) glycine ethyl ester (350mg, 1.76mmol) was added, and the reaction was stirred at room temperature for 5 h. The reaction mixture was washed with EtOAc (5mL) and H2O (5mL) intervalAnd (4) preparing. The organic layer was retained, the aqueous layer was extracted with EtOAc (2X 5 mL). The combined organic layers were washed with brine (5mL) and anhydrous Na2SO4Drying, filtering, and concentrating the filtrate under reduced pressure. The resulting concentrated oil was purified by silica gel chromatography eluting with EtOAc/PE ═ 1:50(V/V) to give (R) -N- (2- ((tert-butoxycarbonyl) amino) -2-phenylacetyl) -N- (thien-2-ylmethyl) glycine ethyl ester (500mg) as a clear oil. Then (R) -N- (2- ((tert-butoxycarbonyl) amino) -2-phenylacetyl) -N- (thien-2-ylmethyl) glycine ethyl ester (200mg, 0.45mmol) was dissolved in 10mL DCM and dissolved completely at room temperature, TFA (332. mu.L, 4.5mmol) was added and the reaction was allowed to react for 1.5h at room temperature, checked by TLC until complete. The reaction mixture was concentrated under reduced pressure, then the residue was added to toluene (about 2mL), and the resulting mixture was concentrated again under reduced pressure. This procedure was repeated twice and the remaining volatiles were removed to give the crude amine containing ethyl (R) -N- (2- ((tert-butoxycarbonyl) amino) -2-phenylacetyl) -N- (thien-2-ylmethyl) glycine in 65.81% yield.1H NMR(400MHz,Chloroform-d)δ:7.49(t,J＝4.1Hz,1H),7.41(d,J＝6.5Hz,1H),7.40-7.37(m,1H),7.37-7.34(m,1H),7.33-7.28(m,1H),7.27-7.19(m,1H),6.91(td,J＝4.9,2.6Hz,1H),6.78-6.73(m,1H),6.04(m,1H),5.79(d,J＝8.0Hz,1H),4.86(s,1H),4.77-4.53(m,1H),4.25-4.19(m,1H),4.17(d,J＝7.1Hz,1H),4.01(m,1H),3.93(s,1H),1.46-1.38(m,9H),1.23(m,3H).
(4) Synthesis of ethyl (R) -N- (2- (((2-oxo-1, 2-dihydroquinolin) -6-yl) sulfonyl) -2-phenylacetyl) -N- (thien-2-ylmethyl) glycine
A stir bar was added to the reaction flask containing the crude amine of (R) -N- (2- ((tert-butoxycarbonyl) amino) -2-phenylacetyl) -N- (thien-2-ylmethyl) glycine ethyl ester and the reaction flask was sealed with a balloon glass tee filled with nitrogen and purged with nitrogen for 3 min. DMF (5mL) was added and 2-oxo-1, 2-dihydroquinoline-6-sulfonyl chloride (140mg, 0.57mmol) was added. After purging stirring at room temperature for 3min under nitrogen, the tee was opened and diisopropylethylamine (188. mu.L, 1.14mmol) was added and the reaction stirred at room temperature for 1h under gas. The reaction mixture was washed with EtOAc (5mL) and H2Partition between O (5 mL). Combine the organic layers with EtOAcThe aqueous layer was extracted (2X 5 mL). The combined organic layers were washed with brine (5mL), dried, filtered, and concentrated under reduced pressure. The resulting oil was purified by silica gel chromatography, eluting with DCM/MeOH ═ 50:1(V/V), to give (R) -N- (2- (((2-oxo-1, 2-dihydroquinolin) -6-yl) sulfonyl) -2-phenylacetyl) -N- (thiophen-2-ylmethyl) glycine ethyl ester as a white powder (120mg, 36.96% yield).1H NMR(300MHz,DMSO-d6)δ:12.02(s,1H),8.53(t,J＝10.1Hz,1H),8.00-7.93(m,1H),7.91(d,J＝10.0Hz,1H),7.74(m,1H),7.48(d,J＝4.9Hz,1H),7.36(q,J＝5.8,3.7Hz,1H),7.28(s,1H),7.25(s,1H),7.22(s,1H),7.20(s,1H),7.18(s,1H),6.99(q,J＝5.3,4.4Hz,1H),6.89(s,1H),6.60(d,J＝9.5Hz,1H),4.66(s,2H),4.49-4.17(m,1H),4.00(dd,J＝7.2,4.3Hz,2H),3.94-3.76(m,2H),1.11(t,J＝7.1Hz,3H).
Example 2
Figure BDA0003462723350000061
Synthesis of ethyl (S) -N- (2- (((2-oxo-1, 2-dihydroquinolin) -6-yl) sulfonyl) -2-phenylacetyl) -N- (thien-2-ylmethyl) glycine
Referring to the synthesis procedure of example 1, the starting material for intermediate 2 in example 1 was replaced with (S) -2- ((tert-butoxycarbonyl) amino) -2-phenylacetic acid to give a white solid powder, i.e., (S) -N- (2- (((2-oxo-1, 2-dihydroquinolin) -6-yl) sulfonyl) -2-phenylacetyl) -N- (thien-2-ylmethyl) glycine ethyl ester.1H NMR(300MHz,DMSO-d6)δ:12.00(s,1H),8.52(m,1H),7.97(d,J＝2.2Hz,1H),7.89(d,J＝9.6Hz,1H),7.71(m,1H),7.46(dd,J＝5.1,1.3Hz,1H),7.25(d,J＝2.0Hz,1H),7.22(d,J＝2.8Hz,1H),7.21(d,J＝2.2Hz,1H),7.18(s,1H),7.16(s,1H),7.14(d,J＝2.2Hz,1H),6.96(dd,J＝5.1,3.5Hz,1H),6.86(d,J＝4.3Hz,1H),6.58(d,J＝9.6Hz,1H),4.67-4.58(m,2H),4.46-4.16(m,1H),3.99(d,J＝6.3Hz,1H),3.90(q,J＝7.1Hz,2H),3.81(d,J＝6.3Hz,1H),1.11-1.06(m,3H).
Example 3
Figure BDA0003462723350000071
Synthesis of (R) -N- (2- (((2-oxoindolin) -5-yl) sulfonyl) -2-phenylacetyl) -N- (thien-2-ylmethyl) glycine ethyl ester
Referring to the synthesis procedure of example 1, the starting material for intermediate 1 in example 1 was replaced with 2-carbonylindole to give a light brown solid powder, namely (R) -N- (2- (((2-oxoindolin) -5-yl) sulfonyl) -2-phenylacetyl) -N- (thien-2-ylmethyl) glycine ethyl ester.1H NMR(300MHz,DMSO-d6)δ:10.75(d,J＝4.7Hz,1H),8.38(t,J＝8.7Hz,1H),7.55(d,J＝8.1Hz,1H),7.46(d,J＝9.6Hz,1H),7.36(s,1H),7.28(s,3H),7.20(s,3H),7.03-6.94(m,1H),6.94(s,1H),6.79(t,J＝7.7Hz,1H),4.72-4.60(m,2H),4.55-4.17(m,1H),4.03(q,J＝7.3Hz,2H),3.94(q,J＝6.9Hz,2H),3.46(s,2H),1.12(d,J＝7.3Hz,3H).
Example 4
Figure BDA0003462723350000072
Synthesis of (S) -N- (2- (((2-oxoindolin) -5-yl) sulfonyl) -2-phenylacetyl) -N- (thien-2-ylmethyl) glycine ethyl ester
Referring to the synthesis procedure of example 1, the starting material for intermediate 1 in example 1 was replaced with 2-carbonylindole and the starting material for intermediate 2 was replaced with (S) -2- ((tert-butoxycarbonyl) amino) -2-phenylacetic acid to give a light brown solid powder, i.e., (S) -N- (2- (((2-oxoindolin) -5-yl) sulfonyl) -2-phenylacetyl) -N- (thien-2-ylmethyl) glycine ethyl ester.1H NMR(300MHz,DMSO-d6)δ:10.70(d,J＝4.6Hz,1H),8.32(dd,J＝9.3,6.7Hz,1H),7.48(dd,J＝5.1,1.3Hz,1H),7.41(s,1H),7.34(s,1H),7.25(s,3H),7.18(s,2H),6.97(dd,J＝5.1,3.5Hz,1H),6.91(d,J＝1.3Hz,1H),6.77(dd,J＝8.3,6.9Hz,1H),4.68-4.59(m,2H),4.51-4.15(m,1H),4.01(q,J＝7.2Hz,2H),3.96-3.87(m,2H),3.44(s,1H),3.39(d,J＝4.7Hz,1H),1.13-1.08(m,3H).
Example 5
Figure BDA0003462723350000073
Synthesis of ethyl (R) -N- (2- (((2, 4-dioxo-1, 2,3, 4-tetrahydroquinazolin-6-yl) sulfonyl) -2-phenylacetyl) -N- (thien-2-ylmethyl) glycine
Referring to the synthesis procedure of example 1, the starting material for intermediate 1 in example 1 was replaced with 2, 4-dihydroxyquinazoline to give a white solid powder, namely (R) -N- (2- (((2, 4-dioxo-1, 2,3, 4-tetrahydroquinazolin-6-yl) sulfonyl) -2-phenylacetyl) -N- (thien-2-ylmethyl) glycine ethyl ester.1H NMR(300MHz,DMSO-d6)δ:11.56(s,1H),11.49(s,1H),8.69(t,J＝8.1Hz,1H),8.14(d,J＝2.3Hz,1H),7.83(m,1H),7.42(m,1H),7.27(s,1H),7.26(s,1H),7.24(s,1H),7.19(s,1H),7.18(s,1H),7.17(s,1H),7.11(t,J＝8.0Hz,1H),7.00-6.92(m,1H),6.90(d,J＝3.4Hz,1H),4.75-4.60(m,2H),4.08-3.95(m,2H),3.94-3.81(m,2H),1.11(q,J＝3.1Hz,3H).
Example 6
Figure BDA0003462723350000081
Synthesis of (S) -N- (2- (((2, 4-dioxo-1, 2,3, 4-tetrahydroquinazolin-6-yl) sulfonyl) -2-phenylacetyl) -N- (thien-2-ylmethyl) glycine ethyl ester
Referring to the synthesis procedure of example 1, the starting material for intermediate 1 in example 1 was replaced with 2, 4-dihydroxyquinazoline and the starting material for intermediate 2 was replaced with (S) -2- ((tert-butoxycarbonyl) amino) -2-phenylacetic acid to give a white solid powder, i.e., (S) -N- (2- (((2, 4-dioxo-1, 2,3, 4-tetrahydroquinazolin-o) -6-yl) sulfonyl) -2-phenylacetyl) -N- (thien-2-ylmethyl) glycine ethyl ester.1H NMR(300MHz,DMSO-d6)δ:11.54(s,2H),8.67(s,1H),8.18-8.11(m,1H),7.84m,1H),7.48(dd,J＝7.7,5.2Hz,1H),7.38(t,J＝4.0Hz,1H),7.28(s,1H),7.27(s,1H),7.20(s,1H),7.19(s,1H),7.15-7.07(m,1H),6.99(dt,J＝8.2,4.8Hz,1H),6.94-6.89(m,1H),4.68(t,J＝7.5Hz,2H),4.51-4.20(m,1H),4.08-3.96(m,2H),3.94-3.77(m,2H),1.12(t,J＝7.5Hz,3H).
Example 7
Figure BDA0003462723350000082
Synthesis of ethyl (R) -N- (2- (((2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol) -5-yl) sulfonyl) -2-phenylacetyl) -N- (thien-2-ylmethyl) glycinate
Referring to the synthesis method of example 1, the raw material of intermediate 1 in example 1 was replaced with 1, 3-dihydro-2H-benzimidazol-2-one to obtain a white solid powder, i.e., (R) -N- (2- (((2-oxo-2, 3-dihydro-1H-benzo [ d-b-l-benzo [)]Imidazole) -5-yl) sulfonyl) -2-phenylacetyl) -N- (thien-2-ylmethyl) glycine ethyl ester.1H NMR(300MHz,DMSO-d6)δ:10.99(d,J＝7.7Hz,1H),10.91(d,J＝9.1Hz,1H),8.34(d,J＝9.1Hz,2H),7.46(dd,J＝5.1,1.3Hz,1H),7.37-7.29(m,1H),7.24(s,3H),7.21(dd,J＝4.0,1.8Hz,1H),7.18(d,J＝1.7Hz,1H),7.16(s,1H),6.96(dd,J＝5.1,3.5Hz,1H),6.88-6.85(m,2H),4.61(s,2H),4.48-4.18(m,2H),4.05-3.95(m,2H),3.91-3.85(m,2H),1.09(d,J＝6.5Hz,3H).
Example 8
Figure BDA0003462723350000091
Synthesis of ethyl (S) -N- (2- (((2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol) -5-yl) sulfonyl) -2-phenylacetyl) -N- (thien-2-ylmethyl) glycinate
Referring to the synthesis procedure of example 1, the starting material for intermediate 1 in example 1 was replaced with 1, 3-dihydro-2H-benzimidazol-2-one and the starting material for intermediate 2 was replaced with (S) -2- ((tert-butoxycarbonyl) amino) -2-phenylacetic acid to give a white solid powder, i.e., (S) -N- (2- (((2-oxo-2, 3-dihydro-1H-benzo [ d-phenyl ] acetic acid)]Imidazole) -5-yl) sulfonyl) -2-phenylacetyl) -N- (thien-2-ylmethyl) glycine ethyl ester.1H NMR(300MHz,DMSO-d6)δ:11.02(d,J＝7.8Hz,1H),10.94(d,J＝9.2Hz,1H),8.37(d,J＝9.2Hz,1H),7.49(d,J＝5.0Hz,1H),7.41-7.31(m,1H),7.26(s,3H),7.23(s,1H),7.20(s,1H),7.19(s,2H),6.99(t,J＝4.2Hz,1H),6.93(s,1H),6.88(d,J＝6.6Hz,1H),4.64(s,2H),4.51-4.20(m,1H),4.09-3.96(m,2H),3.92(d,J＝5.9Hz,2H),1.12(d,J＝6.9Hz,3H).
Example 9
Figure BDA0003462723350000092
Synthesis of ethyl (R) -N- (2- (((2-oxo-2H-chromene) -6-yl) sulfonyl) -2-phenylacetyl) -N- (thien-2-ylmethyl) glycinate
Referring to the synthesis procedure of example 1, the starting material for intermediate 1 in example 1 was replaced with coumarin to give a brown oil, namely ethyl (R) -N- (2- (((2-oxo-2H-chromene) -6-yl) sulfonyl) -2-phenylacetyl) -N- (thien-2-ylmethyl) glycine.1H NMR(300MHz,DMSO-d6)δ:8.71(t,J＝9.7Hz,1H),8.05(dd,J＝8.7Hz,1H),7.98(dd,J＝9.6Hz,1H),7.82(dd,J＝8.7Hz,1H),7.46(d,J＝5.1,1.4Hz,1H),7.28-7.12(m,5H),7.00-6.94(m,1H),6.90(m,1H),6.89-6.85(m,1H),6.60(dd,J＝9.6Hz,1H),4.69-4.63(m,2H),4.47-4.17(m,1H),4.03-3.93(m,2H),3.92-3.83(m,2H),1.09(t,J＝7.1Hz,3H).
Example 10
Figure BDA0003462723350000101
Synthesis of ethyl (S) -N- (2- (((2-oxo-2H-chromene) -6-yl) sulfonyl) -2-phenylacetyl) -N- (thien-2-ylmethyl) glycinate
Referring to the synthesis procedure of example 1, the starting material for intermediate 1 in example 1 was replaced with coumarin and the starting material for intermediate 2 was replaced with (S) -2- ((tert-butoxycarbonyl) amino) -2-phenylacetic acid to give a brown oil, which was ethyl (S) -N- (2- (((2-oxo-2H-chromene) -6-yl) sulfonyl) -2-phenylacetyl) -N- (thien-2-ylmethyl) glycine.1H NMR(300MHz,DMSO-d6)δ:8.71(t,J＝9.7Hz,1H),8.05(dd,J＝9.0Hz,1H),7.98(d,J＝9.6Hz,1H),7.82(dd,J＝9.0,2.3Hz,1H),7.47(d,J＝2.3Hz,1H),7.29-7.12(m,5H),6.96(dd,J＝5.1,3.5Hz,1H),6.90(m,1H),6.89-6.85(m,1H),6.60(d,J＝9.6Hz,1H),4.69-4.59(m,2H),4.47-4.18(m,2H),4.04-3.93(m,2H),3.87(m,2H),1.09(t,J＝7.1Hz,3H).
Example 11
Figure BDA0003462723350000102
Synthesis of ethyl N- (((2-oxo-1, 2-dihydroquinolin-6-yl) sulfonyl) -D-phenylalanine) -N- (thien-2-ylmethyl) glycine
Referring to the synthesis method of example 1, the starting material of intermediate 2 in example 1 was replaced with (tert-butoxycarbonyl) -D-phenylalanine to give a white solid powder, i.e., ethyl N- (((2-oxo-1, 2-dihydroquinolin-6-yl) sulfonyl) -D-phenylalanine) -N- (thien-2-ylmethyl) glycinate.1H NMR(300MHz,DMSO-d6)δ:12.06(s,1H),8.41(dd,J＝8.9,4.3Hz,1H),7.98-7.81(m,2H),7.58-7.50(m,1H),7.24(t,J＝8.3Hz,1H),7.09(s,1H),7.08(s,1H),7.06(d,J＝2.2Hz,1H),7.03(s,1H),7.02(d,J＝1.8Hz,1H),6.98-6.94(m,1H),6.93-6.88(m,1H),6.61(d,J＝9.6Hz,1H),5.05-4.72(m,1H),4.52(s,1H),4.37(m,1H),4.24-4.10(m,1H),4.08(d,J＝3.4Hz,1H),4.07-3.99(m,1H),3.91(s,1H),2.83(m,1H),2.72-2.55(m,1H),1.16(td,J＝7.1,2.5Hz,3H).
Example 12
Figure BDA0003462723350000111
Synthesis of ethyl N- (((2- (2-oxoindolin) -5-yl) sulfonyl) -D-phenylalanine) -N- (thien-2-ylmethyl) glycinate
Referring to the synthesis method of example 1, the raw material of intermediate 1 in example 1 was replaced with 2-carbonyl indole, and the raw material of intermediate 2 was replaced with (tert-butoxycarbonyl) -D-phenylalanine to obtain a white solid powder, i.e., N- (((2- (2-oxoindolin) -5-yl) sulfonyl) -D-phenylalanine) -N- (thien-2-ylmethyl) glycine ethyl ester.1H NMR(400MHz,DMSO-d6)δ:10.72(s,1H),8.19(dd,J＝14.0,9.1Hz,1H),7.51(ddd,J＝5.0,2.2,1.4Hz,1H),7.42-7.37(m,1H),7.18-7.13(m,2H),7.12(d,J＝2.1Hz,1H),7.09-7.06(m,1H),7.05-7.03(m,1H),7.03-6.99(m,1H),6.98(t,J＝1.4Hz,1H),6.96-6.93(m,1H),6.78(dd,J＝8.2,3.3Hz,1H),4.78-4.67(m,1H),4.63-4.50(m,1H),4.33(t,J＝4.5Hz,1H),4.14-4.06(m,2H),4.06-3.99(m,1H),3.94(d,J＝1.3Hz,1H),3.45(s,2H),2.89-2.79(m,1H),2.70-2.54(m,1H),1.16(m,3H).
Example 13
Figure BDA0003462723350000112
Synthesis of ethyl N- (((2- (2-oxoindolin) -5-yl) sulfonyl) -L-phenylalanine) -N- (thien-2-ylmethyl) glycinate
Referring to the synthesis method of example 1, the raw material of intermediate 1 in example 1 was replaced with 2-carbonyl indole, and the raw material of intermediate 2 was replaced with (tert-butoxycarbonyl) -L-phenylalanine to obtain a white solid powder, i.e., N- (((2- (2-oxoindolin) -5-yl) sulfonyl) -L-phenylalanine) -N- (thien-2-ylmethyl) glycine ethyl ester.1H NMR(300MHz,DMSO-d6)δ:10.73(s,1H),8.18(s,1H),7.52-7.45(m,1H),7.44-7.37(m,1H),7.26(m,1H),7.14(d,J＝3.7Hz,1H),7.13-7.12(m,1H),7.11(s,1H),7.05(dd,J＝7.3,2.1Hz,1H),7.02-6.97(m,1H),6.95(dd,J＝3.5,1.2Hz,1H),6.94-6.90(m,1H),6.78(dd,J＝8.2,2.6Hz,1H),4.84(m,1H),4.63-4.48(m,1H),4.32(s,1H),4.14(dd,J＝5.6,4.9Hz,1H),4.10-4.07(m,1H),4.07-4.04(m,1H),3.94(s,1H),3.44(s,2H),2.83(ddd,J＝13.2,8.0,5.0Hz,1H),2.68-2.54(m,1H),1.15(q,J＝7.0Hz,3H).
Example 14
Figure BDA0003462723350000121
Synthesis of ethyl N- (((2, 4-dioxo-1, 2,3, 4-tetrahydroquinazolin-6-yl) sulfonyl) -D-phenylalanine) -N- (thien-2-ylmethyl) glycine
Referring to the synthesis method of example 1, the raw material of intermediate 1 in example 1 was replaced with 2, 4-dihydroxyquinazoline, and the raw material of intermediate 2 was replaced with (tert-butoxycarbonyl) -D-phenylalanine to obtain a white solid powder, i.e., N- (((2, 4-dioxygen) 2-1,2,3, 4-tetrahydroquinazolin-6-yl) sulfonyl) -D-phenylalanine) -N- (thien-2-ylmethyl) glycine ethyl ester.1H NMR(300MHz,DMSO-d6)δ:11.49(m,2H),8.49(dd,J＝11.2,9.0Hz,1H),8.02(d,J＝2.1Hz,1H),7.68(m,1H),7.44(m,1H),7.10(d,J＝4.0Hz,1H),7.07(s,1H),7.07-7.06(m,1H),7.05(s,1H),7.04(s,1H),7.03-6.99(m,1H),6.94(q,J＝1.8Hz,1H),6.91(dd,J＝5.0,3.5Hz,1H),5.02-4.70(m,1H),4.57-4.50(m,1H),4.38(m,1H),4.20-4.06(m,2H),4.04(t,J＝6.0Hz,1H),3.94(s,1H),2.81(m,1H),2.72-2.54(m,1H),1.16(m,3H).
Example 15
Figure BDA0003462723350000122
Synthesis of ethyl N- (((2, 4-dioxo-1, 2,3, 4-tetrahydroquinazolin-6-yl) sulfonyl) -L-phenylalanine) -N- (thien-2-ylmethyl) glycine
Referring to the synthesis method of example 1, the raw material of intermediate 1 in example 1 was replaced with 2, 4-dihydroxyquinazoline, and the raw material of intermediate 2 was replaced with (tert-butoxycarbonyl) -L-phenylalanine to obtain a white solid powder, i.e., ethyl N- (((2, 4-dioxo-1, 2,3, 4-tetrahydroquinazolin-6-yl) sulfonyl) -L-phenylalanine) -N- (thien-2-ylmethyl) glycine.1H NMR(300MHz,DMSO-d6)δ:11.49(m,2H),8.50(m,1H),8.02(d,J＝2.1Hz,1H),7.68(m,1H),7.44(m,1H),7.09(d,J＝4.0Hz,1H),7.07(s,1H),7.06(d,J＝1.6Hz,1H),7.05(s,1H),7.04(d,J＝1.8Hz,1H),7.03-6.99(m,1H),6.94(q,J＝1.4Hz,1H),6.93-6.89(m,1H),5.03-4.71(m,1H),4.54(d,J＝2.1Hz,1H),4.44-4.33(m,1H),4.18-4.06(m,2H),4.06-4.00(m,1H),3.94(s,1H),2.81(m,1H),2.70-2.54(m,1H),1.16(m,3H).
Example 16
Figure BDA0003462723350000131
Synthesis of ethyl N- (((2-oxo-2, 3-dihydro-1H-benzo [ D ] imidazol-5-yl) sulfonyl) -D-phenylalanine) -N- (thien-2-ylmethyl) glycinate
Referring to the synthesis method of example 1, the raw material of intermediate 1 in example 1 was replaced with 1, 3-dihydro-2H-benzimidazol-2-one and the raw material of intermediate 2 was replaced with (tert-butoxycarbonyl) -D-phenylalanine to obtain a white solid powder, i.e., N- (((2-oxo-2, 3-dihydro-1H-benzo [ D ] p-henylalanine)]Imidazol-5-yl) sulfonyl) -D-phenylalanine) -N- (thiophen-2-ylmethyl) glycine ethyl ester.1H NMR(300MHz,DMSO-d6)δ:11.09-10.97(m,1H),10.92(d,J＝1.8Hz,1H),8.19(t,J＝8.9Hz,1H),7.22(m,1H),7.13(d,J＝1.9Hz,1H),7.10(d,J＝1.6Hz,1H),7.09-7.08(m,1H),7.07(d,J＝2.1Hz,1H),7.01(d,J＝2.5Hz,1H),6.99(s,1H),6.92(d,J＝2.4Hz,1H),6.91(d,J＝1.2Hz,1H),6.90(s,1H),6.89(d,J＝2.0Hz,1H),4.52(d,J＝2.9Hz,1H),4.29(d,m,1H),4.14-4.07(m,1H),4.05(dd,J＝7.2,1.0Hz,2H),4.00(d,J＝5.3Hz,1H),3.89(s,1H),2.82(m,1H),2.43(m,1H),1.14(d,J＝7.4Hz,3H).
Example 17
Figure BDA0003462723350000132
Synthesis of ethyl N- (((2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) sulfonyl) -L-phenylalanine) -N- (thien-2-ylmethyl) glycinate
Referring to the synthesis method of example 1, the raw material of intermediate 1 in example 1 was replaced with 1, 3-dihydro-2H-benzimidazol-2-one and the raw material of intermediate 2 was replaced with (tert-butoxycarbonyl) -L-phenylalanine to obtain a white solid powder, i.e., N- (((2-oxo-2, 3-dihydro-1H-benzo [ d ] p-henylalanine)]Imidazol-5-yl) sulfonyl) -L-phenylalanine) -N- (thiophen-2-ylmethyl) glycine ethyl ester.1H NMR(300MHz,DMSO-d6)δ:11.04(s,1H),10.93(s,1H),8.19(t,J＝8.9Hz,1H),7.50-7.37(m,1H),7.22(m,1H),7.13(d,J＝1.8Hz,1H),7.08(td,J＝5.4,2.0Hz,3H),7.01(d,J＝2.6Hz,1H),7.00-6.95(m,1H),6.91(dd,J＝3.0,1.9Hz,2H),6.89(d,J＝2.2Hz,1H),4.82(m,1H),4.52(d,J＝2.9Hz,1H),4.31(s,1H),4.10-4.03(m,2H),4.00(d,J＝5.1Hz,1H),3.89(s,1H),2.82(m,1H),2.43(dd,J＝13.7,8.2Hz,1H),1.14(q,J＝7.2Hz,3H).
Example 18
Figure BDA0003462723350000141
Synthesis of ethyl N- (((2-oxo-2H-chromen-6-yl) sulfonyl) -D-phenylalanine) -N- (thien-2-ylmethyl) glycinate
Referring to the synthesis method of example 1, the raw material of intermediate 1 in example 1 was replaced with coumarin and the raw material of intermediate 2 was replaced with (tert-butoxycarbonyl) -D-phenylalanine to give a brown oil, i.e., ethyl N- (((2-oxo-2H-chromen-6-yl) sulfonyl) -D-phenylalanine) -N- (thien-2-ylmethyl) glycinate.1HNMR(300MHz,DMSO-d6)δ:8.58(dd,J＝8.8,5.5Hz,1H),8.05(d,J＝9.7Hz,1H),7.89m,1H),7.67(m,1H),7.40-7.38(m,1H),7.37(d,J＝1.3Hz,1H),7.12-7.01(m,5H),6.98-6.94(m,1H),6.94-6.88(m,1H),6.61(dd,J＝9.6,1.6Hz,1H),5.04-4.74(m,1H),4.53(s,1H),4.38(m,1H),4.15-4.08(m,1H),4.08(d,J＝9.1Hz,1H),4.03(d,J＝7.2Hz,1H),3.96s,1H),2.82(m,1H),2.72-2.56(m,1H),1.16(t,J＝1.8Hz,3H).
Example 19
Figure BDA0003462723350000142
Synthesis of ethyl N- (((2-oxo-2H-chromen-6-yl) sulfonyl) -L-phenylalanine) -N- (thien-2-ylmethyl) glycinate
Referring to the synthesis method of example 1, the raw material of intermediate 1 in example 1 was replaced with coumarin and the raw material of intermediate 2 was replaced with (tert-butoxycarbonyl) -L-phenylalanine to give a brown oil, i.e., ethyl N- (((2-oxo-2H-chromen-6-yl) sulfonyl) -L-phenylalanine) -N- (thien-2-ylmethyl) glycinate.1H NMR(300MHz,DMSO-d6)δ:8.57(s,1H),8.05(d,J＝9.7Hz,1H),7.88(m,1H),7.67(ddd,J＝34.1,8.7,2.3Hz,1H),7.54-7.38(m,1H),7.38-7.33(m,1H),7.08(s,1H),7.07(s,1H),7.06(s,1H),7.05-7.04(m,1H),7.04-7.01(m,1H),6.95(dd,J＝3.9,2.4Hz,1H),6.93-6.87(m,1H),6.60(dd,J＝9.6,1.6Hz,1H),5.04-4.75(m,1H),4.53(s,1H),4.37(d,J＝18.6Hz,1H),4.16-4.11(m,1H),4.09(d,J＝1.6Hz,1H),4.07-4.02(m,1H),3.95(s,1H),2.82(m,1H),2.62(m,1H),1.16(td,J＝7.1,1.8Hz,3H).
Example 20
Figure BDA0003462723350000151
Synthesis of ethyl N- (((2-oxo-1, 2-dihydroquinolin-6-yl) sulfonyl) -D-tyrosine) -N- (thien-2-ylmethyl) glycine
Referring to the synthesis method of example 1, the raw material of intermediate 2 in example 1 was replaced with (tert-butoxycarbonyl) -D-tyrosine to obtain a white solid powder, i.e., ethyl N- (((2-oxo-1, 2-dihydroquinolin-6-yl) sulfonyl) -D-tyrosine) -N- (thien-2-ylmethyl) glycine.1H NMR(300MHz,DMSO-d6)δ:12.02(s,1H),9.16(d,J＝3.6Hz,1H),8.28(dd,J＝9.1,2.4Hz,1H),7.95-7.87(m,1H),7.63(m,1H),7.52-7.47(m,1H),7.28(dd,J＝8.7,5.5Hz,1H),6.99(d,J＝1.4Hz,1H),6.98(d,J＝3.0Hz,1H),6.89(d,J＝4.5Hz,1H),6.84(d,J＝8.4Hz,1H),6.81-6.77(m,1H),6.76(d,J＝4.6Hz,1H),6.58(dd,J＝9.7,1.8Hz,1H),6.49(dd,J＝6.6,1.9Hz,2H),4.48(d,J＝2.2Hz,1H),4.38-4.27(m,1H),4.11(s,1H),4.10-4.01(m,2H),3.85(s,1H),2.75(d,J＝4.9Hz,1H),2.72-2.67(m,1H),1.15(t,J＝7.1Hz,3H).
Example 21
Figure BDA0003462723350000152
Synthesis of ethyl N- (((2-oxo-1, 2-dihydroquinolin-6-yl) sulfonyl) -L-tyrosine) -N- (thien-2-ylmethyl) glycine
Referring to the synthesis method of example 1, the raw material of intermediate 2 in example 1 was replaced with (tert-butoxycarbonyl) -L-tyrosine to obtain a white solid powder, i.e., ethyl N- (((2-oxo-1, 2-dihydroquinolin-6-yl) sulfonyl) -L-tyrosine) -N- (thien-2-ylmethyl) glycine.1H NMR(300MHz,DMSO-d6)δ:12.05(s,1H),9.19(d,J＝3.7Hz,1H),8.31(d,J＝8.4Hz,1H),7.99-7.87(m,1H),7.65(m,1H),7.56-7.48(m,1H),7.30(dd,J＝8.7,5.6Hz,1H),7.06-6.99(m,2H),7.00(d,J＝3.2Hz,2H),6.92(d,J＝4.6Hz,1H),6.86(d,J＝8.3Hz,1H),6.81(d,J＝4.5Hz,2H),6.78(d,J＝4.5Hz,2H),6.61(d,J＝9.6Hz,1H),6.52(d,J＝2.2Hz,2H),6.53-6.46(m,3H),4.50(s,1H),4.43-4.29(m,1H),4.17(d,J＝5.2Hz,3H),4.15(s,4H),4.08(m,3H),3.88(s,1H),1.17(t,J＝7.1Hz,3H).
Example 22
Figure BDA0003462723350000161
Synthesis of ethyl N- ((2- ((2-oxoindolin) -5-yl) sulfonyl) -D-tyrosine) -N- (thien-2-ylmethyl) glycinate
Referring to the synthesis method of example 1, the raw material of intermediate 1 in example 1 was replaced with 2-carbonyl indole, and the raw material of intermediate 2 was replaced with (tert-butoxycarbonyl) -D-tyrosine to obtain a pink solid powder, i.e., N- ((2- ((2-oxoindolin) -5-yl) sulfonyl) -D-tyrosine) -N- (thien-2-ylmethyl) glycine ethyl ester.1H NMR(400MHz,DMSO-d6)δ:10.70(s,1H),9.20(s,1H),8.10(m,1H),7.50(td,J＝5.1,1.8Hz,1H),7.45(dd,J＝8.2,1.9Hz,1H),7.42-7.38(m,1H),7.02-6.96(m,2H),6.98-6.95(m,1H),6.93(dd,J＝5.0,3.4Hz,1H),6.84-6.81(m,1H),6.81-6.77(m,1H),6.74(d,J＝8.5Hz,1H),6.51(m,2H),4.57(d,J＝6.5Hz,1H),4.23(td,J＝9.2,5.1Hz,1H),4.08(d,J＝7.2Hz,1H),4.07-4.04(m,1H),4.03-3.97(m,1H),3.95(d,J＝7.5Hz,1H),3.45(s,2H),2.73(m,1H),2.69(d,J＝4.8Hz,1H),1.16(d,J＝7.1Hz,3H).
Example 23
Figure BDA0003462723350000162
Synthesis of ethyl N- ((2- ((2-oxoindolin) -5-yl) sulfonyl) -L-tyrosine) -N- (thien-2-ylmethyl) glycine
Referring to the synthesis method of example 1, the raw material of intermediate 1 in example 1 was replaced with 2-carbonyl indole, and the raw material of intermediate 2 was replaced with (tert-butoxycarbonyl) -L-tyrosine to obtain a pink solid powder, i.e., N- ((2- ((2-oxoindolin) -5-yl) sulfonyl group) -L-tyrosine) -N- (thien-2-ylmethyl) glycine ethyl ester.1H NMR(300MHz,DMSO-d6)δ:10.70(s,1H),9.21(s,1H),8.11(m,1H),7.53-7.48(m,1H),7.45(d,J＝8.0Hz,1H),7.43-7.37(m,1H),6.99-6.96(m,1H),6.93(dd,J＝5.0,3.4Hz,1H),6.82(d,J＝8.0Hz,1H),6.80-6.76(m,1H),6.74(d,J＝8.4Hz,1H),6.52(d,J＝2.1Hz,1H),6.50-6.47(m,1H),4.76-4.62(m,1H),4.57(d,J＝4.1Hz,1H),4.29(s,1H),4.15-4.06(m,2H),4.03(d,J＝6.0Hz,1H),3.95(t,J＝4.1Hz,1H),3.44(s,2H),2.72(d,J＝7.0Hz,1H),2.69(d,J＝5.2Hz,1H),1.19-1.13(m,3H).
Example 24
Figure BDA0003462723350000171
Synthesis of ethyl N- ((2, 4-dioxo-1, 2,3, 4-tetrahydroquinazolin-6-yl) sulfonyl) -D-tyrosine) -N- (thien-2-ylmethyl) glycine
Referring to the synthesis procedure of example 1, the starting material for intermediate 1 in example 1 was replaced with 2, 4-dihydroxyquinazoline and the starting material for intermediate 2 was replaced with (tert-butoxycarbonyl) -D-tyrosine to give a white solid powder, i.e., ethyl N- ((2, 4-dioxo-1, 2,3, 4-tetrahydroquinazolin-6-yl) sulfonyl) -D-tyrosine) -N- (thien-2-ylmethyl) glycine.1H NMR(400MHz,DMSO-d6)δ:11.46(s,2H),9.14(s,1H),8.39(m,1H),8.06(d,J＝2.2Hz,1H),7.71(m,1H),7.44(m,1H),7.12(dd,J＝8.7,4.3Hz,1H),7.00(d,J＝4.4Hz,1H),6.91(dd,J＝5.0,3.4Hz,1H),6.83-6.78(m,1H),6.73(d,J＝8.4Hz,1H),6.46(d,J＝1.7Hz,1H),6.44(d,J＝1.7Hz,1H),4.82(m,1H),4.53(d,J＝6.2Hz,1H),4.33(s,1H),4.09(q,J＝7.1Hz,2H),4.06-4.02(m,1H),3.91(s,1H),2.75-2.70(m,1H),2.70-2.65(m,1H),1.18-1.14(m,3H).
Example 25
Figure BDA0003462723350000172
Synthesis of ethyl N- ((2, 4-dioxo-1, 2,3, 4-tetrahydroquinazolin-6-yl) sulfonyl) -L-tyrosine) -N- (thien-2-ylmethyl) glycine
Referring to the synthesis procedure of example 1, the starting material for intermediate 1 in example 1 was replaced with 2, 4-dihydroxyquinazoline and the starting material for intermediate 2 was replaced with (tert-butoxycarbonyl) -L-tyrosine to give a white solid powder, i.e., ethyl N- ((2, 4-dioxo-1, 2,3, 4-tetrahydroquinazolin-6-yl) sulfonyl) -L-tyrosine) -N- (thien-2-ylmethyl) glycine.1H NMR(300MHz,DMSO-d6)δ:11.47(s,2H),9.14(s,1H),8.39(t,J＝9.7Hz,1H),8.05(d,J＝2.2Hz,1H),7.71(m,1H),7.51-7.35(m,1H),7.12(dd,J＝8.6,3.3Hz,1H),7.00(d,J＝4.1Hz,1H),6.91(dd,J＝4.9,3.4Hz,1H),6.81(d,J＝8.5Hz,1H),6.73(d,J＝8.5Hz,1H),6.46(d,J＝1.3Hz,1H),6.44(d,J＝1.3Hz,1H),4.97-4.67(m,1H),4.52(d,J＝3.7Hz,1H),4.34(s,1H),4.13-4.05(m,2H),4.05-4.00(m,1H),3.91(s,1H),2.70(m,1H),2.50-2.39(m,1H),1.16(m,3H).
Example 26
Figure BDA0003462723350000181
Synthesis of ethyl N- (((2-oxo-2, 3-dihydro-1H-benzo [ D ] imidazol-5-yl) sulfonyl) -D-tyrosine) -N- (thien-2-ylmethyl) glycinate
Referring to the synthesis method of example 1, the raw material of intermediate 1 in example 1 was replaced with 1, 3-dihydro-2H-benzimidazol-2-one and the raw material of intermediate 2 was replaced with (tert-butoxycarbonyl) -D-tyrosine to obtain a white solid powder, i.e., N- (((2-oxo-2, 3-dihydro-1H-benzo [ D ] s-tyrosine)]Imidazol-5-yl) sulfonyl) -D-tyrosine) -N- (thien-2-ylmethyl) glycine ethyl ester.1H NMR(300MHz,DMSO-d6)δ:11.04(s,1H),10.94(s,1H),9.17(s,1H),8.09(dd,J＝9.3,3.6Hz,1H),7.43(m,1H),7.26(dd,J＝8.1,1.8Hz,1H),7.22(d,J＝1.5Hz,1H),7.20(d,J＝1.3Hz,1H),6.95(dd,J＝3.3,1.7Hz,1H),6.91-6.87(m,1H),6.82-6.75(m,1H),6.73(d,J＝8.5Hz,1H),6.53(d,J＝1.3Hz,1H),6.50(d,J＝1.2Hz,1H),4.92-4.57(m,1H),4.49(d,J＝6.5Hz,1H),4.26(d,J＝6.3Hz,1H),4.05(dd,J＝7.6,6.4Hz,2H),4.00(s,1H),3.84(s,1H),2.78-2.67(m,1H),2.35(m,1H),1.17-1.10(m,3H).
Example 27
Figure BDA0003462723350000182
Synthesis of ethyl N- (((2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) sulfonyl) -L-tyrosine) -N- (thien-2-ylmethyl) glycinate
Referring to the synthesis method of example 1, the raw material of intermediate 1 in example 1 was replaced with 1, 3-dihydro-2H-benzimidazol-2-one and the raw material of intermediate 2 was replaced with (tert-butoxycarbonyl) -L-tyrosine to obtain a white solid powder, i.e., N- (((2-oxo-2, 3-dihydro-1H-benzo [ d ] s-tyrosine)]Imidazol-5-yl) sulfonyl) -L-tyrosine) -N- (thien-2-ylmethyl) glycine ethyl ester.1H NMR(300MHz,DMSO-d6)δ:11.07(s,1H),10.97(s,1H),9.20(s,1H),8.12(d,J＝9.1Hz,1H),7.45(m,1H),7.28(dd,J＝8.2,1.7Hz,1H),7.24(s,1H),7.22(s,1H),6.96(dd,J＝3.4,1.5Hz,1H),6.93-6.89(m,1H),6.81(d,J＝8.3Hz,1H),6.74(d,J＝8.3Hz,1H),6.55(s,1H),6.52(s,1H),4.96-4.59(m,1H),4.58-4.44(m,1H),4.33-4.21(m,1H),4.11-4.04(m,2H),4.02(s,1H),3.86(s,1H),2.75(m,1H),2.37(m,1H),1.16(td,J＝7.1,6.0Hz,3H).
Example 28
Figure BDA0003462723350000191
Synthesis of ethyl N- (((2-oxo-2H-chromen-6-yl) sulfonyl) -D-tyrosine) -N- (thien-2-ylmethyl) glycinate
Referring to the synthesis method of example 1, the raw material of intermediate 1 in example 1 was replaced with coumarin, and the raw material of intermediate 2 was replaced with (tert-butoxycarbonyl) -D-tyrosine to obtain white solid powder, i.e., ethyl N- (((2-oxo-2H-chromen-6-yl) sulfonyl) -D-tyrosine) -N- (thien-2-ylmethyl) glycine.1H NMR(300MHz,Methanol-d4)δ:7.88-7.80(m,1H),7.80-7.76(m,1H),7.70-7.65(m,1H),7.37(ddd,J＝11.2,4.8,1.6Hz,1H),7.32-7.25(m,1H),7.03-6.96(m,1H),6.95-6.87(m,1H),6.82-6.76(m,1H),6.74-6.68(m,1H),6.48(dd,J＝9.7,1.1Hz,1H),6.43(d,J＝1.7Hz,1H),6.40(d,J＝1.7Hz,1H),4.59(s,3H),4.45-4.37(m,1H),4.29-4.18(m,1H),4.18-4.07(m,2H),4.01(d,J＝3.9Hz,1H),2.90-2.76(m,1H),2.72-2.53(m,1H),1.26(q,J＝2.4Hz,3H).
Example 29
Figure BDA0003462723350000192
Synthesis of ethyl N- (((2-oxo-2H-chromen-6-yl) sulfonyl) -L-tyrosine) -N- (thien-2-ylmethyl) glycinate
Referring to the synthesis method of example 1, the raw material of intermediate 1 in example 1 was replaced with coumarin, and the raw material of intermediate 2 was replaced with (tert-butoxycarbonyl) -L-tyrosine to obtain white solid powder, i.e., ethyl N- (((2-oxo-2H-chromen-6-yl) sulfonyl) -L-tyrosine) -N- (thien-2-ylmethyl) glycine.1H NMR(300MHz,DMSO-d6)δ:9.15(d,J＝5.1Hz,1H),8.55(s,1H),8.06(dd,J＝9.6,2.7Hz,1H),7.87(m,1H),7.69(m,1H),7.45-7.41(m,1H),7.38(d,J＝8.2Hz,1H),7.09(d,J＝2.4Hz,1H),6.99(dd,J＝3.6,1.3Hz,1H),6.94(dd,J＝5.1,3.4Hz,1H),6.85(d,J＝8.3Hz,1H),6.74(d,J＝8.3Hz,1H),6.62(d,J＝9.6Hz,1H),6.49-6.40(m,3H),4.58(s,1H),4.37(s,1H),4.15(d,J＝7.0Hz,2H),4.09(d,J＝7.1Hz,1H),4.00(s,1H),2.80-2.70(m,1H),2.70-2.57(m,1H),1.23-1.18(m,3H).
Example 30
Figure BDA0003462723350000201
Synthesis of ethyl N- (((2-oxo-1, 2-dihydroquinolin-6-yl) sulfonyl) -D-pentyl) -N- (thiophen-2-ylmethyl) glycinate
Referring to the synthesis procedure of example 1, the starting material for intermediate 2 in example 1 was replaced with (tert-butoxycarbonyl) -D-valine to give a white solid powder, i.e., ethyl N- (((2-oxo-1, 2-dihydroquinolin-6-yl) sulfonyl) -D-pentyl) -N- (thien-2-ylmethyl) glycinate.1H NMR(300MHz,DMSO-d6)δ:12.05(s,1H),8.07(m,1H),7.97(dd,J＝9.6,5.6Hz,1H),7.91-7.83(m,1H),7.83-7.73(m,1H),7.50-7.46(m,1H),7.34(dd,J＝8.7,4.2Hz,1H),7.28(dd,J＝4.5,1.9Hz,1H),7.01-6.95(m,1H),6.86-6.81(m,1H),6.60(dt,J＝9.6,2.2Hz,1H),4.84-4.68(m,1H),4.44(m,1H),4.24-4.15(m,1H),4.12-4.05(m,1H),4.01(d,J＝6.8Hz,1H),3.82-3.57(m,1H),1.92(m,1H),1.14(dt,J＝19.3,7.1Hz,3H),0.85(dd,J＝9.8,6.7Hz,3H),0.81-0.70(m,3H).
Example 31
Figure BDA0003462723350000202
Synthesis of ethyl N- (((2-oxo-1, 2-dihydroquinolin-6-yl) sulfonyl) -L-pentyl) -N- (thiophen-2-ylmethyl) glycinate
Referring to the synthesis procedure of example 1, the starting material for intermediate 2 in example 1 was replaced with (tert-butoxycarbonyl) -L-valine to give a white solid powder, i.e., ethyl N- (((2-oxo-1, 2-dihydroquinolin-6-yl) sulfonyl) -L-pentyl) -N- (thien-2-ylmethyl) glycinate.1H NMR(300MHz,DMSO-d6)δ:12.06(s,1H),8.35(d,J＝3.0Hz,1H),8.07(m,1H),7.97(dd,J＝9.6,5.8Hz,1H),7.90-7.73(m,1H),7.50-7.45(m,1H),7.40-7.25(m,1H),7.09(dd,J＝3.5,1.2Hz,1H),7.02-6.96(m,1H),6.60(dt,J＝9.5,2.2Hz,1H),4.88(m,1H),4.55-4.44(m,1H),4.25-4.07(m,1H),3.98(q,J＝6.9Hz,1H),3.84(d,J＝0.8Hz,1H),3.82(s,1H),3.70-3.67(m,1H),2.14(pd,J＝6.9,4.0Hz,1H),1.14(m,2H),0.90(d,J＝7.0Hz,3H),0.78(d,J＝6.8Hz,4H).
Example 32
Figure BDA0003462723350000211
Synthesis of ethyl N- ((2- ((2-oxoindolin) -5-yl) sulfonyl) -D-pentyl) -N- (thien-2-ylmethyl) glycinate
Referring to the synthesis procedure of example 1, the starting material for intermediate 1 in example 1 was replaced with 2-carbonyl indole and the starting material for intermediate 2 was replaced with (tert-butoxycarbonyl) -D-valine to give a light brown solid powder, i.e., ethyl N- ((2- ((2-oxoindolin) -5-yl) sulfonyl) -D-pentyl) -N- (thien-2-ylmethyl) glycine.1HNMR(300MHz,DMSO-d6)δ:10.74(s,1H),7.67-7.62(m,1H),7.61-7.54(m,1H),7.54-7.50(m,1H),7.49-7.45(m,1H),7.01-6.98(m,1H),6.90-6.87(m,1H),4.75(d,J＝2.7Hz,1H),4.51-4.46(m,1H),4.11(td,J＝7.2,2.4Hz,1H),4.01(d,J＝7.1Hz,1H),3.86-3.83(m,1H),3.82(s,1H),3.68(dd,J＝7.9,4.3Hz,1H),3.52(s,1H),3.49(s,1H),1.90(m,1H),1.15(m 3H),0.83(dd,J＝10.4,6.7Hz,3H),0.78(dd,J＝6.8,2.2Hz,3H).
Example 33
Figure BDA0003462723350000212
Synthesis of ethyl N- ((2- ((2-oxoindolin) -5-yl) sulfonyl) -L-pentyl) -N- (thien-2-ylmethyl) glycinate
Referring to the synthesis procedure of example 1, the starting material for intermediate 1 in example 1 was replaced with 2-carbonyl indole and the starting material for intermediate 2 was replaced with (tert-butoxycarbonyl) -L-valine to give a light brown solid powder, i.e., ethyl N- ((2- ((2-oxoindolin) -5-yl) sulfonyl) -L-pentyl) -N- (thien-2-ylmethyl) glycine.1HNMR(300MHz,DMSO-d6)δ:10.74(s,1H),8.34(s,1H),7.64(dd,J＝9.2,5.7Hz,1H),7.56(d,J＝6.8Hz,1H),7.53-7.49(m,1H),7.48(dd,J＝5.1,1.3Hz,1H),7.00(dd,J＝3.6,0.8Hz,1H),6.89(d,J＝3.7Hz,1H),4.75(d,J＝2.7Hz,1H),4.47(s,1H),4.11(td,J＝7.1,2.4Hz,1H),4.01(d,J＝7.1Hz,1H),3.84(d,J＝0.9Hz,1H),3.82(s,1H),3.68(t,J＝3.6Hz,1H),3.52(s,1H),3.49(s,1H),2.14(td,J＝7.0,4.0Hz,1H),1.16(m,3H),0.90(d,J＝7.0Hz,3H),0.79(s,3H).
Example 34
Figure BDA0003462723350000221
Synthesis of ethyl (N- ((2, 4-dioxo-1, 2,3, 4-tetrahydroquinazolin-6-yl) sulfonyl) -D-pentyl) -N- (thien-2-ylmethyl) glycine
With reference to the synthesis of example 1, the starting material for intermediate 1 in example 1 was replaced with 2, 4-dihydroxyquinazoline, the intermediate 2The raw material was replaced with (tert-butoxycarbonyl) -D-valine to give a light brown solid powder, i.e., (N- ((2, 4-dioxo-1, 2,3, 4-tetrahydroquinazolin-6-yl) sulfonyl) -D-pentyl) -N- (thien-2-ylmethyl) glycine ethyl ester.1H NMR(400MHz,DMSO-d6)δ:11.54(d,J＝7.1Hz,1H),11.49(s,1H),8.22(dd,J＝7.9,2.2Hz,1H),8.01(dd,J＝9.2,2.9Hz,1H),7.91(m,1H),7.38(m,1H),7.21(t,J＝8.6Hz,1H),6.98(d,J＝4.1Hz,1H),6.86(d,J＝4.0Hz,1H),4.82-4.69(m,1H),4.53-4.37(m,1H),4.26-4.16(m,1H),4.13-4.03(m,1H),4.02-3.98(m,1H),3.98-3.95(m,1H),3.87-3.62(m,1H),1.90(m,1H),1.15(m,3H),0.85(m,3H),0.76(m,3H).
Example 35
Figure BDA0003462723350000222
Synthesis of ethyl (N- ((2, 4-dioxo-1, 2,3, 4-tetrahydroquinazolin-6-yl) sulfonyl) -L-pentyl) -N- (thien-2-ylmethyl) glycine
Referring to the synthesis procedure of example 1, the starting material for intermediate 1 in example 1 was replaced with 2, 4-dihydroxyquinazoline and the starting material for intermediate 2 was replaced with (tert-butoxycarbonyl) -L-valine to give a light brown solid powder, i.e., (N- ((2, 4-dioxo-1, 2,3, 4-tetrahydroquinazolin-6-yl) sulfonyl) -L-pentyl) -N- (thien-2-ylmethyl) glycine ethyl ester.1H NMR(300MHz,DMSO-d6)δ:11.54(d,J＝5.4Hz,1H),11.49(s,1H),8.22(dd,J＝5.9,2.2Hz,1H),8.00(dd,J＝9.2,2.0Hz,1H),7.96-7.85(m,1H),7.49-7.44(m,1H),7.20(dd,J＝8.6,6.5Hz,1H),7.00-6.96(m,1H),6.86(d,J＝3.8Hz,1H),4.76(d,J＝3.5Hz,1H),4.53-4.37(m,1H),4.26-4.15(m,1H),4.14-4.04(m,1H),4.04-3.99(m,1H),3.97(d,J＝7.0Hz,1H),3.88-3.80(m,1H),2.00-1.81(m,1H),1.15(dt,J＝17.6,7.1Hz,3H),0.92-0.83(m,3H),0.83-0.74(m,3H).
Example 36
Figure BDA0003462723350000231
Synthesis of ethyl N- (((2-oxo-2, 3-dihydro-1H-benzo [ D ] imidazol-5-yl) sulfonyl) -D-pentyl) -N- (thien-2-ylmethyl) glycinate
Referring to the synthesis method of example 1, the raw material of intermediate 1 in example 1 was replaced with 1, 3-dihydro-2H-benzimidazol-2-one and the raw material of intermediate 2 was replaced with (tert-butoxycarbonyl) -D-valine to obtain a white solid powder, i.e., N- (((2-oxo-2, 3-dihydro-1H-benzo [ D ] p-channel-l-alanine)]Imidazol-5-yl) sulfonyl) -D-pentyl) -N- (thiophen-2-ylmethyl) glycine ethyl ester.1H NMR(300MHz,DMSO-d6)δ:11.05(s,1H),10.98(d,J＝7.2Hz,1H),7.67(dd,J＝9.1,2.2Hz,1H),7.47(dd,J＝5.0,1.3Hz,1H),7.36-7.31(m,1H),7.31-7.27(m,1H),7.00-6.96(m,1H),6.96-6.92(m,1H),6.89-6.80(m,1H),4.74(s,1H),4.57-4.37(m,1H),4.08(dd,J＝7.0,2.9Hz,1H),4.02(d,J＝7.0Hz,1H),3.97(d,J＝7.1Hz,1H),3.93-3.82(m,1H),3.60(m,1H),1.88(m,1H),1.14(m,3H),0.82(dd,J＝10.9,6.7Hz,3H),0.73(dd,J＝12.3,6.7Hz,3H).
Example 37
Figure BDA0003462723350000232
Synthesis of ethyl N- (((2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) sulfonyl) -L-pentyl) -N- (thien-2-ylmethyl) glycinate
Referring to the synthesis method of example 1, the raw material of intermediate 1 in example 1 was replaced with 1, 3-dihydro-2H-benzimidazol-2-one and the raw material of intermediate 2 was replaced with (tert-butoxycarbonyl) -L-valine to obtain a white solid powder, i.e., N- (((2-oxo-2, 3-dihydro-1H-benzo [ d ] p-channel-L-alanine)]Imidazol-5-yl) sulfonyl) -L-pentyl) -N- (thiophen-2-ylmethyl) glycine ethyl ester.1H NMR(300MHz,DMSO-d6)δ:11.05(d,J＝3.9Hz,1H),10.98(d,J＝7.4Hz,1H),7.66(d,J＝9.0Hz,1H),7.47(d,J＝5.0Hz,1H),7.37-7.31(m,1H),7.31-7.27(m,1H),7.02-6.96(m,1H),6.96-6.90(m,1H),6.89-6.79(m,1H),4.73(s,1H),4.59-4.36(m,1H),4.08(dd,J＝7.0,2.7Hz,1H),4.02(d,J＝7.0Hz,1H),4.00-3.95(m,1H),3.92-3.82(m,1H),3.60(m,1H),1.88(m,1H),1.14(dt,J＝14.2,7.1Hz,3H),0.82(m,3H),0.73(m,3H).
Example 38
Figure BDA0003462723350000241
Synthesis of ethyl N- (((((2-oxo-2H-chromene) -6-yl) sulfonyl) -D-pentanoyl) -N- (thien-2-ylmethyl) glycinate
Referring to the synthesis method of example 1, the raw material of intermediate 1 in example 1 was replaced with coumarin and the raw material of intermediate 2 was replaced with (tert-butoxycarbonyl) -D-valine to obtain a white solid powder, i.e., ethyl N- (((((2-oxo-2H-chromene) -6-yl) sulfonyl) -D-pentanoyl) -N- (thien-2-ylmethyl) glycine.1H NMR(300MHz,DMSO-d6)δ:8.16-8.13(m,1H),8.12-8.09(m,1H),8.06(t,J＝9.1Hz,1H),7.97(d,J＝2.6Hz,1H),7.54-7.50(m,1H),7.50-7.47(m,1H),7.02-6.97(m,1H),6.87-6.82(m,1H),6.61(dd,J＝9.6,4.1Hz,1H),4.85-4.66(m,1H),4.52-4.36(m,1H),4.22(dd,J＝6.1,3.2Hz,1H),4.13-4.08(m,1H),4.07-4.01(m,1H),3.99(s,1H),3.97(s,1H),1.91(s,1H),1.14(dt,J＝22.1,7.1Hz,3H),0.87(dd,J＝13.1,6.7Hz,3H),0.77(dd,J＝10.5,6.7Hz,3H).
Example 39
Figure BDA0003462723350000242
Synthesis of ethyl N- (((((2-oxo-2H-chromene) -6-yl) sulfonyl) -L-pentanoyl) -N- (thien-2-ylmethyl) glycinate
Referring to the synthesis method of example 1, the raw material of intermediate 1 in example 1 was replaced with coumarin and the raw material of intermediate 2 was replaced with (tert-butoxycarbonyl) -L-valine to obtain a white solid powder, i.e., ethyl N- (((((2-oxo-2H-chromene) -6-yl) sulfonyl) -D-pentanoyl) -N- (thien-2-ylmethyl) glycine.1H NMR(300MHz,DMSO-d6)δ:8.17-8.13(m,1H),8.10(d,J＝2.0Hz,1H),8.05(d,J＝8.9Hz,1H),7.52(d,J＝9.1Hz,1H),7.50-7.47(m,1H),7.02-6.97(m,1H),6.89-6.80(m,1H),6.62(dd,J＝9.6,4.1Hz,1H),4.76(d,J＝5.5Hz,1H),4.30-4.19(m,1H),4.11(dd,J＝7.1,2.5Hz,1H),4.04(t,J＝7.1Hz,1H),4.00-3.94(m,1H),3.85-3.63(m,1H),1.99(s,1H),1.21-1.08(m,3H),0.87(m,3H),0.77(m,3H).
Example 40 assay of OGT inhibitory activity:
the in vitro target activity of the invention takes ultrapure UDP-GlcNAc as glycosyl donor, highly glycosylated CKII3K as acceptor polypeptide and UDP-GloTMThe glycosyltransferase kit converts UDP, a product generated by the OGT catalytic reaction, into ATP, and emits light in the luciferase reaction to be detected. And detecting the generated luminescent signal value by using a spectrophotometer to react the content of UDP generated in the system, thereby measuring and calculating the transferase activity of OGT added into the system. The activity of the reaction enzyme is strong and weak in the light-emitting value, and the reduction of the light-emitting value indicates that the content of UDP generated in an enzyme catalysis reaction system is reduced and the OGT activity is reduced.
The instrument comprises the following steps: spectramax Plus 384 enzyme-labeling instrument (MoLecuLar)
Reagents and solutions:
UDP-GloTMglycosyltransferase assay kit (Progema, USA)
OSMI-1 control, Sigma-Aldrich (MO, USA)
MnCl2Medchemexpress (mce); BSA, Biyuntian
DTT and MgCl2Mecanne, Mecanne
The chemical and chemical industry college of university of Chinese academy of sciences completes the expression and purification of the recombinant full-length ncOGT protein, and the concentration of the mother liquor is 10 mu M
Ultrapure UDP-GlcNAc, Progema, USA
CKII3K polypeptide (KKKYPGGSTPVSSANMM) 96.66% pure, qian yao biotechnology limited, suzhou;
preparation of 25mM CKII3K solution: taking out the polypeptide substrate CKII3K from-80 ℃, standing to room temperature, opening, accurately weighing 1.49mg of CKII3K, dissolving in 33.4 mu L of ultrapure water, subpackaging into the specification of each dosage, and storing at-80 ℃;
packaging 100mM UDP-GlcNAc into dosage specification for each time;
100mM Tris-HCl buffer (pH 7.5) 484.56mg of Tris was accurately weighed and dissolved in 20mL of ultrapure water, 0.1mol/L HCl solution (about 16.12mL) was added, and about 3.88mL of ultrapure water was added to the solution to make 40 mL; adjusting pH to 7.5, mixing 50mL of 0.1mol/L Tris alkali solution with 40.3mL of 0.1mol/L HCl, adding ultrapure water to the mixture until the volume is up to 100mL, and storing the mixture in a refrigerator at 4 ℃ for later use;
4 OGT reaction buffer: 190.42mg of MgCl were accurately weighed29.6mg BSA, 24.68mg DTT were dissolved in 40mL Tris-HCl buffer (pH 7.5) prepared as described above;
1 x OGT reaction buffer containing 5% DMSO (ready to use): 50 μ L DMSO +250 μ L +4 × OGT reaction buffer +700 μ L ultrapure water;
preparing a test medicine solution: will 10-1Compound stock solution of M was diluted to specific concentration with 1 x OGT reaction buffer or/and 1 x OGT reaction buffer containing 5% DMSO;
preparation of a substrate (312.5. mu.M CKII3K + 100. mu.M UDP-GlcNAc) mixture solution (now ready for use): 187.5. mu.L of 4 × OGT reaction buffer +3. mu.L of 10mM UDP-GlcNAc + 3.75. mu.L of 25mM CKII3K + 105.75. mu.L of ultrapure water;
preparation of 500nM ncOGT solution: 37.5 u L4 x OGT reaction buffer +7.5 u L10 u M NCOGT +105 u L ultrapure water;
the method comprises the following specific steps: compound 10 is prepared-1M mother liquor, gradient dilution to 6 concentrations, each concentration three-hole, three times, reaction in 384-hole opaque white microporous plate. Add 2 μ Ι _ of test sample in triplicate to the corresponding wells of the 384-well plate; mu.L of OGT solution was added to the corresponding wells, 2. mu.L of a substrate (312.5. mu.M CKII3K + 100. mu.M UDP-GlcNAc) mixture solution was added to the assay wells, and incubated for 2min with a shaker. Incubating the whole reaction system at 25 ℃ for 60 min; subsequently, 5. mu.L of UDP detection reagent was added to each well to terminate the glycosylation reaction; subsequently, the assay plates were mixed and shaken for 30s, and luminescence was detected after incubation at 25 ℃ for 60 min.
The results are shown in table 1 by measuring the OGT inhibition of the 39 compounds synthesized at a concentration of 20 μ M:
TABLE OGT inhibition of compounds at 120. mu.M concentration
Figure BDA0003462723350000261
Figure BDA0003462723350000271
Figure BDA0003462723350000281
Figure BDA0003462723350000291
N.A.: not Application, indicating that the compound is inactive at the concentration measured;
adata are mean ± SEM of triplicate experiments;
bOSMI-1 at a concentration of 20. mu.M;cOSMI-1 was present at a concentration of 2. mu.M.
Further, the preferred compounds 1,2,3,4, 11, 20, 30 and 31 with better OGT inhibition effect under the concentration of 20 μ M are subjected to percentage measurement of inhibition rate under different concentrations, and IC is calculated50The results are shown in Table 2.
Table 2 IC of preferred compounds to inhibit target OGT50Value of
Figure BDA0003462723350000292
Figure BDA0003462723350000301
aData are mean ± SEM of triplicate experiments;
bmean. + -. SEM representing OSMI-16 replicates
The results show that the molecular structure of the target compound contains different active fragments and different types of pharmacophores, and the inhibition effects of the target compound are obviously different. Analyzing the structure and activity and finding: (1) when the active fragment R1Is composed of
Figure BDA0003462723350000302
Figure BDA0003462723350000303
Regardless of pharmacophore fragment R2Whether the compound is an aromatic ring, an aliphatic ring or an aliphatic chain, the inhibitory activity of the target compound is lost, and the type of the active fragment at the position has a large influence on the activity; (2) bulk comparison R1Is composed of
Figure BDA0003462723350000304
The inhibitory effect of the target Compound (2), R1Is composed of
Figure BDA0003462723350000305
R to which the compound of (1) can be applied2More types; (3) when R is1Are all provided with
Figure BDA0003462723350000306
It was found that benzene rings are superior to benzyl groups in contributing to the inhibitory activity.

Claims (9)

1. An O-GlcNAc transferase inhibitor, comprising a compound represented by formula I or a pharmaceutically acceptable salt thereof:
Figure FDA0003462723340000011
wherein R is1Selected from five-membered or six-membered heterocycles, R2Is selected from the group consisting of1～C4Alkyl, halogen substituted C1～C4Alkyl radical, C1～C4Alkoxy radical, C1～C4Alkoxycarbonyl, C1～C4Acyl, phenyl, optionally substituted phenyl, benzyl or optionally substituted benzyl.
2. The O-GlcNAc transferase inhibitor of claim 1, wherein R is1Is selected from
Figure FDA0003462723340000012
R2Selected from isopropyl, phenyl, benzyl or p-methylphenol.
3. The O-GlcNAc transferase inhibitor of claim 1, wherein said inhibitor is selected from any one of the following compounds:
Figure FDA0003462723340000013
Figure FDA0003462723340000021
。
4. the inhibitor of O-GlcNAc transferase of claim 1, wherein said pharmaceutically acceptable salt is selected from the group consisting of a hydrochloride, a maleate, and a citrate.
5. A process for producing an O-GlcNAc transferase inhibitor according to any one of claims 1 to 4, comprising the steps of:
Figure FDA0003462723340000031
(1) to be provided with
Figure FDA0003462723340000032
The intermediate is obtained by reacting chlorosulfonic acid as the starting material
Figure FDA0003462723340000033
(2) 2-thiophenecarboxaldehyde is obtained by three-step reaction of glycine ethyl ester hydrochloride, amino acid and deamination protection
Figure FDA0003462723340000034
Then and intermediates
Figure FDA0003462723340000035
And (3) preparing the O-GlcNAc transferase inhibitor by reaction.
6. A pharmaceutical composition comprising an O-GlcNAc transferase inhibitor of any one of claims 1-4 and a pharmaceutically acceptable carrier or excipient, and optionally a therapeutic agent.
7. The pharmaceutical composition of claim 6, wherein the excipient is a tablet, capsule, powder, syrup, liquid, suspension, or injection.
8. Use of an inhibitor of O-GlcNAc transferase of any one of claims 1-4 in the manufacture of a medicament for inhibiting the activity of OGT.
9. Use of an inhibitor of O-GlcNAc transferase of any one of claims 1-4 in the manufacture of a medicament for treating or preventing a condition associated with OGT activity.
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CN115192709A (en) * 2022-05-12 2022-10-18 黄淮学院 Use of an inhibitor of O-GlcNAc glycosyltransferase for the manufacture of a medicament for the inhibition of spermatogenesis

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115192709A (en) * 2022-05-12 2022-10-18 黄淮学院 Use of an inhibitor of O-GlcNAc glycosyltransferase for the manufacture of a medicament for the inhibition of spermatogenesis
CN115192709B (en) * 2022-05-12 2023-07-21 黄淮学院 Use of an O-GlcNAc glycosyltransferase inhibitor in the preparation of a medicament for inhibiting spermatogenesis

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