1,4-diphenyl-1H-imidazole and 2,4-diphenylthiazole derivatives and preparation method therefor and use thereof

Abstract

Provided are 1,4-diphenyl-1H-imidazole and 2,4-diphenylthiazole derivatives having a structure represented by Formula I, a preparation method therefor and uses thereof: ##STR00001##
wherein R.sub.1 is any one of H, OH, and OCH.sub.3, R.sub.2 is any one of H, NO.sub.2, CH.sub.3, CF.sub.3, SO.sub.2CH.sub.3, COOCH.sub.3, or CONHCH.sub.3, R.sub.3 is any one of H, NO.sub.2, OCH.sub.3, or CF.sub.3, R.sub.4 is selected from H, CF.sub.3, or Cl, R.sub.5 is any one of H, Cl, CF.sub.3, or NHCH.sub.3, and R.sub.6 is any one of OCF.sub.3, CF.sub.3, or CN; V is either C or N, W is either CH or N, X is a C atom, Y is either CH or N, and Z is either CH or S. This compound can be used in preparation of anti-inflammatory adjuvants, TLR1 or TLR2 agonists, and anti-tumor agents and for regulating the activity activation level of TLR1 and TLR2 alkaline phosphatases in vitro and in vivo.

Claims

1. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound has a structural formula below: Compound 23 ##STR00088##

2. A preparation method of the compound according to claim 1, comprising the following steps: 1) allowing compound A1 ##STR00089## to react as catalyzed by inethyllithium to obtain compound A2 ##STR00090## allowing the compound A2 ##STR00091## to react in a presence of tetrabutylammonium tribromide to obtain compound A3 ##STR00092## 2) allowing compound B1 ##STR00093## to react in methylamine to give an amino-substituted compound B2 ##STR00094## reducing the amino-substituted compound B2 to obtain compound B3 ##STR00095## or aminomethylating compound B5 ##STR00096## to obtain the compound B3; 3) reacting compound B3 with triethyl orthofomiate to form a ring to obtain compound B4 ##STR00097## 4) reacting the compound 134 with the compound A3 to obtain compound B6 ##STR00098## 5) refluxing the compound B6 under acidic conditions to obtain the compound according to claim 1; wherein R.sub.1, R.sub.2 and R.sub.6 in the compounds A3, B1, B2, B3, B4 and B5 for preparing the compound according to claim 1 are as follows: R.sub.1═OH, R.sub.6═CF.sub.3, R.sub.2═SO.sub.2CH.sub.3.

3. A pharmaceutical composition, comprising the compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or an excipient.

4. A method for regulating an activity activation level of URI and TLR2 alkaline phosphatases in vivo, comprising administering the compound according to claim 1 to a subject.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1: Reaction scheme for the preparation of compounds 1-20.

(2) FIG. 2: Reaction scheme for the preparation of compounds 28-47.

(3) FIG. 3: Compound 22 activates TLR1/2 activity in a concentration-dependent manner.

DETAILED DESCRIPTION OF THE EMBODIMENTS

(4) In order to better understand the present invention, the present invention will be further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto.

Example 1: Preparation of Compound 1

Preparation of 1-(2-hydroxy-4-(trifluoromethyl)phenyl)ethanone

(5) 2-hydroxy-4-(trifluoromethyl)benzoic acid (1.0 g, 4.85 mmol) was dissolved in THF (10 mL) in an ice bath, 1.6 M (10 mL) methyllithium was added thereto dropwise, and the reaction mixture was stirred at room temperature for 4 hours. Then it was quenched with distilled water, adjusted to pH=7 with dilute HCl and extracted with ethyl acetate (3×50 mL). The collected organic layer was dried over anhydrous Na.sub.2SO.sub.4, concentrated under reduced pressure, and purified by column chromatography (petroleum ether) to obtain an oily product 1-(2-hydroxy-4-(trifluoromethyl)phenyl)ethanone (750 mg, 75.8%).

Preparation of 2-bromo-1-(2-hydroxy-4-(trifluoromethyl)phenyl)ethanone

(6) The oily 1-(2-hydroxy-4-(trifluoromethyl)phenyl)ethanone (1.0 g, 0.0049 mmol) was dissolved in MeOH (12 mL) and DCM (6 mL) at room temperature. Tetrabutylammonium tribromide (2.59 g, 0.0054 mmol) was dissolved in DCM (12 mL) and added into the aforementioned mixed solution dropwise to react at room temperature for 24 hours. After the reaction was completed, the organic phase was spin-dried under reduced pressure and purified by column chromatography (petroleum ether-ethyl acetate) to obtain yellow oily 2-bromo-1-(2-hydroxy-4-(trifluoromethyl)phenyl)ethanone (1.32 g, 95%).

Preparation of Compound 1

(7) 2-chloro-5-nitrothiobenzamide (243 mg, 1.12 mmol) and 2-bromo-1-(4-(trifluoromethyl)phenyl)ethanone (300 mg, 1.12 mmol) were dissolved in EtOH (5 mL). The reaction solution was allowed to react for 4 hours under reflux, and the reaction was monitored by TLC. After the reaction was completed, the mixture was cooled to produce a precipitate, and the precipitate was filtered out to obtain compound 2-(2-chloro-5-nitrophenyl)-5-(4-(trifluoromethyl)phenyl)thiazole with a yield of 100%.

Example 2: Preparation of Compound 2

(8) The compound 2-(2-chloro-5-nitrophenyl)-5-(4-(trifluoromethyl)phenyl)thiazole (300 mg, 0.78 mmol) and methylamine 40% aqueous solution (263 mg, 3.9 mmol) were dissolved in EtOH (15 mL) to react at room temperature, and the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was extracted with ethyl acetate (3×50 mL) and then washed with water to remove methylamine. The collected organic layer was dried over anhydrous Na.sub.2SO.sub.4, concentrated under reduced pressure, and purified by column chromatography (petroleum ether-ethyl acetate=4:1) to obtain N-methyl-4-nitro-2-(5-(4-(trifluoromethyl)phenyl)thiazol-2-yl)aniline with a yield of 100%.

(9) The compound 2-(methylamino)-5-nitrobenzothioamide (211.2 mg, 1 mmol) and 2-bromo-1-(4-(trifluoromethyl)phenyl)ethanone (300 mg, 1.12 mmol) were dissolved in EtOH (5 mL). The reaction solution was allowed to react for 4 hours under reflux, and the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was cooled to produce a precipitate, and the precipitate was filtered out to obtain compound 2-(2-methylamino-5-nitrophenyl)-5-O-(trifluoromethyl)phenyl)thiazole with a yield of 100%.

Example 3: Preparation of Compounds 3-20

(10) In Example 3, compounds 3-20 were prepared respectively. The preparation steps of the compounds 3-2.0 are the same as those in the preparation of compound 1, except that the raw materials used are different. The differences are shown in Table 1 below:

(11) TABLE-US-00001 TABLE 1 The difference between compounds 3-20 and compound 1 Compound No. Difference from compound 1 in steps  3 Replace 2-chloro-5-nitrothiobenzamide with thiobenzamide  4 Replace 2-chloro-5-nitrothiobenzamide with 3-(trifluoromethyl)thiobenzamide  5 Replace 2-chloro-5-nitrothiobenzamide with 4-(trifluoromethyl)thiobenzamide  6 Replace 2-chloro-5-nitrothiobenzamide with 2-(trifluoromethyl)thiobenzamide  7 Replace 2-chloro-5-nitrothiobenzamide with 3-bis(trifluoromethyl)thiobenzamide  8 Replace 2-chloro-5-nitrothiobenzamide with 4-methoxythiobenzamide  9 Replace 2-chloro-5-nitrothiobenzamide with 4-nitrothiobenzamide 10 Replace 2-chloro-5-nitrothiobenzamide with 3-methylthiobenzamide 11 Replace 2-bromo-1-(4-(trifluoromethyl)phenyl) ethanone with 2-bromo-1-(2-hydroxy-4- (trifluoromethyl)phenyl)ethanone 12 Replace 2-chloro-5-nitrothiobenzamide with 2-(methylamino)-5-nitrothiobenzamide, and replace 2-bromo-1-(4-(trifluoromethyl)phenyl)ethanone with 2-bromo-1-(2-hydroxy-4-(trifluoromethyl)phenyl)ethanone 13 Replace 2-chloro-5-nitrothiobenzamide with thiobenzamide, and replace 2-bromo-1-(4- (trifluoromethyl)phenyl)ethanone with 2- bromo-1-(2-hydroxy-4-(trifluoromethyl)phenyl)ethanone 14 Replace 2-chloro-5-nitrothiobenzamide with 3- (trifluoromethyl)thiobenzamide, and replace 2-bromo-1-(4-(trifluoromethyl)phenyl)ethanone with 2-bromo-1-(2-hydroxy-4-(trifluoromethyl)phenyl)ethanone 15 Replace 2-chloro-5-nitrothiobenzamide with 4- (trifluoromethyl)thiobenzamide, and replace 2-bromo-1-(4-(trifluoromethyl)phenyl)ethanone with 2-bromo-1-(2-hydroxy-4-(trifluoromethyl)phenyl)ethanone 16 Replace 2-chloro-5-nitrothiobenzamide with 2- (trifluoromethyl)thiobenzamide, and replace 2-bromo-1-(4-(trifluoromethyl)phenyl)ethanone with 2-bromo-1-(2-hydroxy-4-(trifluoromethyl)phenyl)ethanone 17 Replace 2-chloro-5-nitrothiobenzamide with 3,5- bis(trifluoromethyl)thiobenzamide, and replace 2-bromo-1-(4-(trifluoromethyl)phenyl)ethanone with 2-bromo-1-(2-hydroxy-4-(trifluoromethyl)phenyl)ethanone 18 Replace 2-chloro-5-nitrothiobenzamide with 4- methoxythiobenzamide, and replace 2-bromo-1-(4- (trifluoromethyl)phenyl)ethanone with 2-bromo-1- (2-hydroxy-4-(trifluoromethyl)phenyl)ethanone 19 Replace 2-chloro-5-nitrothiobenzamide with 4- nitrothiobenzamide, and replace 2-bromo-1-(4- (trifluoromethyl)phenyl)ethanone with 2-bromo- 1-(2-hydroxy-4-(trifluoromethyl)phenyl)ethanone 20 Replace 2-chloro-5-nitrothiobenzamide with 3- methylthiobenzamide, and replace 2-bromo-1-(4- (trifluoromethyl)phenyl)ethanone with 2-bromo- 1-(2-hydroxy-4-(trifluoromethyl)phenyl)ethanone

Example 4: Preparation of Compound 22

1. Preparation of 1-(2-hydroxy-4-(trifluoromethyl)phenyl)ethanone

(12) 2-hydroxy-4-(trifluoromethyl)benzoic acid (1.0 g, 4.85 mmol) was dissolved in THF (10 mL) in an ice bath, 1.6 M (10 mL) methyllithium was added thereto dropwise, and the reaction mixture was stirred at room temperature for 4 hours. Then it was quenched with distilled water and adjusted to pH=7 with dilute HCl and extracted with ethyl acetate (3-50 mL). The collected organic layer was dried over anhydrous Na.sub.2SO.sub.4, concentrated under reduced pressure, and purified by column chromatography (petroleum ether) to obtain an oily product 1-(2-hydroxy-4-(trifluoromethyl)phenyl)ethanone (750 mg, 75.8%).

2. Preparation of 2-bromo-1-(2-hydroxy-4-(trifluoromethyl)phenyl)ethanone

(13) The oily 1-(2-hydroxy-4-(trifluoromethyl)phenyl)ethanone (1.0 g, 0.0049 mmol) was dissolved in MeOH (12 mL) and DCM (6 mL) at room temperature. Tetrabutylammonium tribromide (2.59 g, 0.0054 mmol) was dissolved in DCM (12 mL) and then added into the aforementioned mixed solution dropwise to react at room temperature for 24 hours. After the reaction was completed, the organic phase was spin-dried under reduced pressure and purified by column chromatography (petroleum ether-ethyl acetate) to obtain yellow oily 2-bromo-1-(2-hydroxy-4-(trifluoromethyl)phenyl)ethanone (1.32 g, 95%).

3. Preparation of 1-methyl-5-nitro-1H-benzo[d]imidazole

(14) N1-methyl-4-nitrobenzene-1,2-diamine (251 mg, 1.5 mmol) was dissolved in DMF (4 mL), and triethyl orthoformate (10 mL) was added thereto to form a pale yellow precipitate in concentrated HCl (12 N solution, 167 μL, 5 mmol), filtering was conducted to obtain 1-methyl-5-nitro-1H-benzo[d]imidazole (90 mg, 33.7%) which was then recrystallized in a methanol ice bath.

4. Preparation of 3-(2-(2-hydroxy-4-(trifluoromethyl)phenyl)-2-oxoethyl)-1-methyl-5-nitro-1H-benzo[d]imidazo-3-ium bromide

(15) 2-bromo-1-(2-hydroxy-4-(trifluoromethyl)phenyl)ethanone (566 mg, 2 mmol) and 1-methyl-5-nitro-1H-benzo[d]imidazole (354 mg, 2 mmol) were refluxed in MeOH (20 mL) as a solvent for 12 hours. The reaction mixture was spin-dried to remove the solvent and then treated ultrasonically with acetone to obtain a precipitate. The precipitate was filtered out and dried, and then the filter cake was recrystallized in methanol to prepare 3-(2-(2-hydroxy-4-(trifluoromethyl)phenyl)-2-oxoethyl)-1-methyl-5-nitro-1H-benzo[d]imidazo-3-ium bromide (920 mg, 100%).

5. Preparation of 2-(1-(2-(methylamino)-5-nitrophenyl)-1H-imidazol-4-yl)-5-(trifluoromethyl)phenol

(16) 3-(2-(2-hydroxy-4-(trifluoromethyl)phenyl)-2-oxoethyl)-1-methyl-5-nitro-1H-benzo[d]imidazo-3-ium bromide (920 mg, 12 mmol) was refluxed overnight in acetic acid (10 mL) and ammonium acetate (770 mg, 10 mmol). After the reaction was completed, distilled water (100 mL) was added thereto to precipitate a yellow solid. After suction filtration, the solid was recrystallized to give pure 2-(1-(2-(methylamino)-5-nitrophenyl)-1H-imidazol-4-yl)-5-(trifluoromethyl)phenol (378 mg, 50%).

Example 5: Preparation of Compounds 21, 23, 24, 25

(17) TABLE-US-00002 TABLE 2 The difference between compounds 21, 23, 24, 25 and compound 22 Compound No. Difference from compound 22 in steps 21 Replace the preparation of 2-bromo-1-(2- hydroxy-4-(trifluoromethyl)phenyl)ethanone with 2-bromo-1-(4-(trifluoromethoxy)phenyl)ethanone 23 Replace N1-methyl-4-nitrobenzene-1,2-diamine with N1-methyl-4-(methylsulfonyl)benzene-1,2-diamine 24 Replace N1-methyl-4-nitrobenzene-1,2-diamine with methyl 3-amino-4-(methylamino)benzoate 25 Replace N1-methyl-4-nitrobenzene-1,2-diamine with 3-amino-N-methyl-4-(methylamino)benzamide

Example 6: Preparation of Compound 26

(18) 2-(1-(2-(methylamino)-5-nitrophenyl)-1H-imidazol-4-yl)-5-(trifluoromethyl)phenol (30 mg, 0.08 mmol) was dissolved in thionyl chloride (4 mL) to react at room temperature. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was spin-dried to remove thionyl chloride, and purified by column chromatography (petroleum ether-ethyl acetate=2:1) to obtain yellow 2-(1-(3-chloro-2-(methylamino)-5-nitrophenyl)-1H-imidazol-4-yl)-5-(trifluoromethyl)phenol (750 mg, 75.8%).

Example 7: Preparation of Compound 27

(19) TABLE-US-00003 TABLE 3 The difference between compound 27 and compound 26 Compound No. Difference from compound 26 in steps 27 Replace the preparation of 2-bromo-1-(2-hydroxy-4- (trifluoromethyl)phenyl)ethanone with 4-(2- bromoacetyl)benzonitrile

Example 8: Preparation of Compound 28

(20) 2-(1-(2-(methylamino)-5-nitrophenyl)-1H-imidazol-4-yl)-5-(trifluoromethyl)phenol (30 mg, 0.082 mmol) and K.sub.2CO.sub.3 (101.8 mg, 0.738 mmol) were dissolved in acetone (3 ml) and stirred for 20 minutes. Then methyl iodide (34.9 mg, 0.246 mmol) was added thereto to react at 50° C. and the reaction was monitored by TLC. After the reaction was completed, it was quenched with water and extracted with ethylacetate (3×50 mL). The collected organic layer was dried over anhydrous Na.sub.2SO.sub.4, concentrated under reduced pressure, and purified by column chromatography (petroleum ether-ethyl acetate=1:1) to obtain yellow 2-(4-(2-methoxy-4-(trifluoromethyl)phenyl)-H-imidazol-1-yl)-N-methyl-4-nitroaniline (28.6 mg, 92%).

Example 9: Preparation of Compounds 29, 30, 31, 32, 33, 34, 40, 41, 42

(21) TABLE-US-00004 TABLE 4 The difference between compounds 29, 30, 31, 32, 33, 34, 40, 41, 42 and compound 28 Compound No. Difference from compound 28 in steps 29 Replace CH.sub.3I with CH.sub.3CH.sub.2I 30 Replace CH.sub.3I with C.sub.6H.sub.5CH.sub.2I 31 Replace CH.sub.3I with C.sub.2H.sub.4Br.sub.2 32 Replace CH.sub.3I with C.sub.3H.sub.6Br.sub.2 33 Replace CH.sub.3I with (CH.sub.2).sub.2O(CH.sub.2).sub.2Br.sub.2 34 Replace CH.sub.3I with Cl(CH.sub.2).sub.2O(CH.sub.2).sub.2OH 40 Replace CH.sub.3I with SO.sub.3—Py 41 Replace CH.sub.3I with (CH.sub.2).sub.2O(CH.sub.2).sub.2O(CH.sub.2).sub.2I.sub.2 42 Replace CH.sub.3I with NH.sub.2COCH.sub.2Cl

Example 10: Preparation of Compound 35

(22) 2-(1-(2-(methylamino)-5-nitrophenyl)-1H-imidazol-4-yl)-5-(trifluoromethyl)phenol (10 mg, 0.026 mmol) was dissolved in DCM (20 ml), triethylamine (200 uL) was added thereto, the reaction mixture was stirred in an ice bath for 10 minutes, and then acetyl chloride (2 ml) was added thereto dropwise. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was spin-dried to remove the solvent, and purified by column chromatography (petroleum ether-ethyl acetate=1:1) to obtain yellow (1-(2-(methylamino)-5-nitrophenyl)-1H-imidazol-4-yl)-5-(trifluoromethyl)phenyl acetate (9.2 mg, 85%).

Example 11: Preparation of Compounds 36, 37, 38, 39

(23) TABLE-US-00005 TABLE 5 The difference between compounds 36, 37, 38, 39 and compound 35 Compound No. Difference from compound 35 in steps 36 Replace CH.sub.3COCl with C.sub.7H.sub.15COCl 37 Replace CH.sub.3COCl with C.sub.11H.sub.23COCl 38 Replace CH.sub.3COCl with C.sub.6H.sub.5COCl 39 Replace CH.sub.3COCl with C.sub.7H.sub.15COCl

Example 12: Preparation of Compound 43

(24) 2-(4-(2-(2-bromoethoxy)-4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)-N-methyl-4-nitroaniline (35 mg, 0.082 mmol), potassium iodide (68 mg, 0.41 mmol) was dissolved in THF (4 ml) and 30% ammonia (4 mL), and refluxed overnight in a sealed state. The reaction was monitored by TLC. After the reaction was completed, it was extracted and purified by column chromatography (dichloromethane-methanol=9:1) to obtain yellow 2-(4-(3-(2-aminoethoxy)-4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)-N-methyl-4-nitroaniline (24.5 mg, 71%).

Example 13: Preparation of Compound 44

(25) Biotin (34.8 mg, 0.14 mmol) was dissolved in DMF (4 mL), HATU (80.94 mg, 0.213 mmol) and DIPEA (2 mL) were added thereto, with stirring for 30 minutes. Then 2-(4-(3-(2-aminoethoxy)-4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)-N-methyl-4-nitroaniline (30 mg, 0.071 mmol) was added thereto. The reaction mixture was kept at 45° C. overnight and the reaction was monitored by TLC. After the reaction was completed, it was extracted and purified by column chromatography (ethyl acetate-methanol=9:1) to obtain yellow N-(2-(2-(1-(2-(methylamino)-5-nitrophenyl)-1H-imidazol-4-yl)-5-(trifluoromethyl)phenoxy)ethyl)-5-((3AS, 4S, 6AR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamide (42.76 mg, 93%).

Example 14: Preparation of Compounds 45, 46, 47

(26) TABLE-US-00006 TABLE 6 The difference between compounds 45, 46, 47 and compound 35 Compound No. Difference from compound 44 in steps 45 Replace joining chain (CH.sub.2).sub.2NH.sub.2 with CH.sub.2CH.sub.2 46 Replace joining chain (CH.sub.2).sub.2NH.sub.2 with (CH.sub.2).sub.2O(CH.sub.2).sub.2 47 Replace joining chain (CH.sub.2).sub.2NH.sub.2 with (CH.sub.2).sub.2O(CH.sub.2).sub.2O(CH.sub.2).sub.2

Example 15: Structural Verification of the Compound

(27) ##STR00041##

2-(2-chloro-5-nitrophenyl)-5-(4-(trifluoromethyl)phenyl)thiazole

(28) White solid (276.2 mg, 64.1%). m. p. 169.2-170.2° C. H NMR (400 MHz, CDCl3) δ 9.34 (d, J=2.8 Hz, 1H), 8.23 (dd, J=8.8, 2.8 Hz, 1H), 8.16 (d, J=8.1 Hz, 2H), 7.86 (s, 1H), 7.74 (dd, J=12.4, 8.5 Hz, 3H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ 99.97, 160.97, 153.95, 146.81, 137.96, 136.88, 132.89, 131.83, 130.50, 126.68, 125.84, 124.31, 117.21. MS (EST-TOF) for C.sub.16H.sub.8ClF.sub.3N.sub.2O.sub.2S [M+H].sup.+ calculated 385.76, found 385.96.

(29) ##STR00042##

N-methyl-4-nitro-2-(5-(4-(trifluoromethyl)phenyl)thiazol-2-yl)aniline

(30) Yellow solid (284.9 mg, 96.3%). m.p. 145.3-145.9° C. .sup.1H NMR (400 MHz, DMSO) δ 9.40 (d, J=5.0 Hz, 1H), 8.57-8.37 (m, 2H), 8.24 (d, J=8.2 Hz, 2H), 8.19 (dd, J=9.3, 2.5 Hz, 1H), 7.85 (d, J=8.3 Hz, 2H), 6.97 (d, J=9.5 Hz, 1H), 3.14 (d, 3H). .sup.13C NMR (101 MHz, DMSO) δ 167.39, 152.95, 151.80, 137.26, 135.79, 127.21, 126.27, 125.45, 116.73, 113.68, 111.54, 30.35. MS (ESI-TOF) for C.sub.17H.sub.12F.sub.3N.sub.3O.sub.2S [M+H].sup.+ calculated 380.36, found 380.32.

(31) ##STR00043##

2-phenyl-4-(4-(trifluoromethyl)phenyl)thiazole

(32) White solid (299.2 mg, 98.2%). m.p. 126.1-127.0° C. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.14 (d, J=8.2 Hz, 2H), 8.07 (dd, J=7.4, 2.1 Hz, 2H), 7.73 (d, J=8.3 Hz, 2H), 7.61 (s, 1H), 7.50 (dd, J=5.0, 2.3 Hz, 3H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ 168.34, 154.65, 137.65, 133.41, 130.28, 130.03, 129.70, 128.96, 126.60, 125.68, 122.84, 114.32. MS (ESI-TOF) for C.sub.16H.sub.10F.sub.3NS [M+H].sup.+ calculated 306.32, found 305.59.

(33) ##STR00044##

2-(3-(trifluoromethyl)phenyl)-4-(4-(trifluoromethyl)phenyl)thiazole

(34) White solid (302.1 mg, 80.9%). m.p. 91.7-95.2° C. .sup.1H NMR (400 MHz, CDCl3) δ 8.14 (d, J=8.2 Hz, 2H), 8.07 (dd, J=7.4, 2.1 Hz, 2H), 7.73 (d, J=8.3 Hz, 2H), 7.61 (s, 1H), 7.50 (dd, J=5.0, 2.3 Hz, 3H). .sup.13C NMR (101 MHz, CDCl3) δ 168.34, 154.65, 137.65, 133.41, 130.28, 130.03, 129.70, 128.96, 126.60, 125.68, 122.84, 114.32. MS (ESI-TOF) for C.sub.17H.sub.9F.sub.6NS [M+H].sup.+ calculated 374.32, found 375.11.

(35) ##STR00045##

2,5-bis(4-(trifluoromethyl)phenyl)thiazole

(36) White solid (282 mg, 75.6%). m.p. 126.3-127.8° C. .sup.1H NMR (400 MHz, CDCl3) δ 8.14 (dd, J=17.3, 8.1 Hz, 96H), 7.74 (t, J=7.3 Hz, 96H), 7.65 (s, 18H), 7.28 (s, 3H). .sup.13C NMR (101 MHz, CDCl3) δ 166.40, 155.17, 137.27, 136.42, 131.69, 130.32, 126.77, 125.94, 125.76, 122.75, 115.24. MS (ESI-TOF) for C.sub.17H.sub.9F.sub.6NS [M+H].sup.+ calculated 374.32, found 374.29.

(37) ##STR00046##

2-(2-(trifluoromethyl)phenyl)-5-(4-(trifluoromethyl)phenyl)thiazole

(38) White solid (303.1 mg, 81.2%). m.p. 123.4-126.2° C. .sup.1H NMR (400 MHz, CDCl3) δ 8.11 (d, J=8.2 Hz, 2H), 7.89 (d, J=7.5 Hz, 1H), 7.82-7.56 (m, 6H). .sup.13C NMR (101 MHz, CDCl3) δ 164.64, 154.31, 137.39, 132.40, 132.14, 131.73, 130.17, 129.84, 129.05, 128.74, 127.00, 126.64, 125.71, 125.49, 124.98, 122.79, 122.26, 116.25. MS (ESI-TOF) for C.sub.17H.sub.9F.sub.6NS [M+H].sup.+ calculated 374.32, found 374.78.

(39) ##STR00047##

2-(3,5-bis(trifluoromethyl)phenyl)-4-(4-(trifluoromethyl)phenyl)thiazole

(40) White solid (319.1 mg, 72.3%). m.p. 125.7-126.4° C. .sup.1H NMR (400 MHz, CDCl3) δ 8.49 (s, 2H), 8.15 (d, J=8.1 Hz, 2H), 7.98 (s, 1H), 7.84-7.66 (m, 3H). .sup.13C NMR (101 MHz, CDCl3) δ 164.58, 155.51, 136.84, 135.20, 132.72, 130.59, 130.27, 127.03, 126.49, 125.78, 125.38, 124.32, 123.38, 122.68, 121.61, 118.89, 115.69. MS (ESI-TOF) for C.sub.18H.sub.8F.sub.9NS [M+H].sup.+ calculated 440.31, found 440.95.

(41) ##STR00048##

4-(4-methoxyphenyl)-2-(3-(trifluoromethyl)phenyl)thiazole

(42) White solid (320.58 mg, 95.6%). m.p. 128.7-129.9° C. .sup.1H NMR (400 MHz, CDCl3) δ 8.12 (d, J=7.7 Hz, 2H), 8.05-7.91 (m, 2H), 7.71 (d, J=8.0 Hz, 2H), 7.52 (s, 1H), 7.06-6.88 (m, 2H), 3.90 (d, 3H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ 168.20, 161.33, 154.38, 137.76, 128.09, 126.52, 125.60, 114.27, 113.45, 55.37. MS (ESI-TOF) for CH.sub.2F.sub.3NOS [M+H].sup.+ calculated 336.34, found 337.08.

(43) ##STR00049##

4-(4-nitrophenyl)-2-(3-(trifluoromethyl)phenyl)thiazole

(44) Yellow solid (349.6 mg, 99.8%). m.p. 120.8-121.5° C. .sup.1H NMR (400 MHz, DMSO) δ 8.51 (s, 1H), 8.26 (dd, J=33.7, 6.1 Hz, 6H), 7.80 (d, J=6.3 Hz, 2H). .sup.13C NMR (101 MHz, DMSO) δ 165.01, 154.53, 148.36, 137.46, 127.50, 127.04, 126.03, 124.75, 123.24, 119.59. MS (ESI-TOF) for C.sub.16H.sub.9F.sub.3N.sub.2O.sub.2S [M+H].sup.+ calculated 351.32, found 351.32.

(45) ##STR00050##

2-(m-tolyl)-4-(4-(trifluoromethyl)phenyl)-2,5-dihydrothiazole

(46) White solid (299.8 mg, 93.9%). m.p. 94.8-95.5° C. .sup.1H NMR (400 MHz, CDCl3) δ 8.13 (d, J=8.0 Hz, 2H), 7.90 (s, 1H), 7.85 (d, J=7.7 Hz, 1H), 7.72 (d, J=8.2 Hz, 2H), 7.59 (s, 1H), 7.39 (t, J=7.6 Hz, 1H), 7.30 (d, J=7.6 Hz, 1H), 2.48 (s, 3H). .sup.13C NMR (101 MHz, CDCl3) δ 168.59, 154.58, 138.77, 137.69, 133.31, 131.11, 129.99, 128.86, 127.13, 126.56, 125.63, 123.84, 122.85, 114.23, 21.33. MS (ESI-TOF) for C.sub.17H.sub.14F.sub.3NS [M+H].sup.+ calculated 322.36, found 333.01.

(47) ##STR00051##

2-(2-(2-chloro-5-nitrophenyl)thiazol-5-yl)-5-(trifluoromethyl)phenol

(48) White solid (560.4 mg, 81.6%). m.p. 187.4-188.6° C. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 11.54 (s, 1H), 8.93 (d, J=2.7 Hz, 1H), 8.30 (dd, J=8.8, 2.7 Hz, 1H), 7.94 (s, 1H), 7.80 (d, J=8.8 Hz, 2H), 7.35 (d, J=1.2 Hz, 1H), 7.28 (s, 1H), 7.21 (dd, J=8.2, 1.2 Hz, 1H). .sup.13C NMR (101 MHz, CDCl3) δ 156.09, 132.32, 126.75, 125.44, 125.10, 116.47. MS (ESI-TOF) for C.sub.16H.sub.8ClF.sub.3N.sub.2O.sub.3S [M+H].sup.+ calculated 401.76, found 401.21.

(49) ##STR00052##

2-(2-(2-(methylamino)-5-nitrophenyl)thiazol-5-yl)-5-(trifluoromethyl)phenol

(50) Yellow solid (192.3 mg, 45.8%). m.p. 194.6-198.7° C. .sup.1H NMR (400 MHz, DMSO) δ 11.08 (s, 1H), 9.50 (d, J=4.8 Hz, 1H), 8.48 (d, J=2.2 Hz, 1H), 8.39 (s, 1H), 8.27-8.10 (m, 2H), 7.29 (d, J=7.3 Hz, 2H), 6.96 (d, J=9.4 Hz, 1H), 3.13 (d, 3H). .sup.13C NMR (101 MHz, DMSO) δ 165.55, 155.57, 151.83, 149.65, 135.73, 130.27, 127.26, 125.34, 123.97, 119.10, 116.21, 113.81, 112.90, 111.35, 30.28. MS (ESI-TOF) for C.sub.17H.sub.12F.sub.3N.sub.3O.sub.3S [M+H].sup.+ calculated 396.36, found 397.25.

(51) ##STR00053##

2-(2-phenylthiazol-4-yl)-5-(trifluoromethyl)phenol

(52) White solid (427.6 mg, 90.7%). m.p. 132.5-134.2° C. .sup.1H NMR (400 MHz, CDCl3) δ 12.13 (s, 1H), 7.97-7.88 (m, 2H), 7.69 (d, J=8.1 Hz, 1H), 7.60 (s, 1H), 7.50 (s, 3H), 7.32 (s, 1H), 7.14 (d, J=8.1 Hz, 1H). .sup.13C NMR (101 MHz, CDCl3) δ 168.17, 156.17, 153.04, 131.79, 130.96, 129.17, 126.40, 125.17, 122.51, 122.31, 120.09, 115.78, 115.09, 113.31. MS (ESI-TOF) for C.sub.16H.sub.10F.sub.3NOS [M+H].sup.+ calculated 322.32, found 322.30.

(53) ##STR00054##

5-(trifluoromethyl)-2-(2-(3-(trifluoromethyl)phenyl)thiazol-4-yl)phenol

(54) White solid (302.5 mg, 74.6%). m.p. 108.5-109.8° C. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 11.81 (s, 1H), 8.16 (d, J=7.6 Hz, 2H), 7.76 (dd, J=13.9, 9.4 Hz, 3H), 7.67 (t, J=7.8 Hz, 1H), 7.33 (s, 1H), 7.18 (d, J=8.2 Hz, 1H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ 166.43, 156.05, 153.60, 132.60, 129.89, 129.51, 127.42, 126.56, 123.17, 122.15, 119.81, 115.97, 115.16, 114.23. MS (ESI-TOF) for C.sub.17H.sub.9F.sub.6NOS [M+H].sup.+ calculated 390.31, found 390.39.

(55) ##STR00055##

5-(trifluoromethyl)-2-(2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)phenol

(56) White solid (387.6 mg, 70.3%). m. p. 138.6-139.2° C. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 11.80 (s, 1H), 8.09 (d, J=8.1 Hz, 2H), 7.88-7.69 (m, 4H), 7.34 (s, 1H), 7.19 (d, J=8.2 Hz, 1H). .sup.13C NMR (101 MHz, CDCl3) δ 166.36, 156.11, 153.77, 134.92, 132.75, 132.34, 132.01, 126.74, 126.45, 125.05, 122.35, 119.80, 116.03, 115.22, 114.50. MS (ESI-TOF) for C.sub.17H.sub.9F.sub.6NOS [M+H].sup.+ calculated 390.31, found 389.14.

(57) ##STR00056##

5-(trifluoromethyl)-2-(2-(2-(trifluoromethyl)phenyl)thiazol-5-yl)phenol

(58) White solid (391.3 mg, 71.2%). m.p. 138.9-140.7° C. .sup.1H NMR (400 MHz, CDCl3) δ 11.68 (s, 1H), 7.91 (d, J=7.1 Hz, 1H), 7.83 (s, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.75-7.64 (m, 3H), 7.32 (s, 1H), 7.18 (d, J=8.2 Hz, 1H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ 164.76, 156.17, 153.10, 132.11, 132.02, 130.44, 127.25, 126.54, 119.92, 115.79, 115.41, 115.35. MS (ESI-TOF) for C.sub.1H.sub.9F.sub.6NOS [M+H].sup.+ calculated 390.31, found 391.21.

(59) ##STR00057##

2-(2-(3,5-bis(trifluoromethyl)phenyl)thiazol-4-yl)-5-(trifluoromethyl)phenol

(60) White solid (117.2 mg, 75.6%). m.p. 157.6-158.2° C. .sup.1H NMR (400 MHz, CDCl3) δ 11.48 (s, 1H), 8.36 (s, 2H), 8.03 (s, 1H), 7.82 (s, 1H), 7.77 (d, J=8.2 Hz, 1H), 7.33 (s, 1H), 7.20 (d, J=8.1 Hz, 1H). .sup.13C NMR (101 MHz, CDCl3) δ 164.62, 155.91, 154.13, 133.82, 133.51, 133.17, 132.49, 132.26, 126.71, 126.24, 124.96, 124.08, 122.25, 121.37, 119.52, 118.66, 116.18, 115.24. MS (ESI-TOF) for C.sub.18H.sub.8F.sub.9NOS [M+H].sup.+ calculated 456.31, found 456.02.

(61) ##STR00058##

2-(4-(4-methoxyphenyl)thiazol-2-yl)-5-(trifluoromethyl)phenol

(62) White solid (342.7 mg, 86.4%). m.p. 146.2-147.3° C. .sup.1H NMR (400 MHz, CDCl3) δ 12.25 (s, 1H), 7.91 (d, J=8.5 Hz, 2H), 7.74 (d, J=8.2 Hz, 1H), 7.58 (s, 1H), 7.32 (s, 1H), 7.16 (d, J=8.1 Hz, 1H), 7.02 (d, J=8.6 Hz, 2H), 3.91 (s, 3H). .sup.13C NMR (101 MHz, CDCl3) δ 168.10, 161.84, 156.19, 152.75, 131.49, 128.02, 126.37, 124.73, 120.24, 115.76, 115.06, 115.02, 114.50, 112.29, 55.42. MS (ESI-TOF) for C.sub.7H.sub.12F.sub.3NO.sub.2S [M+H].sup.+ calculated 352.34, found 351.94.

(63) ##STR00059##

2-(4-(4-nitrophenyl)thiazol-2-yl)-5-(trifluoromethyl)phenol

(64) Yellow solid (186.5 mg, 90.7%). m.p. 144.9-145.3° C. .sup.1H NMR (400 MHz, DMSO) δ 11.16 (s, 1H), 8.54 (d, J=4.3 Hz, 1H), 8.46-8.39 (m, 1H), 8.40-8.33 (m, 2H), 8.33-8.23 (m, 2H), 7.30 (s, 2H). .sup.13C NMR (101 MHz, DMSO) δ 163.54, 157.58, 157.48, 155.61, 151.53, 148.49, 138.56, 132.26, 130.40, 129.76, 127.70, 124.95, 124.00, 122.18, 116.10, 113.10. MS (ESI-TOF) for C.sub.16H.sub.9F.sub.3N.sub.2OS [M+H].sup.+ calculated 367.31, found 368.55.

(65) ##STR00060##

2-(2-(m-tolyl)-2,5-dihydrothiazol-4-yl)-5-(trifluoromethyl)phenol

(66) White solid (277.6 mg, 69.4%). m.p. 100.7-101.1° C. .sup.1H NMR (400 MHz, CDCl3) δ 12.17 (s, 1H), 7.78 (d, J=6.7 Hz, 3H), 7.65 (d, J=6.1 Hz, 1H), 7.46-7.35 (m, 1H), 7.33 (dd, J=13.6, 9.7 Hz, 2H), 7.18 (d, J=7.8 Hz, 1H), 2.48 (d, 3H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ 168.41, 156.18, 152.96, 139.07, 131.77, 129.06, 126.91, 126.39, 125.18, 123.65, 122.47, 120.15, 115.77, 115.06, 113.16, 21.30. MS (ESI-TOF) for C.sub.17H.sub.14F.sub.3NOS [M+H].sup.+ calculated 378.36, found 377.66.

(67) ##STR00061##

2-(1-(2-(methylamino)-5-nitrophenyl)-1H-imidazol-4-yl)-5-(trifluoromethoxy)phenol

(68) Yellow solid (203 mg, 86%). m.p. 194.4-195.1° C. .sup.1H NMR (400 MHz, DMSO) δ 8.23 (dd, J=9.2, 2.5 Hz, 1H), 8.02 (d, J=2.7 Hz, 1H), 8.01-7.92 (m, 4H), 7.40 (dd, J=8.9, 0.9 Hz, 2H), 6.87 (d, J=9.4 Hz, 1H), 6.71 (q, J=4.5 Hz, 1H), 2.83 (s, 3H). .sup.13C NMR (101 MHz, DMSO) δ 150.69, 147.38, 140.61, 139.15, 135.55, 134.04, 127.08, 126.54, 124.11, 121.89, 121.67, 121.63, 119.35, 118.28, 110.45, 30.27. MS (ESI-TOF) for C.sub.17H.sub.1F.sub.3N.sub.4O.sub.3 [M+H].sup.+ calculated 379.31, found 378.02.

(69) ##STR00062##

2-(1-(2-(methylamino)-5-nitrophenyl)-1H-imidazol-4-yl)-5-(trifluoromethyl)phenol

(70) Yellow solid (378 mg, 50%). .sup.1H NMR (400 MHz, DMSO) δ 11.83 (s, 1H), 8.25 (dd, J=9.3, 2.6 Hz, 1H), 8.13 (d, J=1.0 Hz, 1H), 8.10-7.97 (m, 3H), 7.21 (d, J=8.0 Hz, 2H), 6.88 (d, J=9.4 Hz, H), 6.73 (d, J=4.8 Hz, 1H), 2.82 (d, 3H). .sup.13C NMR (101 MHz, DMSO) δ 155.24), 150.74, 138.46, 137.90, 135.48, 128.30, 127.25, 126.96, 125.95, 124.43, 122.83, 121.23, 120.09, 115.89, 113.10, 110.44, 30.17. MS (ESI-TOF) for C.sub.7H.sub.13F.sub.3N.sub.4O.sub.3 [M+H].sup.+ calculated 377.31, found 377.52.

(71) ##STR00063##

2-(1-(2-(methylamino)-5-(methylsulfonyl)phenyl)-1H-imidazol-4-yl)-5-(trifluoromethyl)phenol

(72) Pink solid (284 mg, 55%). m.p. 179.4-180.1° C. .sup.1H NMR (400 MHz, DMSO) δ 11.90 (s, 1H), 8.22-7.96 (m, 3H), 7.83 (dd, J=8.8, 2.0 Hz, 1H), 7.67 (d, J=2.0 Hz, 1H), 7.22 (d, J=6.3 Hz, 2H), 6.91 (d, J=8.9 Hz, 1H), 6.23 (d, J=4.7 Hz, 1H), 3.17 (s, 3H), 2.78 (d, 3H). .sup.13C NMR (101 MHz, DMSO) δ 155.34, 149.00, 138.52, 137.79, 130.07, 128.40, 128.09, 127.18, 126.93, 126.42, 125.97, 123.27, 122.74, 121.69, 120.00, 115.90, 113.18, 110.84, 44.61, 30.01. MS (ESI-TOF) for C.sub.8H.sub.6F.sub.3N.sub.3O.sub.3S [M+H].sup.+ calculated 412.40, found 412.44.

(73) ##STR00064##

Methyl 3-(4-(2-hydroxy-4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)-4-(methylamino)benzoate

(74) Grey solid (64 mg, 34%). m.p. 182.2-183.5° C. .sup.1H NMR (400 MHz, DMSO) δ 11.99 (s, 1H), 8.14-7.98 (m, 3H), 7.94 (dd, J=8.7, 1.5 Hz, H), 7.68 (d, J=1.8 Hz, 1H), 7.21 (d, J=6.9 Hz, 2H), 6.84 (d, J=8.8 Hz, 1H), 6.12 (d, J=4.8 Hz, 1H), 4.26 (d, J=7.1 Hz, 1H), 3.80 (s, 2H), 2.77 (d, 3H). .sup.13C NMR (101 MHz DMSO) δ166.06, 155.36, 148.95, 137.76, 132.25, 129.03, 126.87, 122.68, 121.74, 119.95, 116.16, 113.17, 110.67, 79.59, 60.48, 51.96, 29.95, 14.65. MS (ESI-TOF) for C.sub.19H.sub.16F.sub.3N.sub.3O.sub.3 [M+H].sup.+ calculated 392.34, found 392.39.

(75) ##STR00065##

3-(4-(2-hydroxy-4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)-N-methyl-4-(methylamino)benzamide

(76) Grey solid (64 mg, 34%). m.p. 194.9-195.6° C. .sup.1H NMR (400 MHz, DMSO) δ 12.00 (s, 1H), 8.19 (d, J=4.5 Hz, 1H), 8.13-7.97 (m, 3H), 7.88 (dd, J=8.6, 1.9 Hz, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.21 (d, J=6.8 Hz, 2H), 6.80 (d, J=8.7 Hz, 1H), 5.78 (d, 1H), 2.75 (t, 6H). 13C NMR (101 MHz, DMSO) δ 166.00, 155.33, 147.17, 138.34, 137.79, 130.01, 128.26, 126.86, 125.97, 123.27, 122.73, 121.52, 120.09, 115.87, 113.13, 110.50, 30.07, 26.52. MS (ESI-TOF) for C.sub.19H.sub.17F.sub.3N.sub.4O.sub.2 [M+H].sup.+ calculated 391.36, found 391.06.

(77) ##STR00066##

2-(1-(3-chloro-2-(methylamino)-5-nitrophenyl)-1H-imidazol-4-yl)-5-(trifluoromethyl)phenol

(78) Yellow solid (28.39 mg, 86%). m.p. 130.8-131.9° C. .sup.1H NMR (400 MHz, DMSO) δ 11.53 (s, 1H), 8.31 (d, J=2.7 Hz, 1H), 8.21 (d, J=1.1 Hz, 1H), 8.16-8.06 (m, 3H), 7.21 (d, J=6.4 Hz, 2H), 6.87 (d, J=5.3 Hz, 1H), 2.40 (d, 3H). .sup.13C NMR (101 MHz, DMSO) δ 155.06, 147.76, 139.87, 137.31, 135.04, 128.39, 128.08, 127.21, 126.37, 125.78, 122.93, 120.51, 120.11, 115.95, 112.88, 30.06. MS (ESI-TOF) for C.sub.17H.sub.12CF.sub.3N.sub.4O.sub.3 [M+H].sup.+ calculated 411.75, found 411.83.

(79) ##STR00067##

4-(1-(3-chloro-2-(methylamino)-5-nitrophenyl)-1H-imidazol-4-yl)benzonitrile

(80) Yellow solid (34.2 mg, 62%). m. p. 210.8-212.6° C. .sup.1H NMR (400 MHz, DMSO) δ 8.31 (d, J=2.5 Hz, 1H), 8.25 (s, 1H), 8.11 (s, 1H), 8.08 (d, J=2.4 Hz, 1H), 8.02 (d, J=8.2 Hz, 2H), 7.85 (d, J=8.2 Hz, 2H), 6.89 (s, 1H), 2.41 (s, 3H). .sup.13C NMR (101 MHz, DMSO) 147.70, 141.57, 139.64, 138.83, 135.03, 133.09, 126.26, 125.77, 125.39, 122.46, 120.56, 120.08, 119.55, 109.23, 30.20. MS (ESI-TOF) for C.sub.17H.sub.2C.sub.1N.sub.5O.sub.2 [M+H].sup.+ calculated 354.76, found 355.23.

(81) ##STR00068##

2-(4-(2-methoxy-4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)-N-methyl-4-nitroaniline

(82) Yellow solid (28.6 mg, 92%). m.p. 201.5-202.2° C. .sup.1H NMR (400 MHz, DMSO) δ 8.39 (d, J=8.0 Hz, 1H), 8.23 (dd, J=9.3, 2.7 Hz, 1H), 8.01 (d, J=2.7 Hz, 1H), 7.97 (d, J=1.2 Hz, 1H), 7.88 (d, J=1.1 Hz, 1H), 7.40 (d, J=8.2 Hz, 1H), 7.35 (s, 1H), 6.87 (d, J=9.4 Hz, 1H), 6.67 (q, J=4.5 Hz, 1H), 3.99 (s, 3H), 2.82 (d, 3H). .sup.13C NMR (101 MHz, DMSO) δ 156.00, 150.93, 138.41, 136.21, 135.45, 128.22, 127.96, 127.65, 127.33, 127.11, 126.79, 126.12, 124.43, 123.42, 122.35, 121.53, 117.59, 110.33, 108.13, 56.16, 30.18. MS (ESI-TOF) for C.sub.18H.sub.15F.sub.3N.sub.4O.sub.3 [M+H].sup.+ calculated 393.33, found 393.10.

(83) ##STR00069##

2-(4-(2-ethoxy-4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)-N-methyl-4-nitroaniline

(84) Yellow solid (95 mg, 82%). m.p. 208.8-209.8° C. .sup.1H NMR (400 MHz, DMSO) δ 8.39 (d, J=8.0 Hz, 1H), 8.23 (dd, J=9.3, 2.6 Hz, 1H), 8.00 (dd, J=9.9, 1.8 Hz, 2H), 7.81 (d, J=0.8 Hz, 1H), 7.39 (d, J=8.2 Hz, 1H), 7.33 (s, 1H), 6.88 (d, J=9.4 Hz, 1H), 6.68 (d, J=4.8 Hz, 1H), 4.27 (q, 2H), 2.83 (d, 3H), 1.42 (t, J=6.9 Hz, 3H). .sup.13C NMR (101 MHz, DMSO) δ 155.19, 150.77, 138.43, 136.35, 135.54, 127.55, 127.05, 126.78, 124.19, 121.83, 121.54, 117.53, 110.44, 108.86, 64.59, 30.19, 14.88. MS (ESI-TOF) for C.sub.19H.sub.17F.sub.3N.sub.4O.sub.3 [M+H].sup.+ calculated 407.36, found 407.65.

(85) ##STR00070##

2-(4-(2-(benzyloxy)-4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)-N-methyl-4-nitroaniline

(86) Yellow solid (159 mg, 92%). m.p. 217.3-218.4° C. .sup.1H NMR (400 MHz, DMSO) δ 8.40 (d, J=8.0 Hz, 1H), 8.21 (dd, J=9.3, 2.6 Hz, 1H), 7.99 (dd, J=16.5, 2.0 Hz, 2H), 7.77 (d, J=1.1 Hz, 1H), 7.54 (d, J=6.9 Hz, 2H), 7.46 (s, 1H), 7.41 (d, J=8.1 Hz, 1H), 7.39-7.24 (m, 3H), 6.85 (d, J=9.4 Hz, 1H), 6.72 (d, J=4.8 Hz, 1H), 5.39 (s, 2H), 2.82 (d, 3H). .sup.13C NMR (101 MHz, DMSO) δ 154.90, 150.48, 138.34, 136.92, 136.26, 135.50, 128.85, 128.50, 128.30, 127.53, 127.12, 126.97, 123.84, 122.05, 121.46, 117.91, 110.38, 109.72, 70.53, 30.24. MS (ESI-TOF) for C.sub.24H.sub.19F.sub.3N.sub.4O.sub.3 [M+H].sup.+ calculated 467.43, found 467.52.

(87) ##STR00071##

2-(4-(2-(2-bromoethoxy)-4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)-N-methyl-4-nitroaniline

(88) Yellow solid (109 mg, 90%). m.p. 209.3-210.5° C. .sup.1H NMR (400 MHz, DMSO) δ 8.40 (d, J=8.0 Hz, 1H), 8.22 (d, J=9.2 Hz, 1H), 8.07 (s, 1H), 8.03 (s, 2H), 7.49-7.31 (m, 2H), 6.88 (d, J=9.2 Hz, 1H), 6.74 (d, J=3.5 Hz, 1H), 4.58 (s, 2H), 3.98 (s, 2H), 2.83 (d, 3H). .sup.13C NMR (101 MHz, DMSO) δ 154.55, 150.50, 138.34, 135.99, 135.50, 128.00, 127.59, 126.95, 126.02, 123.88, 123.32, 122.51, 121.56, 118.13, 110.42, 109.20, 68.99, 32.13, 30.22. MS (ESI-TOF) for C.sub.19H.sub.6BrF.sub.3N.sub.4O.sub.3 [M+H].sup.+ calculated 486.25, found 486.28.

(89) ##STR00072##

2-(4-(2-(3-bromopropoxy)-4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)-N-methyl-4-nitroaniline

(90) Yellow solid (153 mg, 90%). m.p. 213.3-214.8° C. .sup.1H NMR (400 MHz, DMSO) δ 8.39 (d, J=7.8 Hz, 1H), 8.23 (d, J=9.1 Hz, 1H), 8.02 (s, 2H), 7.82 (s, 1H), 7.41 (d, J=13.2 Hz, 2H), 6.87 (d, J=9.2 Hz, 1H), 6.73 (s, 1H), 4.34 (s, 2H), 3.70 (d, 2H), 2.83 (d, 3H), 2.45-2.21 (m, 2H). .sup.13C NMR (101 MHz, DMSO) δ 154.99, 150.76, 138.48, 136.19, 135.57, 127.79, 127.75, 124.13, 121.95, 121.61, 117.92, 117.88, 110.47, 109.05, 66.90, 40.61, 40.41, 40.20, 39.99, 39.78, 39.57, 39.36, 32.09, 31.83, 30.28. MS (ESI-TOF) for C.sub.2H.sub.18BrF.sub.3N.sub.4O.sub.3 [M+H].sup.+ calculated 500.28, found 500.99.

(91) ##STR00073##

2-(4-(2-(3-bromopropoxy)-4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)-N-methyl-4-nitro aniline

(92) Yellow solid (178 mg, 92%). m. p. 188.1-189.9° C. .sup.1H NMR (400 MHz, DMSO) δ 8.38 (d, J=8.0 Hz, 1H), 8.23 (dd, J=9.3, 2.5 Hz, 1H), 8.06-7.92 (m, 3H), 7.46-7.31 (m, 2H), 6.86 (d, J=9.4 Hz, 1H), 6.67 (d, J=4.7 Hz, 1H), 4.39-4.25 (m, 2H), 3.92-3.81 (m, 2H), 3.73 (t, 2H), 3.42 (t, 2H), 2.82 (d, 3H). .sup.13C NMR (101 MHz, DMSO) δ 155.16, 150.95, 138.46, 136.31, 135.53, 127.47, 127.16, 126.14, 124.36, 123.44, 122.53, 121.62, 117.85, 110.44, 109.14, 70.64, 68.94, 67.99, 32.11, 30.26. MS (ESI-TOF) for C.sub.21H.sub.2BrF.sub.3N.sub.4O.sub.4 [M+H].sup.+ calculated 530.31, found 530.11.

(93) ##STR00074##

2-(2-(2-(1-(2-(methylamino)-5-nitrophenyl)-1H-imidazol-4-yl)-5-(trifluoromethyl)phenoxy)ethoxy)ethanol

(94) Yellow solid (141 mg, 76%). m.p. 172.5-173.6° C. .sup.1H NMR (400 MHz, DMSO) δ 8.37 (d, J=7.9 Hz, 1H), 8.23 (dd, J=9.2, 2.2 Hz, 1H), 7.99 (t, J=4.3 Hz, 3H), 7.40 (d, J=10.8 Hz, 2H), 6.87 (d, J=9.3 Hz, 1H), 6.68 (d, J=4.7 Hz, 1H), 4.46 (t, 1H), 4.33 (d, 2H), 3.84 (d, 2H), 3.42 (t, 2H), 3.32 (s, 2H), 2.83 (d, 3H). .sup.13C NMR (101 MHz, DMSO) δ 155.18, 150.69, 138.32, 136.30, 135.50, 127.35, 124.03, 122.49, 121.57, 117.79, 110.38, 72.66, 69.24, 68.08, 60.49, 30.19. MS (ESI-TOF) for C.sub.21H.sub.21F.sub.3N.sub.4O.sub.5 [M+H].sup.+ calculated 465.41, found 466.56.

(95) ##STR00075##

(1-(2-(methylamino)-5-nitrophenyl)-1H-imidazol-4-yl)-5-(trifluoromethyl)phenyl acetate

(96) Yellow solid (178 mg, 92%). m.p. 134.7-136.1° C. .sup.1H NMR (400 MHz, DMSO) δ 8.34 (d, J=8.2 Hz, 1H), 8.23 (dd, J=9.3, 2.6 Hz, 1H), 8.03 (d, J=2.7 Hz, 2H), 7.83 (s, 1H), 7.75-7.62 (m, 2H), 6.88 (d, J=9.3 Hz, 1H), 6.73 (d, J=4.7 Hz, 1H), 2.82 (d, 3H), 2.38 (s, 3H). .sup.13C NMR (101 MHz, DMSO) δ 169.42, 150.75, 146.94, 139.09, 135.54, 130.99, 128.81, 127.07, 124.32, 122.96, 121.41, 110.43, 30.17, 21.71. MS (ESI-TOF) for C.sub.19H.sub.15F.sub.3N.sub.4O.sub.4 [M+H].sup.+ calculated 421.34, found 421.34.

(97) ##STR00076##

2-(1-(2-(methylamino)-5-nitrophenyl)-1H-imidazol-4-yl)-5-(trifluoromethyl)phenyl octanoate

(98) Yellow solid (105 mg, 91%). m.p. 150.6-152.2° C. .sup.1H NMR (400 MHz, DMSO) δ 8.34 (d, J=8.2 Hz, 1H), 8.23 (dd, J=9.3, 2.4 Hz, 1H), 8.05-7.95 (m, 2H), 7.77 (s, 1H), 7.70 (d, J=8.3 Hz, 1H), 7.62 (s, 1H), 6.87 (d, J=9.3 Hz, 1H), 6.74 (d, J=4.7 Hz, 1H), 2.82 (d, 3H), 2.71 (t, 2H), 1.70-1.55 (m, 2H), 1.26 (ddd, 8H), 0.82 (t, 3H). .sup.13C NMR (101 MHz, DMSO) δ 171.95, 150.68, 146.97, 139.05, 135.86, 135.52, 131.04, 128.81, 127.85, 127.53, 127.06, 125.60, 124.17, 122.99, 121.38, 110.44, 34.06, 31.41, 30.14, 28.73, 24.40, 22.40, 14.22. MS (ESI-TOF) for C.sub.25H.sub.27F.sub.3N.sub.4O.sub.4 [M+H].sup.+ calculated 505.50, found 505.48.

(99) ##STR00077##

2-(1-(2-(methylamino)-5-nitrophenyl)-1H-imidazol-4-yl)-5-(trifluoromethyl)phenyl dodecanoate

(100) Yellow solid (154 mg, 90%). m.p. 158.3-159.6° C. H NMR (400 MHz, DMSO) δ 8.34 (d, J=8.2 Hz, 1H), 8.21 (dd, J=9.2, 2.1 Hz, 1H), 8.05-7.94 (m, 2H), 7.76 (s, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.61 (s, 1H), 6.87 (d, J=9.3 Hz, 1H), 6.75 (d, J=4.6 Hz, 1H), 2.81 (d, 3H), 2.70 (t, 2H), 1.69-1.54 (m, 2H), 1.27-1.12 (m, 17H), 0.84 (t, 4H). .sup.13C NMR (101 MHz, DMSO) δ 171.91, 150.66, 146.96, 139.02, 135.86, 135.51, 131.02, 128.81, 127.85, 127.53, 127.03, 125.59, 124.13, 123.01, 121.35, 121.31, 121.09, 110.42, 34.05, 31.69, 30.12, 29.37, 29.17, 29.11, 29.04, 28.78, 24.38, 22.49, 14.28. MS (ESI-TOF) for C.sub.29H.sub.35F.sub.3N.sub.4O.sub.4 [M+H].sup.+ calculated 561.61, found 561.83.

(101) ##STR00078##

2-(1-(2-(methylamino)-5-nitrophenyl)-1H-imidazol-4-yl)-5-(trifluoromethyl)phenyl benzoate

(102) Yellow solid (186 mg, 90%). m.p. 203.3-204.3° C. .sup.1H NMR (400 MHz, DMSO) δ 8.37 (d, J=8.3 Hz, 1H), 8.22 (t, J=7.9 Hz, 2H), 8.14 (d, J=9.2 Hz, 1H), 8.00 (d, J=9.3 Hz, 1H), 7.89-7.80 (m, 2H), 7.75 (dd, J=18.0, 8.6 Hz, 2H), 7.65 (d, J=9.1 Hz, 1H), 7.60 (t, J=7.8 Hz, 2H), 6.77 (d, J=9.3 Hz, 1H), 6.62 (s, 1H), 2.65 (d, 3H). .sup.13C NMR (101 MHz, DMSO) δ 164.63, 150.23, 147.06, 139.06, 135.91, 135.46, 134.55, 131.23, 130.37, 129.39, 129.26, 128.99, 126.95, 123.73, 121.15, 110.40, 30.04. MS (ESI-TOF) for C.sub.24H.sub.17F.sub.3N.sub.4O.sub.4 [M+H].sup.+ calculated 483.41, found 483.25.

(103) ##STR00079##

(1-(2-(methylamino)-5-nitrophenyl)-1H-imidazol-4-yl)-5-(trifluoromethyl)phenyl cinnamate

(104) Yellow solid (119 mg, 85%). m.p. 209.3-210.2° C. H NMR (400 MHz, DMSO) δ 8.40 (d, J=8.1 Hz, 1H), 8.16 (d, J=9.2 Hz, 1H), 8.03 (s, 1H), 7.98 (s, 1H), 7.93 (d, J=16.0 Hz, 1H), 7.85 (s, 1H), 7.82-7.68 (m, 4H), 7.44 (d, J=6.8 Hz, 3H), 7.07 (d, J=16.0 Hz, 1H), 6.77 (d, J=9.3 Hz, 1H), 6.67 (d, J=4.6 Hz, 1H), 2.67 (d, 3H). C NMR (101 MHz, DMSO) δ 164.92, 150.52, 147.46, 146.88, 139.11, 135.80, 135.50, 134.27, 131.35, 131.15, 129.31, 129.09, 128.82, 127.90, 127.58, 127.01, 124.04, 123.18, 121.52, 121.30, 117.65, 110.38, 30.07. MS (ESI-TOF) for C.sub.26H.sub.19F.sub.3N.sub.4O.sub.4 [M+H].sup.+ calculated 509.45, found 509.38.

(105) ##STR00080##

(1-(2-(methylamino)-5-nitrophenyl)-1H-imidazol-4-yl)-5-(trifluoromethyl)phenyl disulfate

(106) Yellow solid (186 mg, 90%). m.p. 173.3-175.6° C. .sup.1H NMR (400 MHz, DMSO) δ 8.36 (d, J=8.2 Hz, 1H), 8.24 (dd, J=9.3, 2.6 Hz, 1H), 8.08-7.95 (m, 2H), 7.89 (d, J=20.3 Hz, 2H), 7.49 (d, J=7.8 Hz, 1H), 6.88 (d, J=9.4 Hz, 1H), 6.65 (d, J=4.8 Hz, 1H), 2.83 (d, 3H). .sup.13C NMR (101 MHz, DMSO) δ 150.73, 150.19, 138.37, 136.28, 135.51, 129.33, 127.44, 127.18, 124.09, 122.23, 121.41, 119.86, 117.08, 110.50, 30.20. MS (ESI-TOF) for C.sub.7H.sub.3F.sub.3N406S [M+H].sup.− calculated 455.37, found 455.30.

(107) ##STR00081##

2-(4-(2-(2-(2-(2-iodoethoxy)ethoxy)ethoxy)-4-(trifluoromethyl)phenyl)-1H-imidazole-1-yl)-N-methyl-4-nitroaniline

(108) Yellow solid (81 mg, 84%). m.p. 166.7-168.2° C. .sup.1H NMR (400 MHz, CDCl3) δ 8.33 (d, J=7.0 Hz, 2H), 8.16 (d, J=2.4 Hz, 1H), 7.97 (s, 1H), 7.82 (s, 1H), 7.34 (d, J=7.9 Hz, 1H), 7.17 (s, 1H), 6.81 (d, J=9.3 Hz, 1H), 5.19 (s, 1H), 4.39-4.24 (m, 2H), 4.03-3.88 (m, 2H), 3.72-3.62 (m, 2H), 3.58 (t, 2H), 3.55-3.47 (m, 2H), 3.13 (t, 2H), 3.01 (d, 3H). .sup.13C NMR (101 MHz, CDCl3) δ 154.82, 149.79, 136.90, 136.53, 127.34, 127.01, 125.43, 123.71, 121.49, 109.50, 71.72, 70.16, 69.48, 67.31, 30.02, 2.66. MS (ESI-TOF) for C.sub.23H.sub.4F.sub.3IN.sub.4O.sub.5 [M+H].sup.+ calculated 621.36, found 620.81.

(109) ##STR00082##

(2-(1-(2-(methylamino)-5-nitrophenyl)-1H-imidazo-4-yl)-5-(trifluoromethyl)phenoxy)acetamide

(110) Yellow solid (52 mg, 92%). m.p. 226.7-228.9° C. .sup.1H NMR (400 MHz, DMSO) δ 8.37 (d, J=8.0 Hz, 1H), 8.24 (dd, J=9.3, 2.6 Hz, 1H), 8.19 (s, 1H), 8.05-7.96 (m, 2H), 7.59 (s, 1H), 7.43 (d, 0.1=8.2 Hz, 1H), 7.35 (s, 1H), 7.24 (s, 1H), 6.88 (d, J=9.4 Hz, 1H), 6.68 (d, J=4.7 Hz, 1H), 4.74 (s, 2H), 2.83 (d, 3H). .sup.13C NMR (101 MHz, DMSO) δ 169.81, 154.54, 150.78, 138.40, 136.24, 135.52, 127.69, 127.13, 124.20, 123.00, 121.61, 110.44, 99.98, 67.58, 30.26. MS (ESI-TOF) for C.sub.9H.sub.6F.sub.3N.sub.5O.sub.4 [M+H].sup.+ calculated 436.36, found 436.57.

(111) ##STR00083##

2-(4-(3-(2-aminoethoxy)-4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)-N-methyl-4-nitroaniline

(112) Yellow solid (39 mg, 80%). m.p. 136.9-139.5° C. .sup.1H NMR (400 MHz, DMSO) δ 8.37 (d, J=8.0 Hz, 1H), 8.24 (dd, J=9.3, 2.5 Hz, 1H), 8.04 (d, J=2.6 Hz, 1H), 8.01 (s, 1H), 7.96 (s, 1H), 7.49-7.39 (m, 2H), 6.89 (d, J=9.4 Hz, 1H), 6.63 (d, J=4.4 Hz, 1H), 4.37 (t, 2H), 3.28 (d, 4H), 2.83 (d, 3H). .sup.13C NMR NMR (101 MHz, DMSO) δ 154.97, 150.74, 138.40, 136.16, 135.52, 127.91, 127.76, 127.22, 127.01, 126.03, 124.16, 123.33, 122.28, 121.59, 118.05, 110.44, 109.44, 68.90, 30.21. MS (ESI-TOF) for C.sub.19H.sub.18F.sub.3N.sub.5O.sub.3 [M+H].sup.+ calculated 422.37, found 422.02.

(113) ##STR00084##

N-(2-(2-(1-(2-(methylamino)-5-nitrophenyl)-1H-imidazol-4-yl)-5-(trifluoromethyl)phenoxyl)ethyl)-5-((3AS,4S,6AR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamide

(114) Yellow solid (42.76 mg, 93%). m.p. 118.7-120.5° C. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.34-8.19 (m, 2H), 8.12 (d, J=2.4 Hz, 1H), 7.74 (d, 0.1=25.4 Hz, 2H), 7.33 (d, J=8.2 Hz, 1H), 7.14 (dd, J=13.3, 8.0 Hz, 2H), 6.76 (d, J=9.3 Hz, 1H), 6.31 (s, 1H), 5.28 (d, J=4.3 Hz, 1H), 5.12 (s, 1H), 4.35-4.27 (m, 1H), 4.24 (t, 2H), 4.13-4.04 (m, 1H), 3.75 (d, 2H), 2.98 (d, 4H), 2.78 (dd, 1H), 2.54 (d, 1H), 2.11 (t, 2H), 1.50 (d, 4H), 1.28 (d, 3H). .sup.13C NMR (101 MHz, DMSO) δ 172.71, 163.12, 155.07, 150.90, 138.36, 136.06, 135.44, 127.57, 124.42, 121.62, 117.76, 110.33, 108.93, 79.62, 67.67, 61.40, 59.59, 55.82, 53.74, 42.03, 38.31, 35.56, 31.37, 30.22, 28.55, 25.41, 22.47, 14.36, 12.75. MS (ESI-TOF) for C.sub.29H.sub.32F.sub.3N.sub.7O.sub.5S [M+H].sup.+ calculated 648.67, found 647.57.

(115) ##STR00085##

Ethyl 2-(2-(1-(2-(methylamino)-5-nitrophenyl)-1H-imidazol-4-yl)-5-(trifluoromethyl)phenoxy)-5-((3aS, 4S, 6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoate

(116) Yellow solid (67 mg, 71%). m.p. 79.1-80.5° C. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.34-8.24 (m, 2H), 8.12 (d, J=2.5 Hz, 1H), 7.78 (s, 1H), 7.71 (s, 1H), 7.35 (d, J=8.0 Hz, 1H),7.10 (s, 1H), 6.79 (d, J=9.3 Hz, 1H), 5.88 (s, 1H), 5.51 (d, 1H), 5.26 (s, 1H), 4.54 (d, 2H), 4.47-4.37 (m, 1H), 4.30 (t, 2H), 4.24-4.15 (m, 1H), 3.00 (t, 4H), 2.84 (dd, 1H), 2.65 (d, 1H), 2.20 (t, 2H), 2.03 (s, 2H), 1.52-1.42 (m, 3H), 1.28 (d, 3H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ 173.17, 154.50, 150.05, 137.01, 136.62, 127.45, 127.15, 123.89, 121.58, 121.18, 118.06, 109.65, 108.12, 66.49, 61.96, 59.95, 55.37, 40.42, 33.60, 29.95, 28.13, 24.55. MS (ESI-TOF) for C.sub.29H.sub.31F.sub.3N.sub.6O.sub.6S [M+H].sup.+ calculated 649.65, found 649.68.

(117) ##STR00086##

Ethyl ((3aS, 4S, 6aR)-2-(2-(2-(2-(2-(methylamino)-5-nitrophenyl)-1H-imidazol-4-yl)-5-(Trifluoromethyl)phenoxy)ethoxy)yl)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoate

(118) Yellow solid (85 mg, 63%). m.p. 53.2-54.7° C. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.26 (dd, J=9.2, 2.4 Hz, 1H), 8.17 (d, J=7.9 Hz, 1H), 8.10 (d, J=2.5 Hz, 1H), 7.88 (s, 1H), 7.73 (s, 1H), 7.32 (d, J=8.2 Hz, 1H), 7.07 (s, 1H), 6.79 (d, J=9.4 Hz, 1H), 6.08 (d, J=48.6 Hz, 3H), 5.76 (s, 1H), 4.49 (t, 2H), 4.30 (s, 1H), 4.25-4.16 (m, 3H), 4.07 (s, 2H), 3.89 (s, 2H), 3.68-3.60 (m, 2H), 3.10 (d, 2H), 3.01 (d, 3H), 2.86 (d, 3H), 2.17 (s, 2H), 1.66 (s, 3H), 1.53 (d, J=7.0 Hz, 4H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ 173.38, 164.72, 154.68, 150.17, 137.18, 136.44, 127.13, 125.47, 123.82, 121.84, 121.23, 117.80, 109.74, 108.16, 71.64, 68.86, 67.12, 63.08, 62.12, 60.32, 55.55, 40.61, 33.57, 31.52, 30.01, 28.37, 24.51, 22.58, 14.05, 2.93. MS (ESI-TOF) for C.sub.31H.sub.35F.sub.3N.sub.6O.sub.7S [M+H].sup.+ calculated 693.71, found 693.01.

(119) ##STR00087##

Ethyl 5-(2-(2-(2-(2-(methylamino)-5-nitrophenyl)-1H-imidazol-4-yl)-5-(trifluoromethyl)phenoxy Ethoxy)ethoxy)ethyl 5-(3AS,4S,6AR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoate

(120) Yellow solid (22.6 mg, 75%). m.p. 73.1-74.4° C. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.30 (dd, J=9.1, 2.7 Hz, 2H), 8.15 (d, J=2.6 Hz, 1H), 7.92 (d, J=1.2 Hz, 1H), 7.76 (d, J=0.9 Hz, 1H), 7.36 (d, J=7.5 Hz, 1H), 7.17 (s, 1H), 6.78 (d, J=9.3 Hz, 1H), 5.66 (s, 1H), 5.39 (d, 1H), 5.04 (s, 1H), 4.46 (dd, 1H), 4.34-4.27 (m, 2H), 4.25 (dd, 1H), 4.15-4.06 (m, 2H), 3.98-3.88 (m, 2H), 3.65 (dd, 2H), 3.51 (td, 4H), 3.10 (ddd, 1H), 2.98 (t, 3H), 2.88 (d, 1H), 2.71 (d, 1H), 2.28 (t, 2H), 1.68-1.53 (m, 4H), 1.45-1.30 (m, 2H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ 173.52, 163.75, 154.76, 150.12, 137.29, 136.60, 129.20, 127.05, 125.59, 123.79, 122.74, 121.74, 121.34, 117.74, 109.47, 108.20, 70.28, 69.36, 68.94, 67.27, 63.07, 61.83, 60.02, 55.48, 40.42, 33.58, 29.87, 28.21, 24.58. MS (ESI-TOF) for C.sub.33H.sub.39F.sub.3N.sub.6O.sub.8S [M+H].sup.+ calculated 737.76, found 738.86.

Example 16 Detection of TLR1/2 Activation Activity of Compound 22 and Other Compounds

(121) TLR1/2 activation activity was detected using TLR1/2 HEK BLUE cells. TLR1/2 HEK BLUE cells were cultured in DMEM medium containing 10% fetal bovine serum, 1% penicillin and streptomycin, and incubated in a 37° C. cell incubator containing 5% CO.sub.2.

(122) HEK BLUE TLR1/2 cells were spread in a 384-well plate at 20,000 cells/well, cultured at 37° C., 5% CO.sub.2 for 24 hours, 25 μL per well. When the cells grew well, 100 μM compound and doubling-diluted for 11 concentration gradients. After the cells were kept for 24 hours in the CO.sub.2 incubator, 40 μL of indigo blue solution was added to each well of the plate in the dark, and reading was conducted 4 times in an interval of 15 minutes at 620 nm to detect the signal intensity of SEAP in the cell supernatant.

(123) As shown in FIG. 1, compound 22 can significantly activate the signal intensity of TLR1/2 alkaline phosphatase (SEAP), even at a low concentration (15 nM). See Table 7 for the results of other compounds.

(124) The results show that this series of compounds have a good ability to activate TLR1/2 and have good development potential.

(125) TABLE-US-00007 TABLE 7 TLR1/2 activation activity detection results of all the compounds Compound No. TLR1/2 activation activity EC.sub.50 (nM) 1 >1000[‡] 2 >1000 3 >1000[‡] 4 >1000[‡] 5 >1000 6 NA[†] 7 NA[†] 8 NA[†] 9 >1000[‡] 10 NA[†] 11 >1000 12 NA[†] 13 NA[†] 14 NA[†] 15 >1000 16 NA[†] 17 NA[†] 18 >1000[‡] 19 NA[†] 20 NA[†] 21 24.87 ± 6.15 22  4.88 ± 0.79 23  5.14 ± 0.07 24 432.86 ± 0.05  25 45.57 ± 3.15 26 192.19 ± 17.19 27 >1000 28 92.26 ± 12.3 29 >1000 30 >1000 31 >1000 32 >1000 33 >1000 34 >1000 35 18.83 ± 3.65 36 56.32 ± 7.31 37 112.69 ± 12.69 38 16.85 ± 2.79 39 11.98 ± 2.67 40 49.13 ± 3.82 41 >1000 42 >1000 43 >1000 44 764.48 ± 10.18 45 >1000 46 >1000 47 >1000 [†]: Lack of activation effect with the highest concentration of 100 μM. [‡]: The highest SEAP signal value is less than 50% of the activation value of compound 22. NA: No activation.