CN106008394B - Mercaptobenzothiazoler amides compound and its preparation and the purposes as drug - Google Patents

Abstract

The invention relates to the technical field of medicine, in particular to a mercaptobenzothiazole amide compound and its preparation and use as medicine. The mercaptobenzothiazole amide compounds provided by the present invention, including pharmaceutically acceptable salts thereof, have the structure shown in formula (I). The present invention also provides the preparation method of the above-mentioned mercaptobenzothiazole amide compound, including its pharmaceutically acceptable salt, and its application in the preparation of antitumor drugs.

Description

Mercaptobenzothiazole amide compounds and their preparation and use as medicine

Technical field:

The invention relates to the technical field of medicine, specifically, mercaptobenzothiazole amide compounds, their preparation and their use as medicines, especially their application in the preparation of antitumor medicines.

Background technique:

Neddylation (NEDD) pathway is a very important non-lysosomal protein degradation pathway in cells, and is an important regulatory pathway for eukaryotic cells to maintain intracellular protein balance, regulate cell cycle, and maintain cell survival . The neddylation pathway is similar to the ubiquitination pathway, which is mainly catalyzed step by step by ubiquitin activating enzyme (E1, NAE), ubiquitin conjugating enzyme (E2) and ubiquitin ligase (E3), and ubiquitin or ubiquitin analog (NEDD8 ) to the target protein, thereby modifying or degrading the protein. Cullin-RING ligases (CRLs), as an important part of ubiquitin ligases, are key signaling proteins in the Neddylation pathway and regulation, and play an important role in controlling the degradation of cellular proteins. Studies have found that the overexpression of NEDD8 pathway in a variety of tumor cells leads to the abnormal activation of CRLs (Soucy, T.A., et al. An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Clin Cancer Res, 2009, 15, 3912-3916). Small molecule NAE (Chinese name Ubiquitin Activating Enzyme, English full name Ubiquitin Activating Enzyme) inhibitor can inhibit the entire pathway from the upstream of the Neddylation pathway, interfere with the degradation of CRL (English full name Cullin-RING) target protein, and cause the target protein to accumulate in the cell. Sustained Neddylation pathway inhibition can trigger cell cycle-dependent DNA re-replication, leading to cell cycle disorder, DNA synthesis disorder, and finally induction of apoptosis (Soucy, T.A., et al.An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature, 2009, 458, 732-736).

Sulfamic acid ((1S,2S,4R)-4-(4-((1S)-2,3-dihydro-1H-inden-1-ylamino)-7H-pyrrolo[2,3-d] Pyrimidin-7-yl)-2-hydroxycyclopentyl)methyl ester (MLN4924) is the first reported small molecule NAE inhibitor, which is a sulfonamide NAE inhibitor. It is currently in phase I clinical trials and has declared a PCT patent , US patents, etc. (WO2006084281 (A1), US20120330013 (A1)). Preclinical studies have shown that MLN4924 has excellent activity against intestinal cancer, osteosarcoma, liver cancer and breast cancer, etc., and MLN4924 can significantly inhibit tumor growth and mediate tumor cell apoptosis. In recent years, studies have also found that the NAE inhibitor MLN4924 has a synergistic effect on radiotherapy (Dongping, W., et al. Targeting NEDD8-activatedcullin-RING ligases for the treatment of cancer. Cancer Research, 2012, 72, 282-293).

Chinese patent application CN104016987A discloses sulfamic acid ((1S, 2S, 4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo [2,3-D]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl ester hydrochloride as a NAE inhibitor, useful for the treatment of cell proliferative disorders, especially cancer, and other disorders associated with E1 activity .

There are few small-molecule NAE inhibitors reported so far. Except for MLN4924, most of the compounds are not highly active. It is necessary to develop new structural types of highly active compounds.

Invention content:

The purpose of the present invention is to provide a new non-sulfonamide NAE inhibitor, specifically mercaptobenzothiazole amide compounds. Another object of the present invention is to provide a preparation method of mercaptobenzothiazole amide compounds. The third object of the present invention is to provide the application of mercaptobenzothiazole amide compounds as medicines, said application includes the use in the preparation of anti-tumor drugs, such compounds can inhibit the activity of NAE to inhibit the NEDD8 signaling pathway, and finally induce tumor cell apoptosis.

The present invention obtains a small molecule inhibitor with a new structure through virtual screening of commercial databases combined with structural modification. And through tumor cell proliferation inhibition experiments and WB experiments, new non-sulfonamide NAE inhibitors were screened out. The compounds of the present invention can significantly inhibit tumor cell growth and mediate tumor cell apoptosis.

Concrete technical scheme of the present invention is as follows:

As the first aspect of the present invention, a mercaptobenzothiazole amide compound, including its pharmaceutically acceptable salts, has a structure such as formula (I);

_Wherein R is hydrogen, halogen, halogenoid, lower alkyl, lower alkoxy, lower haloalkyl, cycloalkyl, aryl, heteroaryl;

Preferably R is aryl, heteroaryl _;

R is _hydrogen , lower alkyl, lower alkoxy, lower haloalkyl, cycloalkyl, aryl, heteroaryl;

Preferably R is lower alkyl, cycloalkyl, aryl, heteroaryl _;

X is -NHC(O)-, -C(O)NH-, -C(O)O-;

Herein, the term lower alkyl refers to a straight chain or branched chain saturated aliphatic hydrocarbon group having 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and the like. Usually the lower alkyl group preferably has 1 to 4 carbon atoms.

The term lower alkoxy means straight or branched chain alkoxy having 1 to 7 carbon atoms.

The term lower haloalkyl refers to lower alkyl substituted with 1 to 3 halogen atoms.

The term aryl refers to a substituted aryl, and the substitution refers to being substituted by one or more of the following groups: hydrogen, halogen, hydroxyl, nitro, amino, cyano, carboxyl, lower alkyl, lower alkoxy , The aryl group refers to a monovalent monocyclic or bicyclic aromatic carbocyclic hydrocarbon group, preferably a 6-7 membered aromatic ring system, and preferred aryl groups include but are not limited to phenyl, naphthyl.

The term heteroaryl refers to a substituted heteroaryl group, said substitution being substituted by one or more of the following groups: hydrogen, halogen, hydroxy, nitro, amino, cyano, carboxyl, lower alkyl, lower alkane Oxygen, said heteroaryl refers to an aromatic heterocyclic ring system containing at most two rings. Preferred heteroaryl groups include, but are not limited to, thienyl, furyl, indolyl, pyrrolyl, pyridyl, pyrazinyl, oxazolyl, thiazolyl, quinolinyl, pyrimidinyl, imidazole, and tetrazolyl.

The term cycloalkyl refers to a ring containing 3 to 7 carbons, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The term halogen refers to chlorine, bromine, iodine or fluorine.

The term halogenoid refers to cyano, trifluoromethyl, trifluoromethoxy.

The term heteroatom refers to an atom selected from nitrogen, oxygen and sulfur.

Compounds of formula (I), preferably selected from the following compounds:

N-(6-(2-((3-hydroxyphenyl)mercapto)acetamido)benzo[d]thiazol-2-yl)butanamide,

4-trifluoromethyl-N-(6-(2-((3-hydroxyphenyl)mercapto)acetamido)benzo[d]thiazol-2-yl)benzamide,

N-(6-(2-((3-hydroxyphenyl)mercapto)acetamido)benzo[d]thiazol-2-yl)-2-naphthylcarboxamide,

4-fluoro-N-(6-(2-((3-hydroxyphenyl)mercapto)acetamido)benzo[d]thiazol-2-yl)benzamide,

4-methyl-N-(6-(2-((3-hydroxyphenyl)mercapto)acetamido)benzo[d]thiazol-2-yl)benzamide,

3,5-Dimethyl-N-(6-(2-((3-hydroxyphenyl)mercapto)acetamido)benzo[d]thiazol-2-yl)benzamide,

3,5-dichloro-N-(6-(2-((3-hydroxyphenyl)mercapto)acetamido)benzo[d]thiazol-2-yl)benzamide,

N-(6-(2-((3-hydroxyphenyl)mercapto)acetamido)benzo[d]thiazol-2-yl)benzamide,

N-(6-(2-((3-hydroxyphenyl)mercapto)acetamido)benzo[d]thiazol-2-yl)thiophene-2-carboxamide,

N-(6-(2-((4-chlorophenyl)mercapto)acetamido)benzo[d]thiazol-2-yl)butanamide,

4-trifluoromethyl-N-(6-(2-((4-chlorophenyl)mercapto)acetamido)benzo[d]thiazol-2-yl)benzamide,

N-(6-(2-((4-chlorophenyl)mercapto)acetamido)benzo[d]thiazol-2-yl)-2-naphthylcarboxamide,

4-fluoro-N-(6-(2-((4-chlorophenyl)mercapto)acetamido)benzo[d]thiazol-2-yl)benzamide,

4-methyl-N-(6-(2-((4-chlorophenyl)mercapto)acetamido)benzo[d]thiazol-2-yl)-4-(trifluoromethyl)benzamide,

3,5-Dimethyl-N-(6-(2-((4-chlorophenyl)mercapto)acetamido)benzo[d]thiazol-2-yl)-4-(trifluoromethyl)benzene Formamide,

4-trifluoromethyl-N-(6-(2-((2,4-xylyl)mercapto)acetamido)benzo[d]thiazol-2-yl)benzamide,

4-trifluoromethyl-N-(6-(2-(2-naphthylmercapto)acetamido)benzo[d]thiazol-2-yl)benzamide,

4-trifluoromethyl-N-(6-(2-(2-pyrimidinylmercapto)acetamido)benzo[d]thiazol-2-yl)benzamide,

4-trifluoromethyl-N-(6-(2-(2-imidazolylmercapto)acetamido)benzo[d]thiazol-2-yl)benzamide,

4-trifluoromethyl-N-(6-(2-(2-benzimidazolylmercapto)acetamido)benzo[d]thiazol-2-yl)benzamide,

4-trifluoromethyl-N-(6-(2-(2-cyclohexylmercapto)acetamido)benzo[d]thiazol-2-yl)benzamide,

4-trifluoromethyl-N-(6-(2-((4-aminophenyl)mercapto)acetamido)benzo[d]thiazol-2-yl)benzamide,

4-trifluoromethyl-N-(6-(2-((3-carboxypyridine)mercapto)acetamido)benzo[d]thiazol-2-yl)benzamide.

Certain compounds of the present invention can be prepared in the form of pharmaceutically acceptable salts according to conventional methods. Including its organic acid salts and inorganic acid salts: inorganic acids include (but not limited to) hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid, nitric acid, etc., organic acids include (but not limited to) acetic acid, maleic acid, fumaric acid acid, tartaric acid, succinic acid, lactic acid, p-toluenesulfonic acid, salicylic acid, oxalic acid, etc.

As a second aspect of the present invention, the compounds of the present invention can be prepared by the following methods:

The reaction flow formula of preparation method of the present invention is as follows:

The preparation method of the present invention comprises the following steps:

The general method for synthesizing intermediate II: dissolve 2-amino-6-nitrobenzothiazole in anhydrous organic solvents such as dichloromethane, DMF, THF, toluene, benzene, etc., add acid-binding agents such as triethylamine, DMAP , pyridine, etc., and then add dropwise a substituted acid chloride dissolved in the same anhydrous organic solvent under ice-cooling, react at room temperature until the raw materials are completely reacted, and obtain intermediate II through column chromatography.

The general method for synthesizing intermediate III: add intermediate II methanol, ethanol, ethyl acetate, etc. slowly, and then slowly add 5% palladium carbon, pass through hydrogen to react at room temperature until the raw materials are completely reacted, and obtain intermediate III through column chromatography.

The general method for synthesizing intermediate IV: dissolve intermediate III in anhydrous organic solvents such as dichloromethane, DMF, THF, toluene, benzene, etc., add acid-binding agents such as triethylamine, DMAP, pyridine, etc., and then Chloroacetyl chloride dissolved in the same anhydrous organic solvent was added dropwise, reacted at room temperature until the raw materials were completely reacted, and intermediate IV was obtained by column chromatography.

The general method for synthesizing the target product I: dissolve the intermediate IV in anhydrous organic solvents such as methylene chloride, DMF, THF, toluene, benzene, etc., add inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc., Then substituted thiophenol or thiol dissolved in the same anhydrous organic solvent was added dropwise under ice-cooling, reacted at room temperature until the raw materials were completely reacted, and the target product I was obtained by column chromatography.

As a third aspect of the present invention, the present invention provides the above-mentioned mercaptobenzothiazole amide compounds, including pharmaceutically acceptable salts thereof, as NAE inhibitors.

And, the present invention provides the application of the above-mentioned mercaptobenzothiazole amide compounds, including their pharmaceutically acceptable salts, in the preparation of antitumor drugs.

The compound of the present invention can be used to prepare drugs for inhibiting NEDD8 signaling pathway and NAE inhibitory activity.

According to in vitro antitumor activity studies, the compounds of the present invention have good antitumor activity, and they can be used to treat tumors, including esophagus, stomach, intestine, rectum, oral cavity, pharynx, larynx, lung, colon, breast, uterus, endometrium , cancers of the ovary, prostate, testes, bladder, kidney, liver, pancreas, bone, connective tissue, skin, eye, brain, and central nervous system, as well as thyroid cancer, leukemia, Hawking's disease, lymphoma, and myeloma Wait.

The compounds of the invention and their salts have good anti-tumor activity, and the anti-tumor activities of several compounds reach nanomole level in vitro, so the compounds of the invention and their salts can be used to prepare anti-tumor drugs.

The compound of the present invention has radiotherapy synergistic effect, and can be used for radiotherapy sensitization or medicine used in combination with radiotherapy. Other compounds that inhibit the NEDD8 signaling pathway and other compounds that inhibit the activity of NAE for radiosensitization or combined with radiotherapy see literature: Dongping, W., et al. Targeting NEDD8-activated cullin-RINGligases for the treatment of cancer . Cancer Research, 2012, 72, 282-293.

The invention provides a new idea for tumor treatment.

Description of drawings:

Fig. 1 is the western experiment result of some compounds of the present invention.

Detailed ways:

The present invention will be further described below in conjunction with specific embodiments and accompanying drawings. It should be understood that the following examples are only used to illustrate the present invention but not to limit the scope of the present invention.

The experimental methods not indicating specific conditions in the following examples are usually carried out according to conventional conditions, such as the conditions described in "Molecular Cloning: A Laboratory Manual" (New York: Cold Spring Harbor Laboratory Press, 1989) or the conditions provided by the manufacturer .

Example 1: N-(6-nitrobenzo[d]thiazol-2-yl)butanamide

0.2 g (1.0 mmol) of 2-amino-6-nitrobenzothiazole was dissolved in 20 mL of dichloromethane, and 0.28 mL of triethylamine was slowly added dropwise. Dissolve 0.12 mL (1.0 mmol) of butyric anhydride in 1 mL of dichloromethane and slowly add it dropwise to the reaction system. Stir the reaction for 3 h at room temperature. The reaction liquid was extracted twice with water and dichloromethane, and the organic phase was combined, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain a yellow solid with a yield of 90.4%.

¹ H NMR (300MHz, DMSO-d ₆ )δ: 12.73(s, 1H), 9.03(d, J=2.3Hz, 1H), 8.26(dd, J=2.4, 9.0Hz, 1H), 7.86(d, J=8.9Hz, 1H), 2.49(t, 2H), 1.59-1.71(m, 2H), 0.91(t, 3H); ESI-MS(m/z): 264.22(MH ⁺ ).

Example 2: N-(6-aminobenzo[d]thiazol-2-yl)butanamide

Weigh 53mg (0.2mmol) of N-(6-nitrobenzo[d]thiazol-2-yl)butanamide into a 20mL eggplant-shaped bottle, dissolve in 10mL of anhydrous methanol, slowly add 6mg of palladium carbon, and Under protective conditions, stir at room temperature for 4h. Purified by column chromatography to obtain a yellow solid with a yield of 98.7%.

¹ H NMR (300MHz, DMSO-d ₆ )δ: 11.94(s, 1H), 7.35(d, J=8.5Hz, 1H), 6.95(d, J=2.0Hz, 1H), 6.65(dd, J= 2.1,8.5Hz,1H),5.12(s,2H),2.37(t,2H),1.51-1.66(m,2H),0.87(t,3H); ESI-MS(m/z):236.25(MH ⁺ ),234.38(M+H ⁺ ).

Example 3: N-(6-(2-chloroacetylamino)benzo[d]thiazol-2-yl)butanamide

Weigh 85mg (0.36mmol) of the intermediate N-(6-aminobenzo[d]thiazol-2-yl)butyramide, put it in a 50mL eggplant-shaped bottle, add 15mL of anhydrous dichloromethane and 1mL of triethylamine. Measure 36 μL of 2-chloroacetyl chloride, dilute with 1 mL of anhydrous dichloromethane, slowly drop into the reaction system, and stir at room temperature for 2.5 h. The reaction solution was quenched with water, extracted three times with dichloromethane and water, the organic phase was washed twice with saturated brine, combined and concentrated, and purified by column to obtain a yellow solid with a yield of 73.6%.

¹ H NMR (300MHz, DMSO-d ₆ )δ: 12.24(s, 1H), 10.42(s, 1H), 8.26(s, 1H), 7.67(d, J=8.7Hz, 1H), 7.51(d, J=8.7Hz, 1H), 4.26(s, 2H), 2.45(t, 2H), 1.59-1.67(m, 2H), 0.91(t, 3H); ESI-MS(m/z): 312.35(M +H ⁺ ),310.21(MH ⁺ ).

Example 4: N-(6-(2-((3-hydroxyphenyl)mercapto)acetamido)benzo[d]thiazol-2-yl)butanamide

Weigh 70mg (0.19mmol) of the intermediate N-(6-(2-chloroacetylamino)benzo[d]thiazol-2-yl)butanamide and 140mg of potassium carbonate, put them in a 25mL eggplant-shaped bottle, add anhydrous DMF 10mL, 28mg (0.22mmol) of 3-mercaptophenol was slowly added dropwise to the reaction system, and the reaction was stirred at room temperature for 3.5h. Then extracted three times with ethyl acetate and water, washed the organic phase twice with saturated brine, combined and concentrated the organic phases, and purified by column to obtain a light yellow solid with a yield of 69.1%.

¹ H NMR (300MHz, DMSO-d ₆ )δ: 12.26(s, 1H), 10.34(s, 1H), 9.58(s, 1H), 8.26(s, 1H), 7.65(d, J=8.7Hz, 1H), 7.48(d, J=8.7Hz, 1H), 7.10(t, 1H), 6.74-6.84(m, 2H), 6.59(d, J=8.3Hz, 1H), 3.83(s, 2H), 2.44(t, 2H), 1.55-1.70(m, 2H), 0.90(t, 3H); ESI-MS(m/z): 402.30(M+H ⁺ ), 400.26(MH ⁺ ).

Example 5: 4-Trifluoromethyl-N-(6-(2-((3-hydroxyphenyl)mercapto)acetamido)benzo[d]thiazol-2-yl)benzamide

Using the same method as in Example 4, replace N-(6-( 2-Chloroacetamido)benzo[d]thiazol-2-yl)butyramide to obtain a light yellow solid with a yield of 52.1%.

¹ H NMR (300MHz, DMSO-d ₆ )δ: 13.08(s, 1H), 10.28(s, 1H), 9.75(s, 1H), 8.30(d, J=8.3Hz, 2H), 7.94(d, J＝8.3Hz, 2H), 7.62(dd, J＝2.1, 8.7Hz, 1H), 7.34(t, 1H), 7.20(t, 1H), 7.10-7.15(m, 1H), 6.90-6.94(m ,1H),6.64-6.67(m,1H),4.74(s,2H); ESI-MS(m/z):502.24(MH ⁺ ).

Example 6: N-(6-(2-((3-hydroxyphenyl)mercapto)acetamido)benzo[d]thiazol-2-yl)-2-naphthylcarboxamide

Using the same method as in Example 4, replace N-(6-(2-chloroacetyl) with N-(6-(2-chloroacetylamino)benzo[d]thiazol-2-yl)-2-naphthylcarboxamide Amino)benzo[d]thiazol-2-yl)butyramide to obtain a light yellow solid with a yield of 26.0%.

¹ H NMR (300MHz,DMSO-d ₆ )δ:13.00(s,1H),10.40(s,1H),9.59(s,1H),8.84-8.87(m,1H),8.36(s,1H), 8.18(d, J=8.4Hz, 1H), 8.11(t, 1H), 8.06(d, J=8.3Hz, 1H), 7.71-7.73(m, 1H), 7.67-7.69(m, 1H), 7.57 (dd,J=2.1,8.7Hz,1H),7.20(t,1H),7.15(t,1H),6.93-6.96(m,1H),6.83-6.86(m,1H),6.67-6.70(m ,1H),6.61-6.64(m,1H),3.88(s,2H); ESI-MS(m/z):486.24(M+H ⁺ ),970.89(2M+H ⁺ ),484.27(MH ⁺ ) .

Example 7: 4-fluoro-N-(6-(2-((3-hydroxyphenyl)mercapto)acetamido)benzo[d]thiazol-2-yl)benzamide

Using the same method as in Example 4, replace N-(6-(2-chloro Acetylamino)benzo[d]thiazol-2-yl)butyramide to obtain a light yellow solid with a yield of 44.7%.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 12.88(s, 1H), 10.39(s, 1H), 9.59(s, 1H), 8.35(d, J=1.6Hz, 1H), 8.21-8.26( m,2H),7.75(d,J=8.7Hz,1H),7.56(dd,J=2.1,8.7Hz,1H),7.40-7.46(m,2H),7.14(t,1H),6.83-6.87 (m,2H),6.61-6.64(m,1H),3.88(s,2H); ESI-MS(m/z):454.23(M+H ⁺ ),906.78(2M+H ⁺ ),452.25(MH ⁺ ).

Example 8: 4-methyl-N-(6-(2-((3-hydroxyphenyl)mercapto)acetamido)benzo[d]thiazol-2-yl)benzamide

Using the same method as in Example 4, replace N-(6-(2- Chloroacetamido)benzo[d]thiazol-2-yl)butyramide to obtain 41 mg of light yellow solid, yield 46.1%.

¹ H NMR (300MHz, DMSO-d ₆ )δ: 12.76(s, 1H), 10.39(s, 1H), 9.59(s, 1H), 8.35(d, J=1.8Hz, 1H), 8.07(d, J＝8.1Hz, 2H), 7.75(d, J＝8.8Hz, 1H), 7.55(dd, J＝2.1, 8.7Hz, 1H), 7.39(d, J＝8.1Hz, 2H), 7.14(t, 1H),6.81-6.86(m,2H),6.61-6.64(m,1H),3.88(s,2H),2.42(s,3H); ESI-MS(m/z):450.33(M+H ⁺ ),898.93(2M+H ⁺ ),448.27(MH ⁺ ).

Example 9: 3,5-Dimethyl-N-(6-(2-((3-hydroxyphenyl)mercapto)acetamido)benzo[d]thiazol-2-yl)benzamide

Using the same method as in Example 4, replace N-(6- (2-Chloroacetamido)benzo[d]thiazol-2-yl)butanamide to obtain a light yellow solid with a yield of 49.6%.

¹ H NMR (300MHz, DMSO-d ₆ )δ: 12.67(s, 1H), 10.35(s, 1H), 9.55(s, 1H), 8.31(d, J=1.9Hz, 1H), 7.75(s, 2H), 7.71(d, J=8.6Hz, 1H), 7.53(dd, J=2.1, 8.7Hz, 1H), 7.28(s, 1H), 7.11(t, 1H), 6.79-6.83(m, 2H ),6.58-6.61(m,1H),3.84(s,2H),2.35(s,6H); ESI-MS(m/z):464.40(M+H ⁺ 926.96(2M+H ⁺ ),462.26( MH ⁺ ).

Example 10: 3,5-dichloro-N-(6-(2-((3-hydroxyphenyl)mercapto)acetamido)benzo[d]thiazol-2-yl)benzamide

Using the same method as in Example 4, replace N-(6-( 2-Chloroacetamido)benzo[d]thiazol-2-yl)butyramide to obtain a light yellow solid with a yield of 48.0%.

¹ H NMR (300MHz, DMSO-d ₆ )δ: 10.38(s, 1H), 9.74(s, 1H), 9.55(s, 1H), 8.34(s, 1H), 8.13(d, J=1.8Hz, 1H),7.92(s,1H),7.53(dd,J＝2.1,8.7Hz,1H),7.16(t,1H),7.10(t,1H),6.88-6.92(m,1H),6.78-6.82 (m,1H),6.64-6.67(m,1H),6.57-6.61(m,1H),3.84(s,2H); ESI-MS(m/z):502.19(MH ⁺ ).

Example 11: N-(6-(2-((3-hydroxyphenyl)mercapto)acetamido)benzo[d]thiazol-2-yl)benzamide

Using the same method as in Example 4, use N-(6-(2-chloroacetylamino)benzo[d]thiazol-2-yl)benzamide instead of N-(6-(2-chloroacetylamino)benzene and[d]thiazol-2-yl)butyramide to obtain a light yellow solid with a yield of 58.6%.

¹ H NMR (300MHz, DMSO-d ₆ )δ: 12.81(s, 1H), 10.35(s, 1H), 9.54(s, 1H), 8.32(s, 1H), 8.12(d, J=7.4Hz, 2H), 7.65(t, 1H), 7.56(t, 2H), 7.52(dd, J=1.9, 8.5Hz, 1H), 7.11(t, 1H), 6.79-6.83(m, 2H), 6.59(dd , J=2.2, 8.1Hz, 1H), 3.84(s, 2H); ESI-MS (m/z): 436(M+H ⁺ ), 871.00(2M+H ⁺ ), 434.32(MH ⁺ ).

Example 12: N-(6-(2-((3-Hydroxyphenyl)mercapto)acetamido)benzo[d]thiazol-2-yl)thiophene-2-carboxamide

Using the same method as in Example 4, replace N-(6-(2-chloroacetyl) with N-(6-(2-chloroacetylamino)benzo[d]thiazol-2-yl)thiophene-2-carboxamide Amino)benzo[d]thiazol-2-yl)butyramide to obtain a light yellow solid with a yield of 67.4%.

¹ H NMR (300MHz, DMSO-d ₆ )δ: 12.94(s, 1H), 10.38(s, 1H), 9.58(s, 1H), 8.32(s, 2H), 8.01(d, J=4.3Hz, 1H), 7.72(d, J=8.3Hz, 1H), 7.54(dd, J=2.0, 8.7Hz, 1H), 7.28(t, 1H), 7.12(t, 1H), 6.79-6.85(m, 2H ),6.58-6.63(m,1H),3.86(s,2H); ESI-MS(m/z):440.21(MH ⁺ ).

Example 13: N-(6-(2-((4-chlorophenyl)mercapto)acetamido)benzo[d]thiazol-2-yl)butanamide

Using the same method as in Example 4, replacing 3-hydroxythiophenol with 4-chlorothiophenol, a light yellow solid was obtained with a yield of 60.1%.

¹ H NMR (300MHz, DMSO-d ₆ )δ: 12.24(s, 1H), 10.34(s, 1H), 8.23(d, J=2.0Hz, 1H), 7.64(d, J=8.7Hz, 1H) ,7.45(dd,J＝2.1,8.8Hz,1H),7.40-7.44(m,2H),7.36-7.39(m,2H),3.88(s,2H),2.43(t,2H),1.59-1.64 (m, 2H), 0.89 (t, 3H); ESI-MS (m/z): 420.22 (M+H ⁺ ), 418.21 (MH ⁺ ).

Example 14: 4-Trifluoromethyl-N-(6-(2-((4-chlorophenyl)mercapto)acetamido)benzo[d]thiazol-2-yl)benzamide

Using the same method as in Example 4, replacing 3-hydroxythiophenol with 4-chlorothiophenol, a light yellow solid was obtained with a yield of 58.7%.

¹ H NMR (300MHz, DMSO-d ₆ )δ: 13.06(s, 1H), 10.38(s, 1H), 8.31(s, 1H), 8.28(d, J=8.1Hz, 2H), 7.93(d, J＝8.3Hz, 2H), 7.70-7.74(m, 1H), 7.51(dd, J＝2.0, 8.7Hz, 1H), 7.42-7.46(m, 2H), 7.37-7.40(m, 2H), 3.89 (s, 2H); ESI-MS (m/z): 522.40(M+H ⁺ ), 520.26(MH ⁺ ).

Example 15: N-(6-(2-((4-chlorophenyl)mercapto)acetamido)benzo[d]thiazol-2-yl)-2-naphthylcarboxamide

Using the same method as in Example 4, replace 3-hydroxythiophenol with 4-chlorothiophenol, and use N-(6-(2-chloroacetylamino)benzo[d]thiazol-2-yl)-2 N-(6-(2-chloroacetamido)benzo[d]thiazol-2-yl)butanamide was replaced by -naphthylcarboxamide to obtain a light yellow solid with a yield of 65.3%.

¹ H NMR (300MHz, DMSO-d ₆ )δ: 12.67(s, 1H), 10.39(s, 1H), 8.81(s, 1H), 8.31(s, 1H), 8.13(d, J=8.6Hz, 1H), 8.07(t, 2H), 8.02(d, J=8.0Hz, 1H), 7.73(d, J=8.2Hz, 1H), 7.68(t, 1H), 7.64(t, 1H), 7.52( dd,J=2.0,8.7Hz,1H),7.44(d,J=8.6Hz,2H),7.39(d,J=8.6Hz,2H),3.91(s,2H); ESI-MS(m/z ):504.11(M+H ⁺ ),502.29(MH ⁺ ).

Example 16: 4-fluoro-N-(6-(2-((4-chlorophenyl)mercapto)acetamido)benzo[d]thiazol-2-yl)benzamide

Using the same method as in Example 4, 4-chlorothiophenol was used instead of 3-hydroxythiophenol, and 4-fluoro-N-(6-(2-chloroacetylamino)benzo[d]thiazole-2- yl) benzamide instead of N-(6-(2-chloroacetamido)benzo[d]thiazol-2-yl)butyramide to give a light yellow solid in a yield of 25%.

¹ H NMR (300MHz, DMSO-d ₆ )δ: 13.69(s, 1H), 11.23(s, 1H), 9.13(s, 1H), 9.02(q, 2H), 8.55(d, J=8.6Hz, 1H), 8.33(dd, J=2.0, 8.7Hz, 1H), 8.25-8.29(m, 2H), 8.19-8.24(m, 4H), 4.72(s, 2H); ESI-MS(m/z) :470.24(MH ⁺ ).

Example 17: 4-Methyl-N-(6-(2-((4-chlorophenyl)mercapto)acetamido)benzo[d]thiazol-2-yl)-4-(trifluoromethyl) benzamide

Using the same method as in Example 4, replace 3-hydroxybenzenethiol with 4-chlorothiophenol, and use 4-methyl-N-(6-(2-chloroacetylamino)benzo[d]thiazole-2- N-(6-(2-chloroacetamido)benzo[d]thiazol-2-yl)butyramide was replaced by benzamide to obtain a light yellow solid with a yield of 63.8%.

¹ H NMR (300MHz, DMSO-d ₆ )δ: 12.74(s, 1H), 10.39(s, 1H), 8.31(s, 1H), 8.05(d, J=8.1Hz, 2H), 7.73(d, J＝8.6Hz, 1H), 7.52(dd, J＝1.8, 8.7Hz, 1H), 7.44-7.49(m, 2H), 7.39-7.43(m, 2H), 7.35-7.39(m, 2H), 3.91 (s, 2H), 2.41 (s, 3H); ESI-MS (m/z): 468.35 (M+H ⁺ ), 466.26 (MH ⁺ ).

Example 18: 3,5-Dimethyl-N-(6-(2-((4-chlorophenyl)mercapto)acetamido)benzo[d]thiazol-2-yl)-4-(trifluoro Methyl)benzamide

Using the same method as in Example 4, replace 3-hydroxybenzenethiol with 4-chlorothiophenol, and use 3,5-dimethyl-N-(6-(2-chloroacetamido)benzo[d] Thiazol-2-yl)benzamide was substituted for N-(6-(2-chloroacetamido)benzo[d]thiazol-2-yl)butyramide to obtain a light yellow solid with a yield of 70.6%.

¹ H NMR (300MHz, DMSO-d ₆ )δ: 12.69(s, 1H), 10.40(s, 1H), 8.31(d, J=1.8Hz, 1H), 7.76(s, 2H), 7.72(d, J＝8.7Hz, 1H), 7.53(dd, J＝1.9, 8.7Hz, 1H), 7.46(d, J＝8.7Hz, 2H), 7.40(d, J＝8.7Hz, 2H), 7.28(s, 1H), 3.91(s, 2H), 2.36(s, 6H); ESI-MS(m/z): 480.26(M+H ⁺ ).

Example 19: 4-Trifluoromethyl-N-(6-(2-((2,4-xylyl)mercapto)acetamido)benzo[d]thiazol-2-yl)benzamide

Using the same method as in Example 4, 2,4-xylenol was used instead of 3-hydroxythiophenol to obtain 96 mg of light yellow solid with a yield of 73.3%.

¹ H NMR (300MHz, DMSO-d ₆ )δ: 13.09(s, 1H), 10.35(s, 1H), 8.32(s, 2H), 8.30(s, 1H), 7.95(d, J=8.3Hz, 2H), 7.74(d, J=8.7Hz, 1H), 7.53(dd, J=2.0, 8.8Hz, 1H), 7.33(d, J=7.9Hz, 1H), 7.05(s, 1H), 7.01( d, J=8.1Hz, 1H), 3.79(s, 2H), 2.32(s, 3H), 2.24(s, 3H); ESI-MS(m/z): 514.31(MH ⁺ ).

Example 20: 4-Trifluoromethyl-N-(6-(2-(2-naphthylmercapto)acetamido)benzo[d]thiazol-2-yl)benzamide

Using the same method as in Example 4, 2-naphthol was used instead of 3-hydroxythiophenol to obtain a light yellow solid with a yield of 63.0%.

¹ H NMR (300MHz,DMSO-d ₆ )δ:13.09(s,1H),10.48(s,1H),8.35(s,1H),8.32(s,1H),8.30(s,1H),7.91- 7.80(m,3H),7.88(d,J=8.2Hz,2H),7.83(d,J=7.9Hz,1H),7.74(d,J=8.3Hz,1H),7.56(d,J=8.1 Hz, 2H), 7.50-7.53(m, 1H), 7.45-7.50(m, 1H), 4.03(s, 2H); ESI-MS(m/z): 538.40(M+H ⁺ ), 1074.92(2M +H ⁺ ),536.27(MH ⁺ ).

Example 21: 4-Trifluoromethyl-N-(6-(2-(2-pyrimidinylmercapto)acetamido)benzo[d]thiazol-2-yl)benzamide

Using the same method as in Example 4, substituting 2-mercaptopyrimidine for 3-hydroxythiophenol, a light yellow solid was obtained with a yield of 76.2%.

¹ H NMR (300MHz, DMSO-d ₆ )δ: 13.09(s, 1H), 10.47(s, 1H), 8.66(d, J=4.9Hz, 2H), 8.35(s, 1H), 8.31(d, J＝8.2Hz, 2H), 7.95(d, J＝8.2Hz, 2H), 7.75(d, J＝9.0Hz, 1H), 7.59(dd, J＝1.8, 8.8Hz, 1H), 7.24(t, 1H), 4.15(s, 2H); ESI-MS(m/z): 490.30(M+H ⁺ ), 978.80(2M+H ⁺ ), 488.28(MH ⁺ ).

Example 22: 4-Trifluoromethyl-N-(6-(2-(2-imidazolylmercapto)acetamido)benzo[d]thiazol-2-yl)benzamide

Using the same method as in Example 4, substituting 2-mercaptoimidazole for 3-hydroxythiophenol, a light yellow solid was obtained with a yield of 66.1%.

¹ H NMR (300MHz, DMSO-d ₆ )δ: 13.11(s, 1H), 12.36(s, 1H), 10.64(s, 1H), 8.34(d, J=1.7Hz, 1H), 8.31(d, J＝8.3Hz, 2H), 7.96(d, J＝8.3Hz, 2H), 7.75(d, J＝8.6Hz, 1H), 7.55(dd, J＝1.8, 8.8Hz, 1H), 7.09(s, 2H), 3.94(s, 2H); ESI-MS(m/z): 478.20(M+H ⁺ ), 476.17(MH ⁺ ).

Example 23: 4-Trifluoromethyl-N-(6-(2-(2-benzimidazolylmercapto)acetamido)benzo[d]thiazol-2-yl)benzamide

Using the same method as in Example 4, substituting 2-mercaptobenzimidazole for 3-hydroxythiophenol, a light yellow solid was obtained with a yield of 45.7%.

¹ H NMR (300MHz, DMSO-d ₆ )δ: 13.12(s, 1H), 12.68(s, 1H), 10.72(s, 1H), 8.37(d, J=1.7Hz, 1H), 8.31(d, J＝8.2Hz, 2H), 7.95(d, J＝8.4Hz, 2H), 7.75(d, J＝8.7Hz, 1H), 7.58(dd, J＝2.0, 8.8Hz, 1H), 7.53(s, 1H), 7.39(d, J=4.5Hz, 1H), 7.10-7.17(m, 2H), 4.32(s, 2H); ESI-MS(m/z): 528.20(M+H ⁺ ), 526.15( MH ⁺ ).

Example 24: 4-Trifluoromethyl-N-(6-(2-(2-cyclohexylmercapto)acetamido)benzo[d]thiazol-2-yl)benzamide

Using the same method as in Example 4, substituting mercaptocyclohexane for 3-hydroxythiophenol, a yellow solid was obtained with a yield of 34%.

¹ H NMR (300MHz, DMSO-d ₆ )δ: 13.10(s, 1H), 10.25(s, 1H), 8.37(d, J=1.5Hz, 1H), 8.31(d, J=8.1Hz, 2H) ,7.95(d,J=8.2Hz,2H),7.74(d,J=8.7Hz,1H),7.55(dd,J=2.0,8.7Hz,1H),3.36(s,2H),2.54-2.92( m,1H),1.94-2.03(m,2H),1.66-1.73(m,2H),1.54-1.59(m,1H),1.20-1.31(m,5H); ESI-MS(m/z): 494.51(M+H ⁺ ),492.35(MH ⁺ ).

Example 25: 4-Trifluoromethyl-N-(6-(2-((4-aminophenyl)mercapto)acetamido)benzo[d]thiazol-2-yl)benzamide

Using the same method as in Example 4, replacing 3-hydroxythiophenol with 4-aminothiophenol, a light yellow solid was obtained with a yield of 70.4%.

¹ H NMR (300MHz, DMSO-d ₆ )δ: 13.09(s, 1H), 10.17(s, 1H), 8.33(s, 2H), 8.30(s, 1H), 7.95(d, J=8.4Hz, 2H), 7.73(d, J=8.7Hz, 1H), 7.52(dd, J=1.9, 8.7Hz, 1H), 7.17(d, J=8.4Hz, 2H), 6.51(d, J=8.4Hz, 2H), 5.32(s, 2H), 3.57(s, 2H); ESI-MS(m/z): 503.50(M+H ⁺ ), 1004.82(2M+H ⁺ ), 501.27(MH ⁺ ).

Example 26: 4-Trifluoromethyl-N-(6-(2-((3-carboxypyridine)mercapto)acetamido)benzo[d]thiazol-2-yl)benzamide

Using the same method as in Example 4, substituting 2-mercaptonicotinic acid for 3-hydroxythiophenol, a purple solid was obtained with a yield of 64.9%.

¹ H NMR (300MHz, DMSO-d ₆ )δ: 10.33(s, 1H), 8.45(dd, J=2.0, 4.8Hz, 1H), 8.31(d, J=8.0Hz, 2H), 8.26(d, J＝1.5Hz, 1H), 8.12(dd, J＝1.7, 7.4Hz, 1H), 7.90(d, J＝8.1Hz, 2H), 7.64(d, J＝8.6Hz, 1H), 7.52(dd, J=1.7, 78.2Hz, 1H), 7.13(q, 1H), 3.90(s, 2H); ESI-MS(m/z): 531(MH ⁺ ).

Example 27: Tumor cell proliferation inhibition experiment

The compounds of the present invention were tested for inhibition of tumor cell proliferation, using the conventional MTT method (such as "New Drug Pharmacological Research Methods" edited by Lu Qiujun, Chemical Industry Press, 2007: 242-243).

The cell line was HCT116 (human intestinal cancer cell) U2OS (human osteosarcoma cell) for control experiments, and was frozen and passaged by the Pharmacology Laboratory of Shanghai Pharmaceutical Industry Research Institute. The culture medium is DMEM+10%FBS+double antibody.

Preparation of MTT solution: Weigh 0.5 g of MTT, dissolve in 100 mL of phosphate buffered solution (PBS) or phenol red-free medium, filter through a 0.22 μm filter membrane to remove bacteria in the solution, and store at 4°C in the dark.

Sample preparation: After dissolving with DMSO (Merck), add PBS (-) to make a 1000 μg/mL solution or a homogeneous suspension, and then dilute with DMSO-containing PBS (-).

The highly active compound MLN4924 was formulated as a positive control solution under the same conditions.

MTT method: 100 μL of cell suspension with a concentration of 5-6×10 ⁴ cells/mL was added to each well of a 96-well plate, and placed in a 37° C., 5% CO ₂ incubator. After 24 hours, add the sample solution, 10 μL/well, set up duplicate wells, 37 ° C, 5% CO ₂ for 72 hours. Add 20 μL of 5 mg/mL MTT solution to each well, add the dissolving solution after 4 hours of action, 100 μL/well, put in the incubator, measure the 570nm OD value with MK-2 automatic microplate reader after dissolution. Calculate the half inhibitory concentration IC ₅₀ .

The experimental results are shown in Table 1, wherein, the sample refers to the mercaptobenzothiazole amide compound (example: embodiment 4: N-(6-(2-((3-hydroxyphenyl) mercapto) acetyl) prepared in the corresponding examples amino)benzo[d]thiazol-2-yl)butanamide).

Table 1 The half inhibitory concentration IC ₅₀ (unit: μM) of test compounds to tumor cells

The above experimental results show that most of the compounds of the present invention have good antitumor activity, especially the new compounds of Examples 7, 8, 9, 12, 13, 15, 16, 17, 19, 20, 23, 25, the present invention The compound can be used as a good antitumor agent.

Embodiment 28: WB experiment

Western experiments showed that the compounds of Examples 9, 20, and 25 had the same mechanism of action as the positive control drug MLN4924, and grayscale analysis showed that all three compounds could effectively inhibit the interaction between the upstream protein NEDD8 and other proteins in the pathway, and the downstream protein UBC12 in There is obvious accumulation in the cells, and it shows a good concentration dependence, as shown in Figure 1.

Therefore, the mercaptobenzothiazole amide compounds of the present invention can be used to prepare small molecule inhibitors of NAE.

The basic principles, main features and advantages of the present invention have been shown and described above. Those skilled in the art should understand that the present invention is not limited by the above-mentioned embodiments, and that described in the above-mentioned embodiments and the description only illustrates the principles of the present invention, and the present invention also has various aspects without departing from the spirit and scope of the present invention. Variations and improvements all fall within the scope of the claimed invention. The protection scope of the present invention is defined by the appended claims and their equivalents.

Claims (2)

1. the preparation method of a kind of mercaptobenzothiazoler amides compound or its pharmaceutical salts, which is characterized in that preparation method Reaction stream formula is as follows:

Preparation method the following steps are included:

A, synthetic intermediate (II): 2- amino-6-nitrobenzothiazole is dissolved in anhydrous organic solvent, acid binding agent is added, then The substitution acyl chlorides for being dissolved in identical anhydrous organic solvent is added dropwise under ice bath, room temperature reaction is reacted completely to raw material, through pillar layer separation Obtain intermediate (II)；

B, synthetic intermediate (III): intermediate (II) is dissolved in organic solvent, 5% palladium carbon is then slowly added into, is passed through hydrogen chamber Temperature reaction is reacted completely to raw material, obtains intermediate (III) through pillar layer separation；

C, synthetic intermediate (IV): intermediate (III) is dissolved in anhydrous organic solvent, acid binding agent is added, is then added dropwise under ice bath It is dissolved in the chloracetyl chloride of identical anhydrous organic solvent, room temperature reaction is reacted completely to raw material, obtains intermediate through pillar layer separation (IV)；

D, it synthesizes target product (I): intermediate (IV) being dissolved in anhydrous organic solvent, inorganic base is added, is then added dropwise under ice bath It is dissolved in the substitution thiophenol or mercaptan of identical anhydrous organic solvent, room temperature reaction is reacted completely to raw material, obtained through pillar layer separation Target product (I)；

The mercaptobenzothiazoler amides compound is selected from following any:

N- (6- (2- ((3-hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) butyramide,

4- trifluoromethyl-N- (6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,

N- (6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) -2- naphthalenecarboxamide,

The fluoro- N- of 4- (6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,

4- methyl-N- (6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,

3,5- dimethyl-N-(6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,

The chloro- N- of 3,5- bis- (6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,

N- (6- (2- ((3-hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,

N- (6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) thiophene-2-carboxamide derivatives,

N- (6- (2- ((4- chlorphenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) butyramide,

4- trifluoromethyl-N- (6- (2- ((4- chlorphenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,

N- (6- (2- ((4- chlorphenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) -2- naphthalenecarboxamide,

The fluoro- N- of 4- (6- (2- ((4- chlorphenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,

4- methyl-N- (6- (2- ((4- chlorphenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) -4- (trifluoromethyl) benzene Formamide,

3,5- dimethyl-N-(6- (2- ((4- chlorphenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) -4- (fluoroform Base) benzamide,

4- trifluoromethyl-N- (6- (2- ((2,4-xylyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzoyl Amine,

4- trifluoromethyl-N- (6- (2- (2- naphthalene sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,

4- trifluoromethyl-N- (6- (2- (2- pyrimidine sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,

4- trifluoromethyl-N- (6- (2- (2- imidazoles sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,

4- trifluoromethyl-N- (6- (2- (2- benzimidazole sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,

4- trifluoromethyl-N- (6- (2- (2- cyclohexyl sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,

4- trifluoromethyl-N- (6- (2- ((4- aminophenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide, Or

4- trifluoromethyl-N- (6- (2- ((3- carboxyl pyridine) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide.

2. a kind of mercaptobenzothiazoler amides compound or its pharmaceutical salts are in preparation NEDD8 signal pathway inhibitor or NAE suppression Application in preparation, the mercaptobenzothiazoler amides compound are selected from following any:

N- (6- (2- ((3-hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) butyramide,

4- trifluoromethyl-N- (6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,

N- (6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) -2- naphthalenecarboxamide,

The fluoro- N- of 4- (6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,

4- methyl-N- (6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,

3,5- dimethyl-N-(6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,

The chloro- N- of 3,5- bis- (6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,

N- (6- (2- ((3-hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,

N- (6- (2- ((3- hydroxy phenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) thiophene-2-carboxamide derivatives,

N- (6- (2- ((4- chlorphenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) butyramide,

4- trifluoromethyl-N- (6- (2- ((4- chlorphenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,

N- (6- (2- ((4- chlorphenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) -2- naphthalenecarboxamide,

The fluoro- N- of 4- (6- (2- ((4- chlorphenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,

4- methyl-N- (6- (2- ((4- chlorphenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) -4- (trifluoromethyl) benzene Formamide,

3,5- dimethyl-N-(6- (2- ((4- chlorphenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) -4- (fluoroform Base) benzamide,

4- trifluoromethyl-N- (6- (2- ((2,4-xylyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzoyl Amine,

4- trifluoromethyl-N- (6- (2- (2- naphthalene sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,

4- trifluoromethyl-N- (6- (2- (2- pyrimidine sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,

4- trifluoromethyl-N- (6- (2- (2- imidazoles sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,

4- trifluoromethyl-N- (6- (2- (2- benzimidazole sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,

4- trifluoromethyl-N- (6- (2- (2- cyclohexyl sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide,

4- trifluoromethyl-N- (6- (2- ((4- aminophenyl) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide, Or

4- trifluoromethyl-N- (6- (2- ((3- carboxyl pyridine) sulfydryl) acetylamino) benzo [d] thiazol-2-yl) benzamide.