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BENZO FIVE-MEMBERED NITROGEN HETEROCYCLIC COMPOUND AND APPLICATION THEREOF

20230219925 · 2023-07-13

    Inventors

    Cpc classification

    International classification

    Abstract

    The present application relates to a benzo five-membered nitrogen heterocyclic compound and an application thereof. The benzo five-membered nitrogen heterocyclic compound has the structure represented by formula I. The compound can be used as a compound of RORγ receptor inhibitor. The compound can effectively inhibit RORγ proteins and have good selectivity to other nuclear receptor family proteins. The benzo five-membered nitrogen heterocyclic compound or a pharmaceutical composition thereof provided by the present application can be used for preparing a drug for treating, preventing or ameliorating diseases such as inflammations, autoimmune diseases, cell proliferative disorder diseases, sepsis, cancer, neurodegeneration diseases or viral infections, has a good inhibitory effect on the treatment of tumors, especially the treatment of prostate cancer, and also has an amelioration effect on the treatment of other diseases.

    Claims

    1. A benzo five-membered nitrogen heterocyclic compound, comprising a structure represented by Formula I: ##STR00121## wherein, in Formula I, X is selected from ##STR00122##  wherein the squiggle represents a bond of the group; in Formula I, Y is selected from CR.sub.5 or an N atom; in Formula I, Z is selected from an S atom or NR.sub.10; in Formula I, R.sub.1 and R.sub.10 are each independently selected from any one of C1-C10 alkyl substituted with 0 to 3 R.sub.11, C6-C10 aryl substituted with 0 to 3 R.sub.11, C6-C10 aryl-C1-C3 alkyl substituted with 0 to 3 R.sub.11, C2-C10 heteroaryl substituted with 0 to 3 R.sub.11, a C2-C20 heterocyclyl substituted with 0 to 3 R.sub.11, C2-C10 heteroaryl-C1-C3 alkyl substituted with 0 to 3 R.sub.11, a C2-C20 heterocyclyl-C1-C3 alkyl substituted with 0 to 3 R.sub.11, C3-C10 cycloalkyl substituted with 0 to 3 R.sub.11 or C3-C10 cycloalkyl-C1-C3 alkyl substituted with 0 to 3 R.sub.11; R.sub.11 is selected from any one of halogen, cyano, nitro, carboxyl, hydroxyl, amino, C1-C10 alkyl sulfonyl, C1-C10 alkyl sulfonyl substituted with at least one halogen, C1-C10 carbalkoxy, C1-C10 carbalkoxy substituted with at least one halogen, C1-C10 alkyl, C1-C10 alkyl substituted with at least one halogen, C1-C10 alkoxy, C1-C10 alkoxy substituted with at least one halogen, C3-C10 cycloalkyl or C3-C10 cycloalkyl substituted with at least one halogen; in Formula I, R.sub.2 to R.sub.9 are each independently selected from any one of hydrogen, halogen, C1-C10 alkyl, C1-C10 alkyl substituted with at least one halogen, C1-C10 alkoxy, C1-C10 alkoxy substituted with at least one halogen, C1-C10 alkylamide, C1-C10 alkylamide substituted with at least one halogen, C1-C10 cycloalkylamide, C1-C10 cycloalkylamide substituted with at least one halogen, C1-C10 alkylamino, C1-C10 alkylamino substituted with at least one halogen, C3-C10 cycloalkylamino or C3-C10 cycloalkylamino substituted with at least one halogen.

    2. The benzo five-membered nitrogen heterocyclic compound according to claim 1, the C2-C20 heterocyclyl substituted with 0 to 3 R.sub.11 is ##STR00123## wherein the squiggle represents a bond of the group.

    3. The benzo five-membered nitrogen heterocyclic compound according to claim 1, wherein R.sub.11 in R.sub.1 is selected from any one or a combination of at least two of C1-C10 alkyl, halogen, trifluoromethoxy, nitro, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl, amino, methyl sulfonyl or ethyl sulfonyl, preferably, any one or a combination of at least two of cyano, ethoxycarbonyl or ethyl sulfonyl; optionally, each of R.sub.2 to R.sub.5 is hydrogen; optionally, R.sub.6, R.sub.7, R.sub.8 and R.sub.9 are not hydrogen at the same time; optionally, R.sub.6 and R.sub.9 are hydrogen; optionally, R.sub.7 and R.sub.8 are not hydrogen at the same time; optionally, one and only one of R.sub.7 and R.sub.8 is hydrogen; optionally, R.sub.7 and R.sub.8 are each independently selected from any one or a combination of at least two of hydrogen, methyl, methoxy, halogen, trifluoromethyl or C2-C10 alkylamide; optionally, C2-C10 alkylamide is isopropylamide or cyclopentylamide; optionally, R.sub.10 is selected from any one of C1-C10 alkyl, cyclobutyl, cyclobutylmethyl, cyclohexylmethyl, pyridylmethyl, phenylethyl substituted with 0 to 3 R.sub.11 or benzyl substituted with 0 to 3 R.sub.11; optionally, R.sub.11 in R.sub.10 is selected from any one or a combination of at least two of methyl, carboxyl, trifluoromethyl, methoxycarbonyl, halogen, cyano or methylsulfonyl.

    4. The benzo five-membered nitrogen heterocyclic compound according to claim 1, wherein the benzo five-membered nitrogen heterocyclic compound has a structure represented by Formula II: ##STR00124## wherein, in Formula II, X is selected from ##STR00125## in Formula II, R.sub.1 is selected from any one of C1-C10 alkyl substituted with 0 to 3 R.sub.11, C6-C10 aryl substituted with 0 to 3 R.sub.11, C6-C10 aryl C1-C3 alkyl substituted with 0 to 3 R.sub.11 or a C2-C20 heterocyclyl substituted with 0 to 3 R.sub.11; and R.sub.11 is selected from any one of halogen, cyano, nitro, carboxyl, hydroxyl, amino, C1-C10 alkyl sulfonyl, C1-C10 alkyl sulfonyl substituted with at least one halogen, C1-C10 carbalkoxy, C1-C10 carbalkoxy substituted with at least one halogen, C1-C10 alkyl, C1-C10 alkyl substituted with at least one halogen, C1-C10 alkoxy or C1-C10 alkoxy substituted with at least one halogen; in Formula II, R.sub.2 to R.sub.9 are each independently selected from any one of hydrogen, halogen, C1-C10 alkyl, C1-C10 alkyl substituted with at least one halogen, C1-C10 alkoxy or C1-C10 alkoxy substituted with at least one halogen; optionally, in Formula II, R.sub.2 is selected from hydrogen or chlorine; optionally, in Formula II, R.sub.8 is selected from any one of methyl, methoxy or fluorine; optionally, in Formula II, R.sub.7 is hydrogen.

    5. The benzo five-membered nitrogen heterocyclic compound according to claim 1, wherein the benzo five-membered nitrogen heterocyclic compound has a structure represented by Formula III: ##STR00126## wherein, in Formula III, Y is selected from CR.sub.5 or an N atom; in Formula III, R.sub.2 to R.sub.9 are each independently selected from any one of hydrogen, halogen, C1-C10 alkyl, C1-C10 alkyl substituted with at least one halogen, C1-C10 alkoxy, C1-C10 alkoxy substituted with at least one halogen, C1-C10 alkylamide, C1-C10 alkylamide substituted with at least one halogen, C1-C10 cycloalkylamide or C1-C10 cycloalkylamide substituted with at least one halogen; in Formula III, R.sub.10 is selected from any one of C1-C10 alkyl substituted with 0 to 3 R.sub.11, C6-C10 aryl-C1-C3 alkyl substituted with 0 to 3 R.sub.11, C2-C10 heteroaryl-C1-C3 alkyl substituted with 0 to 3 R.sub.11, C3-C10 cycloalkyl substituted with 0 to 3 R.sub.11 or C3-C10 cycloalkyl-C1-C3 alkyl substituted with 0 to 3 R.sub.11; and R.sub.11 is selected from hydrogen, halogen, cyano, carboxyl, C1-C10 alkyl, C1-C10 alkyl substituted with at least one halogen, C1-C10 alkyl sulfonyl, C1-C10 alkyl sulfonyl substituted with at least one halogen, C1-C10 carbalkoxy or C1-C10 carbalkoxy substituted with at least one halogen; in Formula III, R.sub.12 and R.sub.13 are each independently selected from hydrogen, amino, C1-C10 alkyl substituted with 0 to 3 R.sub.14 or C1-C10 alkylamide substituted with 0 to 3 R.sub.14, or R.sub.12 and R.sub.13 form a C3-C6 carbocyclic ring together with a carbon to which R.sub.12 and R.sub.13 are joined; and R.sub.14 is selected from any one of halogen, carboxyl, hydroxyl, amino, C1-C10 alkylamide, C1-C10 alkylamino or C1-C10 carbalkoxy; optionally, R.sub.7 is selected from any one of methyl, methoxy, isopropylamide or cyclopentylamide; optionally, R.sub.8 is selected from any one of methyl, methoxy, trifluoromethyl, isopropylamide or cyclopentylamide; optionally, R.sub.12 and R.sub.13 are each independently selected from any one of hydrogen, amino or methylamide.

    6. The benzo five-membered nitrogen heterocyclic compound according to claim 1, wherein the benzo five-membered nitrogen heterocyclic compound has any one of the following structures: 4-methyl-N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)benzenesulfonamide; 4-(tert-butyl)-N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)benzenesulfonamide; 4-fluoro-N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)benzenesulfonamide; N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-4-nitrobenzenesulfonamide; N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-3-nitrobenzenesulfonamide; N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-2-nitrobenzenesulfonamide; N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-3-(methanesulfonyl)benzenesulfonamide; 2,4-difluoro-N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)benzenesulfonamide; 2,4,6-trimethyl-N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)benzenesulfonamide; 1-ethyl-N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-sulfonamide; N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-1-(p-tolyl)methanesulfonamide; 1-(4-fluorophenyl)-N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)methanesulfonamide; N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-1-(4-(trifluoromethyl)phenyl)-methanesulfonamide; N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-1-(4-nitrophenyl)methanesulfonamide; 1-(4-cyanophenyl)-N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)methanesulfonamide; N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-1-(4-(methylsulfonyl)phenyl)-methanesulfonamide; 4-((N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)sulfamoyl)methyl)methyl benzoate; 4-((N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)sulfamoyl)methyl)benzoic acid; 4-((N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)sulfamoyl)methyl)phenyl propionate; N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-1-(3-nitrophenyl)methanesulfonamide; N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-1-(2-nitrophenyl)methanesulfonamide; 3-((N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)sulfamoyl)methyl)methyl benzoate; 1-(3-aminophenyl)-N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)methanesulfonamide; 2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-acetamide; N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)heptanamide; N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-2-(p-tolyl)acetamide; N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-2-(2-nitrophenyl)acetamide; N-(3-chloro-4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-2-(4-(ethylsulfonyl)-phenyl)acetamide; 2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-fluorobenzo[d]thiazol-2-yl)phenyl)-acetamide; 2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methoxybenzo[d]thiazol-2-yl)phenyl)-acetamide; 2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(4-methylphenylethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide; 2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-propyl-1H-benzo[d]imidazol-2-yl)phenyl)acetamide; N-(4-(1-butyl-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide; 2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-pentyl-1H-benzo[d]imidazol-2-yl)phenyl)acetamide; 2-(4-(ethylsulfonyl)phenyl)-N-(4-(1-isopropyl-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)acetamide; 2-(4-(ethylsulfonyl)phenyl)-N-(4-(1-isobutyl-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)acetamide; 2-(4-(ethylsulfonyl)phenyl)-N-(4-(1-isopentyl-6-methyl-1H-benzo[d]imidazole-2-yl)phenyl)acetamide; N-(4-(1-cyclobutyl-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide; N-(4-(1-(cyclobutylmethyl)-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide; N-(4-(1-(cyclohexylmethyl)-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide; N-(4-(1-benzyl-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide; 2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(4-methylbenzyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide; 2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-phenylethyl-TH-benzo[d]imidazol-2-yl)phenyl)acetamide; 2-(4-(ethylsulfonyl)phenyl)-N-(4-(1-(4-fluorobenzyl)-6-methyl-TH-benzo[d]imidazol-2-yl)phenyl)acetamide; 2-(4-(ethylsulfonyl)phenyl)-N-(4-(1-(3-fluorobenzyl)-6-methyl-TH-benzo[d]imidazol-2-yl)phenyl)acetamide; 2-(4-(ethylsulfonyl)phenyl)-N-(4-(1-(2-fluorobenzyl)-6-methyl-TH-benzo[d]imidazol-2-yl)phenyl)acetamide; N-(4-(1-(2,6-difluorobenzyl)-6-methyl-TH-benzo[d]imidazol-2-yl)phenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide; N-(4-(1-(4-cyanobenzyl)-6-methyl-TH-benzo[d]imidazol-2-yl)phenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide; 2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(4-(methylsulfonyl)benzyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide; 2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide; N-(4-(1-benzyl-6-chloro-1H-benzo[d]imidazol-2-yl)phenyl)-2-(4-ethyl-sulfonyl)phenyl)acetamide; N-(4-(1-benzyl-5-chloro-1H-benzo[d]imidazol-2-yl)phenyl)-2-(4-ethyl-sulfonyl)phenyl)acetamide; (S)-2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide; 2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(pyridin-4-ylmethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide; 2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide; (R)-2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide; 2-(4-(ethylsulfonyl)phenyl)-N-(4-(1-(4-fluorophenethyl)-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)acetamide; 2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide; 4-((2-(4-(2-(4-(ethylsulfonyl)phenyl)acetylamino)phenyl)-6-methyl-1H-benzo[d]imidazol-1-yl)methyl)methyl benzoate; 4-((2-(4-(2-(4-(ethylsulfonyl)phenyl)acetylamino)phenyl)-6-methyl-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid; 2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(pyridin-3-ylmethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide; (R)-2-(4-(ethylsulfonyl)phenyl)-N-(4-(1-(1-(p-tolyl)ethyl)-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide; (R)-2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methoxy-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide; (R)-2-(4-(ethylsulfonyl)phenyl)-N-(4-(5-methyl-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide; (R)-2-(4-(ethylsulfonyl)phenyl)-N-(4-(5-methoxy-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide; (R)-2-(4-(ethylsulfonyl)phenyl)-N-(4-(1-(1-(4-fluorophenyl)ethyl)-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide; (S)-2-(4-(ethylsulfonyl)phenyl)-N-(4-(1-(1-(4-fluorophenyl)ethyl)-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide; (R)-2-(4-(2-(4-(ethylsulfonyl)phenyl)acetylamino)phenyl)-N-isopropyl-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-6-formamide; (R)—N-cyclopentyl-2-(4-(2-(4-(ethylsulfonyl)phenyl)acetylamino)phenyl)-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-6-formamide; (R)-2-(4-(2-(4-(ethylsulfonyl)phenyl)acetylamino)phenyl)-N-isopropyl-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-5-formamide; (R)—N-cyclopentyl-2-(4-(2-(4-(ethylsulfonyl)phenyl)acetylamino)phenyl)-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-5-formamide; 2-acetylamino-2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-((S)-1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide; 2-acetylamino-2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-pentyl-1H-benzo[d]imidazol-2-yl)phenyl)acetamide; 2-acetylamino-2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-((R)-1-(p-tolyl)ethyl)-1H-benzo[d]imidazopyridin-2-yl)phenyl)acetamide; 2-(4-(2-acetylamino-2-(4-(ethylsulfonyl)phenyl)acetylamino)phenyl)-N-isopropyl-1-((R)-1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-5-formamide; 2-(4-(2-acetylamino-2-(4-(ethylsulfonyl)phenyl)acetylamino)phenyl)-N-isopropyl-1-((S)-1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-5-formamide; 2-acetylamino-2-(4-(ethylsulfonyl)phenyl)-N-(6-(6-methyl-1-((S)-1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)pyridin-3-yl)acetamide; 2-acetylamino-2-(4-(ethylsulfonyl)phenyl)-N-(6-(6-methyl-1-pentyl-TH-benzo[d]imidazol-2-yl)pyridin-3-yl)acetamide; 2-acetylamino-2-(4-(ethylsulfonyl)phenyl)-N-(6-(6-methyl-1-((R)-1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)pyridin-3-yl)acetamide; 2-(5-(2-acetylamino-2-(4-(ethylsulfonyl)phenyl)acetylamino)pyridin-2-yl)-N-isopropyl-1-((R)-1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-5-formamide; 2-(5-(2-acetylamino-2-(4-(ethylsulfonyl)phenyl)acetylamino)pyridin-2-yl)-N-isopropyl-1-((S)-1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-5-formamide; N-(4-(1-benzyl-5,6-dimethyl-TH-benzo[d]imidazol-2-yl)phenyl)-2-(4-(ethyl-sulfonyl)phenyl)acetamide; N-(4-(1-benzyl-5,6-dichloro-1H-benzo[d]imidazol-2-yl)phenyl)-2-(4-(ethyl-sulfonyl)phenyl)acetamide; or 2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-TH-benzo[d]imidazol-2-yl)phenyl)acetamide.

    7. A pharmaceutically acceptable salt, isomer, racemate, prodrug, co-crystal complex or solvate of the benzo five-membered nitrogen heterocyclic compound according to claim 1.

    8-11. (canceled)

    12. A pharmaceutical composition, wherein an active ingredient of the pharmaceutical composition comprises the benzo five-membered nitrogen heterocyclic compound according to claim 1.

    13-14. (canceled)

    15. A method for preparing an RORγ receptor inhibitor by using the benzo five-membered nitrogen heterocyclic compound according to claim 1.

    16. The method according to claim 15, wherein the RORγ receptor inhibitor is used for preparing a drug for treating a cancer, a cell proliferative disorder, an inflammatory disease and an autoimmune disease, sepsis, a viral infection or a neurodegenerative disease.

    17. The method according to claim 15, wherein the RORγ receptor inhibitor is used for preparing a drug for treating a cancer.

    18. The method according to claim 15, wherein the RORγ receptor inhibitor is used for preparing a drug for treating prostate cancer.

    19. A method for treating, preventing or ameliorating an inflammation, an autoimmune disease, a cell proliferative disorder, sepsis, a cancer, a viral infection or a neurodegenerative disease, comprising administering an effective amount of the pharmaceutical composition according to claim 12 to subject in need thereof.

    20. The method according to claim 19, wherein the cancer comprises prostate cancer.

    Description

    BRIEF DESCRIPTION OF DRAWINGS

    [0066] FIG. 1 is a diagram illustrating tumor-inhibitory effects of Example 68 in Test Example 5 on 22Rv1 mouse xenograft models.

    [0067] FIG. 2 is a diagram illustrating variations of weights of mice during an administration of Example 68 in Test Example 5.

    DETAILED DESCRIPTION

    [0068] For a better understanding of the present application, examples of the present application are listed below. Those skilled in the art are to understand that examples described herein are merely used for a better understanding of the present application and are not to be construed as specific limitations to the present application.

    [0069] The meanings represented by the English or English abbreviations involved in the following specific embodiments are as follows:

    polyphosphoric acid (PPA); 2-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU); N,N-diisopropylethylamine (DIPEA); dichloromethane (DCM); 1-hydroxybenzotriazole (HOBT); 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI); and dimethylsulfoxide (DMSO).

    [0070] The present application provides representative synthesis routes for the compounds of Formulas II and III. A benzothiazole compound has a structure represented by Formula II and preparation methods including Routes one and two; and a benzimidazole compound has a structure represent by Formula III and preparation methods including Routes three and four.

    [0071] Route one is specifically as follows:

    ##STR00010##

    [0072] The reagents added in each step and the reaction conditions were as follows: (a) KOH, H.sub.2O, refluxed, overnight; (b) PPA, 4-aminobenzoic acid or 4-amino-2-chlorobenzoic acid, 220° C., 4 h; (c) R.sub.1SO.sub.2Cl, pyridine, 80° C., overnight; (d) R.sub.1COOH, HATU, DIPEA, DCM, room temperature, overnight; (e) NaOH, CH.sub.3OH, room temperature, overnight.

    [0073] Route two is specifically as follows:

    ##STR00011##

    [0074] The reagent(s) added in each step and the reaction conditions were as follows: (a) pyridine, 40° C., 1 h; (b) Lawesson reagent, 1,4-dioxane, 110° C., 3 h; (c) NaOH, EtOH, potassium ferricyanide, 90° C., 30 min; (d) Pd/C, H.sub.2, room temperature, 5 h; (e) HATU, DIPEA, DCM, room temperature, overnight.

    [0075] Route three is specifically as follows:

    ##STR00012##

    [0076] The reagents added in each step and the reaction conditions were as follows: (a) R.sub.4NH.sub.2, DIPEA, DMSO, 95° C., overnight; or R.sub.4NH.sub.2, K.sub.2CO.sub.3, DMF, 95° C., 1 h; (b) Fe, AcOH, NH.sub.4Cl, H.sub.2O, 80° C., 1 h; (c) 4-nitrobenzaldehyde, oxone, DMF, room temperature, 1 h; (d) 2-(4-(ethylsulfonyl)phenyl)acetic acid, HATU, DIPEA, DCM, room temperature, overnight; or 2-(4-(ethylsulfonyl)phenyl)acetic acid, HOBT, EDCI, DIPEA, DCM, room temperature, overnight; and (e) NaOH, CH.sub.3OH, room temperature, overnight.

    [0077] Route four is specifically as follows:

    ##STR00013##

    [0078] The reagent(s) added in each step and the reaction conditions were as follows: (a) 5-nitro-2-pyridinecarboxylic acid or 2-((tert-butoxycarbonyl)amino)-2-(4-(ethylsulfonyl)phenyl)acetic acid, HATU, DIPEA, DCM, room temperature, overnight; (b) acetic acid, 120° C., 4.5 h; (c) Fe, AcOH, ammonium chloride, H.sub.2O, 80° C., 1 h; (d) trifluoroacetic acid (TFA), DCM, room temperature, 3 h; and (e) Ac.sub.2O, DCM, Et.sub.3N, room temperature, 3 h.

    [0079] The above preparation methods are for illustrative purposes and not intended to limit the listed compounds or any particular substituent. The numbers of substituents shown in the embodiments do not necessarily correspond to the number used in the claims, and for the sake of clarity, it is shown that a single substituent is joined to a compound that allows for multiple substituents under the definitions of Formulas II and III above and all compounds contained by General Formula I can be obtained through variations in the numbers and substitution positions of the substituents.

    Example 1 4-methyl-N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)benzenesulfonamide

    Step 1: synthesis of 2-amino-5-methylbenzenethiol

    [0080] ##STR00014##

    [0081] 6-methylbenzo[d]thiazol-2-amine (5 g, 30.5 mmol) was suspended in a solution of KOH (25 g, 44.6 mmol) in water (50 mL) and heated to reflux overnight. The reaction was monitored through thin-layer chromatography (TLC). After the reaction was finished, the solution was cooled to ambient temperature and had a pH adjusted to 6 with acetic acid. The solution was filtered, and a thick precipitate was collected and rinsed with water. A residue was partitioned between dichloromethane and water and extracted. An organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuum to obtain a target compound as a yellow solid (3.4 g with a yield of 80%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 6.91 (dd, J=8.2, 1.7 Hz, 1H), 6.81 (d, J=1.4 Hz, 1H), 6.64 (d, J=8.2 Hz, 1H), 5.21 (s, 2H), 2.05 (s, 3H).

    Step 2: synthesis of 4-(6-methylbenzo[d]thiazol-2-yl) aniline

    [0082] ##STR00015##

    [0083] Polyphosphoric acid (20 g) was added to a mixture of 2-amino-5-methylbenzenethiol (2.03 g, 14.58 mmol) and 4-aminobenzoic acid (1.99 g, 14.51 mmol) and heated for 4 h at 220° C. The reaction was monitored through the TLC. After the reaction was finished, the reaction mixture was cooled to ambient temperature, slowly poured into an ice-cold aqueous solution of sodium carbonate (10% w/v) and stirred until a gas ceased to escape. The solution was filtered, and a precipitate was collected and washed with water. A residue was partitioned between ethyl acetate and water and extracted. An organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuum to obtain a crude product. The crude product was purified through silica gel column chromatography (PE:EA=4:1, v/v) to obtain a target compound as a brown solid (3.14 g with a yield of 90%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.80 (s, 1H), 7.77 (d, J=8.3 Hz, 1H), 7.72 (d, J=8.6 Hz, 2H), 7.26 (dd, J=8.3, 1.1 Hz, 1H), 6.65 (d, J=8.6 Hz, 2H), 5.85 (s, 2H), 2.42 (s, 3H).

    Step 3: synthesis of 4-methyl-N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)benzenesulfonamide (4a)

    [0084] ##STR00016##

    [0085] The compounds 4-(6-methylbenzo[d]thiazol-2-yl) aniline (73 mg, 0.3 mmol) and 4-toluenesulfonyl chloride (85.8 mg, 0.45 mmol) were dissolved in pyridine (10 mL) and reacted for 4 h at 80° C. The reaction was monitored through the TLC. After the reaction was finished, the reaction mixture was cooled to room temperature. Dilute hydrochloric acid (30 mL) was added to the reaction mixture and extracted three times (50 mL×3) with ethyl acetate. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and isolated through the silica gel column chromatography (PE:EA=4:1, v/v) to obtain a target compound as a white solid (37 mg with a yield of 31%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 10.71 (s, 1H), 7.93 (d, J=8.7 Hz, 2H), 7.90-7.85 (m, 2H), 7.72 (d, J=8.3 Hz, 2H), 7.37 (d, J=8.2 Hz, 2H), 7.32 (dd, J=8.4, 1.1 Hz, 1H), 7.27 (d, J=8.7 Hz, 2H), 2.43 (s, 3H), 2.32 (s, 3H). MS (ESI), m/z for C.sub.21H.sub.18N.sub.2O.sub.2S.sub.2 ([M+H].sup.+): Calcd 394.51, found 395.0.

    Example 2 4-(tert-butyl)-N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)benzenesulfonamide

    [0086] ##STR00017##

    [0087] A synthesis method was as that in Example 1, and a white solid was obtained with a yield of 79%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.75 (s, 1H), 7.94 (d, J=8.7 Hz, 2H), 7.90-7.84 (m, 2H), 7.78 (d, J=8.5 Hz, 2H), 7.60 (d, J=8.6 Hz, 2H), 7.35-7.26 (m, 3H), 2.44 (s, 3H), 1.25 (s, 9H). MS (ESI), m/z for C.sub.24H.sub.24N.sub.2O.sub.2S.sub.2 ([M+H].sup.+): Calcd 436.59, found 437.2.

    Example 3 4-fluoro-N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)benzenesulfonamide

    [0088] ##STR00018##

    [0089] A synthesis method was as that in Example 1, and a white solid was obtained with a yield of 61%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.76 (s, 1H), 7.95 (d, J=8.7 Hz, 2H), 7.92-7.86 (m, 4H), 7.42 (t, J=8.8 Hz, 2H), 7.33 (dd, 8.4, 0.8 Hz, 1H), 7.28 (d, J=8.7 Hz, 2H), 2.44 (s, 3H). MS (ESI), m/z for C.sub.20H.sub.15FN.sub.2O.sub.2S.sub.2 ([M+H].sup.+): Calcd 398.47, found 398.9.

    Example 4 N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-4-(trifluoromethoxy) benzenesulfonamide

    [0090] ##STR00019##

    [0091] A synthesis method was as that in Example 1, and a white solid was obtained with a yield of 74%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.87 (s, 1H), 8.00-7.92 (m, 4H), 7.91-7.85 (m, 2H), 7.58 (d, J=8.3 Hz, 2H), 7.33 (d, J=8.5 Hz, 1H), 7.29 (d, J=8.7 Hz, 2H), 2.44 (s, 3H). MS (ESI), m/z for C.sub.21H.sub.15F.sub.3N.sub.2O.sub.3S.sub.2 ([M+H].sup.+): Calcd 464.48, found 465.0.

    Example 5 N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-4-nitrobenzenesulfonamide

    [0092] ##STR00020##

    [0093] A synthesis method was as that in Example 1, and a white solid was obtained with a yield of 50%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.04 (s, 1H), 8.39 (d, J=8.9 Hz, 2H), 8.07 (d, J=8.9 Hz, 2H), 7.97 (d, J=8.7 Hz, 2H), 7.91-7.85 (m, 2H), 7.36-7.27 (m, 3H), 2.44 (s, 3H). MS (ESI), m/z for C.sub.20H.sub.15N.sub.3O.sub.4S.sub.2 ([M+H].sup.+): Calcd 425.48, found 426.0.

    Example 6 N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-3-nitrobenzenesulfonamide

    [0094] ##STR00021##

    [0095] A synthesis method was as that in Example 1, and a white solid was obtained with a yield of 38%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.01 (s, 1H), 8.58-8.54 (m, 1H), 8.46 (dd, J=8.2, 1.6 Hz, 1H), 8.21 (d, J=7.9 Hz, 1H), 7.96 (d, J=8.6 Hz, 2H), 7.91-7.85 (m, 3H), 7.36-7.27 (m, 3H), 2.44 (s, 3H). MS (ESI), m/z for C.sub.20H.sub.15N.sub.3O.sub.4S.sub.2 ([M+H].sup.+): Calcd 425.48, found 426.0.

    Example 7 N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-2-nitrobenzenesulfonamide

    [0096] ##STR00022##

    [0097] A synthesis method was as that in Example 1, and a white solid was obtained with a yield of 54%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.16 (s, 1H), 8.07-8.03 (m, 1H), 8.03-7.95 (m, 3H), 7.91-7.81 (m, 4H), 7.36-7.32 (m, 1H), 7.30 (d, J=8.7 Hz, 2H), 2.44 (s, 3H). MS (ESI), m/z for C.sub.20H.sub.15N.sub.3O.sub.4S.sub.2 ([M+H].sup.+): Calcd 425.48, found 426.0.

    Example 8 N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-3-(methanesulfonyl) benzenesulfonamide

    [0098] ##STR00023##

    [0099] A synthesis method was as that in Example 1, and a white solid was obtained with a yield of 34%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.93 (s, 1H), 8.32 (s, 1H), 8.20 (d, J=7.7 Hz, 1H), 8.12 (d, J=8.0 Hz, 1H), 7.96 (d, J=8.6 Hz, 2H), 7.92-7.84 (m, 3H), 7.33 (d, J=8.8 Hz, 1H), 7.29 (d, J=8.6 Hz, 2H), 3.28 (s, 3H), 2.44 (s, 3H). MS (ESI), m/z for C.sub.21H.sub.18N.sub.2O.sub.4S.sub.3 ([M+H].sup.+): Calcd 458.57, found 459.2.

    Example 9 2,4-difluoro-N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)benzenesulfonamide

    [0100] ##STR00024##

    [0101] A synthesis method was as that in Example 1, and a white solid was obtained with a yield of 73%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.13 (s, 1H), 8.03-7.92 (m, 3H), 7.90-7.85 (m, 2H), 7.58-7.50 (m, 1H), 7.36-7.24 (m, 4H), 2.44 (s, 3H). MS (ESI), m/z for C.sub.20H.sub.14F.sub.2N.sub.2O.sub.2S.sub.2 ([M+H].sup.+): Calcd 416.46, found 417.1.

    Example 10 2,4,6-trimethyl-N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)benzenesulfonamide

    [0102] ##STR00025##

    [0103] A synthesis method was as that in Example 1, and a white solid was obtained with a yield of 72%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.69 (s, 1H), 7.92 (d, J=8.7 Hz, 2H), 7.89-7.83 (m, 2H), 7.32 (dd, J=8.4, 0.8 Hz, 1H), 7.13 (d, J=8.7 Hz, 2H), 7.03 (s, 2H), 2.61 (s, 6H), 2.43 (s, 3H), 2.21 (s, 3H). MS (ESI), m/z for C.sub.23H.sub.22N.sub.2O.sub.2S.sub.2 ([M−H].sup.−): Calcd 422.56, found 421.2.

    Example 11 1-ethyl-N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-sulfonamide

    [0104] ##STR00026##

    [0105] A synthesis method was as that in Example 1, and a white solid was obtained with a yield of 19%. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 11.06 (s, 1H), 8.74 (d, J=8.4 Hz, 1H), 8.26 (d, J=7.7 Hz, 1H), 8.13 (d, J=7.0 Hz, 1H), 8.00-7.93 (m, 1H), 7.90-7.81 (m, 4H), 7.32-7.28 (m, 2H), 7.24 (d, J=8.8 Hz, 2H), 3.88 (q, J=7.1 Hz, 2H), 2.42 (s, 3H), 1.22 (t, J=7.2 Hz, 3H). MS (ESI), m/z for C.sub.27H.sub.21N.sub.3O.sub.3S.sub.2 ([M+H].sup.+): Calcd 499.60, found 500.02.

    Example 12 N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-1-(p-tolyl)methanesulfonamide

    [0106] ##STR00027##

    [0107] A synthesis method was as that in Example 1, and a white solid was obtained with a yield of 31%. .sup.1H NMR (400 MHz, DMSO) δ 10.22 (s, 1H), 8.01 (d, J=8.7 Hz, 2H), 7.94-7.87 (m, 2H), 7.38-7.30 (m, 3H), 7.20-7.09 (m, 4H), 4.51 (s, 2H), 2.46 (s, 3H), 2.28 (s, 3H). MS (ESI), m/z for C.sub.22H.sub.20N.sub.2O.sub.2S.sub.2 ([M+H].sup.+): Calcd 408.53, found 409.0.

    Example 13 1-(4-fluorophenyl)-N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)methane sulfonamide

    [0108] ##STR00028##

    [0109] A synthesis method was as that in Example 1, and a white solid was obtained with a yield of 26%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.26 (s, 1H), 8.01 (d, J=8.7 Hz, 2H), 7.94-7.87 (m, 2H), 7.38-7.27 (m, 5H), 7.19 (t, J=8.9 Hz, 2H), 4.60 (s, 2H), 2.46 (s, 3H). MS (ESI), m/z for C.sub.21H.sub.17FN.sub.2O.sub.2S.sub.2 ([M−1].sup.−): Calcd 412.50, found 411.1.

    Example 14 N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-1-(4-(trifluoromethyl)phenyl)methane sulfonamide

    [0110] ##STR00029##

    [0111] A synthesis method was as that in Example 1, and a white solid was obtained with a yield of 47%. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 10.34 (s, 1H), 8.01 (d, J=8.7 Hz, 2H), 7.94-7.88 (m, 2H), 7.74 (d, J=8.2 Hz, 2H), 7.51 (d, J=8.1 Hz, 2H), 7.38-7.30 (m, 3H), 4.75 (s, 2H), 2.46 (s, 3H). MS (ESI), m/z for C.sub.22H.sub.17F.sub.3N.sub.2O.sub.2S.sub.2 ([M+H].sup.+): Calcd 462.51, found 463.0.

    Example 15 N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-1-(4-nitrophenyl)methanesulfonamide

    [0112] ##STR00030##

    [0113] A synthesis method was as that in Example 1, and a white solid was obtained with a yield of 40%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.36 (s, 1H), 8.22 (d, J=8.7 Hz, 2H), 8.02 (d, J=8.6 Hz, 2H), 7.94-7.88 (m, 2H), 7.57 (d, J=8.7 Hz, 2H), 7.38-7.31 (m, 3H), 4.81 (s, 2H), 2.46 (s, 3H). MS (ESI), m/z for C.sub.21H.sub.17N.sub.3O.sub.4S.sub.2 ([M+H].sup.+): Calcd 439.50, found 440.0.

    Example 16 1-(4-cyanophenyl)-N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)methanesulfonamide

    [0114] ##STR00031##

    [0115] A synthesis method was as that in Example 1, and a white solid was obtained with a yield of 22%. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 10.36 (s, 1H), 8.02 (d, J=8.7 Hz, 2H), 7.94-7.88 (m, 2H), 7.85 (d, J=8.2 Hz, 2H), 7.48 (d, J=8.2 Hz, 2H), 7.38-7.30 (m, 3H), 4.75 (s, 2H), 2.46 (s, 3H). MS (ESI), m/z for C.sub.22H.sub.17N.sub.3O.sub.2S.sub.2 ([M+H].sup.+): Calcd 419.52, found 420.0.

    Example 17 N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-1-(4-(methylsulfonyl)phenyl)methane sulfonamide

    [0116] ##STR00032##

    [0117] A synthesis method was as that in Example 1, and a white solid was obtained with a yield of 60%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.37 (s, 1H), 8.02 (d, J=8.7 Hz, 2H), 7.94-7.88 (m, 4H), 7.56 (d, J=8.3 Hz, 2H), 7.39-7.30 (m, 3H), 4.76 (s, 2H), 3.20 (s, 3H), 2.46 (s, 3H). MS (ESI), m/z for C.sub.22H.sub.20N.sub.2O.sub.4S.sub.3 ([M+H].sup.+): Calcd 472.59, found 472.9.

    Example 18 4-((N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)sulfamoyl)methyl)methyl benzoate

    [0118] ##STR00033##

    [0119] A synthesis method was as that in Example 1, and a white solid was obtained with a yield of 30%. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 10.33 (s, 1H), 8.01 (d, J=8.6 Hz, 2H), 7.95-7.89 (m, 4H), 7.43 (d, J=8.2 Hz, 2H), 7.37-7.30 (m, 3H), 4.71 (s, 2H), 3.83 (s, 3H), 2.46 (s, 3H). MS (ESI), m/z for C.sub.23H.sub.20N.sub.2O.sub.4S.sub.2 ([M+H].sup.+): Calcd 452.54, found 453.0.

    Example 19 4-((N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)sulfamoyl)methyl)benzoic acid

    [0120] ##STR00034##

    [0121] Example 18 (40 mg, 0.09 mmol) was dissolved in methanol (5 mL), and NaOH (10 mL, 2 M) was added to the mixture and stirred for 2 h at room temperature. After the reaction was finished, methanol was removed under reduced pressure, and the mixture had a pH adjusted to 5 to 6 with dilute hydrochloric acid (1 M). A precipitated solid was suction filtered to obtain a target compound as a white solid (28.8 mg with a yield of 73%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 10.38 (s, 1H), 8.23 (d, J=8.7 Hz, 2H), 8.02 (d, J=8.7 Hz, 2H), 7.94-7.88 (m, 2H), 7.57 (d, J=8.6 Hz, 2H), 7.38-7.31 (m, 3H), 4.82 (s, 2H), 2.46 (s, 3H). MS (ESI), m/z for C.sub.22H.sub.18N.sub.2O.sub.4S.sub.2 ([M+H].sup.+): Calcd 438.52, found 440.0. MS (ESI), m/z for C.sub.23H.sub.20N.sub.2O.sub.4S.sub.2 ([M+H].sup.+): Calcd 452.54, found 453.0.

    Example 20 4-((N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)sulfamoyl)methyl)phenyl propionate

    [0122] ##STR00035##

    [0123] A synthesis method was as that in Example 1, and a white solid was obtained with a yield of 55%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.30 (s, 1H), 8.01 (d, J=8.7 Hz, 2H), 7.95-7.87 (m, 4H), 7.42 (d, J=8.2 Hz, 2H), 7.38-7.29 (m, 3H), 4.70 (s, 2H), 4.29 (q, J=7.1 Hz, 2H), 2.46 (s, 3H), 1.28 (t, J=7.1 Hz, 3H). MS (ESI), m/z for C.sub.24H.sub.22N.sub.2O.sub.4S.sub.2 ([M+H].sup.+): Calcd 466.57, found 467.1.

    Example 21 N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-1-(3-nitrophenyl)methanesulfonamide

    [0124] ##STR00036##

    [0125] A synthesis method was as that in Example 1, and a white solid was obtained with a yield of 55%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.33 (s, 1H), 8.21 (d, J=8.2 Hz, 1H), 8.16 (s, 1H), 8.00 (d, J=8.7 Hz, 2H), 7.94-7.88 (m, 2H), 7.74 (d, J=7.7 Hz, 1H), 7.67 (t, J=7.8 Hz, 1H), 7.38-7.29 (m, 3H), 4.83 (s, 2H), 2.46 (s, 3H). MS (ESI), m/z for C.sub.21H.sub.17N.sub.3O.sub.4S.sub.2 ([M−H].sup.−): Calcd 439.50, found 438.0.

    Example 22 N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-1-(2-nitrophenyl)methanesulfonamide

    [0126] ##STR00037##

    [0127] A synthesis method was as that in Example 1, and a white solid was obtained with a yield of 20%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.47 (s, 1H), 8.04 (d, J=8.1 Hz, 1H), 8.00 (d, J=8.6 Hz, 2H), 7.94-7.89 (m, 2H), 7.73 (td, J=7.6, 0.7 Hz, 1H), 7.64 (t, J=7.5, Hz, 1H), 7.50 (d, J=7.0 Hz, 1H), 7.35 (dd, J=8.5, 0.8 Hz, 1H), 7.28 (d, J=8.7 Hz, 2H), 5.05 (s, 2H), 2.46 (s, 3H). MS (ESI), m/z for C.sub.21H.sub.17N.sub.3O.sub.4S.sub.2 ([M+H].sup.+): Calcd 439.50, found 440.0.

    Example 23 3-((N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)sulfamoyl)methyl)methyl benzoate

    [0128] ##STR00038##

    [0129] A synthesis method was as that in Example 1, and a white solid was obtained with a yield of 25%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.27 (s, 1H), 8.00 (d, J=8.6 Hz, 2H), 7.95-7.86 (m, 4H), 7.58-7.48 (m, 2H), 7.37-7.28 (m, 3H), 4.71 (s, 2H), 3.83 (s, 3H), 2.46 (s, 3H). MS (ESI), m/z for C.sub.23H.sub.20N.sub.2O.sub.4S.sub.2 ([M+H].sup.+): Calcd 452.54, found 453.0.

    Example 24 1-(3-aminophenyl)-N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)methane sulfonamide

    [0130] ##STR00039##

    [0131] Example 21 (50 mg, 0.11 mmol) and 10% palladium on carbon (about 55% water content) (100 mg) were added to a solvent of MeOH (10 mL) and stirred overnight at room temperature in a hydrogen environment. After the reaction was finished, the mixture was suction filtered with Celite as a filter aid, and a filtrate was concentrated to obtain a crude product. The crude product was isolated through silica gel column chromatography (PE:EA=4:1, v/v) to obtain a target compound as a white solid (13 mg with a yield of 29%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.24 (s, 1H), 8.15-7.78 (m, 4H), 7.47-7.21 (m, 3H), 7.09-6.85 (m, 1H), 6.62-6.45 (m, 2H), 6.44-6.25 (m, 1H), 5.11 (s, 2H), 4.35 (s, 2H), 2.45 (s, 3H). MS (ESI), m/z for C.sub.21H.sub.19N.sub.3O.sub.2S.sub.2 ([M+H].sup.+): Calcd 409.52, found 410.0.

    Example 25 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)acetamide

    [0132] ##STR00040##

    [0133] The compounds 4-(6-methylbenzo[d]thiazol-2-yl)aniline (80 mg, 0.33 mmol), diisopropylethylamine (127.7 mg, 0.99 mmol) and HATU (188.1 mg, 0.495 mmol) were dissolved in DCM (10 mL). The reaction mixture was stirred for 15 min, then the compound 2-(4-(ethylsulfonyl)phenyl)acetic acid (112.86 mg, 0.495 mmol) was added to the reaction mixture, and the obtained mixture was stirred overnight at room temperature. After the reaction was finished, water was added to dilute the mixture and extracted with DCM (20 mL×3). Combined organic layers were dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. A crude product was isolated through silica gel column chromatography (PE:EA=3:1, v/v) to obtain a target compound as a white solid (70 mg with a yield of 47%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.56 (s, 1H), 8.02 (d, J=8.7 Hz, 2H), 7.92-7.83 (m, 4H), 7.79 (d, J=8.7 Hz, 2H), 7.63 (d, J=8.2 Hz, 2H), 7.34 (d, J=8.4 Hz, 1H), 3.86 (s, 2H), 3.32-3.23 (m, 2H), 2.45 (s, 3H), 1.10 (t, J=7.3 Hz, 3H). MS (ESI), m/z for C.sub.24H.sub.22N.sub.2O.sub.3S.sub.2 ([M+H].sup.+): Calcd 450.57, found 451.1.

    Example 26 N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)heptanamide

    [0134] ##STR00041##

    [0135] A synthesis method was as that in Example 25, and a white solid was obtained with a yield of 39%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.16 (s, 1H), 8.00 (d, J=8.7 Hz, 2H), 7.92-7.86 (m, 2H), 7.78 (d, J=8.7 Hz, 2H), 7.34 (d, J=8.4 Hz, 1H), 2.45 (s, 3H), 2.35 (t, J=7.4 Hz, 2H), 1.67-1.55 (m, 2H), 1.35-1.25 (m, 6H), 0.87 (t, J=6.7 Hz, 3H). MS (ESI), m/z for C.sub.21H.sub.24N.sub.2OS ([M+H].sup.+): Calcd 352.50, found 353.1.

    Example 27 N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-2-(p-tolyl)acetamide

    [0136] ##STR00042##

    [0137] A synthesis method was as that in Example 25, and a white solid was obtained with a yield of 23%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ10.44 (s, 1H), 8.01 (d, J=8.7 Hz, 2H), 7.93-7.85 (m, 2H), 7.78 (d, J=8.7 Hz, 2H), 7.34 (d, J=8.8 Hz, 1H), 7.23 (d, J=7.9 Hz, 2H), 7.14 (d, J=7.8 Hz, 2H), 3.63 (s, 2H), 2.45 (s, 3H), 2.28 (s, 3H). MS (ESI), m/z for C.sub.23H.sub.20N.sub.2OS ([M+H].sup.+): Calcd 372.49, found 373.0.

    Example 28 N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-2-(2-nitrophenyl)acetamide

    [0138] ##STR00043##

    [0139] A synthesis method was as that in Example 25, and a white solid was obtained with a yield of 35%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.55 (s, 1H), 8.08 (d, J=7.9 Hz, 1H), 8.02 (d, J=8.7 Hz, 2H), 7.93-7.86 (m, 2H), 7.78-7.70 (m, 3H), 7.62-7.55 (m, 2H), 7.34 (d, J=8.8 Hz, 1H), 4.19 (s, 2H), 2.45 (s, 3H). MS (ESI), m/z for C.sub.22H.sub.17N.sub.3O.sub.3S ([M+H].sup.+): Calcd 403.46, found 404.3.

    Example 29 N-(3-chloro-4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-2-(4-(ethylsulfonyl)phenyl) acetamide

    [0140] ##STR00044##

    [0141] A synthesis method was as that in Example 25, and a white solid was obtained with a yield of 42%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.74 (s, 1H), 8.24 (d, J=8.7 Hz, 1H), 8.05 (d, J=1.8 Hz, 1H), 7.99-7.93 (m, 2H), 7.86 (d, J=8.2 Hz, 2H), 7.66 (dd, J=8.9, 1.9 Hz, 1H), 7.62 (d, J=8.2 Hz, 2H), 7.39 (dd, J=8.4, 0.8 Hz, 1H), 3.88 (s, 2H), 3.28 (q, J=7.6 Hz, 2H), 2.47 (s, 3H), 1.10 (t, J=7.4 Hz, 3H). MS (ESI), m/z for C.sub.24H.sub.21ClN.sub.2O.sub.3S.sub.2 ([M+H].sup.+): Calcd 485.01, found 485.0.

    Example 30 2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-fluorobenzo[d]thiazol-2-yl)phenyl)acetamide

    Step 1: synthesis of N-(4-fluorophenyl)-4-nitrobenzamide

    [0142] ##STR00045##

    [0143] The compound 4-fluoroaniline (2 g, 18.0 mmol) was dissolved in pyridine (10 mL), and then 4-nitrobenzoyl chloride (4.0 g, 21.6 mmol) was added to the mixture slowly to react for 1 h at 40° C. The reaction was monitored through TLC. After the reaction was finished, the reaction mixture was cooled to room temperature. Dilute hydrochloric acid (50 mL) was added to the reaction mixture and extracted three times (50 mL×3) with ethyl acetate. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and isolated through silica gel column chromatography (PE:EA=4:1, v/v) to obtain a target compound as a white solid (3.58 g with a yield of 76%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.60 (s, 1H), 8.37 (d, J=8.8 Hz, 2H), 8.18 (d, J=8.8 Hz, 2H), 7.88-7.70 (m, 2H), 7.22 (t, J=8.9 Hz, 2H).

    Step 2: synthesis of N-(4-fluorophenyl)-4-nitrobenzathioamide

    [0144] ##STR00046##

    [0145] N-(4-fluorophenyl)-4-nitrobenzamide (3.58 g, 13.76 mmol) and Lawesson reagent (2.78 g, 6.88 mmol) were added to a solvent of 1,4-dioxane (20 mL), and the mixture was heated to 110° C. and stirred for 3 h. After the reaction was finished, the reaction system was cooled to room temperature and concentrated under reduced pressure. Then, water was added to the reaction system, and a precipitated solid was suction filtered. A filter cake was washed with water, dried and recrystallized with methanol to obtain a target compound as an orange solid (2.74 g with a yield of 72%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.16 (s, 1H), 8.29 (d, J=8.7 Hz, 2H), 8.01 (d, J=8.6 Hz, 2H), 7.94-7.80 (m, 2H), 7.29 (t, J=8.8 Hz, 2H).

    Step 3: synthesis of 6-fluoro-2-(4-nitrophenyl)benzo[d]thiazol

    [0146] ##STR00047##

    [0147] N-(4-fluorophenyl)-4-nitrobenzathioamide (2.0 g, 7.24 mmol) was dissolved in an aqueous solution of sodium hydroxide (2.9 g, 72.4 mmol) containing ethanol (3 mL) and water (30 mL), and then an aqueous solution (20 mL) of potassium ferricyanide (9.54 g, 28.98 mmol) was added dropwise to the solution. The mixture was stirred for 30 min at 90° C. After the reaction was finished, the reaction system was cooled to room temperature, and a precipitate was precipitated. The precipitated solid was suction filtered. A filter cake was washed with water, dried and recrystallized (EA:PE=1:2, v/v) to obtain a target compound as a yellow solid (1.6 g with a yield of 81%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.38 (d, J=8.8 Hz, 2H), 8.32 (d, J=8.8 Hz, 2H), 8.20-8.11 (m, 2H), 7.47 (td, J=9.1, 2.5 Hz, 1H).

    Step 4: Synthesis of 4-(6-fluorobenzo[d]thiazol-2-yl) aniline

    [0148] ##STR00048##

    [0149] The compound 6-fluoro-2-(4-nitrophenyl)benzo[d]thiazol (0.8 g, 2.92 mmol) and 10% palladium on carbon (about 55% water content) (160 mg) were added to a solvent of MeOH (10 mL) and stirred overnight at room temperature in a hydrogen environment. After the reaction was finished, the mixture was suction filtered with Celite as a filter aid, and a filtrate was concentrated to obtain a crude product. The crude product was isolated through the silica gel column chromatography (PE:EA=4:1, v/v) to obtain a target compound as a white solid (0.5 g with a yield of 70%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.00-7.85 (m, 2H), 7.73 (d, J=8.5 Hz, 2H), 7.30 (td, J=9.0, 2.5 Hz, 1H), 6.67 (d, J=8.5 Hz, 2H), 5.88 (s, 2H).

    Step 5: synthesis of 2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-fluorobenzo[d]thiazol-2-yl)phenyl) acetamide

    [0150] ##STR00049##

    [0151] A synthesis method was as that in Example 25, and a white solid was obtained with a yield of 56%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.59 (s, 1H), 8.07-7.98 (m, 4H), 7.85 (d, J=8.2 Hz, 2H), 7.80 (d, J=8.7 Hz, 2H), 7.63 (d, J=8.2 Hz, 2H), 7.39 (td, J=9.1, 2.6 Hz, 1H), 3.86 (s, 2H), 3.27 (q, J=7.2 Hz, 2H), 1.10 (t, J=7.3 Hz, 3H). MS (ESI), m/z for C.sub.23H.sub.19FN.sub.2O.sub.3S.sub.2 ([M+H].sup.+): Calcd 454.53, found 455.0.

    Example 31 2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methoxybenzo[d]thiazol-2-yl)phenyl) acetamide

    [0152] ##STR00050##

    [0153] A synthesis method was as that in Example 30, and a white solid was obtained with a yield of 56%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.55 (s, 1H), 7.99 (d, J=8.7 Hz, 2H), 7.89 (d, J=8.9 Hz, 1H), 7.85 (d, J=8.2 Hz, 2H), 7.77 (d, J=8.7 Hz, 2H), 7.69 (d, J=2.5 Hz, 1H), 7.62 (d, J=8.3 Hz, 2H), 7.11 (dd, J=8.9, 2.6 Hz, 1H), 3.85 (s, 2H), 3.84 (s, 3H), 3.27 (q, J=7.6 Hz, 2H), 1.10 (t, J=7.3 Hz, 3H). MS (ESI), m/z for C.sub.24H.sub.22N.sub.2O.sub.4S.sub.2 ([M+Na]+): Calcd 466.57, found 489.7.

    Example 32 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(4-methylphenylethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

    Step 1: synthesis of 5-methyl-N-(4-methylphenylethyl)-2-nitroaniline

    [0154] ##STR00051##

    [0155] The compound 3-fluoro-4-nitrotoluene (2.0 g, 12.9 mmol) was dissolved in DMSO (5 mL), and p-methylphenethylamine (5.23 g, 38.7 mmol) and DIPEA (2.51 g, 19.4 mmol) were added to the mixture. The reaction mixture was stirred overnight at 95° C. The reaction was monitored through TLC. After the reaction was finished, water was added to the reaction mixture and extracted with ethyl acetate (50 mL×3). Combined organic layers were dried over anhydrous Na.sub.2S.sub.04 and concentrated under reduced pressure. A crude product was isolated through silica gel column chromatography (PE:EA=50:1, v/v) to obtain a target compound as a yellow solid (2.8 g with a yield of 80%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.09 (s, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.19 (d, J=6.6 Hz, 1H), 7.12 (d, J=5.7 Hz, 1H), 6.88 (s, 1H), 6.51 (d, J=7.9 Hz, 1H), 3.62-3.50 (m, 2H), 2.90 (t, J=6.8 Hz, 2H), 2.31 (s, 3H), 2.27 (s, 3H).

    Step 2: synthesis of 5-methyl-N-(4-methylphenylethyl)benzene-1,2-diamine

    [0156] ##STR00052##

    [0157] Iron powder (3.46 g, 61.8 mmol), ammonium chloride (551.1 mg, 10.3 mmol) and acetic acid (1.24 g, 20.6 mmol) were added to water (20 mL), heated to 50° C. and stirred for 10 min. The compound 5-methyl-N-(4-methylphenylethyl)-2-nitroaniline (2.8 g, 10.3 mmol) was dissolved in DMF (15 mL) and quickly added to the above mixed solution. Stirring was continued for 1 h, and the reaction was monitored through the TLC. After the reaction was finished, the mixture was cooled to room temperature and suction filtered. An aqueous layer had a pH adjusted to 8 to 9 with a solution of sodium carbonate and extracted with ethyl acetate (50 mL×3). Organic layers were combined, washed with a saturated solution of sodium chloride, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to obtain a crude product. The crude product was isolated through the silica gel column chromatography (PE:EA=10:1, v/v) to obtain a target compound as a yellow oily liquid (2.1 g with a yield of 81%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.17 (d, J=8.0 Hz, 2H), 7.11 (d, J=7.9 Hz, 2H), 6.43 (d, J=7.6 Hz, 1H), 6.28 (s, 1H), 6.22 (d, J=7.6 Hz, 1H), 4.36 (t, J=5.5 Hz, 1H), 4.21 (s, 2H), 3.23-3.15 (m, 2H), 2.83 (t, J=7.4 Hz, 2H), 2.27 (s, 3H), 2.12 (s, 3H).

    Step 3: synthesis of 6-methyl-1-(4-methylphenylethyl)-2-(4-nitrophenyl)-1H-benzo[d]imidazole

    [0158] ##STR00053##

    [0159] 5-methyl-N.sup.1-(4-methylphenylethyl)benzene-1,2-diamine (1.3 g, 5.4 mmol), p-nitrobenzaldehyde (816.0 mg, 5.4 mmol) and oxone (1.84 g, 3.0 mmol) were added to DMF (20 mL) and stirred for 1 h at room temperature. The reaction was monitored through the TLC. After the reaction was finished, water was added to the mixture and extracted with ethyl acetate (50 mL×3). Organic layers were combined, washed with a saturated solution of sodium chloride, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to obtain a crude product. The crude product was purified through the silica gel column chromatography (PE:EA=2:1, v/v) to obtain a target compound as a yellow solid (1.78 g with a yield of 86%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.21 (d, J=8.8 Hz, 2H), 7.72 (d, J=8.2 Hz, 1H), 7.48 (d, J=8.8 Hz, 2H), 7.27 (s, 1H), 7.19 (d, J=8.3 Hz, 1H), 6.94 (d, J=7.8 Hz, 2H), 6.64 (d, J=7.9 Hz, 2H), 4.45 (t, J=6.8 Hz, 2H), 3.03 (t, J=6.8 Hz, 2H), 2.57 (s, 3H), 2.29 (s, 3H).

    Step 4: synthesis of 4-(6-methyl-1-(4-methylphenylethyl)-1H-benzo[d]imidazol-2-yl)aniline

    [0160] ##STR00054##

    [0161] The intermediate 6-methyl-1-(4-methylphenylethyl)-2-(4-nitrophenyl)-1H-benzo[d]imidazole was used as a raw material. For a synthesis method, reference was made to step 2. A yellow solid was obtained with a yield of 85%. .sup.1H NMR (400 MHz, DMSO) δ 7.46 (d, J=8.1 Hz, 1H), 7.36 (s, 1H), 7.28 (d, J=8.5 Hz, 2H), 7.04 (d, J=7.8 Hz, 2H), 7.00 (dd, J=8.3, 1.0 Hz, 1H), 6.97 (d, J=8.0 Hz, 2H), 6.65 (d, J=8.5 Hz, 2H), 5.51 (s, 2H), 4.34 (t, J=8.0 Hz, 2H), 2.97 (t, J=7.6 Hz, 2H), 2.45 (s, 3H), 2.25 (s, 3H).

    Step 5: synthesis of 2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(4-methylphenylethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

    [0162] ##STR00055##

    [0163] The compounds 4-(6-methyl-1-(4-methylphenylethyl)-1H-benzo[d]imidazol-2-yl)aniline (150 mg, 0.44 mmol), diisopropylethylamine (170.3 mg, 1.32 mmol) and HATU (250.8 mg, 0.66 mmol) were dissolved in DCM (10 mL). The reaction mixture was stirred for 15 min, then the compound 2-(4-(ethylsulfonyl)phenyl)acetic acid (121.0 mg, 0.53 mmol) was added to the reaction mixture, and the obtained mixture was stirred overnight at room temperature. After the reaction was finished, water was added to dilute the mixture and extracted with DCM (50 mL×3). Organic layers were combined, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. A crude product was isolated through the silica gel column chromatography (DCM:CH.sub.3OH=70:1, v/v) to obtain a target compound as a white solid (70 mg with a yield of 29%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.47 (s, 1H), 7.87 (d, J=8.3 Hz, 2H), 7.71 (d, J=8.6 Hz, 2H), 7.64 (d, J=8.3 Hz, 2H), 7.51 (d, J=8.2 Hz, 1H), 7.48 (d, J=8.7 Hz, 2H), 7.43 (s, 1H), 7.05 (dd, J=8.2, 0.8 Hz, 1H), 6.98 (d, J=7.7 Hz, 2H), 6.86 (d, J=7.9 Hz, 2H), 4.39 (t, J=7.3 Hz, 2H), 3.86 (s, 2H), 3.28 (q, J=7.5 Hz, 2H), 2.95 (t, J=7.3 Hz, 2H), 2.47 (s, 3H), 2.23 (s, 3H), 1.11 (t, J=7.4 Hz, 3H). MS (ESI), m/z for C.sub.33H.sub.33N.sub.3O.sub.3S ([M−H].sup.−): Calcd 551.71, found 550.4.

    Example 33 2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-propyl-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

    [0164] ##STR00056##

    [0165] A synthesis method was as that in Example 32, and a white solid was obtained with a yield of 45%. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 10.51 (s, 1H), 7.86 (d, J=8.2 Hz, 2H), 7.79 (d, J=8.6 Hz, 2H), 7.70 (d, J=8.8 Hz, 2H), 7.64 (d, J=8.2 Hz, 2H), 7.52 (d, J=8.2 Hz, 1H), 7.42 (s, 1H), 7.05 (d, J=8.1 Hz, 1H), 4.21 (t, J=7.4 Hz, 2H), 3.86 (s, 2H), 3.28 (q, J=7.5 Hz, 2H), 2.46 (s, 3H), 1.71-1.64 (m, 2H), 1.10 (t, J=7.4 Hz, 3H), 0.73 (t, J=7.3 Hz, 3H). MS (ESI), m/z for C.sub.27H.sub.29N.sub.3O.sub.3S ([M+H].sup.+): Calcd 475.61, found 476.3.

    Example 34 N-(4-(1-butyl-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-2-(4-(ethylsulfonyl) phenyl)acetamide

    [0166] ##STR00057##

    [0167] A synthesis method was as that in Example 32, and a white solid was obtained with a yield of 26%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.53 (s, 1H), 7.87 (d, J=8.2 Hz, 2H), 7.80 (d, J=8.6 Hz, 2H), 7.71 (d, J=8.6 Hz, 2H), 7.64 (d, J=8.2 Hz, 2H), 7.53 (d, J=8.2 Hz, 1H), 7.45 (s, 1H), 7.08 (d, J=8.1 Hz, 1H), 4.26 (t, J=7.3 Hz, 2H), 3.86 (s, 2H), 3.33-3.23 (m, 2H), 2.47 (s, 3H), 1.71-1.59 (m, 2H), 1.19-1.07 (m, 5H), 0.76 (t, J=7.3 Hz, 3H). MS (ESI), m/z for C.sub.28H.sub.31N.sub.3O.sub.3S ([M+H].sup.+): Calcd 489.63, found 490.5.

    Example 35 2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-pentyl-1H-benzo[d]imidazol-2-yl) phenyl)acetamide

    [0168] ##STR00058##

    [0169] A synthesis method was as that in Example 32, and a white solid was obtained with a yield of 31%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.50 (s, 1H), 7.86 (d, J=8.2 Hz, 2H), 7.79 (d, J=8.6 Hz, 2H), 7.70 (d, J=8.6 Hz, 2H), 7.64 (d, J=8.2 Hz, 2H), 7.52 (d, J=8.2 Hz, 1H), 7.41 (s, 1H), 7.06 (d, J=8.1 Hz, 1H), 4.24 (t, J=7.3 Hz, 2H), 3.86 (s, 2H), 3.28 (q, J=7.2 Hz, 2H), 2.46 (s, 3H), 1.70-1.61 (m, 2H), 1.20-1.06 (m, 7H), 0.75 (t, J=7.0 Hz, 3H). MS (ESI), m/z for C.sub.29H.sub.33N.sub.3O.sub.3S ([M+H].sup.+): Calcd 503.66, found 504.7.

    Example 36 2-(4-(ethylsulfonyl)phenyl)-N-(4-(1-isopropyl-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

    [0170] ##STR00059##

    [0171] A synthesis method was as that in Example 32, and a white solid was obtained with a yield of 28%. .sup.1H NMR (400 MHz, DMSO) δ 10.52 (s, 1H), 7.86 (d, J=8.2 Hz, 2H), 7.78 (d, J=8.5 Hz, 2H), 7.64 (d, J=8.2 Hz, 2H), 7.61-7.56 (m, 3H), 7.51 (d, J=8.2 Hz, 1H), 7.03 (d, J=8.1 Hz, 1H), 4.75-4.63 (m, 1H), 3.86 (s, 2H), 3.28 (q, J=7.3 Hz, 2H), 2.46 (s, 3H), 1.57 (d, J=6.9 Hz, 6H), 1.11 (t, J=7.3 Hz, 3H). MS (ESI), m/z for C.sub.27H.sub.29N.sub.3O.sub.3S ([M+H].sup.+): Calcd 475.61, found 476.3.

    Example 37 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(1-isobutyl-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

    [0172] ##STR00060##

    [0173] A synthesis method was as that in Example 32, and a white solid was obtained with a yield of 27%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.54 (s, 1H), 7.87 (d, J=8.2 Hz, 2H), 7.80 (d, J=8.6 Hz, 2H), 7.73 (d, J=8.6 Hz, 2H), 7.64 (d, J=8.2 Hz, 2H), 7.55 (d, J=8.2 Hz, 1H), 7.50 (s, 1H), 7.10 (d, J=8.2 Hz, 1H), 4.16 (d, J=7.5 Hz, 2H), 3.87 (s, 2H), 3.28 (q, J=7.2 Hz, 2H), 2.47 (s, 3H), 2.01-1.87 (m, 1H), 1.11 (t, J=7.3 Hz, 3H), 0.64 (d, J=6.6 Hz, 6H). MS (ESI), m/z for C.sub.28H.sub.31N.sub.3O.sub.3S ([M+H].sup.+): Calcd 489.63, found 490.5.

    Example 38 2-(4-(ethylsulfonyl)phenyl)-N-(4-(1-isopentyl-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

    [0174] ##STR00061##

    [0175] A synthesis method was as that in Example 32, and a white solid was obtained with a yield of 41%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.50 (s, 1H), 7.87 (d, J=6.9 Hz, 2H), 7.80 (d, J=7.4 Hz, 2H), 7.70 (d, J=7.3 Hz, 2H), 7.64 (d, J=7.0 Hz, 2H), 7.52 (d, J=7.4 Hz, 1H), 7.39 (s, 1H), 7.05 (d, J=7.2 Hz, 1H), 4.33-4.16 (m, 2H), 3.87 (s, 2H), 3.32-3.22 (m, 2H), 2.47 (s, 3H), 1.63-1.52 (m, 2H), 1.51-1.41 (m, 1H), 1.11 (t, J=7.4 Hz, 3H), 0.79 (d, J=5.0 Hz, 6H). MS (ESI), m/z for C.sub.29H.sub.33N.sub.3O.sub.3S ([M+H].sup.+): Calcd 503.66, found 504.7.

    Example 39 N-(4-(1-cyclobutyl-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide

    [0176] ##STR00062##

    [0177] A synthesis method was as that in Example 32, and a white solid was obtained with a yield of 30%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.52 (s, 1H), 7.87 (d, J=8.2 Hz, 2H), 7.79 (d, J=8.5 Hz, 2H), 7.67-7.58 (m, 5H), 7.54 (d, J=8.2 Hz, 1H), 7.09 (d, J=8.2 Hz, 1H), 5.13-5.01 (m, 1H), 3.87 (s, 2H), 3.28 (q, J=7.2 Hz, 2H), 2.76-2.61 (m, 2H), 2.49 (s, 3H), 2.43-2.32 (m, 2H), 1.95-1.70 (m, 2H), 1.11 (t, J=7.3 Hz, 3H). MS (ESI), m/z for C.sub.28H.sub.29N.sub.3O.sub.3S ([M+H].sup.+): Calcd 487.62, found 488.5.

    Example 40 N-(4-(1-(cyclobutylmethyl)-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide

    [0178] ##STR00063##

    [0179] A synthesis method was as that in Example 32, and a white solid was obtained with a yield of 22%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.50 (s, 1H), 7.87 (d, J=8.1 Hz, 2H), 7.79 (d, J=8.5 Hz, 2H), 7.70 (d, J=8.5 Hz, 2H), 7.64 (d, J=8.1 Hz, 2H), 7.50 (d, J=8.2 Hz, 1H), 7.44 (s, 1H), 7.04 (d, J=8.2 Hz, 1H), 4.35 (d, J=7.2 Hz, 2H), 3.86 (s, 2H), 3.32-3.24 (m, 2H), 2.60-2.51 (m, 1H), 2.46 (s, 3H), 1.78-1.57 (m, 4H), 1.54-1.44 (m, 2H), 1.11 (t, J=7.3 Hz, 3H). MS (ESI), m/z for C.sub.29H.sub.31N.sub.3O.sub.3S ([M+H].sup.+): Calcd 501.65, found 502.5.

    Example 41 N-(4-(1-(cyclohexylmethyl)-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide

    [0180] ##STR00064##

    [0181] A synthesis method was as that in Example 32, and a white solid was obtained with a yield of 40%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.50 (s, 1H), 7.87 (d, J=8.2 Hz, 2H), 7.78 (d, J=8.6 Hz, 2H), 7.70 (d, J=8.5 Hz, 2H), 7.64 (d, J=8.1 Hz, 2H), 7.51 (d, J=8.1 Hz, 1H), 7.42 (s, 1H), 7.04 (d, J=8.2 Hz, 1H), 4.17 (d, J=7.2 Hz, 2H), 3.86 (s, 2H), 3.28 (q, J=7.2 Hz, 2H), 2.46 (s, 3H), 1.69-1.56 (m, 1H), 1.53-1.42 (m, 4H), 1.34-1.19 (m, 6H), 1.11 (t, J=7.6 Hz, 3H). MS (ESI), m/z for C.sub.31H.sub.35N.sub.3O.sub.3S ([M+H].sup.+): Calcd 529.70, found 530.7.

    Example 42 N-(4-(1-benzyl-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-2-(4-(ethylsulfonyl) phenyl)acetamide

    [0182] ##STR00065##

    [0183] A synthesis method was as that in Example 32, and a white solid was obtained with a yield of 20%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.48 (s, 1H), 7.85 (d, J=8.2 Hz, 2H), 7.72 (d, J=8.7 Hz, 2H), 7.66 (d, J=8.7 Hz, 2H), 7.64-7.55 (m, 3H), 7.32-7.20 (m, 4H), 7.08 (d, J=8.1 Hz, 1H), 6.99 (d, J=7.2 Hz, 2H), 5.55 (s, 2H), 3.84 (s, 2H), 3.32-3.22 (m, 2H), 2.39 (s, 3H), 1.10 (t, J=7.3 Hz, 3H). MS (ESI), m/z for C.sub.31H.sub.29N.sub.3O.sub.3S ([M+H].sup.+): Calcd 523.65, found 524.3.

    Example 43 2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(4-methylbenzyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

    [0184] ##STR00066##

    [0185] A synthesis method was as that in Example 32, and a white solid was obtained with a yield of 25%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.49 (s, 1H), 7.85 (d, J=8.2 Hz, 2H), 7.73 (d, J=8.7 Hz, 2H), 7.66 (d, J=8.7 Hz, 2H), 7.62 (d, J=8.2 Hz, 2H), 7.57 (d, J=8.2 Hz, 1H), 7.25 (s, 1H), 7.12-7.03 (m, 3H), 6.88 (d, J=7.9 Hz, 2H), 5.49 (s, 2H), 3.84 (s, 2H), 3.27 (q, J=7.2 Hz, 2H), 2.39 (s, 3H), 2.22 (s, 3H), 1.10 (t, J=7.3 Hz, 3H). MS (ESI), m/z for C.sub.32H.sub.31N.sub.3O.sub.3S ([M+H].sup.+): Calcd 537.68, found 538.6.

    Example 44 2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-phenylethyl-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

    [0186] ##STR00067##

    [0187] A synthesis method was as that in Example 32, and a white solid was obtained with a yield of 45%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.48 (s, 1H), 7.87 (d, J=8.2 Hz, 2H), 7.72 (d, J=8.5 Hz, 2H), 7.64 (d, J=8.2 Hz, 2H), 7.55-7.47 (m, 3H), 7.45 (s, 1H), 7.22-7.13 (m, 3H), 7.06 (d, J=8.2 Hz, 1H), 7.02-6.95 (m, 2H), 4.43 (t, J=7.3 Hz, 2H), 3.86 (s, 2H), 3.28 (q, J=7.6 Hz, 2H), 3.01 (t, J=7.3 Hz, 2H), 2.47 (s, 3H), 1.11 (t, J=7.3 Hz, 3H). MS (ESI), m/z for C.sub.32H.sub.31N.sub.3O.sub.3S ([M+H].sup.+): Calcd 537.68, found 538.6.

    Example 45 2-(4-(ethylsulfonyl)phenyl)-N-(4-(1-(4-fluorobenzyl)-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

    [0188] ##STR00068##

    [0189] A synthesis method was as that in Example 32, and a white solid was obtained with a yield of 26%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.48 (s, 1H), 7.85 (d, J=8.3 Hz, 2H), 7.73 (d, J=8.7 Hz, 2H), 7.65 (d, J=8.7 Hz, 2H), 7.62 (d, J=8.2 Hz, 2H), 7.57 (d, J=8.2 Hz, 1H), 7.28 (s, 1H), 7.11 (t, J=8.8 Hz, 2H), 7.07 (d, J=8.4 Hz, 1H), 7.04-6.98 (m, 2H), 5.53 (s, 2H), 3.84 (s, 2H), 3.27 (q, J=7.2 Hz, 2H), 2.40 (s, 3H), 1.10 (t, J=7.3 Hz, 3H). MS (ESI), m/z for C.sub.31H.sub.28FN.sub.3O.sub.3S ([M+H].sup.+): Calcd 541.64, found 542.3.

    Example 46 2-(4-(ethylsulfonyl)phenyl)-N-(4-(1-(3-fluorobenzyl)-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

    [0190] ##STR00069##

    [0191] A synthesis method was as that in Example 32, and a white solid was obtained with a yield of 29%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.48 (s, 1H), 7.85 (d, J=8.3 Hz, 2H), 7.73 (d, J=8.7 Hz, 2H), 7.69-7.56 (m, 5H), 7.36-7.29 (m, 1H), 7.28 (s, 1H), 7.08 (d, J=8.3 Hz, 2H), 6.82 (d, J=9.9 Hz, 1H), 6.76 (d, J=7.8 Hz, 1H), 5.56 (s, 2H), 3.84 (s, 2H), 3.31-3.23 (m, 2H), 2.40 (s, 3H), 1.10 (t, J=7.4 Hz, 3H). MS (ESI), m/z for C.sub.31H.sub.28FN.sub.3O.sub.3S ([M+H].sup.+): Calcd 541.64, found 542.3.

    Example 47 2-(4-(ethylsulfonyl)phenyl)-N-(4-(1-(2-fluorobenzyl)-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

    [0192] ##STR00070##

    [0193] A synthesis method was as that in Example 32, and a white solid was obtained with a yield of 25%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.48 (s, 1H), 7.85 (d, J=8.2 Hz, 2H), 7.72 (d, J=8.6 Hz, 2H), 7.67-7.55 (m, 5H), 7.34-7.25 (m, 2H), 7.20 (t, J=8.7 Hz, 1H), 7.11-7.02 (m, 2H), 6.69 (t, J=7.6 Hz, 1H), 5.57 (s, 2H), 3.84 (s, 2H), 3.27 (q, J=7.2 Hz, 2H), 2.39 (s, 3H), 1.10 (t, J=7.3 Hz, 3H). MS (ESI), m/z for C.sub.31H.sub.28FN.sub.3O.sub.3S ([M+H].sup.+): Calcd 541.64, found 542.3.

    Example 48 N-(4-(1-(2,6-difluorobenzyl)-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide

    [0194] ##STR00071##

    [0195] A synthesis method was as that in Example 32, and a white solid was obtained with a yield of 35%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.49 (s, 1H), 7.86 (d, J=8.2 Hz, 2H), 7.76 (d, J=8.6 Hz, 2H), 7.69 (d, J=8.6 Hz, 2H), 7.64 (d, J=8.1 Hz, 2H), 7.52 (d, J=8.1 Hz, 1H), 7.39-7.28 (m, 1H), 7.18 (s, 1H), 7.07-6.94 (m, 3H), 5.60 (s, 2H), 3.86 (s, 2H), 3.28 (q, J=7.6 Hz, 2H), 2.38 (s, 3H), 1.10 (t, J=7.3 Hz, 3H). MS (ESI), m/z for C.sub.31H.sub.27F.sub.2N.sub.3O.sub.3S ([M+H].sup.+): Calcd 559.63, found 560.3.

    Example 49 N-(4-(1-(4-cyanobenzyl)-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide

    [0196] ##STR00072##

    [0197] A synthesis method was as that in Example 32, and a white solid was obtained with a yield of 31%. H NMR (400 MHz, DMSO-d.sub.6) δ 10.47 (s, 1H), 7.85 (d, J=8.3 Hz, 2H), 7.76 (d, J=8.3 Hz, 2H), 7.71 (d, J=8.7 Hz, 2H), 7.66-7.55 (m, 5H), 7.26 (s, 1H), 7.14 (d, J=8.3 Hz, 2H), 7.08 (d, J=8.3 Hz, 1H), 5.65 (s, 2H), 3.83 (s, 2H), 3.31-3.23 (m, 2H), 2.39 (s, 3H), 1.10 (t, J=7.3 Hz, 3H). MS (ESI), m/z for C.sub.32H.sub.28N.sub.4O.sub.3S ([M+H].sup.+): Calcd 548.66, found 549.2.

    Example 50 2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(4-(methylsulfonyl)benzyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

    [0198] ##STR00073##

    [0199] A synthesis method was as that in Example 32, and a white solid was obtained with a yield of 49%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.49 (s, 1H), 7.90-7.81 (m, 4H), 7.72 (d, J=8.6 Hz, 2H), 7.68-7.56 (m, 5H), 7.29-7.18 (m, 3H), 7.08 (d, J=8.1 Hz, 1H), 5.67 (s, 2H), 3.83 (s, 2H), 3.33-3.23 (m, 2H), 3.17 (s, 3H), 2.39 (s, 3H), 1.09 (t, J=7.2 Hz, 3H). MS (ESI), m/z for C.sub.32H.sub.31N.sub.3O.sub.5S.sub.2 ([M−H].sup.−): Calcd 601.74, found 600.8.

    Example 51 2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

    [0200] ##STR00074##

    [0201] A synthesis method was as that in Example 32, and a white solid was obtained with a yield of 41%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.46 (s, 1H), 8.49 (d, J=4.4 Hz, 1H), 7.85 (d, J=8.1 Hz, 2H), 7.79-7.66 (m, 5H), 7.61 (d, J=8.1 Hz, 2H), 7.56 (d, J=8.2 Hz, 1H), 7.31-7.24 (m, 1H), 7.20 (s, 1H), 7.09 (d, J=7.8 Hz, 1H), 7.05 (d, J=8.2 Hz, 1H), 5.57 (s, 2H), 3.83 (s, 2H), 3.27 (q, J=7.2 Hz, 2H), 2.37 (s, 3H), 1.10 (t, J=7.3 Hz, 3H). MS (ESI), m/z for C.sub.30H.sub.28N.sub.4O.sub.3S ([M+H].sup.+): Calcd 524.64, found 525.4.

    Example 52 N-(4-(1-benzyl-6-chloro-1H-benzo[d]imidazol-2-yl)phenyl)-2-(4-ethylsulfonyl) phenyl)acetamide

    [0202] ##STR00075##

    [0203] A synthesis method was as that in Example 32, and a white solid was obtained with a yield of 37%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.51 (s, 1H), 7.85 (d, J=8.3 Hz, 2H), 7.77-7.67 (m, 5H), 7.65-7.59 (m, 3H), 7.32-7.19 (m, 4H), 6.97 (d, J=7.1 Hz, 2H), 5.61 (s, 2H), 3.84 (s, 2H), 3.27 (q, J=7.3 Hz, 2H), 1.10 (t, J=7.4 Hz, 3H). MS (ESI), m/z for C.sub.30H.sub.26ClN.sub.3O.sub.3S ([M+H].sup.+): Calcd 544.07, found 544.4.

    Example 53 N-(4-(1-benzyl-5-chloro-1H-benzo[d]imidazol-2-yl)phenyl)-2-(4-ethylsulfonyl) phenyl)acetamide

    [0204] ##STR00076##

    [0205] A synthesis method was as that in Example 32, and a white solid was obtained with a yield of 35%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.52 (s, 1H), 7.85 (d, J=8.1 Hz, 2H), 7.78-7.67 (m, 5H), 7.62 (d, J=8.1 Hz, 2H), 7.51 (d, J=8.6 Hz, 1H), 7.31-7.20 (m, 4H), 6.97 (d, J=7.0 Hz, 2H), 5.60 (s, 2H), 3.84 (s, 2H), 3.27 (q, J=7.2 Hz, 2H), 1.10 (t, J=7.3 Hz, 3H). MS (ESI), m/z for C.sub.30H.sub.26ClN.sub.3O.sub.3S ([M+H].sup.+): Calcd 544.07, found 544.3. HPLC analysis: MeOH (1‰ NH.sub.3.Math.H.sub.2O)—H.sub.2O (75:25), t.sub.R=17.64 min, 96.13% purity.

    Example 54 (S)-2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

    Step 1: synthesis of (S)-4-(6-methyl-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)aniline

    [0206] ##STR00077##

    [0207] 3-fluoro-4-nitrotoluene and (S)-1-(4-methylphenyl)ethylamine were used as raw materials. For a synthesis method, reference was made to steps 1 to 4 in Example 31. A light yellow solid was obtained with a yield of 93%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.47 (d, J=8.1 Hz, 1H), 7.31 (d, J=8.4 Hz, 2H), 7.14 (d, J=8.0 Hz, 2H), 7.05 (d, J=8.0 Hz, 2H), 6.94 (d, J=8.1 Hz, 1H), 6.88 (s, 1H), 6.66 (d, J=8.4 Hz, 2H), 5.80 (q, J=6.8 Hz, 1H), 5.54 (s, 2H), 2.27 (s, 3H), 2.26 (s, 3H), 1.90 (d, J=7.1 Hz, 3H).

    Step 2: synthesis of (S)-2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

    [0208] ##STR00078##

    [0209] 2-(4-(ethylsulfonyl)phenyl)acetic acid (121.0 mg, 0.53 mmol), HOBT (89.2 mg, 0.66 mmol), EDCI (126.5 mg, 0.66 mol) and diisopropylethylamine (170.6 mg, 1.32 mmol) were dissolved in DCM (10 mL). The reaction mixture was stirred for 15 min, then the compound (S)-4-(6-methyl-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)aniline (150.2 mg, 0.44 mmol) was added to the reaction mixture, and the obtained mixture was stirred overnight at room temperature. After the reaction was finished, water was added to dilute the mixture and extracted with DCM (50 mL×3). Organic layers were combined, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. A crude product was isolated through silica gel column chromatography (PE:EA=1:1, v/v) to obtain a target compound as a white solid (53.4 mg with a yield of 22%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.51 (s, 1H), 7.85 (d, J=8.1 Hz, 2H), 7.77 (d, J=8.5 Hz, 2H), 7.66-7.58 (m, 4H), 7.53 (d, J=8.1 Hz, 1H), 7.14 (d, J=7.8 Hz, 2H), 7.05 (d, J=7.9 Hz, 2H), 6.99 (d, J=8.3 Hz, 1H), 6.95 (s, 1H), 5.82-5.72 (m, 1H), 3.85 (s, 2H), 3.31-3.22 (m, 2H), 2.29 (s, 3H), 2.26 (s, 3H), 1.92 (d, J=7.0 Hz, 3H), 1.10 (t, J=7.3 Hz, 3H). MS (ESI), m/z for C.sub.33H.sub.33N.sub.3O.sub.3S ([M+H].sup.+): Calcd 551.71, found 552.8.

    Example 55 Synthesis of 2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(pyridin-4-ylmethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

    Step 1: synthesis of 5-methyl-2-nitro-N-(pyridin-4-ylmethyl)aniline

    [0210] ##STR00079##

    [0211] 3-fluoro-4-nitrotoluene (2 g, 12.9 mmol), 4-picolylamine (1.68 g, 15.5 mmol) and potassium carbonate (2.68 g, 19.4 mmol) were dissolved in DMF (20 mL) and reacted for 1 h at 80° C. The reaction was monitored through TLC. After the reaction was finished, the reaction mixture was cooled to room temperature. Water was added to dilute the reaction mixture and extracted three times (50 mL×3) with ethyl acetate. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and isolated through silica gel column chromatography (PE:EA=4:1, v/v) to obtain a target compound as a yellow solid (2.2 g with a yield of 70%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.72 (t, J=6.2 Hz, 1H), 8.51 (d, J=5.9 Hz, 2H), 7.99 (d, J=8.7 Hz, 1H), 7.34 (d, J=5.5 Hz, 2H), 6.65 (s, 1H), 6.52 (dd, J=8.8, 0.8 Hz, 1H), 4.68 (d, J=6.4 Hz, 2H), 2.19 (s, 3H).

    Step 2: synthesis of 4-(6-methyl-1-(pyridin-4-ylmethyl)-1H-benzo[d]imidazol-2-yl)aniline

    [0212] ##STR00080##

    [0213] The intermediate 5-methyl-2-nitro-N-(pyridin-4-ylmethyl)aniline was used as a raw material. For a synthesis method, reference was made to steps 2 to 4 in Example 31. A yellow solid was obtained with a yield of 69%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.49 (d, J=6.0 Hz, 2H), 7.53 (d, J=8.2 Hz, 1H), 7.32 (d, J=8.6 Hz, 2H), 7.15 (s, 1H), 7.04 (dd, J=8.2, 0.8 Hz, 1H), 6.98 (d, J=5.9 Hz, 2H), 6.60 (d, J=8.6 Hz, 2H), 5.60-5.47 (m, 4H), 2.37 (s, 3H).

    Step 3: synthesis of 2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(pyridin-4-ylmethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

    [0214] ##STR00081##

    [0215] The intermediate 4-(6-methyl-1-(pyridin-4-ylmethyl)-1H-benzo[d]imidazol-2-yl)aniline was used as a raw material. For a synthesis method, reference was made to step 2 in Example 54. A white solid was obtained with a yield of 26%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.55 (s, 1H), 8.43 (m, 2H), 7.84 (d, J=8.3 Hz, 2H), 7.72 (d, J=8.7 Hz, 2H), 7.66-7.57 (m, 5H), 7.24 (s, 1H), 7.09 (dd, J=8.2, 0.8 Hz, 1H), 6.97-6.93 (m, 2H), 5.58 (s, 2H), 3.84 (s, 2H), 3.26 (q, J=7.6 Hz, 2H), 2.39 (s, 3H), 1.10 (t, J=7.3 Hz, 3H). MS (ESI), m/z for C.sub.30H.sub.28N.sub.4O.sub.3S ([M+H].sup.+): Calcd 524.64, found 525.4.

    Example 56 2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

    [0216] ##STR00082##

    [0217] A synthesis method was as that in Example 54, and a white solid was obtained with a yield of 25%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.52 (s, 1H), 7.85 (d, J=8.2 Hz, 2H), 7.77 (d, J=8.6 Hz, 2H), 7.66-7.58 (m, 4H), 7.53 (d, J=8.2 Hz, 1H), 7.14 (d, J=8.0 Hz, 2H), 7.05 (d, J=8.0 Hz, 2H), 6.99 (d, J=8.4 Hz, 1H), 6.95 (s, 1H), 5.76 (q, J=6.8 Hz, 2H), 3.85 (s, 2H), 3.27 (q, J=7.2 Hz, 2H), 2.29 (s, 3H), 2.26 (s, 3H), 1.92 (d, J=7.1 Hz, 3H), 1.10 (t, J=7.3 Hz, 3H). MS (ESI), m/z for C.sub.33H.sub.33N.sub.3O.sub.3S ([M+H].sup.+): Calcd 551.71, found 552.6.

    Example 57 (R)-2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

    [0218] ##STR00083##

    [0219] A synthesis method was as that in Example 54, and a white solid was obtained with a yield of 18%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.52 (s, 1H), 7.85 (d, J=8.2 Hz, 2H), 7.77 (d, J=8.5 Hz, 2H), 7.66-7.58 (m, 4H), 7.53 (d, J=8.2 Hz, 1H), 7.14 (d, J=8.0 Hz, 2H), 7.05 (d, J=8.0 Hz, 2H), 6.99 (d, J=8.2 Hz, 1H), 6.95 (s, 1H), 5.76 (q, J=6.8 Hz, 1H), 3.85 (s, 2H), 3.27 (q, J=7.2 Hz, 2H), 2.29 (s, 3H), 2.26 (s, 3H), 1.92 (d, J=7.1 Hz, 3H), 1.10 (t, J=7.4 Hz, 3H). MS (ESI), m/z for C.sub.33H.sub.33N.sub.3O.sub.3S ([M+H].sup.+): Calcd 551.71, found 552.7.

    Example 58 2-(4-(ethylsulfonyl)phenyl)-N-(4-(1-(4-fluorophenethyl)-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

    [0220] ##STR00084##

    [0221] A synthesis method was as that in Example 54, and a white solid was obtained with a yield of 29%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.47 (s, 1H), 7.87 (d, J=8.4 Hz, 2H), 7.72 (d, J=8.7 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H), 7.53-7.47 (m, 3H), 7.43 (s, 1H), 7.05 (dd, J=8.2, 0.8 Hz, 1H), 6.99-6.94 (m, 4H), 4.44 (t, J=7.3 Hz, 2H), 3.86 (s, 2H), 3.31-3.23 (m, 2H), 2.98 (t, J=7.4 Hz, 2H), 2.46 (s, 3H), 1.11 (t, J=7.4 Hz, 3H). MS (ESI), m/z for C.sub.32H.sub.30FN.sub.3O.sub.3S ([M−H].sup.−): Calcd 555.67, found 554.7.

    Example 59 2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

    [0222] ##STR00085##

    [0223] A synthesis method was as that in Example 54, and a white solid was obtained with a yield of 23%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.48 (s, 1H), 7.85 (d, J=8.1 Hz, 2H), 7.75-7.54 (m, 9H), 7.26 (s, 1H), 7.18 (d, J=8.1 Hz, 2H), 7.08 (d, J=8.1 Hz, 1H), 5.65 (s, 2H), 3.83 (s, 2H), 3.32-3.22 (m, 2H), 2.39 (s, 3H), 1.09 (t, J=7.3 Hz, 3H). MS (ESI), m/z for C.sub.32H.sub.28F.sub.3N.sub.3O.sub.3S ([M−H].sup.−): Calcd 591.65, found 590.3.

    Example 60 4-((2-(4-(2-(4-(ethylsulfonyl)phenyl)acetylamino)phenyl)-6-methyl-1H-benzo[d]imidazol-1-yl)methyl)methyl benzoate

    [0224] ##STR00086##

    [0225] A synthesis method was as that in Example 54, and a white solid was obtained with a yield of 29%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.48 (s, 1H), 7.88 (d, J=8.2 Hz, 2H), 7.84 (d, J=8.3 Hz, 2H), 7.70 (d, J=8.7 Hz, 2H), 7.66-7.56 (m, 5H), 7.24 (s, 1H), 7.12 (d, J=8.2 Hz, 2H), 7.08 (dd, J=8.2, 0.4 Hz, 1H), 5.63 (s, 2H), 3.83 (s, 2H), 3.81 (s, 3H), 3.27 (q, J=7.2 Hz, 2H), 2.38 (s, 3H), 1.09 (t, J=7.3 Hz, 3H). MS (ESI), m/z for C.sub.33H.sub.31N.sub.3O.sub.5S ([M+H].sup.+): Calcd 581.69, found 582.4.

    Example 61 4-((2-(4-(2-(4-(ethylsulfonyl)phenyl)acetylamino)phenyl)-6-methyl-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

    [0226] ##STR00087##

    [0227] Example 60 was used as a raw material. For a synthesis method, reference was made to Example 19. A white solid was obtained with a yield of 69%. .sup.1H NMR (500 MHz, DMSO) δ 10.78 (s, 1H), 7.87 (d, J=8.2 Hz, 2H), 7.84 (d, J=8.2 Hz, 2H), 7.81 (d, J=8.3 Hz, 2H), 7.74-7.66 (m, 3H), 7.62 (d, J=7.9 Hz, 2H), 7.43 (s, 1H), 7.26 (d, J=7.9 Hz, 1H), 7.18 (d, J=8.0 Hz, 2H), 5.71 (s, 2H), 3.87 (s, 2H), 3.27 (q, J=7.5 Hz, 2H), 2.42 (s, 3H), 1.09 (t, J=7.3 Hz, 3H). MS (ESI), m/z for C.sub.32H.sub.29N.sub.3O.sub.5S ([M+H].sup.+): Calcd 567.66, found 568.7.

    Example 62 2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(pyridin-3-ylmethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

    [0228] ##STR00088##

    [0229] A synthesis method was as that in Example 54, and a white solid was obtained with a yield of 44%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.51 (s, 1H), 8.46-8.40 (t, J=2.8 Hz, 1H), 8.26 (s, 1H), 7.85 (d, J=8.1 Hz, 2H), 7.74 (d, J=8.5 Hz, 2H), 7.67 (d, J=8.6 Hz, 2H), 7.62 (d, J=8.1 Hz, 2H), 7.58 (d, J=8.3 Hz, 1H), 7.35 (s, 1H), 7.31-7.25 (m, 2H), 7.08 (d, J=8.1 Hz, 1H), 5.61 (s, 2H), 3.85 (s, 2H), 3.28 (q, J=7.6 Hz, 2H), 2.40 (s, 3H), 1.10 (t, J=7.3 Hz, 3H). MS (ESI), m/z for C.sub.30H.sub.28N.sub.4O.sub.3S ([M+H].sup.+): Calcd 524.64, found 525.4.

    Example 63 (R)-2-(4-(ethylsulfonyl)phenyl)-N-(4-(1-(1-(p-tolyl)ethyl)-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

    [0230] ##STR00089##

    [0231] A synthesis method was as that in Example 54, and a white solid was obtained with a yield of 44%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.57 (s, 1H), 7.89-7.84 (m, 3H), 7.82 (d, J=8.5 Hz, 2H), 7.69 (d, J=8.3 Hz, 2H), 7.63 (d, J=7.9 Hz, 2H), 7.50 (d, J=8.5 Hz, 1H), 7.37 (s, 1H), 7.16 (d, J=7.8 Hz, 2H), 7.10 (d, J=7.8 Hz, 2H), 5.95-5.83 (m, 1H), 3.86 (s, 2H), 3.31-3.22 (m, 2H), 2.26 (s, 3H), 1.94 (d, J=6.9 Hz, 3H), 1.10 (t, J=7.3 Hz, 3H). MS (ESI), m/z for C.sub.33H.sub.30F3N.sub.3O.sub.3S ([M−H].sup.−): Calcd 605.68, found 604.4.

    Example 64 (R)-2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methoxy-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

    [0232] ##STR00090##

    [0233] A synthesis method was as that in Example 54, and a white solid was obtained with a yield of 27%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.53 (s, 1H), 7.86 (d, J=8.2 Hz, 2H), 7.78 (d, J=8.6 Hz, 2H), 7.66-7.59 (m, 4H), 7.54 (d, J=8.8 Hz, 1H), 7.15 (d, J=8.0 Hz, 2H), 7.09 (d, J=8.0 Hz, 2H), 6.81 (dd, J=8.8, 2.2 Hz, 1H), 6.53 (d, J=1.9 Hz, 1H), 5.76 (q, J=6.8 Hz, 1H), 3.85 (s, 2H), 3.62 (s, 3H), 3.28 (q, J=7.4 Hz, 2H), 2.26 (s, 3H), 1.91 (d, J=7.1 Hz, 3H), 1.10 (t, J=7.3 Hz, 3H). MS (ESI), m/z for C.sub.33H.sub.33N.sub.3O.sub.4S ([M−H].sup.−): Calcd 567.70, found 566.4.

    Example 65 (R)-2-(4-(ethylsulfonyl)phenyl)-N-(4-(5-methyl-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

    [0234] ##STR00091##

    [0235] A synthesis method was as that in Example 54, and a white solid was obtained with a yield of 31%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.54 (s, 1H), 7.85 (d, J=8.3 Hz, 2H), 7.78 (d, J=8.6 Hz, 2H), 7.67-7.60 (m, 4H), 7.44 (s, 1H), 7.12 (d, J=8.0 Hz, 2H), 7.04 (d, J=8.0 Hz, 2H), 6.98 (d, J=8.3 Hz, 1H), 6.88 (d, J=8.2 Hz, 1H), 5.76 (q, J=7.1 Hz, 1H), 3.85 (s, 2H), 3.28 (q, J=7.4 Hz, 2H), 2.35 (s, 3H), 2.24 (s, 3H), 1.92 (d, J=7.0 Hz, 3H), 1.09 (t, J=7.3 Hz, 3H). MS (ESI), m/z for C.sub.33H.sub.33N.sub.3O.sub.3S ([M−H].sup.−): Calcd 551.71, found 550.4.

    Example 66 (R)-2-(4-(ethylsulfonyl)phenyl)-N-(4-(5-methoxy-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide (27f)

    [0236] ##STR00092##

    [0237] A synthesis method was as that in Example 54, and a white solid was obtained with a yield of 25%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.53 (s, 1H), 7.85 (d, J=7.8 Hz, 2H), 7.78 (d, J=8.2 Hz, 2H), 7.69-7.58 (m, 4H), 7.17 (s, 1H), 7.12 (d, J=7.5 Hz, 2H), 7.05 (d, J=7.5 Hz, 2H), 6.98 (d, J=8.9 Hz, 1H), 6.70 (d, J=8.8 Hz, 1H), 5.82-5.69 (m, 1H), 3.85 (s, 2H), 3.75 (s, 3H), 3.33-3.22 (m, 2H), 2.25 (s, 3H), 1.91 (d, J=6.7 Hz, 3H), 1.10 (t, J=7.2 Hz, 3H). MS (ESI), m/z for C.sub.33H.sub.33N.sub.3O.sub.4S ([M+H].sup.+): Calcd 567.70, found 568.8.

    Example 67 (R)-2-(4-(ethylsulfonyl)phenyl)-N-(4-(1-(1-(4-fluorophenyl)ethyl)-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

    [0238] ##STR00093##

    [0239] A synthesis method was as that in Example 54, and a white solid was obtained with a yield of 39%. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 10.58 (s, 1H), 7.91-7.84 (m, 3H), 7.82 (d, J=7.9 Hz, 2H), 7.69 (d, J=8.1 Hz, 2H), 7.63 (d, J=7.5 Hz, 2H), 7.51 (d, J=8.1 Hz, 1H), 7.35 (s, 1H), 7.30-7.23 (m, 2H), 7.22-7.15 (m, 2H), 5.96-5.96 (m, 1H), 3.86 (s, 2H), 3.32-3.23 (m, 2H), 1.96 (d, J=6.5 Hz, 3H), 1.10 (t, J=7.1 Hz, 3H). MS (ESI), m/z for C.sub.32H.sub.27F.sub.4N.sub.3O.sub.3S ([M−H].sup.−): Calcd 609.64, found 608.2. HPLC analysis: MeOH—H.sub.2O (85:15), t.sub.R=13.02 min, 98.08% purity.

    Example 68 (S)-2-(4-(ethylsulfonyl)phenyl)-N-(4-(1-(1-(4-fluorophenyl)ethyl)-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

    [0240] ##STR00094##

    [0241] A synthesis method was as that in Example 54, and a white solid was obtained with a yield of 28%. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 10.58 (s, 1H), 7.90-7.83 (m, 3H), 7.82 (d, J=8.6 Hz, 2H), 7.69 (d, J=8.6 Hz, 2H), 7.63 (d, J=8.2 Hz, 2H), 7.51 (d, J=8.1 Hz, 1H), 7.35 (s, 1H), 7.29-7.24 (m, 2H), 7.18 (t, J=8.8 Hz, 2H), 5.92 (q, J=6.8 Hz, 1H), 3.86 (s, 2H), 3.28 (q, J=7.4 Hz, 2H), 1.96 (d, J=7.1 Hz, 3H), 1.10 (t, J=7.3 Hz, 3H). MS (ESI), m/z for C.sub.32H.sub.27F.sub.4N.sub.3O.sub.3S ([M−H].sup.−): Calcd 609.64, found 608.3.

    Example 69 (R)-2-(4-(2-(4-(ethylsulfonyl)phenyl)acetylamino)phenyl)-N-isopropyl-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-6-formamide

    Step 1: Synthesis of 3-fluoro-N-isopropyl-4-nitrobenzamide

    [0242] ##STR00095##

    [0243] 3-Fluoro-4-nitrobenzoic acid and isopropylamine were used as raw materials. For a synthesis method, reference was made to step 5 in Example 31. A yellow solid was obtained with a yield of 95%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.59 (d, J=7.2 Hz, 1H), 8.25 (t, J=8.1 Hz, 1H), 7.97 (dd, J=12.1, 1.5 Hz, 1H), 7.87 (d, J=8.5 Hz, 1H), 4.14-4.02 (m, 1H), 1.18 (d, J=6.6 Hz, 6H).

    Step 2: synthesis of (R)-2-(4-(2-(4-(ethylsulfonyl)phenyl)acetylamino)phenyl)-N-isopropyl-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-6-formamide

    [0244] ##STR00096##

    [0245] 3-Fluoro-N-isopropyl-4-nitrobenzamide and (R)-1-(4-methylphenyl)ethylamine were used as raw materials. For a synthesis method, reference was made to Example 53. A white solid was obtained with a yield of 26%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.57 (s, 1H), 8.14 (d, J=7.8 Hz, 1H), 7.85 (d, J=8.3 Hz, 2H), 7.79 (d, J=8.7 Hz, 2H), 7.76-7.60 (m, 7H), 7.14 (d, J=8.1 Hz, 2H), 7.05 (d, J=8.0 Hz, 2H), 5.88-5.80 (m, 1H), 4.10-4.01 (m, 1H), 3.86 (s, 2H), 3.32-3.22 (m, 2H), 2.25 (s, 3H), 1.97 (d, J=7.1 Hz, 3H), 1.14 (d, J=6.5 Hz, 6H), 1.10 (t, J=7.4 Hz, 3H). MS (ESI), m/z for C.sub.36H.sub.38N.sub.4O.sub.4S ([M−H].sup.−): Calcd 622.78, found 621.0.

    Example 70 (R)—N-cyclopentyl-2-(4-(2-(4-(ethylsulfonyl)phenyl)acetylamino)phenyl)-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-6-formamide

    [0246] ##STR00097##

    [0247] A synthesis method was as that in Example 69, and a white solid was obtained with a yield of 12%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.55 (s, 1H), 8.19 (d, J=7.0 Hz, 1H), 7.85 (d, J=8.3 Hz, 2H), 7.79 (d, J=8.3 Hz, 2H), 7.76-7.57 (m, 7H), 7.14 (d, J=7.3 Hz, 2H), 7.05 (d, J=7.7 Hz, 2H), 5.89-5.78 (m, 1H), 4.23-4.12 (m, 1H), 3.85 (s, 2H), 3.33-3.22 (m, 2H), 2.25 (s, 3H), 1.97 (d, J=7.0 Hz, 3H), 1.92-1.79 (m, 2H), 1.75-1.62 (m, 2H), 1.59-1.44 (m, 4H), 1.09 (t, J=7.3 Hz, 3H). MS (ESI), m/z for C.sub.38H.sub.40N.sub.4O.sub.4S ([M+H].sup.+): Calcd 648.82, found 650.0.

    Example 71 (R)-2-(4-(2-(4-(ethylsulfonyl)phenyl)acetylamino)phenyl)-N-isopropyl-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-5-formamide

    [0248] ##STR00098##

    [0249] A synthesis method was as that in Example 69, and a white solid was obtained with a yield of 29%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.57 (s, 1H), 8.18 (s, 1H), 8.14 (d, J=6.7 Hz, 1H), 7.86 (d, J=7.6 Hz, 2H), 7.81 (d, J=7.7 Hz, 2H), 7.68 (d, J=7.3 Hz, 2H), 7.63 (d, J=7.5 Hz, 2H), 7.57 (d, J=7.9 Hz, 1H), 7.17-7.09 (m, 3H), 7.08-7.00 (m, 2H), 5.88-5.74 (m, 1H), 4.16-4.02 (m, 1H), 3.86 (s, 2H), 3.31-3.22 (d, J=7.1 Hz, 2H), 2.24 (s, 3H), 1.96 (d, J=4.8 Hz, 3H), 1.16 (d, J=5.5 Hz, 6H), 1.13-1.07 (m, 3H). MS (ESI), m/z for C.sub.36H.sub.38N.sub.4O.sub.4S ([M+H].sup.+): Calcd 622.78, found 623.3.

    Example 72 (R)—N-cyclopentyl-2-(4-(2-(4-(ethylsulfonyl)phenyl)acetylamino)phenyl)-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-5-formamide

    [0250] ##STR00099##

    [0251] A synthesis method was as that in Example 69, and a white solid was obtained with a yield of 11%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.56 (s, 1H), 8.24-8.15 (m, 2H), 7.85 (d, J=8.1 Hz, 2H), 7.80 (d, J=8.6 Hz, 2H), 7.67 (d, J=8.6 Hz, 2H), 7.62 (d, J=8.1 Hz, 2H), 7.56 (d, J=8.5 Hz, 1H), 7.16-7.09 (m, 3H), 7.04 (d, J=7.9 Hz, 2H), 5.86-5.76 (m, 1H), 4.28-4.17 (m, 1H), 3.86 (s, 2H), 3.33-3.23 (m, 2H), 2.24 (s, 3H), 1.96 (d, J=6.9 Hz, 3H), 1.92-1.80 (m, 2H), 1.76-1.64 (m, 2H), 1.58-1.48 (m, 4H), 1.09 (t, J=7.3 Hz, 3H). MS (ESI), m/z for C.sub.38H.sub.40N.sub.4O.sub.4S ([M+H].sup.+): Calcd 648.82, found 649.9.

    Example 73 2-acetylamino-2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-((S)-1-(p-tolyl) ethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

    Step 1: synthesis of tert-butyl(1-(4-(ethylsulfonyl)phenyl)-2-((4-(6-methyl-1-((S)-1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)phenyl)amino)-2-oxoethyl)carbamate

    [0252] ##STR00100##

    [0253] (S)-4-(6-methyl-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)aniline and 2-((tert-butyloxycarbonyl)amino)-2-(4-(ethylsulfonyl)phenyl)acetic acid were used as raw materials. For a synthesis method, reference was made to step 5 in Example 31. A white solid was obtained with a yield of 46%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.62 (s, 1H), 7.89 (d, J=8.2 Hz, 2H), 7.82-7.69 (m, 5H), 7.60 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.2 Hz, 1H), 7.12 (d, J=7.9 Hz, 2H), 7.04 (d, J=7.9 Hz, 2H), 6.98 (d, J=8.3 Hz, 1H), 6.94 (s, 1H), 5.74 (q, J=7.2 Hz, 1H), 5.52 (d, J=7.2 Hz, 1H), 3.31-3.20 (m, 2H), 2.28 (s, 3H), 2.25 (s, 3H), 1.90 (d, J=7.0 Hz, 3H), 1.40 (s, 9H), 1.08 (t, J=7.3 Hz, 3H).

    Step 2: synthesis of 2-amino-2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-((S)-1-(p-tolyl) ethyl)-1H-benzo[d]imidazopyridin-2-yl)phenyl)acetamide

    [0254] ##STR00101##

    [0255] Tert-butyl(1-(4-(ethylsulfonyl)phenyl)-2-((4-(6-methyl-1-((S)-1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)phenyl)amino)-2-oxoethyl)carbamate (190 mg, 0.28 mmol) was dissolved in DCM (10 mL). TFA (5 mL) was added dropwise to the mixture and reacted for 3 h at room temperature. After the reaction was finished, the organic solvent was removed, and a mixed solvent of ethyl acetate and petroleum ether was recrystallized to obtain a target product as a white solid (130 mg with a yield of 82%). MS (ESI), m/z for C.sub.33H.sub.34N.sub.4O.sub.3S ([M+H].sup.+): Calcd 566.72, found 567.5.

    Step 3: synthesis of 2-acetylamino-2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-((S)-1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

    [0256] ##STR00102##

    [0257] 2-Amino-2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-((S)-1-(p-tolyl)ethyl)-1H-benzo[d]imidazopyridin-2-yl)phenyl)acetamide (130 mg, 0.23 mmol) was dissolved in DCM (10 mL), then triethylamine (23.3 mg, 0.23 mmol) and acetic anhydride (23.5 mg, 0.23 mmol) were added to the mixture, and the mixture was stirred to react for 3 h at room temperature. After the reaction was finished, water was added to dilute the mixture and extracted with DCM (50 mL×3). Organic layers were combined, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. A crude product was isolated through silica gel column chromatography (PE:EA=1:4, v/v) to obtain a target compound as a white solid (86.8 mg with a yield of 62%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.74 (s, 1H), 8.89 (d, J=7.8 Hz, 1H), 7.91 (d, J=8.3 Hz, 2H), 7.80-7.73 (m, 4H), 7.61 (d, J=8.6 Hz, 2H), 7.53 (d, J=8.2 Hz, 1H), 7.13 (d, J=8.1 Hz, 2H), 7.05 (d, J=8.0 Hz, 2H), 6.99 (d, J=8.5 Hz, 1H), 6.94 (s, 1H), 5.82 (d, J=7.8 Hz, 1H), 5.75 (q, J=6.9 Hz, 1H), 3.31-3.23 (m, 2H), 2.29 (s, 3H), 2.25 (s, 3H), 1.96 (s, 3H), 1.91 (d, J=7.1 Hz, 3H), 1.09 (t, J=7.3 Hz, 3H). MS (ESI), m/z for C.sub.35H.sub.36N.sub.4O.sub.4S ([M+H].sup.+): Calcd 608.76, found 609.8.

    [0258] Isomer 1 (Example 74) and Isomer 2 (Example 75) of Example 73

    [0259] Example 73 (2.72 g) was purified through supercritical fluid chromatography (SFC) chiral separation (Chiralpak IC, 0.46 cm ID×15 cm L, 214 nm, hexane/ethanol=30/70 (V/V), 1 mL/min, 35° C.) to obtain two corresponding isomers: Isomer 1 (Example 74) (Peak 1, 1.25 g, >98% ee, white solid) and Isomer 2 (Example 75) (Peak 2, 1.31 g, >98% ee, white solid). Note: no single crystal of the compound was available at present, and no absolute configuration of the compound can be determined.

    [0260] Example 74: Isomer 1 (R or S).sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 10.75 (s, 1H), 8.91 (d, J=7.7 Hz, 1H), 7.91 (d, J=7.6 Hz, 2H), 7.79-7.73 (m, 4H), 7.61 (d, J=7.8 Hz, 2H), 7.53 (d, J=8.2 Hz, 1H), 7.13 (d, J=7.6 Hz, 2H), 7.04 (d, J=7.6 Hz, 2H), 6.99 (d, J=8.1 Hz, 1H), 6.94 (s, 1H), 5.82 (d, J=7.7 Hz, 1H), 5.74 (q, J=6.2 Hz, 1H), 3.28 (q, J=7.4 Hz, 2H), 2.29 (s, 3H), 2.25 (s, 3H), 1.95 (s, 3H), 1.91 (d, J=7.0 Hz, 3H), 1.09 (t, J=7.9 Hz, 3H). MS (ESI), m/z for C.sub.35H.sub.36N.sub.4O.sub.4S ([M+H].sup.+): Calcd 608.76, found 609.8.

    [0261] Example 75: Isomer 2 (S or R).sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 10.75 (s, 1H), 8.91 (d, J=7.8 Hz, 1H), 7.91 (d, J=7.7 Hz, 2H), 7.79-7.74 (m, 4H), 7.61 (d, J=8.0 Hz, 2H), 7.53 (d, J=8.1 Hz, 1H), 7.13 (d, J=7.6 Hz, 2H), 7.04 (d, J=7.6 Hz, 2H), 6.99 (d, J=8.2 Hz, 1H), 6.94 (s, 1H), 5.82 (d, J=7.6 Hz, 1H), 5.74 (q, J=6.3 Hz, 1H), 3.28 (q, J=7.5 Hz, 2H), 2.29 (s, 3H), 2.25 (s, 3H), 1.95 (s, 3H), 1.91 (d, J=7.0 Hz, 3H), 1.09 (t, J=7.3 Hz, 3H). MS (ESI), m/z for C.sub.35H.sub.36N.sub.4O.sub.4S ([M+H].sup.+): Calcd 608.76, found 609.8.

    Example 76 2-acetylamino-2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-pentyl-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

    [0262] ##STR00103##

    [0263] A synthesis method was as that in Example 73, and a white solid was obtained with a yield of 47%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.72 (s, 1H), 8.89 (d, J=7.6 Hz, 1H), 7.93 (d, J=8.1 Hz, 2H), 7.81-7.74 (m, 4H), 7.70 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.1 Hz, 1H), 7.40 (s, 1H), 7.04 (d, J=8.1 Hz, 1H), 5.83 (d, J=7.6 Hz, 1H), 4.23 (t, J=7.1 Hz, 2H), 3.33-3.24 (m, 2H), 2.46 (s, 3H), 1.96 (s, 3H), 1.70-1.58 (m, 2H), 1.20-1.04 (m, 7H), 0.74 (t, J=6.9 Hz, 3H). MS (ESI), m/z for C.sub.31H.sub.36N.sub.4O.sub.4S ([M+H].sup.+): Calcd 560.71, found 561.8.

    Example 77 2-acetylamino-2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-((R)-1-(p-tolyl) ethyl)-1H-benzo[d]imidazopyridin-2-yl)phenyl)acetamide

    [0264] ##STR00104##

    [0265] A synthesis method was as that in Example 73, and a white solid was obtained with a yield of 45%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.75 (s, 1H), 8.90 (d, J=7.8 Hz, 1H), 7.91 (d, J=8.4 Hz, 2H), 7.80-7.73 (m, 4H), 7.61 (d, J=8.6 Hz, 2H), 7.53 (d, J=8.2 Hz, 1H), 7.13 (d, J=8.1 Hz, 2H), 7.04 (d, J=7.9 Hz, 2H), 6.98 (d, J=8.6 Hz, 1H), 6.94 (s, 1H), 5.82 (d, J=7.8 Hz, 1H), 5.74 (q, J=6.9 Hz, 1H), 3.28 (q, J=7.4 Hz, 2H), 2.29 (s, 3H), 2.25 (s, 3H), 1.95 (s, 3H), 1.91 (d, J=7.1 Hz, 3H), 1.09 (t, J=7.3 Hz, 3H). MS (ESI), m/z for C.sub.35H.sub.36N.sub.4O.sub.4S ([M+H].sup.+): Calcd 608.76, found 609.7.

    Example 78 2-(4-(2-acetylamino-2-(4-(ethylsulfonyl)phenyl)acetylamino)phenyl)-N-isopropyl-1-((R)-1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-5-formamide

    [0266] ##STR00105##

    [0267] A synthesis method was as that in Example 73, and a white solid was obtained with a yield of 46%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.78 (s, 1H), 8.91 (d, J=7.7 Hz, 1H), 8.18 (s, 1H), 8.13 (d, J=8.1 Hz, 1H), 7.92 (d, J=8.4 Hz, 2H), 7.80 (d, J=8.6 Hz, 2H), 7.77 (d, J=8.3 Hz, 2H), 7.68 (d, J=8.5 Hz, 2H), 7.57 (d, J=8.8 Hz, 1H), 7.18-7.09 (m, 3H), 7.04 (d, J=7.8 Hz, 2H), 5.85-5.75 (m, 2H), 4.15-4.03 (m, 1H), 3.33-3.24 (m, 2H), 2.24 (s, 3H), 1.98-1.91 (m, 6H), 1.15 (d, J=6.6 Hz, 6H), 1.09 (t, J=7.3 Hz, 3H). MS (ESI), m/z for C.sub.38H.sub.41N.sub.5O.sub.5S ([M+H].sup.+): Calcd 679.84, found 680.8.

    Example 79 2-(4-(2-acetylamino-2-(4-(ethylsulfonyl)phenyl)acetylamino)phenyl)-N-isopropyl-1-((S)-1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-5-formamide

    [0268] ##STR00106##

    [0269] A synthesis method was as that in Example 73, and a white solid was obtained with a yield of 40%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.79 (s, 1H), 8.91 (d, J=7.8 Hz, 1H), 8.18 (s, 1H), 8.13 (d, J=7.7 Hz, 1H), 7.92 (d, J=8.4 Hz, 2H), 7.80 (d, J=8.6 Hz, 2H), 7.77 (d, J=8.4 Hz, 2H), 7.68 (d, J=8.6 Hz, 2H), 7.57 (dd, J=8.6, 1.3 Hz, 1H), 7.17-7.09 (m, 3H), 7.04 (d, J=7.7 Hz, 2H), 5.86-5.75 (m, 2H), 4.15-4.03 (m, 1H), 3.33-3.23 (m, 2H), 2.24 (s, 3H), 1.99-1.91 (m, 6H), 1.16 (d, J=6.6 Hz, 6H), 1.09 (t, J=7.3 Hz, 3H). MS (ESI), m/z for C.sub.38H.sub.41N.sub.5O.sub.5S ([M+Na]+): Calcd 679.84, found 702.4.

    Example 80 2-acetylamino-2-(4-(ethylsulfonyl)phenyl)-N-(6-(6-methyl-1-((S)-1-(p-tolyl) ethyl)-1H-benzo[d]imidazol-2-yl)pyridin-3-yl)acetamide

    Step 1: synthesis of (S)-5-methyl-N.SUP.1.-(1-(p-tolyl)ethyl)benzene-1,2-diamine

    [0270] ##STR00107##

    [0271] 3-Fluoro-4-nitrotoluene and (S)-1-(4-methylphenyl)ethylamine were used as raw materials. For a synthesis method, reference was made to steps 1 and 2 in Example 31. A yellow-purple liquid was obtained with a yield of 90%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.24 (d, J=7.5 Hz, 2H), 7.08 (d, J=7.4 Hz, 2H), 6.40 (d, J=7.6 Hz, 1H), 6.13 (d, J=7.4 Hz, 1H), 6.02 (s, 1H), 4.71 (d, J=6.2 Hz, 1H), 4.52-4.29 (m, 3H), 2.24 (s, 3H), 1.94 (s, 3H), 1.41 (d, J=6.5 Hz, 3H).

    Step 2: synthesis of (S)—N-(4-methyl-2-((1-(p-tolyl)ethyl)amino)phenyl)-5-nitropyridine

    [0272] ##STR00108##

    [0273] (S)-5-methyl-N.sup.1-(1-(p-tolyl)ethyl)benzene-1,2-diamine and 5-nitro-2-pyridinecarboxylic acid were used as raw materials. For a synthesis method, reference was made to step 5 in Example 31. A yellow solid was obtained with a yield of 75%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.34 (s, 1H), 9.47 (d, J=2.4 Hz, 1H), 8.81 (dd, J=8.6, 2.5 Hz, 1H), 8.38 (d, J=8.6 Hz, 1H), 7.31 (d, J=7.9 Hz, 2H), 7.21 (d, J=7.9 Hz, 1H), 7.09 (d, J=7.8 Hz, 2H), 6.43 (d, J=8.1 Hz, 1H), 6.32 (s, 1H), 5.30 (d, J=6.4 Hz, 1H), 4.52-4.42 (m, 1H), 2.25 (s, 3H), 2.09 (s, 3H), 1.38 (d, J=6.6 Hz, 3H).

    Step 3: synthesis of (S)-6-methyl-2-(5-nitropyridin-2-yl)-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazole

    [0274] ##STR00109##

    [0275] (S)—N-(4-methyl-2-((1-(p-tolyl)ethyl)amino)phenyl)-5-nitropyridine (3.25 g, 8.32 mmol) was dissolved in glacial acetic acid (150 mL), and the solution was refluxed and stirred for 4.5 h at 120° C. After the reaction was finished, the solution was washed with saturated NaHCO.sub.3 until acetic acid was completely eliminated and then extracted multiple times with ethyl acetate. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and isolated through silica gel column chromatography (PE:EA=5:1, v/v) to obtain a target compound as a bright yellow solid (2.69 g with a yield of 87%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.46 (d, J=2.2 Hz, 1H), 8.76 (dd, J=8.8, 2.6 Hz, 1H), 8.59 (d, J=8.8 Hz, 1H), 7.65 (d, J=8.3 Hz, 1H), 7.32 (q, J=6.4 Hz, 1H), 7.21 (d, J=7.9 Hz, 2H), 7.14 (d, J=7.9 Hz, 2H), 7.07 (d, J=8.3 Hz, 1H), 6.99 (s, 1H), 2.30 (s, 3H), 2.26 (s, 3H), 1.98 (d, J=7.1 Hz, 3H).

    Step 4: synthesis of (S)-6-(6-methyl-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)pyridin-3-amine

    [0276] ##STR00110##

    [0277] (S)-6-methyl-2-(5-nitropyridin-2-yl)-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazole was used as a raw material. For a synthesis method, reference was made to step 2 in Example 31. A white solid was obtained with a yield of 71%. .sup.1H NMR (400 MHz, DMSO) δ 8.01-7.95 (m, 2H), 7.47 (d, J=8.2 Hz, 1H), 7.31 (q, J=7.0 Hz, 1H), 7.18 (d, J=8.1 Hz, 2H), 7.12 (d, J=8.1 Hz, 2H), 7.08 (dd, J=8.6, 2.8 Hz, 1H), 6.93 (d, J=8.2 Hz, 1H), 6.85 (s, 1H), 5.80 (s, 2H), 2.25 (s, 6H), 1.90 (d, J=7.1 Hz, 3H).

    Step 5: synthesis of tert-butyl(1-(4-(ethylsulfonyl)phenyl)-2-((6-(6-methyl-1-((S)-1-(p-tolyl) ethyl)-1H-benzo[d]imidazol-2-yl)pyridin-3-yl)amino)-2-oxoethyl)carbamate

    [0278] ##STR00111##

    [0279] (S)-5-(6-methyl-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)pyridin-2-amine and 2-((tert-butyloxycarbonyl)amino)-2-(4-(ethylsulfonyl)phenyl)acetic acid were used as raw materials. For a synthesis method, reference was made to step 5 in Example 31. A white solid was obtained with a yield of 39%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.84 (s, 1H), 8.86 (d, J=1.5 Hz, 1H), 8.29-8.20 (m, 2H), 7.94-7.85 (m, 3H), 7.78 (d, J=8.3 Hz, 2H), 7.55 (d, J=8.3 Hz, 1H), 7.26-7.16 (m, 3H), 7.12 (d, J=7.8 Hz, 2H), 6.99 (d, J=8.3 Hz, 1H), 6.92 (s, 1H), 3.33-3.22 (m, 2H), 2.27 (s, 3H), 2.25 (s, 3H), 1.92 (dd, J=6.9, 2.7 Hz, 3H), 1.40 (s, 9H), 1.09 (t, J=7.3 Hz, 3H).

    Step 6: synthesis of 2-amino-2-(4-(ethylsulfonyl)phenyl)-N-(6-(6-methyl-1-((S)-1-(p-tolyl) ethyl)-1H-benzo[d]imidazol-2-yl)pyridin-3-yl)acetamide

    [0280] ##STR00112##

    [0281] Tert-butyl(1-(4-(ethylsulfonyl)phenyl)-2-((6-(6-methyl-1-((S)-1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)pyridin-3-yl)amino)-2-oxoethyl)carbamate was used as a raw material. For a synthesis method, reference was made to step 2 in Example 72. A white solid was obtained with a yield of 80%. MS (ESI), m/z for C.sub.32H.sub.33N.sub.5O.sub.3S ([M+H].sup.+): Calcd 567.71, found 568.8.

    Step 7: synthesis of 2-acetylamino-2-(4-(ethylsulfonyl)phenyl)-N-(6-(6-methyl-1-((S)-1-(p-tolyl) ethyl)-1H-benzo[d]imidazol-2-yl)pyridin-3-yl)acetamide

    [0282] ##STR00113##

    [0283] 2-Amino-2-(4-(ethylsulfonyl)phenyl)-N-(6-(6-methyl-1-((S)-1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)pyridin-3-yl)acetamide was used as a raw material. For a synthesis method, reference was made to step 3 in Example 72. A white solid was obtained with a yield of 70%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.96 (s, 1H), 8.95 (d, J=7.7 Hz, 1H), 8.87 (s, 1H), 8.31-8.19 (m, 2H), 7.92 (d, J=8.3 Hz, 2H), 7.77 (d, J=8.3 Hz, 2H), 7.55 (d, J=8.2 Hz, 1H), 7.26-7.15 (m, 3H), 7.12 (d, J=7.8 Hz, 2H), 6.99 (d, J=8.0 Hz, 1H), 6.92 (s, 1H), 5.83 (d, J=7.6 Hz, 1H), 3.33-3.23 (m, 2H), 2.27 (s, 3H), 2.25 (s, 3H), 1.96 (s, 3H), 1.92 (dd, J=7.0, 1.7 Hz, 3H), 1.09 (t, J=7.3 Hz, 3H). MS (ESI), m/z for C.sub.34H.sub.35N.sub.5O.sub.4S ([M+H].sup.+): Calcd 609.75, found 610.7.

    Example 81 2-acetylamino-2-(4-(ethylsulfonyl)phenyl)-N-(6-(6-methyl-1-pentyl-1H-benzo[d]imidazol-2-yl)pyridin-3-yl)acetamide

    [0284] ##STR00114##

    [0285] A synthesis method was as that in Example 80, and a white solid was obtained with a yield of 63%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.91 (s, 1H), 8.97-8.88 (m, 2H), 8.27 (d, J=8.5 Hz, 1H), 8.18 (d, J=7.7 Hz, 1H), 7.93 (d, J=7.8 Hz, 2H), 7.78 (d, J=7.9 Hz, 2H), 7.55 (d, J=8.0 Hz, 1H), 7.42 (s, 1H), 7.07 (d, J=7.8 Hz, 1H), 5.82 (d, J=7.3 Hz, 1H), 4.81-4.67 (m, 2H), 3.33-3.23 (m, 2H), 2.47 (s, 3H), 1.97 (s, 3H), 1.79-1.67 (m, 2H), 1.31-1.20 (m, 4H), 1.10 (t, J=7.2 Hz, 3H), 0.81 (t, J=6.4 Hz, 3H). MS (ESI), m/z for C.sub.30H.sub.35N.sub.5O.sub.4S ([M+H].sup.+): Calcd 561.70, found 562.7.

    Example 82 2-acetylamino-2-(4-(ethylsulfonyl)phenyl)-N-(6-(6-methyl-1-((R)-1-(p-tolyl) ethyl)-1H-benzo[d]imidazol-2-yl)pyridin-3-yl)acetamide

    [0286] ##STR00115##

    [0287] A synthesis method was as that in Example 80, and a white solid was obtained with a yield of 65%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.96 (s, 1H), 8.95 (d, J=7.7 Hz, 1H), 8.87 (d, J=1.8 Hz, 1H), 8.30-8.21 (m, 2H), 7.92 (d, J=8.4 Hz, 2H), 7.77 (d, J=8.4 Hz, 2H), 7.55 (d, J=8.2 Hz, 1H), 7.26-7.16 (m, 3H), 7.12 (d, J=8.0 Hz, 2H), 6.99 (d, J=8.3 Hz, 1H), 6.92 (s, 1H), 5.83 (d, J=7.7 Hz, 1H), 3.28 (q, J=7.3 Hz, 2H), 2.27 (s, 3H), 2.25 (s, 3H), 1.96 (s, 3H), 1.92 (dd, J=7.1, 1.9 Hz, 3H), 1.09 (t, J=7.3 Hz, 3H). MS (ESI), m/z for C.sub.34H.sub.35N.sub.5O.sub.4S ([M+H].sup.+): Calcd 609.75, found 610.7.

    Example 83 2-(5-(2-acetylamino-2-(4-(ethylsulfonyl)phenyl)acetylamino)pyridin-2-yl)-N-isopropyl-1-((R)-1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-5-formamide

    [0288] ##STR00116##

    [0289] A synthesis method was as that in Example 80, and a white solid was obtained with a yield of 49%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.00 (s, 1H), 8.95 (d, J=7.7 Hz, 1H), 8.92 (d, J=2.1 Hz, 1H), 8.34-8.23 (m, 2H), 8.20 (d, J=0.8 Hz, 1H), 8.12 (d, J=7.7 Hz, 1H), 7.92 (d, J=8.4 Hz, 2H), 7.77 (d, J=8.4 Hz, 2H), 7.55 (dd, J=8.6, 1.4 Hz, 1H), 7.25 (q, J=7.0 Hz, 1H), 7.18 (d, J=8.1 Hz, 2H), 7.15-7.07 (m, 3H), 5.84 (d, J=7.7 Hz, 1H), 4.14-4.03 (m, 1H), 3.33-3.24 (m, 2H), 2.24 (s, 3H), 1.99-1.91 (m, 6H), 1.15 (d, J=6.5 Hz, 6H), 1.09 (t, J=7.3 Hz, 3H). MS (ESI), m/z for C.sub.37H.sub.40N.sub.6O.sub.5S ([M+Na]+): Calcd 680.82, found 703.3.

    Example 84 2-(5-(2-acetylamino-2-(4-(ethylsulfonyl)phenyl)acetylamino)pyridin-2-yl)-N-isopropyl-1-((S)-1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-5-formamide

    [0290] ##STR00117##

    [0291] A synthesis method was as that in Example 80, and a white solid was obtained with a yield of 33%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.00 (s, 1H), 8.95 (d, J=7.7 Hz, 1H), 8.91 (d, J=2.2 Hz, 1H), 8.34-8.24 (m, 2H), 8.20 (s, 1H), 8.12 (d, J=7.9 Hz, 1H), 7.92 (d, J=8.3 Hz, 2H), 7.77 (d, J=8.4 Hz, 2H), 7.55 (dd, J=8.7, 1.2 Hz, 1H), 7.25 (q, J=6.8 Hz, 1H), 7.18 (d, J=8.0 Hz, 2H), 7.10 (m, 3H), 5.84 (d, J=8.0 Hz, 1H), 4.13-4.02 (m, 1H), 3.32-3.25 (m, 2H), 2.24 (s, 3H), 1.98-1.90 (m, 6H), 1.15 (d, J=6.5 Hz, 6H), 1.09 (t, J=7.4 Hz, 3H). MS (ESI), m/z for C.sub.37H.sub.40N.sub.6O.sub.5S ([M−H].sup.−): Calcd 680.82, found 679.5.

    Example 85 N-(4-(1-benzyl-5,6-dimethyl-1H-benzo[d]imidazol-2-yl)phenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide

    [0292] ##STR00118##

    [0293] 1-Chloro-4,5-dimethyl-2-nitrobenzene and benzylamine were used as raw materials. For a synthesis method, reference was made to Example 32. A white solid was obtained with a yield of 43%. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.21 (s, 1H), 7.83-7.70 (m, 2H), 7.60-7.50 (m, 3H), 7.49-7.38 (m, 4H), 7.35-7.24 (m, 3H), 7.10-6.96 (m, 3H), 5.36 (s, 2H), 3.77 (s, 2H), 3.14-2.99 (m, 2H), 2.36 (s, 3H), 2.33 (s, 3H), 1.28-1.18 (m, 3H). MS (ESI), m/z for C.sub.32H.sub.31N.sub.3O.sub.3S ([M+H].sup.+): Calcd 537.68, found 538.6.

    Example 86 N-(4-(1-benzyl-5,6-dichloro-1H-benzo[d]imidazol-2-yl)phenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide

    [0294] ##STR00119##

    [0295] 1,2-Dichloro-4-fluoro-5-nitrobenzene and benzylamine were used as raw materials. For a synthesis method, reference was made to Example 32. A white solid was obtained with a yield of 47%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.52 (s, 1H), 7.99 (s, 1H), 7.91 (s, 1H), 7.85 (d, J=8.2 Hz, 2H), 7.77-7.68 (m, 4H), 7.61 (d, J=8.2 Hz, 2H), 7.32-7.20 (m, 3H), 6.96 (d, J=7.0 Hz, 2H), 5.63 (s, 2H), 3.84 (s, 2H), 3.27 (q, J=7.3 Hz, 2H), 1.10 (t, J=7.3 Hz, 3H). MS (ESI), m/z for C.sub.30H.sub.25C.sub.12N.sub.3O.sub.3S ([M+H].sup.+): Calcd 578.51, found 578.4.

    Example 87 2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1H-benzo[d]imidazol-2-yl) phenyl)acetamide

    [0296] ##STR00120##

    [0297] N-(4-(1-benzyl-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide (100 mg, 0.19 mmol) was dissolved in methanol (20 mL), and Pd—C (100 mg) was added to the mixture. The reaction mixture was stirred overnight at room temperature under hydrogen protection. After the reaction was finished, the reaction mixture was filtered by Celite, concentrated for the solvent to be removed and purified through silica gel column chromatography (PE:EA=4:1, v/v) to obtain a target compound as a white solid (65.9 mg with a yield of 80%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.49 (s, 1H), 8.08 (d, J=8.8 Hz, 2H), 7.86 (d, J=8.3 Hz, 2H), 7.75 (d, J=8.8 Hz, 2H), 7.63 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.2 Hz, 1H), 7.34 (s, 1H), 7.01 (dd, J=8.2, 1.0 Hz, 1H), 3.85 (s, 2H), 3.28 (q, J=7.4 Hz, 2H), 2.42 (s, 3H), 1.10 (t, J=7.4 Hz, 3H). MS (ESI), m/z for C.sub.24H.sub.23N.sub.3O.sub.3S ([M+H].sup.+): Calcd 433.53, found 434.5.

    Test Example 1 In Vitro Intravital Experiment

    [0298] In the present test example, a protein thermal stability shift assay (TSA) technique was used for detecting abilities of the compounds of the present application to bind to and stabilize RORγ proteins.

    [0299] Experimental materials: 2 μL of interest protein hRORγ (final concentration: 10 μM), 2 μL of an SYPRO Orange fluorescent stain, 10 μL of each compound (final concentration: 200 μM), 2 μL of a buffer, 4 μL of deionized water, an HSP-96-well reaction plate, and a positive inhibitor: SR2211.

    [0300] Experimental method: each component was added to the HSP-96-well reaction plate in the above volume, centrifuged at 1000 r/min at room temperature for 1 min and incubated on ice for 30 min. The incubated 96-well reaction plate was placed in a Real-time polymerase chain reaction (PCR) apparatus with a starting temperature of 30° C. and an ending temperature of 80° C. The apparatus was read every five seconds, and the temperature was increased by 0.3° C. per reading. A file was saved, and data was analyzed by GraphPad Prism 7 software.

    [0301] The luciferase detection technique and TSA detection technique were used for verifying the results, respectively. The results of the luciferase detection technique are shown in Table 1, and the results of the TSA detection technique are shown in Table 2.

    TABLE-US-00001 TABLE 1 A Examples 26, 32, 34, 35, 36, 37, 38, 42, 43, 44, 45, 46, 47, 48, 49, 51, 52, 53, 54, 55, 56, 57, 58, 59, 62, 63, 64, 67, 68, 69, 70, 71, 72, 73, 74, 76, 77, 80, 81 and 82 B Examples 25, 29, 33, 39, 40, 41, 60, 65, 66, 75, 85 and 86 C Examples 1, 3, 4, 5, 9, 10, 12, 15, 16, 17, 20, 30, 50, 78, 79, 83, 84 and 87 D Examples 2, 6, 7, 8, 11, 13, 14, 18, 19, 21, 22, 23, 24, 27, 28, 31 and 61 Note: “A” means that IC.sub.50 < 0.1 μM, “B” means that 0.1 μM ≤ IC.sub.50 < 1 μM, “C” means that 1 μM ≤ IC.sub.50 < 10 μM, and “D” means that 10 μM ≤ IC.sub.50 <100 μM.

    TABLE-US-00002 TABLE 2 A Examples 5, 35, 37, 42, 43, 44, 45, 46, 47, 51, 52, 54, 55, 56, 57, 62, 63, 64, 65, 66, 67, 68, 73, 74, 76, 77, 80, 81, 82, 83, 85 and 86 B Examples 25, 29, 30, 31, 32, 33, 34, 36, 38, 39, 40, 41, 48, 49, 50, 53, 58, 59, 60, 69, 70, 71, 72, 78, 79 and 84 C Examples 1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 27, 28, 61, 75 and 87 Note: “A” means that ΔT.sub.m ≤ 5° C., “B” means that 5° C. < ΔT.sub.m < 10° C., and “C” means that ΔT.sub.m ≥ 10° C.

    [0302] The activity data in Tables 1 and 2 indicate that the compounds provided by the present application can better inhibit the transcriptional activity of RORγ and significantly enhance the thermal stability of RORγ protein.

    Test Example 2 Selectivity Test for RORγ and Homologous Proteins Thereof

    [0303] In the present test example, the selectivity of the compounds in Examples 35, 54, 57, 67, 68 and 74 for RORγ and homologous proteins thereof in the luciferase experiment was evaluated.

    [0304] Experimental materials: human renal epithelial cell line 293T cells, a DMEM medium containing 10% fetal bovine serum, a 96-well clear plate, a dual reporter gene detection assay kit, an Opti-MEM Reagent, a Lipo-fectamine 2000 Transfection Reagent, recombinant plasmids: Gal4-RORγLBD (25 ng), RORE_Luc (25 ng), pG5-luc and a luciferase (Renilla), and a positive inhibitor: SR2211.

    [0305] Experimental method: the human renal epithelial cell line 293T cells were cultured in the DMEM containing 10% fetal bovine serum. On the day before transfection, cells were prepared in the 96-well plate with a cell density of 1.5×10.sup.4 cells/well. After 24 hours of adherent growth, transient transfection was performed with the transfection reagent Lipo-fectamine 2000 through a method of dual reporter gene co-transfection. The transfection reagent and the plasmids were separately diluted with the Opti-MEM Reagent. Gal4-RORγLBD (25 ng), pG5-luc genes (25 ng) and Renilla (5 ng) were added to each well, and after 24 hours of co-transfection, compounds having different concentrations were added. After 24 hours of incubation, the luciferase dual reporter gene detection assay kit was used for detecting luminescence signals. Three duplicate wells were set for each sample, and IC.sub.50 values (half maximal inhibitory concentrations) were calculated by software.

    [0306] Experimental results: the activity data of RORγ and the homologous proteins thereof in Examples 35, 54, 57, 67, 68 and 74 of the present application in the luciferase experiment are shown in Table 3.

    TABLE-US-00003 TABLE 3 Gal4-LBD IC.sub.50 (μM) .sup.a Example RORγ RORα RORβ LXRα FXR SR2211 0.24 ± 0.09 >20 >20 >20 >20 Example 35  0.004 ± 0.0003 >20 >20 >20 >20 Example 54 0.011 ± 0.002 >20 >20 >20 >20 Example 57 0.009 ± 0.004 >20 >20 >20 >20 Example 67 0.024 ± 0.003 >20 >20 >20 >20 Example 68 0.064 ± 0.014 >20 >20 >20 >20 Example 74 0.032 ± 0010  >20 >20 >20 >20

    [0307] The experimental results indicate that the compounds provided by the present application have specific selectivity for RORγ and, in particular, the compounds in Examples 35, 54, 57, 67, 68 and 74 exhibit more excellent selectivity for RORγ protein relative to proteins of other nuclear receptors.

    Test Example 3 Test for Inhibitory Effects on Proliferation of Cell Lines of AR-Positive Prostate Cancer

    [0308] In the present test example, inhibitory effects of the compounds in Examples 35, 54, 67, 68 and 74 on proliferation of AR-positive prostate cancer cell lines were evaluated.

    [0309] Experimental materials: a fluorescence signal detection instrument EnSpire Alpha 2390 Multimode Plate Reader (manufactured by PerkinElmer), a 384-well clear-bottom microplate, a Cell-Titer GLO Luminescence Reagent, prostate cancer cell lines LNCaP, C4-2B and 22Rv1, a medium and fetal bovine serum required for cell culture, and positive drugs: Enzalutamide and SR2211.

    [0310] Experimental method: 20 μL of a medium containing 500 to 1000 cells to be detected (the actual number of cells was related to cell cycle and cell volume) was plated into each well of the 384-well clear-bottom microplate. After 12 hours, 10 μL of a culture medium containing the compound (the compound had a concentration of 5-100 nM) was added to each well. After incubation with the compound for 72-96 h, the Cell-Titer GLO Reagent was added to each well, and the plate was shaken for 20 min to lyse the cells. After incubation for 10 min, the cells were centrifuged for 1 min, and luminescence 384 signal values were measured. An inhibition curve was fitted by GraphPad Prism software, and IC.sub.50 was calculated.

    [0311] Experimental results: the antiproliferative activity of the compounds in Examples 35, 54, 67, 68 and 74 against the AR-positive prostate cancer cell lines is shown in Table 4.

    TABLE-US-00004 TABLE 4 Cell Viability IC.sub.50 (μM).sup.a Cmpd LNCaP C4-2B 22Rv1 Enzalutamide 42.37 ± 2.37  23.56 ± 0.61  36.66 ± 4.21 SR2211 6.14 ± 0.04 5.38 ± 0.27 13.34 ± 1.22 Example 35 9.22 ± 0.02 5.76 ± 0.05 14.36 ± 0.46 Example 54 4.82 ± 1.08 4.40 ± 0.18 11.10 ± 0.72 Example 67 8.07 ± 0.66 6.20 ± 0.60  4.62 ± 0.91 Example 68 6.33 ± 0.47 6.82 ± 0.72  8.27 ± 0.75 Example 74 5.20 ± 0.14 4.19 ± 0.34 10.36 ± 1.01

    [0312] As can be seen from the results in Table 4, the compounds provided by the present application may have IC.sub.50 values much lower than the currently marketed drug Enzalutamide and have better inhibitory effects on the proliferation of the prostate cancer cells.

    Test Example 4 Pharmacokinetic Evaluations

    [0313] In the present test example, pharmacokinetic evaluations on Examples 67 and 68 were carried out.

    [0314] Experimental materials: the pharmacokinetic analyses were carried out by Shanghai Medicilon Corporation. Sprague-Dawley (SD) rats were provided by Shanghai Super-B&K Laboratory Animal Corp., Ltd.

    [0315] Experimental method: the compound was dissolved in a solution containing 5% dimethylacetamide (DMA), 10% Solutol and 85% Saline as a stock solution. The stock solution was orally administered to three SD rats at a dose of 25 mg/kg and administered to three SD rats through intravenous injection at a single dose of 5 mg/kg. Blood was collected from jugular veins before the oral administration and 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after the oral administration. Blood was collected from jugular veins before the intravenous injection and 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after the intravenous injection. About 200 μL of the blood samples were collected into heparinized tubes and then immediately centrifuged at 8000 r/min for 6 minutes to obtain blood plasma. The obtained blood plasma was storaged at −80° C. until analysis.

    [0316] Experimental results: the pharmacokinetic data in Examples 67 and 68 are shown in Table 5.

    TABLE-US-00005 TABLE 5 Example 67 Example 68 Parameter iv (5 mg/kg) po (25 mg/kg) iv (5 mg/kg) po (25 mg/kg) Cmax 18428.00 ± 2512.70 ± 14820.70 ± 5730.26 ± (μg/L) 2047.25 564.18 656.68 937.74 T.sub.max (h) 0.08 ± 0.00 4.00 ± 0.00 0.08 ± 0.00 4.00 ± 0.00 AUC.sub.(0-t) 27847.06 ± 16536.55 ± 24734.89 ± 40078.46 ± (μg/L .Math. h) 1739.28 4280.42 1990.06 11231.62 AUC.sub.(0-∞) 28434.14 ± 16778.29 ± 25096.48 ± 41917.70 ± (μg/L .Math. h) 1927.93 4464.78 2142.86 12487.47 T.sub.1/2 (h) 4.72 ± 0.59 3.65 ± 0.58 4.19 ± 0.83 4.98 ± 0.80 Cl 0.18 ± 0.01 — 0.20 ± 0.02 — (L/h/kg) Vz (L/kg) 1.20 ± 0.10 — 1.20 ± 0.20 — F (%) — 11.88 ± 3.07  — 32.41 ± 9.08  Note: “—” represents that the data was not measured.

    [0317] The experimental results indicate that the compounds provided by the present application have good pharmacokinetic properties.

    Test Example 5 In Vivo Pharmacodynamic Study of 22Rv1 Xenograft Mouse Models

    [0318] Experimental purpose: a xenograft mouse experiment was used for verifying inhibitory effects of the compounds of the present application on tumors in vivo.

    [0319] Experimental methods: three-week-old male mice (strain: NOD/MrkBomTac-Prkdc.sup.scid) were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd and used for xenograft tumor establishment. 22Rv1 tumor cells were subcutaneously inoculated on a side of a lower abdomen of each mouse, and each mouse was injected with 3×10.sup.6 cells. The cells were suspended in 100 μL of phosphate-buffered saline (PBS) and Matrigel (at a ratio of 1:1). When the tumor volumes reached about 100 mm.sup.3, the mice were randomly divided into groups (n=6-7 per group) and then administered through oral gavage. The compound in Example 68 was dissolved in an administration vehicle containing 15% polyoxyethylene ether (35) castor oil (Cremophor EL), Calbiochem, 82.5% PBS and 2.5% DMSO and administered five days a week for three continuous weeks. The length (L) and width (W) of the tumor mass were measured by a caliper, and the volume was expressed in mm.sup.3 and calculated according to the following formula: V=π/6×(L×W.sup.2). TGI was calculated according to the following formula: TGI=[1−(T−T.sub.0)/(C−C.sub.0)]×100, where T denoted a mean tumor volume on a specific day of the experiment and T.sub.0 denoted a mean tumor volume at the beginning of the treatment; similarly, C and C.sub.0 denoted a mean tumor volume on a specific day of the experiment and a mean tumor volume of a blank group at the beginning of the treatment, respectively.

    [0320] In Test Example 5, mouse xenograft tumor models were used for the test in the experiment. 22Rv1 prostate cancer cell xenograft mouse models were selected, the compound in Example 68 was orally administered at a dose of 10 mg/kg or 40 mg/kg five days a week for three weeks, and variations of tumor volumes in mice were observed. Data represented mean tumor volume standard deviation (n=6-7 per group) in each treatment group.

    [0321] The results of the inhibitory effects of the compound in Example 68 on the tumors in the 22Rv1 mouse xenograft models are shown in FIGS. 1 and 2. FIG. 1 shows that the compound in Example 68 can significantly inhibit the tumors from growing in the mice at a dose of 10 mg/kg (TGI=83%). The compound at a dose of 40 mg/kg can not only significantly inhibit the tumors from growing in the mice but also sustainably and completely eliminate the tumors for a long time (TGI=109%). In addition, FIG. 2 shows that the mice had no apparent variations in weight and behaved normally in the case where the compound in Example 68 was administered at all doses. These results indicate that the compound in Example 68 has a significant inhibitory effect on the tumor growth in vivo on the 22Rv1 mouse xenograft models without any apparent toxic effect.

    [0322] These compounds effectively bind to and inhibit the transcription of RORγ receptor proteins, thereby inhibiting a downstream signaling pathway and achieving effects such as inhibition of tumor growth and amelioration of inflammation. Example 68 specifically exhibits the inhibitory effect of the compound on the prostate tumor growth in vivo. Available and reported evidences also suggest that this type of compound has a potential to treat diseases such as a cancer, a cell proliferative disorder, an inflammatory disease and an autoimmune disease, sepsis and a viral infection.

    [0323] The applicant has stated that although the benzo five-membered nitrogen heterocyclic compound and the use thereof in the present application are described through the preceding examples, the present application is not limited to the preceding examples, which means that the implementation of the present application does not necessarily depend on the preceding examples. It is to be apparent to those skilled in the art that any improvements made to the present application, equivalent replacements of raw materials of the product of the present application, additions of adjuvant ingredients, selections of specific manners, etc., all fall within the protection scope and the disclosure scope of the present application.