COMPOUNDS FOR INHIBITING TNIK AND MEDICAL USES THEREOF

Abstract

The present disclosure provides the compound having inhibitory property against TNIK having a specific chemical structure or its pharmaceutically acceptable salt. The present disclosure also provides a composition comprising the compound or its pharmaceutically acceptable salt. The present disclosure also provides a medical use of the compound, its salt or the composition comprising the compound or its pharmaceutically acceptable salt for treating or preventing cancer. The present disclosure also provides a method of treatment or prevention of cancer comprising administering the compound, its salt or the composition comprising the compound or its salt to a subject in need of such treatment or prevention.

Claims

1.-17. (canceled)

18. A method for treating or preventing cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Chemical Formula 1: ##STR00393## or a pharmaceutically acceptable salt thereof, in the Chemical Formula 1, Y is CH, Z is C—V, A is —OH, —NHR.sup.2, —NHSO.sub.2R.sup.3, —NHCO.sub.2—C.sub.1-6 alkyl, —NHCON—C.sub.1-6 alkyl, or —NHCOR.sup.4, B is H, —C.sub.1-3 haloalkyl, C.sub.1-3 alkyl, halogen, or C.sub.1-3 alkoxy, V is H, —CH.sub.2OH, F, —OH, or —NHCOCH.sub.3, X is H or F, W is a substituted or unsubstituted phenyl, wherein, R.sup.2 is CF.sub.3, C.sub.1-3 alkyl, —CH.sub.2CH.sub.2-morpholin, or phenyl, R.sup.3 is C.sub.1-3 alkyl, or substituted or unsubstituted phenyl, and R.sup.4 is C.sub.1-3 alkyl, —CF.sub.3, —CH.sub.2CH.sub.2Cl, —CH.sub.2CH.sub.2NMe.sub.2, —CH.sub.2NMe.sub.2, or —CH.sub.2CH.sub.2-morpholin.

19. The method of claim 18, in the Chemical Formula 1, wherein W is ##STR00394## ##STR00395##

20. The method of claim 19, wherein W is: ##STR00396##

21. The method of claim 18, wherein, R.sup.2 is CF.sub.3, or C.sub.1-3 alkyl, R.sup.3 is C.sub.1-3 alkyl, R.sup.4 is C.sub.1-3 alkyl, —CF.sub.3, —CH.sub.2CH.sub.2Cl, —CH.sub.2CH.sub.2NMe.sub.2, —CH.sub.2NMe.sub.2, or —CH.sub.2CH.sub.2-morpholin.

22. The method of claim 18, in the Chemical Formula 1, wherein B is C.sub.1-3 alkyl, or halogen.

23. The method of claim 18, wherein V is H, or F.

24. The method of claim 18, wherein: R.sup.3 is C.sub.1-3 alkyl, and R.sup.4 is C.sub.1-3 alkyl, CF.sub.3, —CH.sub.2CH.sub.2Cl, —CH.sub.2CH.sub.2NMe.sub.2, —CH.sub.2NMe.sub.2, or —CH.sub.2CH.sub.2-morpholin.

25. The method of claim 18, wherein A is —OH, —NHSO.sub.2R.sup.3, —NHCO.sub.2—C.sub.1-6 alkyl, - or —NHCOR.sup.4.

26. The compound of claim 20, wherein A is —OH, —NHSO.sub.2R.sup.3, —NHCO.sub.2—C.sub.1-6 alkyl, - or —NHCOR.sup.4.

27. The method of claim 20, wherein: B is C.sub.1-3 alkyl, or halogen; V is H, or F; R.sup.3 is C.sub.1-3 alkyl, and R.sup.4 is C.sub.1-3 alkyl, CF.sub.3, —CH.sub.2CH.sub.2Cl, —CH.sub.2CH.sub.2NMe.sub.2, —CH.sub.2NMe.sub.2, or —CH.sub.2CH.sub.2-morpholin.

28. The method of claim 27, wherein A is —OH, —NHSO.sub.2R.sup.3, —NHCO.sub.2—C.sub.1-6 alkyl, - or —NHCOR.sup.4.

29. The method of claim 18, wherein the compound is 4-((5-(4-methoxyphenyl)-1H-pyrazol-3-yl)amino)-3-methylphenol, 4-((5-(4-aminophenyl)-1H-pyrazol-3-yl)amino)-3-methylphenol, 4-((5-(4-aminophenyl)-1H-pyrazol-3-yl)amino)-3-methoxyphenol, 4-((5-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-3-methylphenol, 4-((5-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)phenol, 3-fluoro-4-((5-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)phenol, N-(4-((5-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl) methanesulfonamide, N-(4-((5-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)acetamide, 4-((4-fluoro-5-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-3-methylphenol, N-(4-((5-(4-(dimethylamino)phenyl)-1H-pyrazol-3-yl)amino)phenyl)acetamide, 4-(5-(4-(dimethylamino)phenyl)-1H-pyrazol-3-yl)amino)-3-methylphenol, 3-ethyl-4-((5-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)phenol, 4-(3-((4-hydroxy-2-methylphenyl)amino)-1H-pyrazol-5-yl)-2-methylphenol, N-(4-((5-(4-hydroxy-3-methylphenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl) acetamide, 2-fluoro-4-(3-((4-hydroxy-2-methylphenyl)amino)-1H-pyrazol-5-yl)phenol, 4-((5-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-3-(trifluoromethyl)phenol, 2-fluoro-4-((5-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)phenol, N-(4-((5-(4-(1H-imidazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl) methanesulfonamide, N-(4-((5-(4-(1H-imidazol-1-yl)phenyl)-4-fluoro-1H-pyrazol-3-yl)amino)-3-methylphenyl) methanesulfonamide, 4-((5-(4-(1H-imidazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-ethylphenol, 3-chloro-4-((5-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)phenol, 4-((5-(4-(1H-pyrazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-ethylphenol, N-(4-((5-(4-(1H-pyrazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl) acetamide, N-(3-chloro-4-((5-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)phenyl)acetamide, N-(3-chloro-4-((5-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)phenyl) methanesulfonamide, 3-ethyl-4-((5-(4-iodophenyl)-1H-pyrazol-3-yl)amino)phenol, N-(4-((5-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)butyramide, 2,2,2-trifluoro-N-(4-((5-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl) acetamide, 4-(3-((4-amino-2-methylphenyl)amino)-1H-pyrazol-5-yl)phenol, N-(3-ethyl-4-((5-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)phenyl)acetamide, N-(2-fluoro-4-((5-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-5-methylphenyl) methanesulfonamide, ethyl (4-((5-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)carbamate, N-(4-((5-(3-fluoro-4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl) methanesulfonamide, 4-(3-((2-ethyl-4-hydroxyphenyl)amino)-1H-pyrazol-5-yl)-2-fluorophenol, 1-(4-((5-(3-fluoro-4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)-3-methylurea, 2-fluoro-4-(3-((2-fluoro-4-hydroxyphenyl)amino)-1H-pyrazol-5-yl)phenol, N-(4-((5-(4-(1H-imidazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)phenyl)acetamide, N-(4-((5-(4-(1H-imidazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)phenyl) methanesulfonamide, 4-((5-(4-(1H-imidazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-fluorophenol, 4-((5-(4-(1H-imidazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-(trifluoromethyl)phenol, N-(4-((5-(4-(1H-imidazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-chlorophenyl) acetamide, 4-((5-(4-(1H-imidazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-2-fluorophenol, 4-((5-(4-(1H-imidazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-chlorophenol, N-(4-((5-(4-(1H-imidazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-2-fluoro-5-methylphenyl)acetamide, N-(4-((5-(4-(1H-pyrazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)-3-chloropropanamide, N-(4-((5-(4-(1H-pyrazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)-3-morpholinopropanamide, 2-(dimethylamino)-N-(4-((5-(3-fluoro-4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)acetamide, N-(4-((5-(3-fluoro-4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)-3-morpholinopropanamide, 3-(dimethylamino)-N-(4-((5-(3-fluoro-4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)propanamide, N-(4-((5-(4-(1H-pyrazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)methanesulfonamide, 4-((5-(4-(1H-pyrazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-(trifluoromethyl)phenol, 4-((5-(4-(1H-pyrazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-fluorophenol, N-(4-((5-(4-iodophenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)methanesulfonamide, 4-((5-(4-(1H-pyrazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-2-fluorophenol, 4-((5-(4-(1H-pyrazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-chlorophenol, 3-methyl-4-((5-phenyl-1H-pyrazol-3-yl)amino)phenol, N-(3-methyl-4-((5-phenyl-1H-pyrazol-3-yl)amino)phenyl)acetamide, N-(3-methyl-4-((5-phenyl-1H-pyrazol-3-yl)amino)phenyl)methanesulfonamide, N-(4-((5-(4-methoxyphenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl) methanesulfonamide, N-(4-((5-(4-bromophenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl) methanesulfonamide, N-(4-((5-(3-fluoro-4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl) methanesulfonamide, N-(3-methyl-4-((5-(4-morpholinophenyl)-1H-pyrazol-3-yl)amino)phenyl)acetamide, 3-methyl-4-((5-(4-morpholinophenyl)-1H-pyrazol-3-yl)amino)phenol, N-(3-methyl-4-((5-(4-morpholinophenyl)-1H-pyrazol-3-yl)amino)phenyl) methanesulfonamide, N-(4-((5-(4-fluorophenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl) methanesulfonamide, 1-(4-((5-(4-(1H-pyrazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)-3-methylurea, methyl (4-((5-(4-(1H-pyrazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl) carbamate, ethyl (4-((5-(4-(1H-pyrazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl) carbamate, N-(3-methyl-4-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)-1H-pyrazol-3-yl)amino)phenyl) acetamide, N-(3-methyl-4-((5-(4-(2-oxopiperidin-1-yl)phenyl)-1H-pyrazol-3-yl)amino)phenyl) acetamide, 1-(4-(3-((4-hydroxy-2-methylphenyl)amino)-1H-pyrazol-5-yl)phenyl)azetidin-2-one, N-(3-chloro-4-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)-1H-pyrazol-3-yl)amino)phenyl) acetamide, 4-(5-(4-(dimethylamino)phenyl)-4-fluoro-1H-pyrazol-3-yl)amino)-3-methylphenol, 1-(4-((5-(benzo[b]thiophen-2-yl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)-3-methylurea, N-(4-((5-(4-(1H-pyrazol-1-yl)phenyl)-4-fluoro-1H-pyrazol-3-yl)amino)-3-methylphenyl) methanesulfonamide, N-(3-chloro-4-((5-(4-methoxyphenyl)-1H-pyrazol-3-yl)amino)phenyl)acetamide, 4-((5-(3-(1H-pyrazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-methylphenol, N-(4-((5-(3-(1H-pyrazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl) methanesulfonamide, N-(4-((5-(4-(1H-pyrazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl) isobutyramide, 1-(4-(4-fluoro-3-((4-hydroxy-2-methylphenyl)amino)-1H-pyrazol-5-yl)phenyl) pyrrolidin-2-one, N-(4-((5-(4-(1H-pyrazol-1-yl)phenyl)-4-fluoro-1H-pyrazol-3-yl)amino)-3-methylphenyl) acetamide, methyl (4-((5-(4-(1H-pyrazol-1-yl)phenyl)-4-fluoro-1H-pyrazol-3-yl)amino)-3-methylphenyl) carbamate, ethyl (4-((5-(4-(1H-pyrazol-1-yl)phenyl)-4-fluoro-1H-pyrazol-3-yl)amino)-3-methylphenyl) carbamate, 4-((4-fluoro-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)amino)-3-methylphenol, 1-(4-((5-(4-(1H-pyrazol-1-yl)phenyl)-4-fluoro-1H-pyrazol-3-yl)amino)-3-methylphenyl)-3-methylurea, 3-ethyl-4-((4-fluoro-5-(4-iodophenyl)-1H-pyrazol-3-yl)amino)phenol, 3-methyl-4-((5-(3-(pyridin-3-yl)phenyl)-1H-pyrazol-3-yl)amino)phenol, 3-methyl-4-((5-(4-(pyridin-3-yl)phenyl)-1H-pyrazol-3-yl)amino)phenol, 4-((5-(4-(4-fluoro-1H-pyrazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-methylphenol, N-(4-((5-(4-(4-fluoro-1H-pyrazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl) methanesulfonamide, 3-ethyl-4-((5-(3-iodophenyl)-1H-pyrazol-3-yl)amino)phenol, 4-((5-(2′-fluoro-5′-methoxy-[1,1′-biphenyl]-3-yl)-1H-pyrazol-3-yl)amino)-3-methylphenol, 4-((5-(4-(1H-pyrazol-4-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-methylphenol, 3-methyl-4-((5-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)-1H-pyrazol-3-yl)amino)phenol, 4-((5-(2-fluoro-5′-methoxy-[1,1′-biphenyl]-4-yl)-1H-pyrazol-3-yl)amino)-3-methylphenol, 4-((5-(4-(1H-pyrazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-2-fluoro-5-methylphenol, 2-fluoro-4-((5-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-5-methylphenol, 3-methyl-4-((5-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1H-pyrazol-3-yl)amino)phenol, 4-((5-(4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-methylphenol, 3-methyl-4-((5-(4-(3-(trifluoromethyl)-1H-pyrazol-4-yl)phenyl)-1H-pyrazol-3-yl)amino)phenol, 4-((5-(4-(1H-pyrazol-4-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-ethylphenol, 1-(4-((5-(4-(1H-pyrazol-4-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)-3-methylurea, methyl (4-((5-(4-(1H-pyrazol-4-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl) carbamate, 4-((5-(4-(1H-pyrazol-4-yl)phenyl)-1H-pyrazol-3-yl)amino)-2-fluoro-5-methylphenol, 1-(4-((5-(2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-yl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)-3-methylurea, methyl (4-((5-(2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-yl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)carbamate, (4-((5-(4-methoxyphenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)carbamate, 4-((5-(4-(1H-pyrazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-2,5-difluorophenol, 1-methyl-3-(3-methyl-4-((5-(4-(methylsulfonyl)phenyl)-1H-pyrazol-3-yl)amino) phenyl)urea, methyl (3-methyl-4-((5-(4-(methylsulfonyl)phenyl)-1H-pyrazol-3-yl)amino)phenyl) carbamate, 1-methyl-3-(3-methyl-4-((5-(4-(3-(trifluoromethyl)-1H-pyrazol-4-yl)phenyl)-1H-pyrazol-3-yl)amino)phenyl)urea, methyl (3-methyl-4-((5-(4-(3-(trifluoromethyl)-1H-pyrazol-4-yl)phenyl)-1H-pyrazol-3-yl)amino)phenyl)carbamate, 1-(4-((5-(4-bromophenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)-3-methylurea, methyl (4-((5-(4-bromophenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)carbamate, methyl (3-methyl-4-((5-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1H-pyrazol-3-yl)amino)phenyl)carbamate, 3-methyl-4-((5-(4-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)amino)phenol, methyl (3-methyl-4-((5-(4-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)amino)phenyl) carbamate, methyl (4-((5-(3-fluoro-4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl) carbamate, methyl (4-((5-(4-chlorophenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)carbamate, or methyl (4-((5-(4-aminophenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)carbamate.

30. The method of claim 18, wherein the compound is 3-ethyl-4-((5-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)phenol 4-((5-(4-(dimethylamino)phenyl)-1H-pyrazol-3-yl)amino)-3-methylphenol N-(4-((5-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)methanesulfonamide N-(4-((5-(4-(1H-imidazol-1-yl)phenyl)-4-fluoro-1H-pyrazol-3-yl)amino)-3-methylphenyl)methanesulfonamide 4-((5-(4-(1H-pyrazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-ethylphenol, N-(3-ethyl-4-((5-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)phenyl)acetamide, 2-fluoro-4-((5-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-5-methylphenol, 1-(4-((5-(4-methoxyphenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)-3-methylurea, (4-((5-(4-methoxyphenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)carbamate, 1-(4-((5-(4-bromophenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)-3-methylurea, methyl (4-((5-(4-aminophenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)carbamate, N-(4-((5-(4-(1H-pyrazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl) acetamide, N-(4-((5-(4-(1H-pyrazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl) methanesulfonamide, 1-(4-((5-(4-(1H-pyrazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)-3-methylurea, methyl (4-((5-(4-(1H-pyrazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl) carbamate, or ethyl (4-((5-(4-(1H-pyrazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl) carbamate.

31. The method of claim 18, wherein the compound is: N-(4-((5-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)methanesulfonamide, 3-ethyl-4-((5-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)phenol, N-(4-((5-(4-(1H-imidazol-1-yl)phenyl)-4-fluoro-1H-pyrazol-3-yl)amino)-3-methylphenyl)methanesulfonamide, or 4-((5-(4-(1H-pyrazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-ethylphenol.

32. The method of claim 18, further comprising administering to a subject in need thereof a therapeutically effective amount of irinotecan or its pharmaceutically acceptable salt.

33. The method of claim 18, wherein the cancer is colorectal cancer, breast cancer, brain tumor, gastric cancer, liver cancer, ovarian cancer, lung cancer, gastrointestinal cancer, leukemia, or melanoma.

34. The method of claim 19, further comprising administering to a subject in need thereof a therapeutically effective amount of irinotecan or its pharmaceutically acceptable salt.

35. The method of claim 19, wherein the cancer is colorectal cancer, breast cancer, brain tumor, gastric cancer, liver cancer, ovarian cancer, lung cancer, gastrointestinal cancer, leukemia, or melanoma.

36. The method of claim 29, further comprising administering to a subject in need thereof a therapeutically effective amount of irinotecan or its pharmaceutically acceptable salt.

37. The method of claim 29, wherein the cancer is colorectal cancer, breast cancer, brain tumor, gastric cancer, liver cancer, ovarian cancer, lung cancer, gastrointestinal cancer, leukemia, or melanoma.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0206] FIGS. 1, 2 and 3 are graphs showing the results of the mouse xenograft test performed with the compounds according to some examples of the present disclosure.

MODE FOR THE INVENTION

[0207] Hereinafter, the present disclosure is described in considerable detail with examples to help those skilled in the art understand the present disclosure. However, the following examples are offered by way of illustration and are not intended to limit the scope of the invention. It is apparent that various changes may be made without departing from the spirit and scope of the invention or sacrificing all of its material advantages.

[0208] Preparation of Compounds of the Present Disclosure

[0209] Reagents and solvents used below were purchased from Aldrich Chemical Co. (Milwaukee, Wis. USA). .sup.1H-NMR spectra were evaluated with Bruker Avance 300 MHz, Bruker Avance III HD 300 MHz, Bruker Avance 500 MHz NMR spectrometer and so on.

[0210] Below, the illustrating synthetic examples of some compounds of the present disclosure are described, and other compounds can be prepared by the similar method to one described below with different starting or reacting materials.

Synthesis Example 1: Preparation of Compound 2

Step 1. 1-(4-chlorophenyl)-3,3-bis(methylthio)prop-2-en-1-one

[0211] ##STR00307##

[0212] 4-chloroacetophenone (5.4 mL, 66.6 mmol) and benzene (220 mL) were mixed at ambient temperature in a 500 mL round flask. After cooled using an ice bath. NaH (5.32 g, 133.0 mmol, 2.0 eq.) was added slowly and stirred for 5 minutes. Carbon disulfide (6.0 mL, 99.9 mmol, 1.5 eq.) was added slowly and stirred at ambient temperature for 5 minutes, and then iodomethane (12.4 mL, 199.8 mmol, 3.0 eq.) was added slowly and stirred at ambient temperature for 5 minutes. After that, N, N-dimethylacetamide (13 mL, 139.9 mmol, 2.1 eq.) was added slowly and stirred at ambient temperature for 3 hours. After the reaction ended, H.sub.2O was added for quenching, and the reactant was extracted with EtOAc. The organic solvent layer wad dried over MgSO.sub.4 and concentrated in vacuo. After that, it was filtered with Et.sub.2O to provide the compound as a yellow solid (8.1 g) (yield: 47%).

Step 2. (Z)-3-((4-(benzyloxy)phenyl)amino)-1-(4-chlorophenyl)-3-(methylthio)prop-2-en-1-on

[0213] ##STR00308##

[0214] 1-(4-chlorophenyl)-3,3-bis(methylthio)prop-2-en-1-one (1.94 g, 7.5 mmol) prepared in Step 1 and toluene (40 mL) were stirred in a 100 mL round flask. Then BF.sub.3.OEt.sub.2 (200 μL, 1.5 mmol, 0.2 eq.) was added, and 4-benzyloxyaniline (2.65 g, 11.25 mmol, 1.5 eq.) was added. After that, the reaction mixture was reacted under reflux for 24 hours. After the reaction ended, the solvent was removed with a rotavapor and the remaining reactant was filtered with MeOH to provide the compound as a yellow solid (1.83 g) (yield: 60%).

Step 3. N-(4-(benzyloxy)phenyl)-5-(4-chlorophenyl)-1H-pyrazol-3-amine

[0215] ##STR00309##

[0216] (Z)-3-((4-(benzyloxy)phenyl)amino)-1-(4-chlorophenyl)-3-(methylthio)prop-2-en-1-one (410 mg, 1.0 mmol) prepared in Step 2, t-BuOH (7 mL) and AcOH (75 μL) were mixed in a 50 mL round flask. Then Hydrazine hydrate (75 μL, 1.5 mmol, 1.5 eq.) was added and reacted under reflux for 3 hours. After the reaction ended, the solvent was removed with a rotavapor and the reaction was filtered with MeOH to provide the compound as a yellow solid (336 mg) (yield: 89%).

Step 4. 4-((5-(4-chlorophenyl)-1H-pyrazol-3-yl)amino)phenol

[0217] ##STR00310##

[0218] N-(4-(benzyloxy)phenyl)-5-(4-chlorophenyl)-1H-pyrazol-3-amine (94 mg, 0.25 mmol) prepared in Step 3 and dichloromethane (10 mL) were stirred at −78° C. for 15 minutes in a 50 mL round flask, BBr.sub.3 (1M in DCM) (1.2 mL) was added slowly and stirred at ambient temperature for 30 minutes. After the reaction ended, it was cooled using an ice bath and MeOH was added for quenching. The solvent was removed with a rotavapor. The reactant was extracted with H.sub.2O (50 ml) and EtOAc (50 mL×3), and the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. After that, silica gel column chromatography (EtOAc:Hex) was performed to provide the compound as a white solid (50 mg) (yield: 70%).

[0219] .sup.1H-NMR (300 MHz, DMSO-d6) δ 12.31 (s, 1H), 8.67 (s, 1H), 7.97 (s, 1H), 7.73 (d, 2H, J=9.0 Hz), 7.47 (d, 2H, J=6.0 Hz), 7.12 (s, 1H), 6.62 (d, 2H, J=6.0 Hz), 6.17 (s, 1H).

Synthesis Example 2: Preparation of 4-((5-(4-chlorophenyl)-1H-pyrazol-3-yl)amino)-3-isopropoxyphenol (Compound 28)

Step 1. 3-isopropoxy-4-nitrophenol

[0220] ##STR00311##

[0221] THF (30 mL) and NaH (1.2 g, 30.0 mmol, 3.0 eq.) were stirred in a 100 mL round flask. i-PrOH (2.3 mL, 30.0 mmol, 3.0 eq.) was added and then stirred at ambient temperature for 10 minutes. After that, 3-fluoro-4-nitrophenol (1.57 g, 10.0 mmol) was added and reacted under reflux for 12 hours. After the reaction ended, it was cooed at ambient temperature and H.sub.2O was added for quenching. The reactant was extracted with 1N HCl (50 ml) and EtOAc (50 mL×3), and the organic solvent layer was dried MgSO.sub.4 and concentrated in vacuo. After that, silica gel column chromatography (EtOAc:Hex) was performed to provide the compound as a dark brown solid (1.87 g) (yield: 95%).

Step 2. 4-amino-3-isopropoxyphenol

[0222] ##STR00312##

[0223] 3-isopropoxy-4-nitrophenol (1.87 g, 9.48 mmol) prepared in Step 1 and EtOAc/THF (10/10 mL) were stirred at ambient temperature in a 100 mL round flask. Pd/C (370 mg, 20 wt %) was added and stirred at ambient temperature for 24 hours. After the reaction ended, the solvent was removed with a celite filter, and silica gel column chromatography (EtOAc:Hex) was performed to provide the compound (836 mg) (yield: 53%).

Step 3. 4-((5-(4-chlorophenyl)-1H-pyrazol-3-yl)amino)-3-isopropoxyphenol

[0224] ##STR00313##

[0225] 1-(4-chlorophenyl)-3,3-bis(methylthio)prop-2-en-1-one (259 mg, 1.0 mmol) prepared in Step 1 for preparation of Compound 2 and Toluene (10 mL) were stirred in a vial for microwave reaction. BF.sub.3.OEt.sub.2 (25 μL, 0.2 mmol, 0.2 eq.) and 4-amino-3-isopropoxyphenol (251 mg, 1.5 mmol, 1.5 eq.) prepared in Step 2 were added and reacted at 120° C. for 24 hours. After the reaction ended, the solvent was removed with a rotavapor, and extracted with H.sub.2O (50 ml) and EtOAc (50 mL×3). And, the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. t-BuOH (10 mL), AcOH (75 μL) and Hydrazine hydrate (75 μL, 1.5 mmol, 1.5 eq.) were added and reacted under reflux for 24 hours. After the reaction ended, the solvent was removed with a rotavapor, and extracted with H.sub.2O (50 ml) and EtOAc (50 mL×3). Then, the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. After that, silica gel column chromatography (EtOAc:Hex) was performed to provide the compound as a dark brown solid (2 steps, 96 mg) (yield: 28%).

[0226] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.37 (s, 1H), 8.80 (s, 1H), 7.73 (d, J=8.1 Hz, 2H), 7.47 (d, J=8.0 Hz, 2H), 6.77 (s, 1H), 6.43 (d, J=2.7 Hz, 1H), 6.35-6.23 (m, 2H), 4.51 (p, J=6.0 Hz, 1H), 1.30 (d, J=6.0 Hz, 6H).

Synthesis Example 3: Preparation of 3-ethyl-4-((5-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)phenol (Compound 81)

Step 1. 3-ethyl-4-nitrophenol

[0227] ##STR00314##

[0228] EtOH/conc.HCl (45 mL/45 mL) and 3-ethylphenol (74 mmol, 11 mL) were added in a 250 mL RBF. The mixture was stirred in an ice bath for 30 minutes. NaNO.sub.2 (1.5 eq, 7.8 g) then was added slowly and stirred to provide a solid. The reactant was stirred for 30 minutes and then water (100 mL) was added to end the reaction. The produced solid was filtered to provide 3-ethyl-4-nitrophenol (10.38 g) as a brown solid (yield: 84%).

Step 2. 4-amino-3-ethylphenol

[0229] ##STR00315##

[0230] 3-ethyl-4-nitrophenol (62 mmol, 10.4 g) was dissolved in EA/MeOH (90/10 mL) and Pd/C (1.0 g) was added. The mixture was reacted with a hedrogenator for 4 hours. After the reaction ended, Pd/C was removed using a cellite filter and the solvent was removed under reduced pressure. The solid was filtered with EA to provide 4-amino-3-ethylphenol (7.99 g) (yield: 94%).

Step 3. (Z)-1-(4-(benzyloxy)phenyl)-3-((2-ethyl-4-hydroxyphenyl)amino)-3-(methylthio)prop-2-en-1-one

[0231] ##STR00316##

[0232] 1-(4-(benzyloxy)phenyl)-3,3-bis(methylthio)prop-2-en-1-one (496 mg, 1.5 mmol) and toluene (15 mL) were stirred in a 100 mL round flask. BF.sub.3.OEt.sub.2 (37 μL, 0.3 mmol, 0.2 eq.) was added and then 4-amino-3-ethylphenol 3-aminophenol (308 mg, 2.25 mmol, 1.5 eq.) prepared in in Step 2 was added. The mixture was reacted under reflux for 24 hours. After the reaction ended, the solvent was removed with a rotavapor, and the reactant was extracted with H.sub.2O (50 ml) and EtOAc (50 mL×3). The organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. After that, silica gel column chromatography (EtOAc:Hex) was performed to provide the compound (298 mg) (yield: 47%).

Step 4. 4-((5-(4-(benzyloxy)phenyl)-1H-pyrazol-3-yl)amino)-3-ethylphenol

[0233] ##STR00317##

[0234] (Z)-1-(4-(benzyloxy)phenyl)-3-((2-ethyl-4-hydroxyphenyl)amino)-3-(methylthio)prop-2-en-1-one (250 mg, 0.6 mmol), t-BuOH (8 mL), and AcOH (46 μL) were stirred in a 50 ml round flask. Hydrazine hydrate (46 μL, 0.75 mmol, 1.5 eq.) was added and reacted under reflux for 24 hours. After the reaction ended, the solvent was removed with a rotavapor and the reactant was filtered with MeOH to provide the compound (227 mg) (yield: 99%).

Step 5. 3-ethyl-4-((5-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)phenol

[0235] ##STR00318##

[0236] 4-((5-(4-(benzyloxy)phenyl)-1H-pyrazol-3-yl)amino)-3-ethylphenol (300 mg, 0.78 mmol) prepared in Step 4 and DCM (8 mL) were stirred at −78° C. for 15 minutes in a 50 mL round flask. BBr.sub.3 (1M in DCM) (3.9 mL) was added slowly and the mixture was stirred at ambient temperature for 3 hours. After the reaction ended, the reactant was cooled using an ice bath and MeOH was used for quenching, and the solvent was removed with a rotavapor. The reactant was extracted with H.sub.2O (50 ml) and EtOAc (50 mL×3), and the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. After that, silica gel column chromatography (EtOAc:Hex) was performed to provide the compound (44 mg) (yield: 20%).

[0237] .sup.1H NMR (500 MHz, DMSO) δ 12.01-11.82 (m, 1H), 9.57 (s, 1H), 8.78 (s, 1H), 7.48 (d, J=8.6 Hz, 2H), 7.25 (s, 1H), 6.89 (s, 1H), 6.78 (d, J=8.6 Hz, 2H), 6.58 (d, J=2.7 Hz, 1H), 6.51 (dd, J=8.6, 2.8 Hz, 1H), 5.87 (s, 1H), 2.56 (q, J=7.5 Hz, 2H), 1.13 (t, J=7.5 Hz, 3H).

Synthesis Example 4: Preparation of N1-(5-(4-chlorophenyl)-1H-pyrazol-3-yl)-N4-phenylbenzene-1,4-diamine (Compound 30)

Step 1. tert-butyl (4-nitrophenyl)(phenyl)carbamate

[0238] ##STR00319##

[0239] 4-nitrodiphenylamine (1.07 g, 5.0 mmol) and DCM (30 mL) were stirred in a 100 mL round flask. Et.sub.3N (1.4 mL, 10.0 mmol, 2.0 eq.) and (Boc).sub.2O (1.64 g, 7.5 mmol, 1.5 eq.) were added and the mixture was reacted under reflux for 24 hours. After the reaction ended, the solvent was removed with a rotavapor, and extracted with H.sub.2O (50 ml) and DCM (50 mL×3). The organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. Next step was performed without purification.

Step 2. tert-butyl (4-aminophenyl)(phenyl)carbamate

[0240] ##STR00320##

[0241] Tert-butyl (4-nitrophenyl)(phenyl)carbamate of tert-butyl (4-nitrophenyl)(phenyl)carbamate (2.53 g, 8.0 mmol) prepared in Step 1 and THF (60 mL) were stirred in a 500 mL round flask. MeOH (6 mL) and H.sub.2O (90 mL) were added, and then NaS.sub.2O.sub.4 (12.54 g, 72.0 mmol, 9.0 eq.) and NaHCO.sub.3 (6.05 g, 72.0 mmol, 9.0 eq.) were added slowly, and the mixture was stirred for 5 minutes. After the reaction ended, the reactant was extracted several times with EtOAc and the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. After that, silica gel column chromatography (EtOAc:Hex) was performed to provide the compound (2 steps, 597 mg) (yield: 42%).

Step 3. N1-(5-(4-chlorophenyl)-1H-pyrazol-3-yl)-N4-phenylbenzene-1,4-diamine

[0242] ##STR00321##

[0243] 1-(4-chlorophenyl)-3,3-bis(methylthio)prop-2-en-1-one (259 mg, 1.0 mmol) and Toluene (10 mL) were stirred in a vial for microwave reaction. BF.sub.3.OEt.sub.2 (25 μL, 0.2 mmol, 0.2 eq.) and tert-butyl (4-aminophenyl)(phenyl)carbamate (426 mg, 1.5 mmol, 1.5 eq.) prepared in Step 2 were added and reacted at 120° C. for 24 hours. After the reaction ended, the solvent was removed with a rotavapor, and the reactant was extracted with H.sub.2O (50 ml) and EtOAc (50 mL×3). The organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. t-BuOH (10 mL), AcOH (75 μL) and Hydrazine hydrate (75 μL, 1.5 mmol, 1.5 eq.) were added and reacted under reflux for 24 hours. After the reaction ended, the solvent was removed with a rotavapor. The reactant was extracted with H.sub.2O (50 ml) and EtOAc (50 mL×3), and the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. After that, silica gel column chromatography (EtOAc:Hex) was performed to provide the compound (2 steps, 154 mg) (yield: 43%).

[0244] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.43 (s, 1H), 8.28 (s, 1H), 7.80-7.67 (m, 3H), 7.51 (s, 2H), 7.29 (s, 1H), 7.13 (t, J=7.6 Hz, 2H), 6.99 (d, J=8.2 Hz, 2H), 6.88 (d, J=8.0 Hz, 2H), 6.66 (t, J=7.3 Hz, 1H), 6.26 (s, 1H).

Synthesis Example 5: Preparation of 4-fluoro-N-(4-((5-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)phenyl)benzenesulfonamide (Compound 52)

Step 1. 4-fluoro-N-(4-nitrophenyl)benzenesulfonamide

[0245] ##STR00322##

[0246] 4-nitroaniline (1.41 g, 10.0 mmol) and DCM (30 mL) were stirred in a 100 mL round flask. Pyridine (2.4 mL, 30.0 mmol, 3.0 eq.) was added and cooled with an ice bath, 4-fluorobenzenesulfonyl chloride (1.98 g, 10.0 mmol, 1.0 eq.) was added slowly and the mixture was stirred at ambient temperature for 24 hours. After the reaction ended, the solvent was removed with a rotavapor. The reactant was extracted with H.sub.2O (50 ml) and EtOAc (50 mL×3), and the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. The produced solid was filtered with Ether to provide the compound (2.9 g) (yield: 98%).

Step 2. N-(4-aminophenyl)-4-fluorobenzenesulfonamide

[0247] ##STR00323##

[0248] 4-fluoro-N-(4-nitrophenyl)benzenesulfonamide (2.9 g, 9.8 mmol) prepared in Step 1 and EtOAc/MeOH (30/30 mL) were stirred at ambient temperature in a 250 mL round flask. Pd/C (580 mg, 20 wt %) was added and stirred at ambient temperature for 24 hours. After the reaction ended, Pd/C was removed with a celite filter and the solvent was removed with a rotavapor. After that, silica gel column chromatography (EtOAc:Hex) was performed to provide the compound (2.09 g) (yield: 80%).

Step 3. N-(4-((5-(4-(benzyloxy)phenyl)-1H-pyrazol-3-yl)amino)phenyl)-4-fluorobenzenesulfonamide

[0249] ##STR00324##

[0250] 1-(4-(benzyloxy)phenyl)-3,3-bis(methylthio)prop-2-en-1-one (496 mg, 1.5 mmol) and Toluene (15 mL) were stirred in a vial for microwave reaction. BF.sub.3.OEt.sub.2 (37 μL, 0.3 mmol, 0.2 eq.) and N-(4-aminophenyl)-4-fluorobenzenesulfonamide (599 mg, 2.25 mmol, 1.5 eq.) prepared in Step 2 were added and reacted at 120° C. for 24 hours. After the reaction ended, the solvent was removed with a rotavapor H.sub.2O (50 ml) and the reactant was extracted with EtOAc (50 mL×3). Then the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. t-BuOH (30 mL), AcOH (113 μL) and Hydrazine hydrate (113 μL, 2.25 mmol, 1.5 eq.) were added and reacted under reflux for 24 hours. After the reaction ended, the solvent was removed with a rotavapor, and the reactant was extracted with H.sub.2O (50 ml) and EtOAc (50 mL×3). Then the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. After that, silica gel column chromatography (EtOAc:Hex) was performed to provide the compound (2 steps, 476 mg) (yield: 62%).

Step 4. 4-fluoro-N-(4-((5-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)phenyl)benzenesulfonamide

[0251] ##STR00325##

[0252] N-(4-((5-(4-(benzyloxy)phenyl)-1H-pyrazol-3-yl)amino)phenyl)-4-fluorobenzenesulfonamide (257 mg, 0.5 mmol) prepared in Step 3 and EtOAc/MeOH (8/8 mL) were stirred at ambient temperature in a round flask. Pd/C (51 mg, 20 wt %) was added and stirred at ambient temperature for 24 hours. After the reaction ended, Pd/C was removed with a celite filter and the solvent was removed with a rotavapor. After that, silica gel column chromatography (EtOAc:Hex) was performed to provide the compound (168 mg) (yield: 79%).

[0253] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.17 (s, 1H), 9.66 (s, 2H), 8.37 (s, 1H), 7.76 7.65 (m, 2H), 7.51 (d, J=8.3 Hz, 2H), 7.37 (t, J=8.7 Hz, 2H), 7.19 (d, J=8.4 Hz, 2H), 6.89-6.75 (m, 4H), 6.02 (s, 1H).

Synthesis Example 6: Preparation of N-(4-((5-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)methanesulfonamide (Compound 58)

Step 1. N-(3-methyl-4-nitrophenyl)methanesulfonamide

[0254] ##STR00326##

[0255] 3-methyl-4-nitroaniline (1.57 g, 10.0 mmol) and DCM (30 mL) were stirred in a 100 mL round flask. Pyridine (2.4 mL, 30.0 mmol, 3.0 eq.) was added and the mixture was cooled using an ice bath. Then methanesulfonyl chloride (774 μL, 10.0 mmol, 1.0 eq.) was added slowly and stirred at ambient temperature for 24 hours. After the reaction ended, the solvent was removed with a rotavapor and the reactant was extracted with H.sub.2O (50 ml) and EtOAc (50 mL×3). Then the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. The produced solid was filtered with ether to provide the compound (1.98 g) (yield: 86%).

Step 2. N-(4-amino-3-methylphenyl)methanesulfonamide

[0256] ##STR00327##

[0257] N-(3-methyl-4-nitrophenyl)methanesulfonamide (1.98 g, 8.6 mmol) prepared in Step 1 and EtOAc/MeOH (40/40 mL) were stirred at ambient temperature in a 250 mL round flask. Pd/C (400 mg, 20 wt %) was added and stirred at ambient temperature for 24 hours. After the reaction ended. Pd/C was removed with a celite filter, and the solvent was removed with a rotavapor. After that, silica gel column chromatography (EtOAc:Hex) was performed to provide the compound (1.36 g) (yield: 79%).

Step 3. N-(4-((5-(4-(benzyloxy)phenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)methanesulfonamide

[0258] ##STR00328##

[0259] 1-(4-(benzyloxy)phenyl)-3,3-bis(methylthio)prop-2-en-1-one (496 mg, 1.5 mmol) and Toluene (15 mL) were stirred in a MV vial. BF.sub.3.OEt.sub.2 (37 μL, 0.3 mmol, 0.2 eq.) and N-(4-amino-3-methylphenyl)methanesulfonamide (451 mg, 2.25 mmol, 1.5 eq.) prepared in Step 2 were added and reacted at 120° C. for 24 hours. After the reaction ended, the solvent was removed with a rotavapor and the reactant was extracted with H.sub.2O (50 ml) and EtOAc (50 mL×3). Then the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. t-BuOH (30 mL), AcOH (113 μL) and Hydrazine hydrate (113 μL, 2.25 mmol, 1.5 eq.) were added and reacted under reflux for 24 hours. After the reaction ended, the solvent was removed with a rotavapor. The reactant was extracted with H.sub.2O (50 ml) and EtOAc (50 mL×3), and then the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. After that, silica gel column chromatography (EtOAc:Hex) was performed to provide the compound (2 steps, 543 mg) (yield: 81%).

Step 4. N-(4-((5-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)methanesulfonamide

[0260] ##STR00329##

[0261] N-(4-((5-(4-(benzyloxy)phenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)methanesulfonamide (224 mg, 1.0 mmol) prepared in Step 3 and EtOAc/MeOH/THF (10/10/10 mL) were stirred at ambient temperature in a round flask. Pd/C (90 mg, 20 wt %) was added and stirred at ambient temperature for 48 hours. After the reaction ended, Pd/C was removed with a celite filter and the solvent was removed with a rotavapor. After that, silica gel column chromatography (EtOAc:Hex) was performed to provide the compound (24 mg) (yield: 13%).

[0262] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.21 (s, 1H), 9.63 (s, 1H), 9.17 (s, 1H), 7.68 (s, 1H), 7.51 (d, J=8.5 Hz, 2H), 7.29 (s, 1H), 6.94 (d, J=8.9 Hz, 2H), 6.81 (d, J=8.5 Hz, 2H), 6.15 (s, 1H), 2.86 (s, 3H), 2.22 (s, 3H).

Synthesis Example 7: Preparation of N-(4-((5-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)acetamide (Compound 59)

Step 1. N-(3-methyl-4-nitrophenyl)acetamide

[0263] ##STR00330##

[0264] 3-methyl-4-nitroaniline (3.14 g, 20.0 mmol) and pyridine (20 mL) were stirred in a 100 mL round flask. The mixture was cooled in an ice bath, and acetic anhydride (1.9 mL, 20.0 mmol, 2.0 eq.) was added slowly and stirred at ambient temperature for 24 hours. After the reaction ended, the reactant was extracted with H.sub.2O (50 ml) and EtOAc (50 mL×3), and then the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. Next step was performed without purification.

Step 2. N-(4-amino-3-methylphenyl)acetamide

[0265] ##STR00331##

[0266] N-(3-methyl-4-nitrophenyl)acetamide (4.78 g, 24.6 mmol) and EtOAc/MeOH (100/100 mL) were stirred at ambient temperature in a round flask. Pd/C (1.9 g, 40 wt %) was added and stirred at ambient temperature for 24 hours. After the reaction ended, Pd/C was removed with a celite filter and the solvent was removed with a rotavapor. After that, silica gel column chromatography (EtOAc:Hex) was performed to provide the compound (2 steps, 1.85 g) (yield: 56%).

Step 3. N-(4-((5-(4-(benzyloxy)phenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)acetamide

[0267] ##STR00332##

[0268] 1-(4-(benzyloxy)phenyl)-3,3-bis(methylthio)prop-2-en-1-one (496 mg, 1.5 mmol) and toluene (15 mL) were stirred in a MW vial. BF.sub.3.OEt.sub.2 (37 μL, 0.3 mmol, 0.2 eq.) and N-(4-amino-3-methylphenyl)acetamide (451 mg, 2.25 mmol, 1.5 eq.) were added and reacted at 120° C. for 24 hours. After the reaction ended, the solvent was removed with a rotavapor. Then the reactant was extracted with H.sub.2O (50 ml) and EtOAc (50 mL×3), and the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. t-BuOH (30 mL), AcOH (113 VL) and Hydrazine hydrate (113 μL, 2.25 mmol, 1.5 eq.) were added and reacted under reflux for 24 hours. After the reaction ended, the solvent was removed with a rotavapor. The reactant was extracted with H.sub.2O (50 ml) and EtOAc (50 mL×3), and the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. Next step was performed without purification.

Step 4. N-(4-((5-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)acetamide

[0269] ##STR00333##

[0270] N-(4-((5-(4-(benzyloxy)phenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)acetamide (610 mg, 1.48 mmol) prepared in Step 3 and EtOAc/MeOH (10/10 mL) were stirred at ambient temperature in a round flask. Pd/C (120 mg, 20 wt %) was added and stirred at ambient temperature for 48 hours. After the reaction ended, Pd/C was removed with a celite filter and the solvent was removed with a rotavapor. After that, silica gel column chromatography (EtOAc:Hex) was performed to provide the compound (3 steps, 24 mg) (yield: 34%).

[0271] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.14 (s, 1H), 9.62 (s, 1H), 7.51 (d, J=8.2 Hz, 2H), 7.30 (s, 1H), 7.27-7.15 (m, 2H), 6.80 (d, J=8.2 Hz, 2H), 6.10 (s, 1H), 2.20 (s, 3H), 1.98 (s, 3H).

Synthesis Example 8: Preparation of 2,2,2-trifluoro-N-(4-((5-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)acetamide (Compound 151)

Step 1. 2,2,2-trifluoro-N-(3-methyl-4-nitrophenyl)acetamide

[0272] ##STR00334##

[0273] 3-methyl-4-nitroaniline (1.0 g, 6.6 mmol) and DCM (55 mL) were stirred at −78° C. in a 100 mL round flask. Tridluoroacetic anhydride (1.4 mL, 9.9 mmol, 1.5 eq.) was added slowly and then trimethylamine (3.4 mL, 18.48 mmol, 2.8 eq.) was added and stirred for 3 hours. After the reaction ended, the reactant was cooled in an ice bath, and 1N HCl was added and extracted with DCM several times. Then the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. After that, silica gel column chromatography (EtOAc:Hex) was performed to provide the compound (1.5 g) (yield: 92%).

Step 2. N-(4-amino-3-methylphenyl)-2,2,2-trifluoroacetamide

[0274] ##STR00335##

[0275] 2,2,2-trifluoro-N-(3-methyl-4-nitrophenyl)acetamide (1.5 g, 6.0 mmol) prepared in Step 1 and EtOAc/MeOH (20/15 mL) were stirred at ambient temperature in a round flask. Pd/C (300 mg, 20 wt %) was added and stirred at ambient temperature for 24 hours. After the reaction ended, Pd/C was removed with a celite filter and the solvent was removed with a rotavapor. After that, silica gel column chromatography (EtOAc:Hex) was performed to provide the compound (1.19 g) (yield: 91%).

Step 3. (Z)—N-(4-((3-(4-(benzyloxy)phenyl)-1-(methylthio)-3-oxoprop-1-en-1-yl)amino)-3-methylphenyl)-2,2,2-trifluoroacetamide

[0276] ##STR00336##

[0277] 1-(4-(benzyloxy)phenyl)-3,3-bis(methylthio)prop-2-en-1-one (350 mg, 1.06 mmol) and THF (4 mL) were stirred in a round flask. BF.sub.3.OEt.sub.2 (26 μL, 0.22 mmol, 0.2 eq.) was added and ino-3-methylphenyl)-2,2,2-trifluoroacetamide (347 mg, 1.59 mmol, 1.5 eq.) prepared in Step 2 was added and reacted under reflux for 24 hours. After the reaction ended, the solvent was removed with a rotavapor. The reactant was extracted with H.sub.2O (50 ml) and EtOAc (50 mL×3), and then the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. After that, silica gel column chromatography (EtOAc:Hex) was performed to provide the compound (228 mg) (yield: 43%).

Step 4. N-(4-((5-(4-(benzyloxy)phenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)-2,2,2-trifluoro acetamide

[0278] ##STR00337##

[0279] (Z)—N-(4-((3-(4-(benzyloxy)phenyl)-1-(methylthio)-3-oxoprop-1-en-1-yl)amino)-3-methylphenyl)-2,2,2-trifluoroacetamide (220 mg, 0.45 mmol) prepared in Step 3,t-BuOH (2 mL) and AcOH (33 μL) were stirred in a round flask. Hydrazine hydrate (33 μL, 0.68 mmol, 1.5 eq.) was added and reacted under reflux for 20 hours. After the reaction ended, the solvent was removed with a rotavapor. The reactant was filtered with MeOH to provide the compound (152 mg) (yield: 73%).

Step 5. 2,2,2-trifluoro-N-(4-((5-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)acetamide

[0280] ##STR00338##

[0281] N-(4-((5-(4-(benzyloxy)phenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)-2,2,2-trifluoroacetamide (150 mg, 0.32 mmol) prepared in Step 4 and EtOAc/MeOH (3/3 mL) were stirred at ambient temperature in a round flask. Pd/C (30 mg, 20 wt %) was added and stirred at ambient temperature for 24 hours. After the reaction ended, the solvent was removed with a celite filter. After that, silica gel column chromatography (EtOAc:Hex ) was performed to provide the compound (yield: 49%).

[0282] .sup.1H NMR (300 MHz, DMSO) δ 12.24 (s, 1H), 10.94 (s, 1H), 9.63 (s, 1H), 7.71 (s, 1H), 7.52 (d, J=8.2 Hz, 2H), 7.37-7.31 (m, 3H), 6.81 (d, J=8.1 Hz, 2H), 6.18 (s, 1H), 2.24 (s, 3H).

Synthesis Example 9: Preparation of 1-(4-((5-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)-3-methylurea (Compound 159)

Step 1. 1-(4-amino-3-methylphenyl)-3-methylurea

[0283] ##STR00339##

[0284] Triphosgene (5.94 g, 20.0 mmol, 1.0 eq.) and THF were stirred at 0° C. in a 250 mL round flask. 3-methyl-4-nitroaniline (3.14 g, 20.0 mmol) in THF was added slowly and stirred at ambient temperature for 1 hour. The reactant was cooled in an ice bath, and methylamine (40% in MeOH, 1.5 mL, 1.0 eq.) was added slowly and stirred at ambient temperature for 24 hours. After the reaction ended, the reactant was extracted with H.sub.2O (50 ml) and EtOAc (50 mL×3), and the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. EtOAc/MeOH (100/100 mL) was added and then Pd/C (1.7 g, 20 wt %) was added, and the mixture was stirred at ambient temperature for 24 hours. After the reaction ended, Pd/C was removed with a celite filter and the solvent was removed with a rotavapor. After that, silica gel column chromatography (EtOAc:Hex ) was performed to provide the compound (2.11 g) (yield: 59%).

Step 2. 1-(4-((5-(4-((tert-butyldimethylsilyl)oxy)phenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)-3-methylurea

[0285] ##STR00340##

[0286] 1-(4-((tert-butyldimethylsilyl)oxy)phenyl)-3,3-bis(methylthio)prop-2-en-1-one (709 mg, 2.0 mmol) and Toluene (15 mL) were stirred in a MW vial. BF.sub.3.OEt.sub.2 (49 μL, 0.3 mmol, 0.2 eq.) and 1-(4-amino-3-methylphenyl)-3-methylurea (538 mg, 3.0 mmol, 1.5 eq.) prepared in Step 1 were added and reacted at 120° C. for 24 hours. After the reaction ended, the solvent was removed with a rotavapor. The reactant was extracted with H.sub.2O (50 ml) and EtOAc (50 mL×3), and the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. t-BuOH (10 mL), AcOH (113 μL) and Hydrazine hydrate (150 μL, 3.0 mmol, 1.5 eq.) were added and reacted under reflux for 24 hours. After the reaction ended, the solvent was removed with a rotavapor. Then reactant was extracted with H.sub.2O (50 ml) and EtOAc (50 mL×3), and the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. After that, silica gel column chromatography (EtOAc:Hex) was performed to provide the compound (2 steps, 775 mg) (yield: 86%).

Step 3. 1-(4-((5-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)-3-methylurea

[0287] ##STR00341##

[0288] The Compound (774 mg, 1.71 mmol, 1.0 eq.) of Step 2 and THF were stirred at 0° C. in a 50 mL round flask. TBAF (2.24 g, 8.55 mmol) was added slowly and stirred at ambient temperature for 5 minutes. After the reaction ended, the reactant was extracted with H.sub.2O (50 ml) and EtOAc (50 mL×3), and then the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. After that, silica gel column chromatography (EtOAc:Hex) was performed to provide the compound (69 mg) (yield: 10%).

[0289] .sup.1H NMR (300 MHz, Chloroform-d) δ 7.85 (d, J=7.9 Hz, 2H), 7.35 (s, 1H), 7.23 (s, 1H), 7.12 (d, J=8.4 Hz, 1H), 6.88 (d, J=7.9 Hz, 2H), 6.76 (s, 1H), 6.13 (s, 1H), 3.78 (s, 3H), 2.21 (s, 3H).

Synthesis Example 10: Preparation of 4-(3-((2-methyl-4-((2-morpholinoethyl)amino)phenyl)amino)-1H-pyrazol-5-yl)phenol (Compound 164)

Step 1. 3-methyl-N1-(2-morpholinoethyl)benzene-1,4-diamine

[0290] ##STR00342##

[0291] 5-fluoro-2-nitrotoluene (1.2 mL, 10.0 mmol) and THF were stirred in a 100 mL round flask. Trimethylamine (2.8 mL, 20.0 mmol, 2.0 eq.) and 4-(2-aminoethyl)morpholine (3.9 mL, 30.0 mmol, 3.0 eq.) were added and reacted under reflux for 48 hours. After the reaction ended, the solvent was removed with a rotavapor. The reactant was extracted with H.sub.2O (50 ml) and DCM (50 mL×3), and then the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. The produced compound (3.9 g) and EtOAc/MeOH/THF (50/70/70 mL) were added in a 250 mL round flask and then Pd/C (800 mg, 20 wt %) was added and stirred at ambient temperature for 24 hours. After the reaction ended, Pd/C was removed with a celite filter and the solvent was removed with a rotavapor. After that, silica gel column chromatography (EtOAc:Hex) was performed to provide the compound (2.14 g) (yield: 91%).

Step 2. N1-(5-(4-(benzyloxy)phenyl)-1H-pyrazol-3-yl)-2-methyl-N4-(2-morpholinoethyl)benzene-1,4-diamine

[0292] ##STR00343##

[0293] 1-(4-(benzyloxy)phenyl)-3,3-bis(methylthio)prop-2-en-1-one (660 mg, 2.0 mmol) and Toluene (10 mL) were stirred in a MW vial. BF.sub.3.OEt.sub.2 (49 μL, 0.3 mmol, 0.2 eq.) and the aniline (706 mg, 3.0 mmol, 1.5 eq.) prepared in Step 1 were added and reacted at 120° C. for 24 hours. After the reaction ended, the solvent was removed with a rotavapor. The reactant was extracted with H.sub.2O (50 ml) and EtOAc (50 mL×3), and then the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. t-BuOH (10 mL), AcOH (150 μL) and Hydrazine hydrate (150 μL, 3.0 mmol, 1.5 eq.) were added and reacted under reflux for 24 hours. After the reaction ended, the solvent was removed with a rotavapor. The reactant was extracted with H.sub.2O (50 ml) and EtOAc (50 mL×3), and then the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. After that, silica gel column chromatography (EtOAc:Hex) was performed to provide the compound (2 steps, 460 mg) (yield: 48%).

Step 3. 4-(3-((2-methyl-4-((2-morpholinoethyl)amino)phenyl)amino)-1H-pyrazol-5-yl)phenol

[0294] ##STR00344##

[0295] N1-(5-(4-(benzyloxy)phenyl)-1H-pyrazol-3-yl)-2-methyl-N4-(2-morpholinoethyl)benzene-1,4-diamine (450 mg, 0.93 mmol) prepared in Step 2 and EtOAc/MeOH/THF (5/10/10 mL) were stirred at ambient temperature in a round flask. Pd/C (90 mg, 20 wt %) was added and stirred at ambient temperature for 24 hours. After the reaction ended. Pd/C was removed with a celite filter and the solvent was removed with a rotavapor. After that, silica gel column chromatography (EtOAc:Hex) was performed to provide the compound (140 mg) (yield: 68%).

[0296] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 11.87 (s, 1H), 9.57 (s, 1H), 7.47 (d, J=8.6 Hz, 2H), 7.19 (d, J=8.5 Hz, 1H), 6.80 (d, J=3.1 Hz, 2H), 6.76 (s, 11H), 6.44 (d, J=2.4 Hz, 1H), 6.38 (dd, J=8.6, 2.6 Hz, 1H), 5.82 (s, 1H), 4.85 (s, 1H), 3.67-3.52 (m, 4H), 3.08 (t, J=6.8 Hz, 2H), 2.47 (s, 2H), 2.45-2.36 (m, 4H), 2.14 (s, 3H).

Synthesis Example 11: Preparation of 1-(4-(4-((5-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)piperazin-1-yl)ethan-1-one (Compound 166)

Step 1. 1-(4-(4-amino-3-methylphenyl)piperazin-1-yl)ethan-1-one

[0297] ##STR00345##

[0298] 5-fluoro-2-nitrotoluene (1.2 mL, 10.0 mmol) and THF (20 mL) were stirred in a 100 mL round flask. Et.sub.3N (2.8 mL, 20.0 mmol, 2.0 eq.) and 1-acetylpiperazine (3.7 mL, 30.0 mmol, 3.0 eq.) were added and reacted under reflux for 48 hours. After the reaction ended, the reactant was cooled at ambient temperature, and then the solvent was removed with a rotavapor. The reactant was extracted with H.sub.2O (50 ml) and EtOAc (50 mL×3), and then the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. EtOAc/MeOH/THF (50/50/50 mL) was added to the produced compound and the mixture was stirred at ambient temperature. Pd/C (600 mg, 20 wt %) was added and stirred at ambient temperature for 48 hours. After the reaction ended, Pd/C was removed with a celite filter and the solvent was removed with a rotavapor. After that, silica gel column chromatography (EtOAc:Hex) was performed to provide the compound (1.99 g) (yield: 85%).

Step 2. 1-(4-(4-((5-(4-(benzyloxy)phenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)piperazin-1-yl)ethan-1-one

[0299] ##STR00346##

[0300] 1-(4-(benzyloxy)phenyl)-3,3-bis(methylthio)prop-2-en-1-one (660 mg, 2.0 mmol) and Toluene (10 mL) were stirred in a MW vial. BF.sub.3.OEt.sub.2 (49 μL, 0.3 mmol, 0.2 eq.) and 1-(4-(4-amino-3-methylphenyl)piperazin-1-yl)ethan-1-one (700 mg, 3.0 mmol, 1.5 eq.) prepared in Step 1 were added and reacted at 120° C. for 24 hours. After the reaction ended, the solvent was removed with a rotavapor. The reactant was extracted with H.sub.2O (50 ml) and EtOAc (50 mL×3), and then the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. EtOH (10 mL) and Hydrazine hydrate (150 μL, 3.0 mmol, 1.5 eq.) were added and reacted under reflux for 24 hours. After the reaction ended, the solvent was removed with a rotavapor. The reactant was extracted with H.sub.2O (50 ml) and EtOAc (50 mL×3), and then the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. After that, silica gel column chromatography (EtOAc:Hex) was performed to provide the compound (2 steps, 277 mg) (yield: 29%).

Step 3. 1-(4-(4-((5-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)piperazin-1-yl)ethan-1-one

[0301] ##STR00347##

[0302] 1-(4-(4-((5-(4-(benzyloxy)phenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)piperazin-1-yl)ethan-1-one (270 mg, 0.56 mmol) prepared in Step 2 and EtOAc/MeOH/THF (5/10/10 mL) were stirred at ambient temperature in a round flask. Pd/C (60 mg, 20 wt %) was added and stirred at ambient temperature for 24 hours. After the reaction ended, Pd/C was removed with a celite filter and the solvent was removed with a rotavapor. After that, silica gel column chromatography (EtOAc:Hex) was performed to provide the compound (153 mg) (yield: 70%).

[0303] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.06 (s, 1H), 9.65 (s, 1H), 7.49 (d, J=8.7 Hz, 2H), 7.04 (s, 1H), 6.79 (d, J=8.9 Hz, 3H), 6.70 (dd, J=8.7, 2.8 Hz, 1H), 6.01 (s, 1H), 3.56 (q, J=4.3 Hz, 4H), 2.97 (dt, J=19.4, 5.1 Hz, 4H), 2.20 (s, 3H), 2.03 (s, 3H).

Synthesis Example 12: Preparation of 4-(3-((2-methyl-4-(piperazin-1-yl)phenyl)amino)-1H-pyrazol-5-yl)phenol (Compound 169)

Step 1. 5-(4-(benzyloxy)phenyl)-N-(2-methyl-4-(piperazin-1-yl)phenyl)-1H-pyrazol-3-amine

[0304] ##STR00348##

[0305] 1-(4-(benzyloxy)phenyl)-3,3-bis(methylthio)prop-2-en-1-one (660 mg, 2.0 mmol) and Toluene (10 mL) were stirred in a MW vial. BF.sub.3.OEt.sub.2 (49 μL, 0.3 mmol, 0.2 eq.) and 1-(4-(4-amino-3-methylphenyl)piperazin-1-yl)ethan-1-one (700 mg, 3.0 mmol, 1.5 eq.) prepared in Step 1 of Compound 166 synthesis were added and reacted at 120° C. for 24 hours. After the reaction ended, the solvent was removed with a rotavapor. The reactant was extracted with H.sub.2O (50 ml) and EtOAc (50 mL×3), and then the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. t-BuOH (10 mL), AcOH (150 μL) and Hydrazine hydrate (150 μL, 3.0 mmol, 1.5 eq.) were added and reacted under reflux for 24 hours. After the reaction ended, the solvent was removed with a rotavapor. The reactant was extracted with H.sub.2O (50 ml) and EtOAc (50 mL×3), and then the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. After that, silica gel column chromatography (EtOAc:Hex) was performed to provide the compound (2 steps, 377 mg) (yield: 43%).

Step 2. 4-(3-((2-methyl-4-(piperazin-1-yl)phenyl)amino)-1H-pyrazol-5-yl)phenol

[0306] ##STR00349##

[0307] 5-(4-(benzyloxy)phenyl)-N-(2-methyl-4-(piperazin-1-yl)phenyl)-1H-pyrazol-3-amine (241 mg, 0.55 mmol) prepared in Step 1 and EtOAc/MeOH/THF (10/10/10 mL) were stirred at ambient temperature in a round flask. Pd/C (50 mg, 20 wt %) was added and stirred at ambient temperature for 24 hours. After the reaction ended, Pd/C was removed with a celite filter and the solvent was removed with a rotavapor. After that, silica gel column chromatography (EtOAc:Hex) was performed to provide the compound (92 mg) (yield: 48%).

[0308] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.08 (s, 1H), 9.63 (s, 1H), 8.82 (s, 2H), 7.49 (d, J=8.6 Hz, 2H), 7.09 (s, 1H), 6.80 (d, J=8.6 Hz, 3H), 6.73 (dd, J=8.8, 2.9 Hz, 1H), 6.03 (s, 1H), 3.33 (s, 4H), 3.17 (d, J=4.2 Hz, 4H), 2.21 (s, 3H).

Synthesis Example 13: Preparation of N1-(5-(4-nitrophenyl)-1H-pyrazol-3-yl)benzene-1,4-diamine (Compound 21)

Step 1. 3,3-bis(methylthio)-1-(4-nitrophenyl)prop-2-en-1-one

[0309] ##STR00350##

[0310] 4-nitroacetophenone (2.4 g, 14.5 mmol) and benzene (73 mL) were stirred at ambient temperature in a round flask. The mixture was cooled in an ice bath, and then NaH (1.16 g, 29.0 mmol, 2.0 eq.) was added slowly and stirred at ambient temperature for 5 minutes. Carbon disulfide (1.3 mL, 21.8 mmol, 1.5 eq.) was added slowly and stirred at ambient temperature for 5 minutes. Iodomethane (2.7 mL, 43.5 mmol, 3.0 eq.) was then added slowly and stirred at ambient temperature for 5 minutes. N, N-dimethylacetamide (2.8 mL, 30.5 mmol, 2.1 eq.) was added slowly and stirred at ambient temperature for 3 hours. After the reaction ended, H.sub.2O was added for quenching, and the reactant was extracted with EtOAc and then the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. Then the reactant was filtered with Et.sub.2O to provide the compound (2.2 g) (yield: 56%).

Step 2. (Z)-3-((4-aminophenyl)amino)-3-(methylthio)-1-(4-nitrophenyl)prop-2-en-1-one

[0311] ##STR00351##

[0312] 3,3-bis(methylthio)-1-(4-nitrophenyl)prop-2-en-1-one (269 mg, 1.0 mmol) prepared in Step 1 and toluene (4 mL) were stirred in a round flask. BF.sub.3.OEt.sub.2 (25 μL, 0.2 mmol, 0.2 eq.) was added and 1,4-phenylenediamine (162 mg, 1.5 mmol, 1.5 eq.) was added, and then reacted under reflux for 24 hours. After the reaction ended, the solvent was removed with a rotavapor. The reactant was extracted with MeOH to provide the compound (290 mg) (yield: 88%).

Step 3. N1-(5-(4-nitrophenyl)-1H-pyrazol-3-yl)benzene-1,4-diamine

[0313] ##STR00352##

[0314] (Z)-3-((4-aminophenyl)amino)-3-(methylthio)-1-(4-nitrophenyl)prop-2-en-1-one (290 mg, 0.88 mmol) prepared in Step 2, t-BuOH (10 mL) and AcOH (45 μL) were stirred in a round flask. Hydrazine hydrate (45 μL, 1.3 mmol, 1.5 eq.) was added and reacted under reflux for 20 hours. After the reaction ended, the solvent was removed with a rotavapor. The reactant was extracted with MeOH to provide the compound (250 mg) (yield: 85%).

[0315] .sup.1H-NMR (300 MHz, DMSO-d6) δ 12.58 (s, 1H), 8.23-8.21 (m, 2H), 7.97-7.64 (m, 2H) 7.83 (s, 11H), 7.02 (s, 1H), 6.50-6.47 (m, 2H), 6.27 (s, 1H)

Synthesis Example 14: Preparation of N1-(5-(4-aminophenyl)-1H-pyrazol-3-yl)benzene-1,4-diamine (Compound 22)

[0316] ##STR00353##

[0317] N1-(5-(4-nitrophenyl)-1H-pyrazol-3-yl)benzene-1,4-diamine (207 mg, 0.7 mmol) and THF/MeOH (5/5 mL) were stirred at ambient temperature in a 50 mL round flask. Pd/C (20 mg, 10 wt %) was added and stirred at ambient temperature for 24 hours. After the reaction ended, Pd/C was removed with a celite pad and the solvent was removed with a rotavapor. After that, silica gel column chromatography (DCM:MeOH) was performed to provide the compound (120 mg) (yield: 65%).

[0318] .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 7.33 (d, 2H, J=8.3 Hz), 7.03 (d, 2H, J=8.2 Hz), 6.72-6.65 (m, 4H), 6.02 (s, 1H).

Synthesis Example 15: Preparation of 4-((5-(4-aminophenyl)-1H-pyrazol-3-yl)amino)-3-methoxyphenol (Compound 34)

Step 1. 3-methoxy-4-nitrophenol

[0319] ##STR00354##

[0320] MeOH (10 mL) and Na (368 mg, 2.0 eq.) were stirred in a 100 mL round flask. 3-fluoro-4-nitrophenol (1.26 g, 8.0 mmol) was added and reacted under reflux for 12 hours. After the reaction ended, the reactant was cooled at ambient temperature, and then the solvent was removed with a rotavapor. The reactant was extracted with 1N HC (50 ml) and DCM (50 mL×3), and then the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo to provide the compound (1.23 g) (yield: 91%).

Step 2. 4-amino-3-methoxyphenol

[0321] ##STR00355##

[0322] 3-methoxy-4-nitrophenol (1.23 g, 7.2 mmol) prepared in Step 1 and EtOAc/THF (10/10 mL) were stirred at ambient temperature in a 100 mL round flask. Pd/C (240 mg, 20 wt %) was added and stirred at ambient temperature for 24 hours. After the reaction ended, the solvent was removed with a celite filter. After that, silica gel column chromatography (EtOAc:Hex) was performed to provide the compound (410 mg) (yield: 41%).

Step 3. 3-methoxy-4-((5-(4-nitrophenyl)-1H-pyrazol-3-yl)amino)phenol

[0323] ##STR00356##

[0324] 3,3-bis(methylthio)-1-(4-nitrophenyl)prop-2-en-1-one (404 mg, 1.5 mmol) and Toluene (15 mL) were stirred in a MW vial. BF.sub.3.OEt.sub.2 (38 μL, 0.3 mmol, 0.2 eq.) and 4-amino-3-methoxyphenol (313 mg, 2.25 mmol, 1.5 eq.) prepared in Step 2 were added and reacted at 120° C. for 24 hours. After the reaction ended, the solvent was removed with a rotavapor. The reactant was extracted with H.sub.2O (50 ml) and EtOAc (50 mL×3), and then the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. t-BuOH (10 mL), AcOH (113 μL) and Hydrazine hydrate (113 μL, 2.25 mmol, 1.5 eq.) were added and reacted under reflux for 24 hours. After the reaction ended, the solvent was removed with a rotavapor. The reactant was extracted with H.sub.2O (50 ml) and EtOAc (50 mL×3), and then the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. After that, silica gel column chromatography (EtOAc:Hex) was performed to provide the compound (2 steps, 51 mg) (yield: 10%).

Step 4. 4-((5-(4-aminophenyl)-1H-pyrazol-3-yl)amino)-3-methoxyphenol

[0325] ##STR00357##

[0326] 3-methoxy-4-((5-(4-nitrophenyl)-1H-pyrazol-3-yl)amino)phenol (50 mg, 0.15 mmol) prepared in Step 3 and MeOH/EtOAc (3/3 mL) were stirred at ambient temperature in a round flask. Pd/C (10 mg, 20 wt %) was added and stirred at ambient temperature for 24 hours. After the reaction ended, the solvent was removed with a celite filter. After that, silica gel column chromatography (EtOAc:Hex) was performed to provide the compound (13 mg) (yield: 30%).

[0327] .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.40 (d, J=8.2 Hz, 2H), 7.26 (d, J=8.5 Hz, 1H), 6.73 (d, J=8.2 Hz, 2H), 6.47 (d, J=2.6 Hz, 1H), 6.35 (dd. J=8.5, 2.6 Hz, 1H), 6.05 (s, 1H), 3.84 (s, 3H).

Synthesis Example 16: Preparation of 4-((5-(4-aminophenyl)-1H-pyrazol-3-yl)amino)-3-methylphenol (Compound 24)

[0328] ##STR00358##

[0329] 3-methyl-4-((5-(4-nitrophenyl)-1H-pyrazol-3-yl)amino)phenol (88 mg, 0.28 mmol) and MeOH/THF/EtOAc (2/2/2 mL) were stirred at ambient temperature in a round flask. Pd/C (9 mg, 10 wt %) was added and stirred at ambient temperature for 24 hours. After the reaction ended, the solvent was removed with a celite filter. After that, silica gel column chromatography (EtOAc:Hex) was performed to provide the compound as a brown solid (15 mg) (yield: 20%).

[0330] .sup.1H-NMR (300 MHz, CD.sub.3OD) δ 7.37 (d, 2H, J=8.5 Hz), 7.10 (d, 1H, J=8.5 Hz), 6.71 (d, 2H, J=8.5 Hz), 6.64-6.63 (m, 1H), 6.57 (dd, 1H, J=8.6, 2.8 Hz), 5.81 (s, 1H), 2.20 (s, 3H).

Synthesis Example 17: Preparation of 4-fluoro-N-(4-(3-((4-hydroxy-2-methylphenyl)amino)-1H-pyrazol-5-yl)phenyl)benzenesulfonamide (Compound 256)

[0331] ##STR00359##

[0332] Compound 24 (112 mg, 0.4 mmol) and DCM (3 mL) were stirred in a 100 mL round flask. Pyridine (97 μL, 1.2 mmol, 3.0 eq.) was added and the mixture was cooled in an ice bath. After that, 4-fluorobenzenesulfonyl chloride (79 mg, 0.4 mmol, 1.0 eq.) was added slowly and stirred at ambient temperature for 24 hours. After the reaction ended, the solvent was removed with a rotavapor. The reactant was extracted with H.sub.2O (50 ml) and DCM (50 mL×3), and then the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. After that, silica gel column chromatography (EtOAc:Hex) was performed to provide the compound as a brown solid (80 mg) (yield: 46%).

[0333] .sup.1H NMR (300 MHz, Chloroform-d) δ 8.08 (dd, J=8.6, 5.0 Hz, 2H), 7.75 (dd, J=8.7, 5.1 Hz, 2H), 7.59 (d, J=8.4 Hz, 2H), 7.21 (t, J=8.5 Hz, 2H), 7.12-7.00 (m, 4H), 6.75 (s, 1H), 6.72-6.62 (m, 2H), 5.48 (s, 1H), 4.98 (s, 1H), 2.21 (s, 3H).

Synthesis Example 18: Preparation of 4-((4-fluoro-5-(4-nitrophenyl)-1H-pyrazol-3-yl)amino)-3-methylphenol (Compound 71)

[0334] ##STR00360##

[0335] (Z)-3-((4-hydroxy-2-methylphenyl)amino)-3-(methylthio)-1-(4-nitrophenyl)prop-2-en-1-one (344 mg, 1.0 mmol) and CH.sub.3CN (7 mL) were stirred in a 25 mL round flask. The mixture was cooled in an ice bath, and Selectfluor (373 mg, 1.0 mmol, 1.0 eq.) was slowly added and stirred for 30 minutes at 0° C. After the reaction ended, H.sub.2O (50 ml) was added and extracted with DCM (50 mL×3). After that, the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. i-PrOH (5 mL) and Hydrazine hydrate (50 μL, 1.0 mmol, 1.0 eq.) were added and stirred at 80° C. for 2 hours. After the reaction ended, the reactant was cooled at ambient temperature and the solvent was removed with a rotavapor. After that, the reactant was filtered with MeOH to provide the compound (2 steps, 158 mg) (yield: 48%).

[0336] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.81 (s, 1H), 8.35 (d, J=8.5 Hz, 2H), 7.97 (d, J=8.5 Hz, 2H), 7.04 (s, 1H), 6.73 (s, 1H), 6.56 (s, 1H), 6.47 (d, J=8.6 Hz, 1H), 2.16 (s, 3H).

Synthesis Example 19: Preparation of 4-((5-(4-aminophenyl)-4-fluoro-1H-pyrazol-3-yl)amino)-3-methylphenol (Compound 56)

[0337] ##STR00361##

[0338] Compound 71 (150 mg, 0.46 mmol) and EtOAc/MeOH/THF (5/5/5 mL) were stirred at ambient temperature in a round flask. Pd/C (30 mg, 20 wt %) was added and stirred at ambient temperature for 24 hours. After the reaction ended, the solvent was removed with a celite filter. After that, silica gel column chromatography (EtOAc:Hex) was performed to provide the compound (58 mg) (yield: 42%).

[0339] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.01 (s, 1H), 8.69 (s, 1H), 7.35 (d, J=9.1 Hz, 2H), 6.86 (s, 1H), 6.68 (s, 1H), 6.63 (d, J=8.2 Hz, 2H), 6.53 (s, 1H), 6.44 (d, J=8.2 Hz, 1H), 5.36 (s, 2H), 2.16 (s, 3H).

Synthesis Example 20: Preparation of N-(3-(3-((4-hydroxy-2-methylphenyl)amino)-1H-pyrazol-5-yl)phenyl)acetamide (Compound 84)

Step 1. tert-butyl acetyl(3-acetylphenyl)carbamate

[0340] ##STR00362##

[0341] N-(3-acetylphenyl)acetamide (10 mmol, 1.77 g), (Boc).sub.2O (1.5 eq, 3.2 g) and ACN (35 mL) were added in a 100 ml Round-bottom flask. Triethyl amine (2.0 eq, 2.8 mL) and DMAP (0.2 eq. 24 mg) were added to the mixture and stirred at 78° C. for 3 days. After the reaction ended, the solvent was removed under reduced pressure. The reactant was then extracted with H.sub.2O/EA three times, and the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. After that, silica gel column chromatography was performed to provide the compound, tert-butyl acetyl(3-acetylphenyl)carbamate (1.63 g) (yield: 59%).

Step 2. tert-butyl acetyl(3-(3,3-bis(methylthio)acryloyl)phenyl)carbamate

[0342] ##STR00363##

[0343] Tert-butyl acetyl(3-acetylphenyl)carbamate (1.5 g, 5.4 mmol), benzene (18 mL), and NaH (432 mg, 2.0 eq) were added in a 100 mL RBF at 0° C. and stirred at ambient temperature. After 5 minutes, carbon disulfide (0.67 mL, 1.5 eq) was added and stirred at ambient temperature. After 5 minutes, iodomethane (1.03 mL, 3.0 eq) was added and stirred at ambient temperature. After 5 minutes, N,N-dimethylacetamide (1.05 mL, 2.1 eq) was added and stirred at ambient temperature for 3 hours. After the reaction ended, H.sub.2O (60 mL) was added for quenching, and the reactant was extracted with EtOAc (100 mL×3) and dried over MgSO.sub.4 and concentrated in vacuo. The solvent was removed and silica gel column chromatography was performed to provide tert-butyl acetyl(3-(3,3-bis(methylthio)acryloyl)phenyl)carbamate (255 mg) (yield: 12%).

Step 3. N-(3-(3-((4-hydroxy-2-methylphenyl)amino)-1H-pyrazol-5-yl)phenyl)acetamide

[0344] ##STR00364##

[0345] S.M. (0.65 mmol) and aniline derivative (1.5 eq) were dissolved in toluene (7 mL) in a 20 mL vial. Boron trifluoride diethyl etherate (0.2 eq) was added to the solution. The sealed vial was stirred at 120° C. for 6 hours. After the reaction ended, the solvent was removed under reduced pressure and the reactant was extracted with H.sub.2O/EA three times. The organic solvent layer was dried over MgSO.sub.4. The solvent was concentrated in vacuo. t-BuOH (5 mL) was added to the obtained intermediate, and hydrazine (1.5 eq) and acetic acid (1.5 eq) was added and stirred at 95° C. for 16 hours. After the reaction ended, the solvent was removed under reduced pressure and the reactant was extracted with H.sub.2O/EA three times. The organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. Then silica gel column chromatography was performed to provide N-(3-(3-((4-hydroxy-2-methylphenyl)amino)-1H-pyrazol-5-yl)phenyl)acetamide (11 mg) (yield: 5%).

[0346] .sup.1H NMR (300 MHz, CDCl3) δ 7.70 (s, 1H), 7.54 (dd, J=5.5, 3.2 Hz, 1H), 7.14 (d, J=8.6 Hz, 2H), 6.74-6.61 (m, 3H), 5.99 (s, 1H), 2.23 (s, 3H), 2.17 (s, 3H).

Synthesis Example 21: Preparation of methyl 4-(3-((4-hydroxy-2-methylphenyl)amino)-1H-pyrazol-5-yl)benzoate (Compound 90)

Step 1. methyl 4-(3,3-bis(methylthio)acryloyl)benzoate

[0347] ##STR00365##

[0348] 4-methylesterlacetophenone (2.0 g, 11.2 mmol) and benzene (37 mL) were stirred at ambient temperature in a round flask. The mixture was cooled in an ice bath, and NaH (538 mg, 22.4 mmol, 2.0 eq.) was added slowly and stirred at ambient temperature for 5 minutes. Carbon disulfide (1.0 mL, 16.8 mmol, 1.5 eq.) was added slowly to the reactant and stirred at ambient temperature for 5 minutes. After that, iodomethane (2.1 mL, 33.7 mmol, 3.0 eq.) was added slowly to the reactant and stirred at ambient temperature for 5 minutes. N, N-dimethylacetamide (2.2 mL, 23.6 mmol, 2.1 eq.) was added slowly to the reactant and stirred at ambient temperature for 3 hours. After the reaction ended, H.sub.2O was added for quenching. The reactant was extracted with EtOAc and the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. After that, the reactant was filtered with Et.sub.2O to provide the compound (yield: 72%).

Step 2. methyl (Z)-4-(3-((4-hydroxy-2-methylphenyl)amino)-3-(methylthio)acryloyl)benzoate

[0349] ##STR00366##

[0350] Methyl 4-(3,3-bis(methylthio)acryloyl)benzoate (1.7 g, 6.0 mmol) prepared in Step 1 and toluene (20 mL) were stirred at ambient temperature in a 250 mL round flask. Boron trifluoride (170 mg, 1.2 mmol, 0.2 eq) and 4-amino-3-methylphenol (1.1 g, 9.0 mmol, 1.5 eq) were added and stirred at 120° C. for 24 hours. After the reaction ended, toluene was removed with a rotavapor, and the reactant was extracted with sat. NaHCO.sub.3 (30 ml) and ethyl acetate (30 mL×2). The organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. Silica gel column chromatography (EtOAc:Hex=1:9) was performed to provide the reactant. The reactant was sonicated in DCM and filtered to the compound (yield: 79%).

Step 3. methyl 4-(3-((4-hydroxy-2-methylphenyl)amino)-1H-pyrazol-5-yl)benzoate

[0351] ##STR00367##

[0352] Methyl (Z)-4-(3-((4-hydroxy-2-methylphenyl)amino)-3-(methylthio)acryloyl)benzoate (1.5 g, 4.3 mmol) prepared in Step 2, t-BuOH (13 mL), acetic acid (1.0 mL), and hydrazine hydrate (206 mg, 6.44 mmol, 1.5 eq.) were stirred at 95° C. for 18 hours in a 250 mL round flask. After the reaction ended, the solvent was removed with a rotavapor. The reactant was extracted with H.sub.2O (30 mL) and DCM (30 mL×3), and was dried over MgSO.sub.4 and concentrated in vacuo. Silica gel column chromatography (EtOAc:Hex=1:4) was performed to provide the reactant. The reactant was sonicated in DCM and filtered to the compound (yield: 49%).

[0353] .sup.1H NMR (300 MHz, CDCl3) δ 8.11 (s, 1H), 8.06 (d, J=8.2 Hz, 2H), 7.98 (d, J=8.2 Hz, 1H), 7.68-7.60 (m, 2H), 7.19 (d, J=8.5 Hz, 1H), 6.71 (d, J=2.9 Hz, 1H), 6.66 (dd. J=8.5, 2.8 Hz, 1H), 6.13 (s, 1H), 5.53 (s, 1H), 3.93 (s, 3H), 2.23 (s, 3H)

Synthesis Example 22: Preparation of 4-(3-((4-hydroxy-2-methylphenyl)amino)-1H-pyrazol-5-yl)benzoic acid (Compound 91)

[0354] ##STR00368##

[0355] Compound 90 (1.95 mmol, 630 mg) was stirred and dissolved in the solvent (H.sub.2O:THF:EtOH=2.0:1.0:2.0) in a 50 ml round bottom flask. Lithium hydroxide (9.74 mmol, 5.0 eq, 408.8 mg) was added and stirred at room temperature for 4 hours. After the reaction ended, solvent was removed for concentration. 30 ml of H.sub.2O was added to the reactant, and 6 N HCl was added dropwise to adjust the pH to 1.0. The reactant was extracted with ethyl acetate (30 ml×3). The organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo to provide the compound as a white solid (yield: 13%).

[0356] .sup.1H NMR (300 MHz, DMSO) δ 12.67 (s, 1H), 8.81 (s, 1H), 8.01 (d, J=12.4 Hz, 1H). 7.95 (d, J=7.9 Hz, 2H), 7.81 (d, J=8.6 Hz, 2H), 7.17 (d, J=8.3 Hz, 1H), 7.10 (s, 1H), 6.58 (s, 1H), 6.52 (d, J=8.1 Hz, 1H), 6.12 (s, 1H), 2.16 (s, 3H)

Synthesis Example 23: Preparation of (3-((5-(4-aminophenyl)-1H-pyrazol-3-yl)amino)-4-methylphenyl)methanol (Compound 96)

Step 1. (4-methyl-3-((5-(4-nitrophenyl)-1H-pyrazol-3-yl)amino)phenyl)methanol

[0357] ##STR00369##

[0358] 3,3-bis(methylthio)-1-(4-nitrophenyl)prop-2-en-1-one (808 mg, 3.0 mmol) and Toluene (20 mL) were added in a MW vial. BF.sub.3.OEt.sub.2 (74 μL, 0.6 mmol, 0.2 eq.) and 3-amino-4-methylbenzylalcohol (636 mg, 4.5 mmol, 1.5 eq.) were added and reacted at 120° C. for 24 hours. After the reaction ended, the solvent was removed with a rotavapor. The reactant was extracted with H.sub.2O (50 ml) and EtOAc (50 mL×3), and then the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. t-BuOH (25 mL), AcOH (150 μL) and Hydrazine hydrate (150 μL, 4.5 mmol, 1.5 eq.) were added and reacted under reflux for 24 hours. After the reaction ended, the solvent was removed with a rotavapor. The reactant was extracted with H.sub.2O (50 ml) and EtOAc (50 mL×3), and then the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. Silica gel column chromatography (EtOAc:Hex) was performed to provide the compound (2 steps, 200 mg) (yield: 21%).

Step 2. 3-((5-(4-aminophenyl)-11H-pyrazol-3-yl)amino)-4-methylphenyl)methanol

[0359] ##STR00370##

[0360] Compound 96 (200 mg, 0.68 mmol) and EtOAc/MeOH/THF (5/5/5 mL) were stirred at ambient temperature in a round flask. Pd/C (40 mg, 20 wt %) was added and stirred at ambient temperature for 24 hours. After the reaction ended, the solvent was removed with a celite filter. Silica gel column chromatography (EtOAc:Hex) was performed to provide the compound (63 mg) (yield: 31%).

[0361] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.60 (s, 1H), 7.35 (d, J=8.1 Hz, 2H), 7.16 (s, 1H), 6.99 (d, J=7.3 Hz, 1H), 6.61 (t, J=9.6 Hz, 3H), 6.08 (s, 1H), 5.28 (s, 2H), 4.98 (s, 1H), 4.37 (s, 2H), 2.20 (s, 3H).

Synthesis Example 24: Preparation of N-(4-((5-(4-(1H-pyrazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)-3-chloro propanamide (Compound 180)

Step 1. 1-(4-(1H-pyrazol-1-yl)phenyl)ethan-1-one

[0362] ##STR00371##

[0363] 4′-iodoacetophenone (1.23 g, 5.0 mmol), pyrazole (0.68 g, 10.0 mmol, 2.0 eq), Cu(OAc).sub.2 (91 mg, 0.5 mmol, 0.1 eq.), Cs.sub.2CO.sub.3 (3.3 mg, 10.0 mmol, 2.0 eq.) and DMF (5 mL) were stirred at 110° C. in the scaled vial. The same reaction was repeated four times. After the reaction ended, all the reactant was combined and filtered with a celite pad. The filtrate was concentrated with a rotavapor and extracted with H.sub.2O (50 ml) and EtOAc (50 mL×3). The organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. After that, silica gel column chromatography (EtOAc:Hex) was performed and filtered with Et.sub.2O and Hex to provide the compound (2.91 g) (yield: 78%).

Step 2. 1-(4-(1H-pyrazol-1-yl)phenyl)-3,3-bis(methylthio)prop-2-en-1-one

[0364] ##STR00372##

[0365] 1-(4-(1H-pyrazol-1-yl)phenyl)ethan-1-one (1.26 g, 6.8 mmol) and THF (25 mL) were stirred at ambient temperature in a 100 mL round flask. The mixture was cooled in an ice bath, and NaH (544 mg, 13.6 mmol, 2.0 eq.) was added slowly and stirred at ambient temperature for 5 minutes. CS.sub.2 (620 μL, 10.2 mmol, 1.5 eq.) was added slowly and stirred at ambient temperature for 5 minutes. Mel (1.3 mL, 20.4 mmol, 3.0 eq.) was added slowly and stirred at 50° C. for 12 hours. After the reaction ended, H.sub.2O was added for quenching, and the reactant was extracted with EtOAc. The organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. After that, Et.sub.2O was added to the reactant and sonicated and filtered to provide the compound (1.3 g) (yield: 66%).

Step 3. (Z)-1-(4-(1H-pyrazol-1-yl)phenyl)-3-((2-methyl-4-nitrophenyl)amino)-3-(methylthio)prop-2-en-1-one

[0366] ##STR00373##

[0367] 1-(4-(1H-pyrazol-1-yl)phenyl)-3,3-bis(methylthio)prop-2-en-1-one (871 mg, 3.0 mmol) prepared in Step 2 and toluene (15 mL) were stirred in a round flask. BF.sub.3.OEt.sub.2 (74 μL, 0.6 mmol, 0.2 eq.) was added and then 2-methyl-4-nitroaniline (685 mg, 4.5 mmol, 1.5 eq.) was added to the mixture. The mixture was stirred and reacted under reflux for 48 hours. After the reaction ended, the solvent was removed with a rotavapor and the reactant was filtered with MeOH to provide the compound (1.22 g) (yield: 77%).

Step 4. 5-(4-(1H-pyrazol-1-yl)phenyl)-N-(2-methyl-4-nitrophenyl)-1H-pyrazol-3-amine

[0368] ##STR00374##

[0369] (Z)-1-(4-(1H-pyrazol-1-yl)phenyl)-3-((2-methyl-4-nitrophenyl)amino)-3-(methylthio)prop-2-en-1-one (1.22 g, 3.1 mmol) prepared in Step 3, t-BuOH (30 mL) and AcOH (233 μL) were stirred in a round flask. Hydrazine hydrate (233 μL, 4.65 mmol, 1.5 eq.) was added and reacted under reflux for 24 hours. After the reaction ended, the solvent was removed with a rotavapor and the reactant was filtered with MeOH to provide the compound (1.02 g) (yield: 91%).

Step 5. tert-butyl 5-(4-(1H-pyrazol-1-yl)phenyl)-3-((tert-butoxycarbonyl)(2-methyl-4-nitrophenyl)amino)-1H-pyrazole-1-carboxylate

[0370] ##STR00375##

[0371] 5-(4-(1H-pyrazol-1-yl)phenyl)-N-(2-methyl-4-nitrophenyl)-1H-pyrazol-3-amine (1.51 g, 4.2 mmol) prepared in Step 4 and THF were stirred in a 250 mL round flask. DMAP (103 mg, 0.84 mmol, 0.2 eq.), Et.sub.3N (1.8 mL, 12.6 mmol, 3.0 eq.), and (Boc).sub.2O (2.75 g, 12.6 mmol, 3.0 eq.) were added and stirred for 24 hours. After the reaction ended, the solvent was removed with a rotavapor. The reactant was extracted with H.sub.2O (50 ml) and EtOAc (50 mL×3), and the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. After that, silica gel column chromatography (EtOAc:Hex) was performed to provide the compound (1.54 g) (yield: 99%).

Step 6. tert-butyl 5-(4-(1H-pyrazol-1-yl)phenyl)-3-((4-amino-2-methylphenyl)(tert-butoxycarbonyl)amino)-1H-pyrazole-1-carboxylate

[0372] ##STR00376##

[0373] tert-butyl 5-(4-(1H-pyrazol-1-yl)phenyl)-3-((tert-butoxycarbonyl)(2-methyl-4-nitrophenyl)amino)-1H-pyrazole-1-carboxylate (1.54 g, 2.75 mmol) prepared in Step 5 and MeOH/THF (10/10 mL) were stirred at ambient temperature in a round flask. Pd/C (300 mg, 20 wt %) was added and stirred at ambient temperature for 48 hours. After the reaction ended, the solvent was removed with a celite filter. After that, silica gel column chromatography (EtOAc:Hex) was performed to provide the compound (1.16 g) (yield: 79%).

Step 7. tert-butyl 5-(4-(1H-pyrazol-1-yl)phenyl)-3-((tert-butoxycarbonyl)(4-(3-chloropropanamido)-2-methylphenyl)amino)-1H-pyrazole-1-carboxylate

[0374] ##STR00377##

[0375] tert-butyl 5-(4-(1H-pyrazol-1-yl)phenyl)-3-((4-amino-2-methylphenyl)(tert-butoxycarbonyl)amino)-1H-pyrazole-1-carboxylate prepared in Step 6 and THF (15 mL) were stirred in a 100 mL round flask, 3-chloropropionyl chloride (600 μL, 6.21 mmol, 3.0 eq.) was added and reacted at 50° C. for 24 hours. After the reaction ended, the solvent was removed with a rotavapor. The reactant was extracted with H.sub.2O (50 ml) and EtOAc (50 mL×3), and the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. Next step was performed without purification.

Step 8. N-(4-((5-(4-(1H-pyrazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)-3-chloro propanamide

[0376] ##STR00378##

[0377] tert-butyl 5-(4-(1H-pyrazol-1-yl)phenyl)-3-((tert-butoxycarbonyl)(4-(3-chloropropanamido)-2-m ethylphenyl)amino)-1H-pyrazole-1-carboxylate prepared in Step 7 and THF (10 mL) were stirred in a 100 mL round flask. Morpholine (450 μL, 5.1 mmol, 3.0 eq.) was added and reacted at 50° C. for 24 hours. After the reaction ended, the solvent was removed with a rotavapor. The reactant was extracted with H.sub.2O (50 ml) and EtOAc (50 mL×3), and the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. After that, silica gel column chromatography (EtOAc:Hex) was performed to provide both tert-butyl (5-(4-(1H-pyrazol-1-yl)phenyl)-1H-pyrazol-3-yl)(4-(3-chloropropanamido)-2-methylphenyl)carbamate (360 mg) (yield: 41%) and N-(4-((5-(4-(1H-pyrazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)-3-chloro propanamide (16 mg) (yield: 2%).

[0378] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.47 (s, 1H), 9.79 (s, 1H), 8.55 (d, J=2.5 Hz, 1H), 7.96-7.74 (m, 5H), 7.60 (s, 1H), 7.39-7.24 (m, 3H), 6.57 (t, J=2.1 Hz, 1H), 6.31 (s, 1H), 3.87 (t, J=6.3 Hz, 2H), 2.77 (t, J=6.3 Hz, 2H), 2.23 (s, 3H).

Synthesis Example 25: Preparation of N-(4-((5-(4-(1H-pyrazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)-3-morpholinopropanamide (Compound 181)

Step 1. tert-butyl (5-(4-(1H-pyrazol-1-yl)phenyl)-1H-pyrazol-3-yl)(2-methyl-4-(3-morpholinopropanamido)phenyl)carbamate

[0379] ##STR00379##

[0380] tert-butyl (5-(4-(1H-pyrazol-1-yl)phenyl)-1H-pyrazol-3-yl)(4-(3-chloropropanamido)-2-methylphenyl)carbamate (360 mg, 0.69 mmol) obtained as a by-product in Step 8 of the preparation of Compound 180 and THF (10 mL) were stirred in a 100 mL round flask. Morpholine (180 μL, 2.07 mmol, 3.0 eq.) was added and reacted under reflux for 24 hours. After the reaction ended, the solvent was removed with a rotavapor. The reactant was extracted with H.sub.2O (50 ml) and EtOAc (50 mL×3), and the organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. After that, silica gel column chromatography (DCM:MeOH) was performed to provide the compound (310 mg) (yield: 79%).

Step 2. N-(4-((5-(4-(1H-pyrazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)-3-morpholinopropanamide

[0381] ##STR00380##

[0382] tert-butyl (5-(4-(1H-pyrazol-1-yl)phenyl)-1H-pyrazol-3-yl)(2-methyl-4-(3-morpholinopropanamido)phenyl)carbamate (300 mg, 0.52 mmol) prepared in Step 1 and DCM (5 mL) were stirred in a 100 mL round flask. The mixture was cooled in an ice bath, and TFA (1.2 mL, 15.6 mmol, 30.0 eq.) was added and stirred at room temperature for 30 hours. After the reaction ended, the reactant was extracted with H.sub.2O (50 ml) and EtOAc (50 mL×3), and the organic solvent layer was washed with sat. NaHCO.sub.3. The reactant was dried over MgSO.sub.4 and concentrated in vacuo. After that, the reactant was filtered with DCM to provide the compound (81 mg) (yield: 33%).

[0383] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.92 (s, 1H), 9.62 (s, 1H), 8.55 (d, J=2.5 Hz, 1H), 7.91 (d, J=8.8 Hz, 2H), 7.84 (d, J=8.9 Hz, 2H), 7.77 (d, J=1.7 Hz, 11H), 7.50 (d, J=8.7 Hz, 1H), 7.35 (d, J=2.4 Hz, 2H), 7.29 (dd, J=8.6, 2.5 Hz, 1H), 6.60-6.54 (m, 1H), 6.32 (s, 1H), 4.00 (d, J=12.8 Hz, 12H), 2.23 (s, 3H).

Synthesis Example 26: Preparation of N-(4-((5-(4-fluorophenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)methanesulfonamide (Compound 204)

[0384] ##STR00381##

[0385] XPhos Pd G1 (5 mol %, 0.0113 mmol, 5.4 mg), XPhos (7 mol %, 0.0158 mmol, 11.6 mg), NaO-tBu (2.1 eq, 0.475 mmol, 45 mg), pyrazole amine (1.0 eq, 0.226 mol, 40 mg), N-(4-bromo-3-methylphenyl)methanesulfonamide (1.2 eq, 0.271 mmol, 71 mg), and degassed t-BuOH (4 mL) were added in a microwave vial. The vial was irradiated at 150° C. for 4 hours by microwave. The vial was cooled to room temperature and the solvent was removed under reduced pressure. The reactant was diluted with EA, and extracted with distilled water and NH.sub.4Cl solution. The organic solvent layer was dried over Na.sub.2SO.sub.4 and filtered. The reactant was concentrated in vacuo, and separated by column chromatography to provide the compound as a brown liquid (11 mg) (yield: 13%).

Synthesis Example 27: Preparation of 4-((5-(2′-fluoro-5′-methoxy-[1,1′-biphenyl]-3-yl)-1H-pyrazol-3-yl)amino)-3-methylphenol (Compound 246)

Step 1. 1-(2′-fluoro-5′-methoxy-[1,1′-biphenyl]-3-yl)-3,3-bis(methylthio)prop-2-en-1-one

[0386] ##STR00382##

[0387] 1-(3-iodophenyl)-3,3-bis(methylthio)prop-2-en-1-one (700 mg, 2.0 mmol), 2-fluoro-5-methoxyphenylboronic acid (340 mg, 2.0 mmol, 1.0 eq.), Pd(PPh.sub.3).sub.2Cl.sub.2 (264 mg, 0.6 mmol, 30 mol %), and K.sub.2CO.sub.3 (553 mg, 4.0 mmol, 2.0 eq.) were added to a mixture of H.sub.2O (2 mL) and 1,4-dioxane (4 mL) in a round flask and stirred at 90° C. for 24 hours. After the reaction ended, the solvent was removed with a celite filter. The reactant was extracted with H.sub.2O (30 mL) and ethyl acetate (30 mL×3), and then dried over MgSO.sub.4 and concentrated in vacuo. Then, silica gel column chromatography (EtOAc:Hex) was performed to provide the compound (297 mg) (yield: 43%).

Step 2. (Z)-1-(2′-fluoro-5′-methoxy-[1,1′-biphenyl]-3-yl)-3-((4-hydroxy-2-methylphenyl)amino)-3-(methylthio)prop-2-en-1-one

[0388] ##STR00383##

[0389] 1-(2′-fluoro-5′-methoxy-[1,1′-biphenyl]-3-yl)-3,3-bis(methylthio)prop-2-en-1-one (297 mg, 0.88 mmol) prepared in Step 1 and toluene (9 mL) were stirred in a round flask. BF.sub.3.OEt.sub.2 (21 μL, 0.17 mmol, 0.2 eq.) was added, and then 4-amino-3-methylphenol (157 mg, 1.28 mmol, 1.5 eq.) was added to the mixture. The mixture was reacted under reflux for 24 hours. After the reaction ended, the reactant was extracted with H.sub.2O (30 mL) and ethyl acetate (30 mL×3), and dried over MgSO.sub.4 and concentrated in vacuo. Then, silica gel column chromatography (EtOAc:Hex) was performed to provide the compound (133 mg) (yield: 37%).

Step 3. 4-((5-(4-(1H-pyrazol-4-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-methylphenol

[0390] ##STR00384##

[0391] (Z)-1-(2′-fluoro-5′-methoxy-[1,1′-biphenyl]-3-yl)-3-((4-hydroxy-2-methylphenyl)amino)-3-(methylthio)prop-2-en-1-one (133 mg, 0.31 mmol) prepared in Step 2, t-BuOH (3 mL) and AcOH (23 μL) were stirred in a round flask. Hydrazine hydrate (23 μL, 0.46 mmol, 1.5 eq.) was added and the mixture was reacted under reflux for 24 hours. After the reaction ended, the reactant was extracted with H.sub.2O (30 mL) and ethyl acetate (30 mL×3), and dried over MgSO.sub.4 and concentrated in vacuo. Then, silica gel column chromatography (EtOAc:Hex) was performed to provide the compound (96 mg) (yield: 79%).

[0392] .sup.1H NMR (300 MHz, Chloroform-d) δ 7.74 (q, J=1.7 Hz, 1H), 7.58 (dt, J=7.6, 1.5 Hz, 1H), 7.54-7.47 (m, 1H), 7.42 (t, J=7.6 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 7.06 (dd, J=9.9, 8.9 Hz, 1H), 6.94 (dd. J=6.3, 3.1 Hz, 1H), 6.83 (dt, J=8.9, 3.5 Hz, 1H), 6.67-6.58 (m, 2H), 6.07 (s, 1H), 3.80 (s, 3H), 2.13 (s, 3H).

Synthesis Example 28: Preparation of 4-((5-(4-(1H-pyrazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-2-fluoro-5-methylphenol (Compound 274)

Step 1. 2-fluoro-5-methyl-4-nitrophenol

[0393] ##STR00385##

[0394] 2-fluoro-5-methylphenol (4.3 mL, 39.0 mmol), AcOH (12 mL), and H.sub.2SO.sub.4 (1.7 mL) were stirred in a 25 mL round flask. The mixture was cooled in an ice bath. NaNO.sub.2 (2.7 g, 39.0 mmol, 1.0 eq.) in H.sub.2O (7.0 mL) was added slowly to the reactant and then stirred at room temperature for 1 hour. The prepared orange solid was filtered and put in a 25 mL round flask to which H.sub.2O (19.0 mL) and HNO.sub.3 (4.0 mL) were added. The mixture was stirred at 40° C. for 2 hours (until the solid became pale yellow). After the reaction ended, the prepared solid was filtered with H.sub.2O to provide a beige solid (3.13 g) (yield: 47%).

Step 2. 4-amino-2-fluoro-5-methylphenol

[0395] ##STR00386##

[0396] 2-fluoro-5-methyl-4-nitrophenol (3.13 g) prepared in Step 1, THF/H.sub.2O (30/30 mL), Fe (4.09 g, 73.2 mmol, 4.0 eq.), and NH.sub.4Cl (3.92 g, 73.2 mol, 4.0 eq.) were added in a 250 mL round flask and reacted under reflux for 4 hours. After the reaction ended, a celite filtration was performed and the reactant was extracted with H.sub.2O and EtOAc. The organic solvent layer was dried over MgSO.sub.4 and concentrated in vacuo. After that, silica gel column chromatography (EtOAc:Hex) was performed. The reactant was sonicated in Et.sub.2O and filtered to provide a beige solid (984 mg) (yield: 38%).

Step 3. 4-((5-(4-(1H-pyrazol-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-2-fluoro-5-methylphenol

[0397] ##STR00387##

[0398] 1-(4-(1H-pyrazol-1-yl)phenyl)-3,3-bis(methylthio)prop-2-en-1-one (436 mg, 1.5 mmol) and Toluene (15 mL) were stirred in a MW vial. BF.sub.3.OEt.sub.2 (37 JAL, 0.3 mmol, 0.2 eq.) and 4-amino-2-fluoro-5-methylphenol (254 mg, 1.8 mmol, 1.2 eq.) prepared in Step 2 were added hereto and reacted under reflux for 24 hours. After the reaction ended, the solvent was removed with a rotavapor, and the reactant was extracted with H.sub.2O (50 ml) and EtOAc (50 mL×3). The organic layer was dried over MgSO.sub.4 and concentrated in vacuo. EtOH (15 mL) and Hydrazine hydrate (112 μL, 2.25 mmol, 1.5 eq.) were added hereto and the mixture was reacted under reflux. After the reaction ended, the solvent was removed with a rotavapor, and the reactant was extracted with H.sub.2O (50 ml) and EtOAc (50 mL×3). The organic layer was dried over MgSO.sub.4 and and concentrated in vacuo. After that, silica gel column chromatography (EtOAc:Hex) was performed to provide a white solid (2 steps, 65 mg) (yield: 12%).

[0399] .sup.1H NMR (300 MHz, DMSO-d 6) δ 12.47 (s, 1H), 10.43 (s, 1H), 8.56 (d, J=2.5 Hz, 1H), 8.42 (s, 1H), 7.92 (d, J=8.5 Hz, 2H), 7.84 (d, J=8.5 Hz, 2H), 7.77 (d, J=1.7 Hz, 1H), 7.14 (s, 1H), 6.90 (d, J=6.9 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 6.57 (t, J=2.1 Hz, 1H), 6.24 (s, 1H), 4.49 (s, 2H).

Synthesis Example 29: Preparation of 4-((5-(4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-methylphenol (Compound 277)

Step 1. tert-butyl 3-((tert-butoxycarbonyl)(4-hydroxy-2-methylphenyl)amino)-5-(4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl)-1H-pyrazole-1-carboxylate

[0400] ##STR00388##

[0401] tert-butyl 5-(4-bromophenyl)-3-((tert-butoxycarbonyl)(4-hydroxy-2-methylphenyl)amino)-1H-pyrazole-1-carboxylate (100 mg, 0.18 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (61 mg, 0.27 mmol, 1.5 eq.), Pd(PPh.sub.3).sub.2Cl.sub.2 (16 mg, 0.036 mmol, 20 mol %), and Na.sub.2CO.sub.3 (38 mg, 0.36 mmol, 2.0 eq.) were added to a mixture of EtOH (1 mL), H.sub.2O (1 mL) and DMF (2 mL) in a round flask, and then stirred at 80° C. for 19 hours. After the reaction ended, the solvent was removed with a celite filter. The reactant was extracted with H.sub.2O (30 mL) and ethyl acetate (30 mL×3), and dried over MgSO.sub.4 and concentrated in vacuo. Then, silica gel column chromatography (EtOAc:Hex) was performed to provide the compound (46 mg) (yield: 50%).

Step 2. 4-((5-(4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl)-1H-pyrazol-3-yl)amino)-3-methylphenol

[0402] ##STR00389##

[0403] tert-butyl 3-((tert-butoxycarbonyl)(4-hydroxy-2-methylphenyl)amino)-5-(4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl)-11H-pyrazole-1-carboxylate (46 mg, 0.08 mmol) prepared in Step 1 and DCM (1 mL) were stirred at room temperature in a round flask. The mixture was cooled in an ice bath. TFA (61 μL, 0.8 mmol, 10.0 eq.) was added to the mixture and stirred at room temperature for 5 hours. After the reaction ended, the reactant was extracted with H.sub.2O (30 mL) and ethyl acetate (30 mL×3). The organic layer was washed with sat. NaHCO.sub.3 and then dried over MgSO.sub.4 and concentrated in vacuo. Then, silica gel column chromatography (EtOAc:Hex) was performed to provide the compound (17 mg) (yield: 59%).

[0404] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.85 (s, 1H), 7.70-7.54 (m, 4H), 7.05 (s, 1H), 6.58 (s, 1H), 6.52 (d, J=8.6 Hz, 1H), 6.07 (s, 1H), 2.15 (s, 3H), 1.24 (s, 1H), 1.07 (s, 1H).

Synthesis Example 30: Preparation of methyl (4-((5-(4-methoxyphenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)carbamate (Compound 286)

Step 1. methyl (3-methyl-4-nitrophenyl)carbamate

[0405] ##STR00390##

[0406] 3-methyl-4-nitroaniline (15.2 g, 100.0 mmol) and DCM (500 mL) were stirred in a 1000 mL round flask. Pyridine (24.0 mL, 300.0 mmol, 3.0 eq.) was added to the mixture in an ice bath, and methyl chloroformate (9.3 mL, 120.0 mmol, 1.2 eq.) was added slowly and stirred at room temperature for 5 hours. After the reaction ended, H.sub.2O was added and the reactant was extracted with EtOAc. The organic layer was dried over MgSO.sub.4 and concentrated in vacuo. Then, the reactant was sonicated in Et.sub.2O to provide the compound (20.0 g) (yield: 95%).

Step 2. methyl (4-amino-3-methylphenyl)carbamate

[0407] ##STR00391##

[0408] methyl (3-methyl-4-nitrophenyl)carbamate (20.0 g, 95.0 mmol) and THF/MeOH (250/250 mL), Pd/C (4 g, 20 wt %) were added in a hydrogenator flask, and reacted with a hydrogenator for 24 hours. After the reaction ended, the solvent was removed with a celite filter, and silica gel column chromatography (EtOAc:Hex) was performed to provide the brown oil (8.6 g) (yield: 50%).

Step 3. (4-((5-(4-methoxyphenyl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)carbamate

[0409] ##STR00392##

[0410] 1-(4-methoxyphenyl)-3,3-bis(methylthio)prop-2-en-1-one (509 mg, 2.0 mmol) and Toluene (15 mL) were stirred in a MW vial. BF.sub.3.OEt.sub.2 (49 μL, 0.4 mmol, 0.2 eq.) and methyl (4-amino-3-methylphenyl)carbamate (433 mg, 2.4 mmol, 1.2 eq.) prepared in Step 2 were added and reacted under reflux for 24 hours. After the reaction ended, the solvent was removed with a rotavapor. The reactant was extracted with H.sub.2O (50 ml) and EtOAc (50 mL×3). The organic layer was dried over MgSO.sub.4 and concentrated in vacuo. EtOH (15 mL) and Hydrazine hydrate (150 μL, 3.0 mmol, 1.5 eq.) were added to the reactant and reacted under reflux for 24 hours. After the reaction ended, the solvent was removed with a rotavapor. The reactant was extracted with H.sub.2O (50 ml) and EtOAc (50 mL×3), and the organic layer was dried over MgSO.sub.4 and concentrated in vacuo. Silica gel column chromatography (EtOAc:Hex) was performed to provide the compound (2 steps, 258 mg) (yield: 37%).

[0411] .sup.1H NMR (300 MHz, DMSO-d 6) δ 12.22 (s, 1H), 8.92 (s, 1H), 7.62 (d, J=8.6 Hz, 3H), 7.51-7.32 (m, 5H), 7.19 (s, 1H), 7.07 (d, J=8.4 Hz, 2H), 6.69 (d, J=9.9 Hz, 1H), 6.12 (s, 1H), 5.15 (s, 2H), 2.14 (s, 3H).

[0412] The compounds of the present disclosure were synthesized using the method described above by adjusting starting materials and/or intermediates. Results of .sup.1H NMR tests are written in Table 3 below.

TABLE-US-00003 TABLE 3 CompoundNo. 1H NMR 1 .sup.1H-NMR (300 MHz, DMSO-d6) δ 7.48 (d, 2H, J = 8.3 Hz), 7.33-7.30 (m, 2H), 7.19 (d, 2H, J = 8.4 Hz), 7.07-6.86 (m, 6H), 6.68 (d, 2H, J = 8.3 Hz), 6.17 (s, 1H), 5.98 (s, NH), 3.85 (s, 3H). 2 .sup.1H-NMR (300 MHz, DMSO-d6) δ 12.31 (s, 1H), 8.67 (s, 1H), 7.97 (s, 1H), 7.73 (d, 2H, J = 9.0 Hz), 7.47 (d, 2H, J = 6.0 Hz), 7.12 (s, 1H), 6.62 (d, 2H, J = 6.0 Hz), 6.17 (s, 1H). 3 .sup.1H-NMR (300 MHz, DMSO-d6) δ 7.69 (d, 2H, J = 9.0 Hz), 7.11 (d, 2H, J = 9.0 Hz), 7.02 (d, 2H, J = 9.0 Hz), 6.68 (d, 2H, J = 9.0 Hz), 6.15 (s, 1H), 3.79 (s, 3H). 4 .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 7.41-6.84 (m, 4H), 7.11 (d, 2H, J = 8.9 Hz), 6.85 (d, 2H, J = 8.7 Hz), 5.95 (s, 1H), 2.41 (s, 3H). 5 .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 7.50 (d, 2H, J = 8.2 Hz), 7.41 (d, 2H, J = 8.5 Hz), 7.35 (d, 1H, J = 8.5 Hz), 7.16-7.05 (m, 2H), 6.24 (s, 1H), 5.74 (s, NH), 2.26 (s, 3H). 6 .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 7.49-7.47 (m, 2H), 7.40 (d, 1H, J = 8.4 Hz), 7.13-7.09 (m, 2H), 6.96 (d, 2H, 8.6 Hz), 6.18 (s, 1H), 5.76 (s, NH), 3.85 (s, 3H), 2.25 (s, 3H). 7 .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 7.42 (d, 1H, 8.5 Hz), 7.29 (s, 1H), 7.13-7.06 (m, 4H), 6.10 (s, 1H), 5.83 (s, NH), 2.40 (s, 3H), 2.36 (s, 3H), 2.26 (s, 3H). 8 .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 7.51-7.48 (m, 2H), 7.41-7.26 (m, 3H), 6.93-6.84 (m, 2H), 6.15 (s, 1H), 5.30 (s, 1H), 2.27 (s, 3H). 9 .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 7.50-7.46 (m, 2H), 7.38-7.27 (m, 1H), 6.94-6.85 (m, 4H), 6.11 (s, 1H), 5.64 (s, 1H), 3.84 (s, 3H), 2.25 (s, 3H). 10 .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 7.40-7.35 (m, 2H), 7.32-7.21 (m, 3H), 6.91-9.80 (m, 2H), 6.05 (s, 1H), 5.73(s, NH), 2.42 (s, 3H), 2.26 (s, 3H). 11 .sup.1H-NMR (300 MHz, DMSO-d6) δ 9.11 (s, 1H), 7.79 (d, 2H J = 8.9 Hz), 7.66 (d, 2H, J = 8.7 Hz), 7.38 (d, 2H, J = 8.5 Hz), 7.00 (d, 2H, J = 8.8 Hz), 6.23 (s, 1H), 4.23 (q, 2H, J = 7.0 Hz), 3.78 (s, 3H), 1.28 (t, J = 7.1 Hz). 12 .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 7.48 (d, 2H, J = 8.7 Hz), 7.21 (d, 1H, J = 8.5 Hz), 6.92 (d, 2H, J = 8.9 Hz), 6.69-6.61 (m, 1H), 6.00 (s, 1H), 3.83 (s, 3H), 2.21 (s, 3H). 13 .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 6.77 (d, 2H, J = 8.9 Hz), 6.20 (d, 2H, J = 8.2 Hz), 6.15 (d, 2H, J = 8.9 Hz), 5.90(d, 2H, J = 8.3 Hz), 5.24 (s, 1H), 3.00 (s, 3H). 14 .sup.1H-NMR (300 MHz, DMSO-d6) δ 9.63 (s, 1H), 8.27 (s, 1H), 7.64 (d, 2H, J = 8.3 Hz), 7.37 (d, 2H, 8.5 Hz), 7.28-7.25 (m, 2H), 6.99 (d, 2H, J = 8.4 Hz), 6.11 (s, 1H), 3.79 (s, 3), 1.99 (s, 3H). 15 .sup.1H-NMR (300 MHz, DMSO-d6) δ 12.50 (s, 1H), 9.08 (s, 1H), 7.78 (d, 2H J = 8.8 Hz), 7.65 (d, 2H, J = 8.2 Hz), 7.39 (d, 2H, J = 8.5 Hz), 6.99 (d, 2H, J = 8.3 Hz), 6.21 (s, 1H), 3.75 (s, 3H). 16 .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 7.51-7.48 (m, 2H), 7.08-7.02 (m, 1H), 6.97-6.94 (m, 2H), 6.57-6.56 (m, 1H), 6.53-6.50 (m, 1H), 6.26-6.22 (2H), 3.85 (s, 3H). 17 .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 7.81 (s, 1H), 7.57-7.54 (m, 1H), 7.49 (d, 2H, J = 8.7 Hz), 7.44-7.42 (m, 1H), 7.35-7.30 (m, 1H),), 6.96 (d, 2H, J = 8.7 Hz), 6.21 (s, 1H), 6.14 (s, 1H), 4.37 (q, 2H, J = 7.1 Hz), 3.85 (s, 3H), 1.39 (t, 3H J = 7.1 Hz) 18 .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 12.14 (s, NH), 9.75 (s, 1H), 8.38 (s, 1H), 7.63 (d, 1H, J = 8.4 Hz), 7.50 (s, 1H), 7.08-6.91 (m, 4H), 6.15 (s, 1H), 3.78 (s, 3H), 2.00 (s, 3H). 19 .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 7.46 (d, J = 8.5 Hz), 7.12 (t, 1H, J = 7.5 Hz), 6.95 (d, 2H, J = 8.6 Hz), 6.84-6.83 (m, 1H), 6.65-6.62 (m, 1H), 6.39-6.36 (m, 2H), 6.20 (s, 1H), 6.03-6.02 (m, 1H) 4.12 (q, 2H, J = 7.2 Hz), 3.85 (s, 3H), 1.26 (t, 3H, J = 7.1 Hz) 20 .sup.1H-NMR (300 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.06 (s, 1H), 7.65 (d, 2H, J = 8.4 Hz), 7.53-7.50 (m, 1H), 7.31-7.27 (m, 2H), 7.00 (d, 2H, J = 8.4 H), 6.14 (s, 1H), 3.78 (s, 3H). 21 .sup.1H-NMR (300 MHz, DMSO-d6) δ) 12.58 (s, 1H), 8.23-8.21 (m, 2H), 7.97-7.64 (m, 2H) 7.83 (s, 1H), 7.02 (s, 1H), 6.50-6.47 (m, 2H), 6.27 (s, 1H) 22 .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 7.33 (d, 2H, J = 8.3 Hz), 7.03 (d, 2H, J = 8.2 Hz), 6.72-6.65 (m, 4H), 6.02 (s, 1H). 23 .sup.1H-NMR (300 MHz, CD.sub.3OD) δ 8.21 (d, 2H, J = 8.9 Hz), 7.86 (d, 2H, J = 8.9 Hz), 7.07 (d, 2H, J = 8.5 Hz), 6.66 (s, 1H), 6.60 (dd, 1H, 8.6, 2.8 Hz), 6.04 (s, 1H), 2.20 (s, 3H). 24 .sup.1H-NMR (300 MHz, CD.sub.3OD) δ 7.37 (d, 2H, J = 8.5 Hz), 7.10 (d, 1H, J = 8.5 Hz), 6.71 (d, 2H, J = 8.5 Hz), 6.64-6.63 (m, 1H), 6.57 (dd, 1H, J = 8.6, 2.8 Hz), 5.81 (s, 1H), 2.20 (s, 3H). 25 .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 8.27 (d, 2H, J = 8.6 Hz), 7.77 (d, 2H, J = 8.6 Hz), 7.04 (d, 2H, J = 8.5 Hz), 6.81 (d, 2H, J = 8.5 Hz). 26 .sup.1H-NMR (300 MHz, DMSO-d6) δ 12.32 (s, NH), 8.60 (s, 1H), 7.62 (d, 2H, J = 8.7 Hz), 7.40-7.33 (m, 3H), 7.20-6.95 (m, 9H), 6.36-6.29 (m, 2H), 6.17-6.09 (m, 2H), 5.21 (s, NH), 3.78 (s, 3H). 27 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.27 (s, 1H), 8.87 (s, 1H), 7.71 (d, J = 8.3 Hz, 2H), 7.48 (d, J = 8.2 Hz, 2H), 7.04 (s, 1H), 6.43 (s, 1H), 6.29 (d, J = 8.4 Hz, 2H), 3.79 (s, 3H). 28 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.37 (s, 1H), 8.80 (s, 1H), 7.73 (d, J = 8.1 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 6.77 (s, 1H), 6.43 (d, J = 2.7 Hz, 1H), 6.35- 6.23 (m, 2H), 4.51 (p, J = 6.0 Hz, 1H), 1.30 (d, J = 6.0 Hz, 6H). 29 .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.65 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 8.3 Hz, 2H), 7.02 (s, 2H), 6.67 (d, J = 8.2 Hz, 2H), 6.12 (s, 1H), 3.01 (t, J = 7.5 Hz, 2H), 1.62 (q, J = 7.2 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H). 30 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.43 (s, 1H), 8.28 (s, 1H), 7.80-7.67 (m, 3H), 7.51 (s, 2H), 7.29 (s, 1H), 7.13 (t, J = 7.6 Hz, 2H), 6.99 (d, J = 8.2 Hz, 2H), 6.88 (d, J = 8.0 Hz, 2H), 6.66 (t, J = 7.3 Hz, 1H), 6.26 (s, 1H). 31 .sup.1H NMR (300 MHz, Chloroform-d) δ 7.50 (d, J = 8.7 Hz, 2H), 7.34 (t, J = 7.9 Hz, 2H), 7.12 (dt, J = 7.4, 3.1 Hz, 2H), 6.99 (dd, J = 13.0, 8.2 Hz, 4H), 6.64- 6.52 (m, 3H), 5.98 (s, 1H), 2.13 (s, 3H). 32 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.23 (s, 1H), 8.81 (s, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.3 Hz, 2H), 7.08 (s, 1H), 6.57 (d, J = 2.9 Hz, 1H), 6.51 (dd, J = 8.6, 2.7 Hz, 1H), 6.05 (s, 1H), 2.14 (s, 3H). 33 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.52 (s, 1H), 12.18 (s, 1H), 8.84 (s, 1H), 7.87 (d, J = 7.3 Hz, 4H), 7.17 (s, 1H), 6.61-6.47 (m, 2H), 6.17 (s, 1H), 2.15 (s, 3H). 34 .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.40 (d, J = 8.2 Hz, 2H), 7.26 (d, J = 8.5 Hz, 1H), 6.73 (d, J = 8.2 Hz, 2H), 6.47 (d, J = 2.6 Hz, 1H), 6.35 (dd, J = 8.5, 2.6 Hz, 1H), 6.05 (s, 1H), 3.84 (s, 3H). 35 .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.41 (d, J = 8.6 Hz, 2H), 7.24 (d, J = 8.6 Hz, 1H), 6.74 (d, J = 8.6 Hz, 2H), 6.48 (d, J = 2.6 Hz, 1H), 6.36 (dd, J = 8.5, 2.6 Hz, 1H), 6.09 (s, 1H), 4.55 (p, J = 6.1 Hz, 1H), 1.36 (d, J = 6.0 Hz, 6H). 36 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 11.79 (s, 1H), 7.67 (s, 1H), 7.33 (d, J = 8.2 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 6.57 (d, J = 8.3 Hz, 2H), 6.47 (d, J = 8.4 Hz, 2H), 5.85 (s, 1H), 5.26 (s, 2H), 4.88 (s, 1H), 2.90 (t, J = 7.0 Hz, 2H), 1.54 (q, J = 7.2 Hz, 2H), 0.93 (t, J = 7.4 Hz, 3H). 37 .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.42 (d, J = 8.6 Hz, 2H), 7.21-7.07 (m, 5H), 7.02 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 7.8 Hz, 2H), 6.77-6.71 (m, 2H), 6.06 (s, 1H). 38 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 11.85 (s, 1H), 8.63 (s, 1H), 7.86 (s, 1H), 7.34 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.3 Hz, 2H), 6.59 (t, J = 8.9 Hz, 4H), 5.88 (s, 1H), 5.27 (s, 2H). 39 .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 11.98 (s, 1H), 9.58 (s, 1H), 7.49 (d, J = 8.5 Hz, 2H), 6.90 (s, 1H), 6.79 (d, J = 8.5 Hz, 2H), 6.56 (d, J = 2.8 Hz, 1H), 6.50 (dd, J = 8.5, 2.9 Hz, 1H), 5.91 (s, 1H), 2.15 (s, 3H). 40 .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.02 (s, 1H), 9.62 (s, 1H), 8.63 (s, 1H), 7.90 (s, 1H), 7.51 (d, J = 8.3 Hz, 2H), 7.17 (s, 1H), 6.81 (d, J = 8.3 Hz, 2H), 6.65-6.59 (m, 2H), 5.98 (s, 1H). 41 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.05 (s, 1H), 8.75 (s, 1H), 7.31 (s, 1H), 7.01 (dd, J = 17.9, 10.2 Hz, 2H), 6.86-6.77 (m, 2H), 6.55 (s, 1H), 6.53-6.46 (m, 2H), 5.87 (s, 1H), 5.11 (s, 2H), 2.14 (s, 3H). 42 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.14 (s, 1H), 8.79 (s, 1H), 7.78-7.67 (m, 2H), 7.24 (t, J = 8.7 Hz, 3H), 7.03 (s, 1H), 6.57 (d, J = 2.8 Hz, 1H), 6.51 (dd, J = 8.6, 2.7 Hz, 1H), 6.03 (s, 1H), 2.15 (s, 3H). 43 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 11.89 (s, 1H), 9.14 (s, 1H), 7.74 (s, 1H), 7.52 (s, 1H), 7.32 (d, J = 8.4 Hz, 2H), 6.62-6.52 (m, 3H), 6.49 (dd, J = 8.9, 2.7 Hz, 1H), 5.92 (s, 1H), 5.28 (s, 2H). 44 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 11.96 (s, 1H), 8.90 (s, 1H), 8.18 (s, 1H), 7.35 (d, J = 8.2 Hz, 3H), 6.85 (d, J = 9.3 Hz, 1H), 6.77 (t, J = 9.2 Hz, 1H), 6.58 (d, J = 8.3 Hz, 2H), 5.89 (s, 1H), 5.30 (s, 2H), 3.35 (s, 3H), 2.08 (s, 3H). 45 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.29 (s, 1H), 8.78 (s, 1H), 7.78 (d, J = 7.9 Hz, 2H), 7.71 (d, J = 8.1 Hz, 4H), 7.47 (t, J = 7.5 Hz, 2H), 7.38 (d, J = 7.1 Hz, 1H), 7.05 (s, 1H), 6.57 (s, 1H), 6.52 (d, J = 7.3 Hz, 1H), 6.11 (s, 1H), 2.17 (s, 3H). 46 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.31 (s, 1H), 8.79 (s, 1H), 7.79 (d, J = 8.2 Hz, 2H), 7.73 (s, 2H), 7.67 (t, J = 10.0 Hz, 5H), 7.29 (s, 1H), 7.05 (s, 1H), 6.57 (s, 1H), 6.52 (dd, J = 8.8, 2.4 Hz, 1H), 6.11 (s, 1H), 2.16 (s, 3H). 47 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.27 (s, 1H), 8.92 (s, 1H), 8.82 (s, 1H), 8.48 (d, J = 3.7 Hz, 1H), 8.06 (d, J = 8.1 Hz, 1H), 7.42 (t, J = 6.5 Hz, 1H), 7.13 (s, 1H), 6.57 (s, 1H), 6.52 (d, J = 8.8 Hz, 1H), 6.13 (s, 1H), 2.15 (s, 3H). 48 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.01 (s, 1H), 9.69 (s, 1H), 8.33 (s, 1H), 7.76-7.65 (m, 2H), 7.37 (t, J = 9.2 Hz, 4H), 7.19 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 6.58 (d, J = 8.2 Hz, 2H), 5.93 (s, 1H), 5.29 (s, 2H). 49 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.04 (s, 1H), 9.62 (s, 1H), 9.17 (s, 1H), 7.71 (s, 1H), 7.58 (s, 1H), 7.48 (d, J = 8.2 Hz, 2H), 6.80 (d, J = 8.3 Hz, 2H), 6.57 (d, J = 13.1 Hz, 1H), 6.50 (dd, J = 9.1, 2.0 Hz, 1H), 6.00 (s, 1H). 50 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.03 (s, 1H), 9.12 (s, 1H), 8.37 (s, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 7.8 Hz, 2H), 7.04 (d, J = 8.9 Hz, 2H), 6.58 (d, J = 8.9 Hz, 2H), 5.97 (s, 1H), 5.30 (s, 2H), 2.86 (s, 3H). 51 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.19 (s, 1H), 9.64 (s, 1H), 9.13 (s, 1H), 8.42 (s, 1H), 7.52 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 8.3 Hz, 2H), 6.06 (s, 1H), 2.86 (s, 3H). 52 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.17 (s, 1H), 9.66 (s, 2H), 8.37 (s, 1H), 7.76-7.65 (m, 2H), 7.51 (d, J = 8.3 Hz, 2H), 7.37 (t, J = 8.7 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 6.89-6.75 (m, 4H), 6.02 (s, 1H). 53 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.14 (s, 1H), 9.64 (s, 2H), 8.27 (s, 1H), 7.52 (d, J = 8.3 Hz, 2H), 7.35 (s, 2H), 7.26 (s, 2H), 6.81 (d, J = 7.4 Hz, 2H), 6.04 (s, 1H), 2.09 (s, 3H). 54 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 11.98 (s, 1H), 9.63 (s, 1H), 8.23 (s, 1H), 7.36 (d, J = 8.4 Hz, 4H), 7.25 (d, J = 8.3 Hz, 2H), 6.58 (d, J = 8.2 Hz, 2H), 5.95 (s, 1H), 5.29 (s, 2H), 1.98 (s, 3H). 55 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.05 (s, 1H), 9.13 (s, 1H), 7.62 (s, 1H), 7.35 (d, J = 8.3 Hz, 2H), 7.23 (s, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.58 (d, J = 8.4 Hz, 2H), 6.06 (s, 1H), 5.29 (s, 2H), 2.86 (s, 3H), 2.21 (s, 3H). 56 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.01 (s, 1H), 8.69 (s, 1H), 7.35 (d, J = 9.1 Hz, 2H), 6.86 (s, 1H), 6.68 (s, 1H), 6.63 (d, J = 8.2 Hz, 2H), 6.53 (s, 1H), 6.44 (d, J = 8.2 Hz, 1H), 5.36 (s, 2H), 2.16 (s, 3H). 57 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.03 (s, 1H), 9.71 (s, 1H), 7.73 (dd, J = 8.6, 5.1 Hz, 2H), 7.50 (s, 1H), 7.43-7.29 (m, 4H), 7.17 (s, 1H), 6.76 (s, 1H), 6.74-6.68 (m, 1H), 6.58 (d, J = 8.2 Hz, 2H), 6.02 (s, 1H), 5.28 (s, 2H), 2.12 (s, 3H). 58 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.21 (s, 1H), 9.63 (s, 1H), 9.17 (s, 1H), 7.68 (s, 1H), 7.51 (d, J = 8.5 Hz, 2H), 7.29 (s, 1H), 6.94 (d, J = 8.9 Hz, 2H), 6.81 (d, J = 8.5 Hz, 2H), 6.15 (s, 1H), 2.86 (s, 3H), 2.22 (s, 3H). 59 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.14 (s, 1H), 9.62 (s, 1H), 7.51 (d, J = 8.2 Hz, 2H), 7.30 (s, 1H), 7.27-7.15 (m, 2H), 6.80 (d, J = 8.2 Hz, 2H), 6.10 (s, 1H), 2.20 (s, 3H), 1.98 (s, 3H). 66 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.13 (s, 1H), 8.85 (s, 1H), 8.74 (d, J = 2.5 Hz, 1H), 8.13 (dd, J = 8.3, 2.5 Hz, 1H), 7.53 (s, 1H), 7.18 (s, 1H), 6.57 (s, 1H), 6.52 (d, J = 9.0 Hz, 1H), 6.11 (s, 1H), 2.14 (s, 3H). 67 .sup.1H NMR (300 MHz, Acetone-d.sub.6) δ 8.24 (d, J = 8.7 Hz, 2H), 7.99 (d, J = 8.7 Hz, 2H), 7.61 (t, J = 9.6 Hz, 1H), 7.19 (s, 1H), 6.68-6.54 (m, 2H), 6.42 (s, 1H). 68 .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 8.22 (d, J = 8.9 Hz, 2H), 7.86 (d, J = 9.0 Hz, 2H), 7.03 (d, J = 12.2 Hz, 1H), 6.85-6.75 (m, 2H), 6.31 (s, 1H). 69 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.79 (s, 1H), 9.66 (s, 1H), 8.54 (s, 1H), 8.28 (d, J = 8.5 Hz, 2H), 8.01 (d, J = 8.5 Hz, 2H), 7.72 (dd, J = 8.6, 5.2 Hz, 2H), 7.38 (t, J = 8.7 Hz, 2H), 7.14 (s, 2H), 6.88 (d, J = 8.4 Hz, 2H), 6.47 (s, 1H). 70 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.74 (s, 1H), 9.22 (s, 1H), 8.28 (d, J = 8.5 Hz, 2H), 8.01 (d, J = 8.5 Hz, 2H), 7.53 (s, 1H), 6.97 (d, J = 11.9 Hz, 2H), 6.50 (s, 1H), 2.88 (s, 3H), 2.23 (s, 3H). 71 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.81 (s, 1H), 8.35 (d, J = 8.5 Hz, 2H), 7.97 (d, J = 8.5 Hz, 2H), 7.04 (s, 1H), 6.73 (s, 1H), 6.56 (s, 1H), 6.47 (d, J = 8.6 Hz, 1H), 2.16 (s, 3H). 72 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.74 (s, 1H), 9.84 (s, 1H), 8.27 (d, J = 8.5 Hz, 2H), 7.99 (d, J = 8.4 Hz, 2H), 7.81-7.69 (m, 2H), 7.46 (s, 1H), 7.38 (t, J = 8.8 Hz, 2H), 6.82 (s, 1H), 6.76 (d, J = 8.1 Hz, 1H), 6.48 (s, 1H), 2.14 (s, 3H). 73 .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.34 (s, 1H), 8.76 (s, 1H), 8.32 (s, 1H), 7.82 (d, J = 11.3 Hz, 4H), 7.72 (s, 2H), 7.13 (s, 2H), 6.58 (s, 2H), 6.53 (s, 1H), 6.15 (s, 1H), 2.17 (d, J = 2.9 Hz, 4H). 74 .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.38 (s, 1H), 8.70 (s, 1H), 8.33 (d, J = 1.2 Hz, 1H), 8.00 (s, 1H), 7.86 (d, J = 8.5 Hz, 2H), 7.81 (t, J = 1.3 Hz, 1H), 7.73 (d, J = 8.3 Hz, 2H), 7.13 (t, J = 1.2 Hz, 1H), 6.68-6.62 (m, 2H), 6.24 (s, 1H). 75 .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.36 (s, 1H), 8.66 (s, 1H), 8.01 (s, 1H), 7.81 (d, J = 8.0 Hz, 2H), 7.79-7.71 (m, 4H), 7.49 (t, J = 7.7 Hz, 2H), 7.39 (t, J = 7.3 Hz, 1H), 7.20 (d, J = 8.1 Hz, 2H), 6.65 (d, J = 8.4 Hz, 2H), 6.21 (s, 1H). 76 .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.37 (s, 1H), 8.67 (s, 1H), 8.01 (s, 1H), 7.82 (d, J = 8.0 Hz, 2H), 7.76 (d, J = 8.3 Hz, 2H), 7.72-7.65 (m, 4H), 7.20 (s, 1H), 6.65 (d, J = 8.4 Hz, 2H), 6.22 (s, 1H). 80 .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 11.93 (s, 1H), 8.71 (s, 1H), 7.54-7.46 (m, 2H), 7.33 (s, 1H), 6.87 (s, 1H), 6.77-6.71 (m, 2H), 6.56 (d, J = 2.9 Hz, 1H), 6.50 (dd, J = 8.5, 2.9 Hz, 1H), 5.90 (s, 1H), 2.93 (s, 6H). 81 .sup.1H NMR (500 MHz, DMSO) δ 12.01-11.82 (m, 1H), 9.57 (s, 1H), 8.78 (s, 1H), 7.48 (d, J = 8.6 Hz, 2H), 7.25 (s, 1H), 6.89 (s, 1H), 6.78 (d, J = 8.6 Hz, 2H), 6.58 (d, J = 2.7 Hz, 1H), 6.51 (dd, J = 8.6, 2.8 Hz, 1H), 5.87 (s, 1H), 2.56 (q, J = 7.5 Hz, 2H), 1.13 (t, J = 7.5 Hz, 3H). 82 1H NMR (300 MHz, DMSO) δ 12.06-11.76 (m, 1H), 9.46 (s, 1H), 8.62 (s, 1H), 7.86 (s, 1H), 7.38 (s, 1H), 7.30 (dd, J = 8.3, 2.4 Hz, 1H), 7.11 (d, J = 8.6 Hz, 2H), 6.77 (d, J = 8.4 Hz, 1H), 6.59 (d, J = 8.6 Hz, 2H), 5.93 (s, 1H), 2.13 (s, 3H). 83 .sup.1H NMR (300 MHz, CD3OD) δ 7.44-7.26 (m, 4H), 7.14 (d, J = 8.5 Hz, 2H), 6.77 (d, J = 8.4 Hz, 1H), 6.10 (s, 1H), 2.22 (s, 3H), 2.08 (s, 3H). 84 .sup.1H NMR (300 MHz, CDCl3) δ 7.70 (s, 1H), 7.54 (dd, J = 5.5, 3.2 Hz, 1H), 7.14 (d, J = 8.6 Hz, 2H), 6.74-6.61 (m, 3H), 5.99 (s, 1H), 2.23 (s, 3H), 2.17 (s, 3H). 85 1H NMR (300 MHz, DMSO) δ 11.87 (s, 1H), 9.41 (s, 1H), 8.67 (s, 1H), 7.33 (s, 1H), 7.32 (t, J = 9.2 Hz, 2H), 6.83 (s, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.54-6.39 (m, 1H), 5.83 (s, 1H), 2.09 (s, 6H). 86 .sup.1H NMR (500 MHz, DMSO) δ 12.13-12.04 (m, 1H), 9.63 (s, 1H), 9.50 (s, 1H), 7.51 (s, 1H), 7.43 (d, J = 2.2 Hz, 1H), 7.34 (dd, J = 8.3, 2.3 Hz, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.24 (dd, J = 8.7, 2.4 Hz, 1H), 7.17 (s, 1H), 6.81 (d, J = 8.3 Hz, 1H), 6.09 (s, 1H), 2.21 87(s, 3H), 2.16 (s, 3H), 1.99 (s, 3H). 87 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.20 (t, J = 7.8 Hz, 1H), 7.11 (d, J = 7.9 Hz, 2H), 7.07 (s, 1H), 6.75 (d, J = 8.5 Hz, 1H), 6.66 (s, 1H), 6.60 (dd, J = 8.5, 2.7 Hz, 1H), 5.92 (s, 3H), 2.21 (s, 3H) 88 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.35 (d, J = 12.3 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.91 (t, J = 8.7 Hz, 1H), 6.64 (s, 1H), 6.58 (dd, J = 8.4, 2.8 Hz, 1H), 5.85 (d, J = 1.4 Hz, 1H), 2.19 (s, 3H) 89 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.49 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 6.99 (s, 1H), 6.94 (d, J = 8.9 Hz, 1H), 6.82 (d, J = 8.4 Hz, 2H), 6.07 (s, 1H) 90 .sup.1H NMR (300 MHz, CDCl3) δ 8.11 (s, 1H), 8.06 (d, J = 8.2 Hz, 2H), 7.98 (d, J = 8.2 Hz, 1H), 7.68-7.60 (m, 2H), 7.19 (d, J = 8.5 Hz, 1H), 6.71 (d, J = 2.9 Hz, 1H), 6.66 (dd, J = 8.5, 2.8 Hz, 1H), 6.13 (s, 1H), 5.53 (s, 1H), 3.93 (s, 3H), 2.23 (s, 3H) 91 .sup.1H NMR (300 MHz, DMSO) δ 12.67 (s, 1H), 8.81 (s, 1H), 8.01 (d, J = 12.4 Hz, 1H), 7.95 (d, J = 7.9 Hz, 2H), 7.81 (d, J = 8.6 Hz, 2H), 7.17 (d, J = 8.3 Hz, 1H), 7.10 (s, 1H), 6.58 (s, 1H), 6.52 (d, J = 8.1 Hz, 1H), 6.12 (s, 1H), 2.16 (s, 3H) 92 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.38 (dd, J = 12.2, 2.1 Hz, 1H), 7.29 (d, J = 8.2 Hz, 1H), 7.03 (d, J = 8.8 Hz, 2H), 6.94 (t, J = 8.7 Hz, 1H), 6.70 (d, J = 8.8 Hz, 2H), 6.05 (s, 3H) 93 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.49 (s, 1H), 8.79 (d, J = 2.5 Hz, 1H), 8.70 (s, 1H), 8.22-8.11 (m, 1H), 8.06 (s, 1H), 7.58 (s, 1H), 7.15 (s, 1H), 6.91 (s, 1H), 6.64 (d, J = 8.4 Hz, 2H), 6.31 (s, 1H). 94 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.11 (s, 1H), 9.63 (s, 1H), 8.91 (s, 1H), 8.21 (s, 1H), 7.51 (d, J = 8.7 Hz, 2H), 6.87-6.74 (m, 4H), 5.98 (s, 1H). 95 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 11.91 (s, 1H), 8.83 (s, 1H), 8.19 (s, 1H), 7.81 (d, J = 9.5 Hz, 1H), 7.31 (dt, J = 8.6, 5.6 Hz, 5H), 7.05 (s, 1H), 6.57 (d, J = 2.8 Hz, 1H), 6.50 (td, J = 6.9, 6.4, 3.4 Hz, 2H), 5.85 (s, 1H), 5.13 (s, 2H), 2.13 (s, 3H). 96 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.60 (s, 1H), 7.35 (d, J = 8.1 Hz, 2H), 7.16 (s, 1H), 6.99 (d, J = 7.3 Hz, 1H), 6.61 (t, J = 9.6 Hz, 3H), 6.08 (s, 1H), 5.28 (s, 2H), 4.98 (s, 1H), 4.37 (s, 2H), 2.20 (s, 3H). 97 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.06 (s, 1H), 8.72 (s, 1H), 8.24 (s, 1H), 7.95 (s, 1H), 7.82 (d, J = 9.5 Hz, 1H), 7.41-7.23 (m, 5H), 7.05 (s, 1H), 6.62 (d, J = 8.3 Hz, 2H), 6.51 (d, J = 9.6 Hz, 1H), 6.02 (s, 1H), 5.14 (s, 2H). 98 .sup.1H NMR (300 MHz, DMSO) δ 12.11 (s, 1H), 8.72 (s, 1H), 7.94 (s, 1H), 7.15 (d, J = 3.6 Hz, 1H), 7.04 (q, J = 9.1, 8.6 Hz, 2H), 6.77 (s, 1H), 6.63 (d, J = 8.7 Hz, 2H), 5.89 (s, 1H), 2.44 (s, 3H) 99 .sup.1H NMR (300 MHz, DMSO) δ 9.92 (s, 1H), 8.74 (s, 1H), 7.96 (s, 1H), 7.47 (s, 1H), 7.36 (s, 1H), 7.08 (d, J = 5.3 Hz, 2H), 6.63 (d, J = 8.6 Hz, 2H), 6.43 (q, J = 8.5 Hz, 1H), 5.97 (s, 1H) 100 .sup.1H NMR (300 MHz, DMSO) δ 8.81 (s, 1H), 7.14 (d, J = 8.5 Hz, 1H), 7.11-7.02 (m, 2H), 6.73 (s, 1H), 6.56 (s, 1H), 6.51 (dd, J = 8.5, 2.8 Hz, 1H), 6.43-6.37 (m, 1H), 5.77 (s, 1H), 2.43 (s, 3H), 2.13 (s, 3H) 101 .sup.1H NMR (300 MHz, DMSO) δ 12.04 (s, 1H), 8.84 (s, 1H), 7.44 (d, J = 4.8 Hz, 1H), 7.32 (d, J = 3.6 Hz, 1H), 7.16-7.01 (m, 3H), 6.57 (s, 1H), 6.51 (d, J = 8.4 Hz, 1H), 5.83 (s, 1H), 2.14 (s, 3H) 102 .sup.1H NMR (300 MHz, DMSO) δ 9.65 (s, 1H), 7.37-7.20 (m, 3H), 7.15 (s, 1H), 6.77 (s, 2H), 6.42 (s, 1H), 6.00 (d, J = 2.5 Hz, 1H), 2.44 (s, 2H), 2.19 (s, 2H), 1.99 (s, 3H) 103 .sup.1H NMR (300 MHz, DMSO) δ 11.85 (s, 1H), 8.91 (s, 1H), 7.15 (s, 2H), 7.05 (s, 1H), 6.93 (s, 1H), 6.58 (s, 1H), 6.52 (dd, J = 9.0, 2.5 Hz, 1H), 5.81 (s, 1H), 2.13 (s, 3H) 104 .sup.1H NMR (300 MHz, DMSO) δ 12.42 (s, 1H), 8.84 (s, 1H), 8.06 (s, 1H), 7.83 (s, 1H), 7.67 (s, 1H), 7.11 (d, J = 8.0 Hz, 1H), 6.86-6.76 (m, 1H), 6.66 (d, J = 8.2 Hz, 2H), 6.16 (s, 1H) 105 .sup.1H NMR (300 MHz, DMSO) δ 12.18 (s, 1H), 8.94 (s, 1H), 7.80 (s, 1H), 7.63 (s, 1H), 7.29 (s, 1H), 6.97 (s, 1H), 6.60 (s, 1H), 6.54 (d, J = 8.7 Hz, 1H), 5.93 (s, 1H), 2.14 (s, 3H) 109 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.53 (s, 1H), 8.32 (s, 1H), 7.86 (d, J = 8.4 Hz, 2H), 7.80 (s, 1H), 7.73 (d, J = 8.3 Hz, 2H), 7.38 (s, 1H), 7.12 (s, 1H), 6.97 (d, J = 8.7 Hz, 2H), 6.38 (s, 1H), 2.88 (s, 3H), 2.24 (s, 3H). 110 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.34 (s, 1H), 7.90-7.76 (m, 5H), 7.23 (s, 1H), 7.14 (s, 1H), 6.98 (d, J = 2.1 Hz, 1H), 6.92 (dd, J = 8.3, 2.5 Hz, 1H), 2.87 (s, 3H), 2.24 (s, 3H). 111 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.84 (s, 1H), 8.30 (s, 1H), 7.81 (d, J = 8.6 Hz, 2H), 7.79 (s, 1H), 7.68 (d, J = 8.5 Hz, 2H), 7.18 (d, J = 8.4 Hz, 1H), 7.11 (s, 1H), 7.03 (s, 1H), 6.59 (d, J = 2.8 Hz, 1H), 6.53 (dd, J = 8.5, 2.9 Hz, 1H), 6.06 (s, 1H), 2.62-2.53 (m, 2H), 1.13 (t, J = 7.5 Hz, 3H). 112 .sup.1H NMR (300 MHz, DMSO) δ 11.7 (s, 1H), 8.61 (s, 1H), 7.80 (s, 1H), 7.13 (s, 2H), 7.04 (s, 1H), 6.71 (s, 1H), 6.60 (s, 1H), 6.29 (s, 1H), 5.73 (s, 1H), 3.62 (s, 3H) 115 .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 11.91 (s, 1H), 9.01 (s, 1H), 7.92 (s, 1H), 7.77 (s, 1H), 7.62 (s, 1H), 7.34 (s, 3H), 6.97 (s, 1H), 6.63 (s, 1H), 6.57 (d, J = 8.5 Hz, 1H), 5.94 (s, 1H), 2.59-2.53 (m, 2H), 1.14 (t, J = 7.5 Hz, 3H). 117 .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.87 (s, 1H), 8.04 (d, J = 7.9 Hz, 1H), 7.94 (s, 1H), 7.45 (dt, J = 22.4, 7.3 Hz, 2H), 7.11 (s, 1H), 6.61 (d, J = 2.8 Hz, 1H), 6.55 (dd, J = 8.5, 2.9 Hz, 1H), 6.03 (s, 1H), 2.58 (q, J = 7.4 Hz, 2H), 1.15 (t, J = 7.5 Hz, 3H). 119 .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 11.92 (s, 1H), 8.96 (s, 1H), 7.17 (t, J = 3.7 Hz, 1H), 7.06 (d, J = 3.9 Hz, 1H), 7.04-6.98 (m, 1H), 6.61 (d, J = 2.9 Hz, 1H), 6.55 (dd, J = 8.5, 2.8 Hz, 1H), 5.78 (s, 1H), 2.56-2.51 (m, 2H), 1.14-1.08 (m, 3H). 121 .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.10 (s, 1H), 9.04 (s, 1H), 7.78 (d, J = 3.2 Hz, 1H), 7.60 (d, J = 3.3 Hz, 1H), 7.32 (s, 1H), 6.93 (d, J = 8.5 Hz, 1H), 6.64 (s, 1H), 6.58 (d, J = 8.4 Hz, 1H), 5.83 (s, 1H), 2.55 (d, J = 7.1 Hz, 2H), 1.12 (t, J = 7.5 Hz, 3H). 123 .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.18 (s, 1H), 8.81 (s, 1H), 8.13 (s, 2H), 7.37 (d, J = 32.0 Hz, 3H), 7.20-6.92 (m, 2H), 6.57 (d, J = 29.6 Hz, 3H), 2.62- 2.54 (m, 2H), 1.66 (s, H), 1.15 (t, J = 7.5 Hz, 3H). 125 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.98 (s, 1H), 10.56 (s, 1H), 8.81 (s, 1H), 8.16 (d, J = 10.8 Hz, 3H), 8.04 (d, J = 10.5 Hz, 2H), 7.82 (d, J = 8.7 Hz, 2H), 7.39 (s, 1H), 6.08 (s, 1H), 2.26 (s, 3H), 2.10 (s, 3H). 126 .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.17 (s, 1H), 9.63 (s, 1H), 9.20 (s, 1H), 7.70 (s, 1H), 7.51 (d, J = 8.6 Hz, 2H), 7.19 (s, 1H), 6.87-6.76 (m, 3H), 6.68 (dd, J = 8.9, 2.8 Hz, 1H), 6.14 (s, 1H). 127 .sup.1H NMR (300 MHz, CDCl3) δ 7.84-7.74 (m, 2H), 7.60 (s, 1H), 7.38-7.28 (m, 3H), 7.18-7.14 (m, 2H), 6.23 (s, 1H), 5.80 (s, 1H), 2.20 (s, 3H), 2.17 (s, 3H). 128 .sup.1H NMR (300 MHz, CDCl3) δ 8.07 (dd, J = 9.0, 2.2 Hz, 1H), 7.91 (dd, J = 6.2, 2.2 Hz, 1H), 7.58 (s, 1H), 7.44-7.38 (m, 3H), 7.34 (d, J = 2.1 Hz, 1H), 7.20- 7.13 (m, 2H), 6.29 (s, 1H), 5.85 (s, 1H), 2.26 (s, 3H), 2.16 (s, 3H). 132 .sup.1H NMR (300 MHz, DMSO) δ 8.91 (d, J = 1.7 Hz, 2H), 8.48 (d, J = 3.8 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.41 (s, 1H), 7.12 (s, 2H), 6.59 (d, J = 2.5 Hz, 1H), 6.53 (d, J = 8.6 Hz, 1H), 6.09 (s, 1H), 2.55 (q, J = 7.5 Hz, 2H), 1.12 (t, J = 7.5 Hz, 3H). 133 .sup.1H NMR (300 MHz, DMSO) δ 8.93 (s, 1H), 8.87 (s, 1H), 8.60 (s, 1H), 8.35 (s, 1H), 7.18 (s, 1H), 6.59 (d, J = 2.2 Hz, 1H), 6.53 (dd, J = 8.7, 2.5 Hz, 1H), 6.21 (s, 1H), 2.15 (s, 3H). 135 .sup.1H NMR (300 MHz, DMSO) δ 12.54 (s, 1H), 9.26 (s, 1H), 7.85-7.60 (m, 3H), 7.01-6.97 (m, 2H), 6.27 (s, 1H), 2.90 (s, 3H), 2.23 (s, 3H). 137 .sup.1H NMR (300 MHz, DMSO) δ 9.60 (s, 1H), 7.95 (d, J = 5.4 Hz, 2H), 7.04 (d, J = 5.4 Hz, 2H), 6.85 (d, J = 5.0 Hz, 1H), 6.73 (d, J = 1.4 Hz, 1H), 6.66 (dd, J = 5.0, 1.4 Hz, 1H), 6.39 (s, 1H), 3.59 (t, J = 2.9 Hz, 4H), 3.45 (d, J = 2.9 Hz, 2H), 3.38 (d, J = 3.0 Hz, 2H), 2.41-2.35 (m, 2H), 2.05(s, 3H), 1.12 (t, J = 4.5 Hz, 3H). 138 .sup.1H NMR (300 MHz, DMSO) δ 12.15 (s, 1H), 8.84 (s, 1H), 8.54 (d, J = 2.5 Hz, 1H), 7.89-7.75 (m, 5H), 7.19 (s, 1H), 7.02 (s, 1H), 6.59-6.52 (m, 3H), 6.04 (s, 1H), 2.56 (q, J = 7.4 Hz, 2H), 1.12 (t, J = 7.4 Hz, 3H). 140 .sup.1H NMR (300 MHz, MeOD) δ 7.80 (d, J = 7.8 Hz, 1H), 7.59 (s, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.23-7.08 (m, 3H), 6.68 (d, J = 2.7 Hz, 1H), 6.62 (dd, J = 8.5, 2.7 Hz, 1H), 5.99 (s, 1H), 2.27 (s, 3H). 141 .sup.1H NMR (300 MHz, DMSO) δ 7.77 (d, J = 7.3 Hz, 1H), 7.57 (s, 1H), 7.41 (d, J = 7.7 Hz, 1H), 7.20-7.10 (m, 3H), 6.69 (d, J = 2.7 Hz, 1H), 6.61 (dd, J = 8.5, 2.9 Hz, 1H), 5.94 (s, 1H), 2.65 (q, J = 7.5 Hz, 2H), 1.23 (t, J = 7.5 Hz, 3H). 142 .sup.1H NMR (300 MHz, DMSO) δ 12.31 (s, 1H), 9.83 (s, 1H), 9.66 (s, 1H), 7.89 (d, J = 7.5 Hz, 1H), 7.76 (s, 1H), 7.52-7.48 (m, 3H), 7.28-7.25 (m, 1H), 6.82 (d, J = 8.3 Hz, 2H), 6.25 (s, 1H), 2.00 (s, 3H). 143 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.24 (s, 1H), 10.18 (s, 1H), 9.69 (s, 1H), 8.70 (s, 1H), 7.84 (s, 1H), 7.52 (s, 1H), 7.48 (d, J = 3.9 Hz, 2H), 6.81 (d, J = 8.3 Hz, 2H), 6.11 (s, 1H), 2.25 (s, 3H), 2.03 (s, 3H). 146 .sup.1H NMR (300 MHz, MeOD) δ 7.75 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.5 Hz, 1H), 6.70 (d, J = 2.7 Hz, 1H), 6.62 (dd, J = 8.5, 2.8 Hz, 1H), 5.93 (s, 1H), 2.63 (q, J = 7.5 Hz, 2H), 1.21 (t, J = 7.5 Hz, 3H). 147 .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.12 (s, 1H), 9.61 (s, 1H), 9.56 (s, 1H), 7.55-7.48 (m, 2H), 7.34 (d, J = 2.4 Hz, 1H), 7.26 (dd, J = 8.7, 2.5 Hz, 1H), 7.19 (s, 1H), 6.82-6.78 (m, 2H), 6.10 (s, 1H), 2.24 (d, J = 7.2 Hz, 2H), 2.21 (d, J = 1.9 Hz, 3H), 1.60 (h, J = 7.4 Hz, 2H), 0.91 (t, J = 7.4 Hz, 3H). 148 .sup.1H NMR (300 MHz, DMSO) δ 9.99 (s, 1H), 8.40 (s, 1H), 8.22 (s, 1H), 7.99 (d, J = 8.5 Hz, 2H), 7.88 (s, 1H), 7.83 (d, J = 8.0 Hz, 2H), 7.55 (s, 1H), 7.46 (s, 1H), 7.15 (s, 1H), 7.00 (s, 1H), 6.74 (s, 1H), 2.09 (s, 3H), 2.06 (s, 3H). 149 .sup.1H NMR (300 MHz, DMSO) δ 12.21 (s, 1H), 9.61 (s, 1H), 7.30 (s, 1H), 7.26-7.22 (m, 5H), 7.13 (s, 1H), 6.07 (s, 1H), 2.16 (s, 6H), 1.98 (s, 3H). 150 .sup.1H NMR (300 MHz, DMSO) δ 11.91 (s, 1H), 8.71 (s, 1H), 8.41 (s, 1H), 7.28-7.23 (m, 2H), 6.85 (s, 1H), 6.55-6.48 (m, 2H), 5.87 (s, 1H), 2.18 (s, 6H), 2.14 (s, 3H). 151 .sup.1H NMR (300 MHz, DMSO) δ 12.24 (s, 1H), 10.94 (s, 1H), 9.63 (s, 1H), 7.71 (s, 1H), 7.52 (d, J = 8.2 Hz, 2H), 7.37-7.31 (m, 3H), 6.81 (d, J = 8.1 Hz, 2H), 6.18 (s, 1H), 2.24 (s, 3H). 152 .sup.1H NMR (300 MHz, DMSO) δ 11.84 (s, 1H), 9.54 (s, 1H), 7.46 (d, J = 8.7 Hz, 2H), 7.09 (s, 1H), 6.76 (d, J = 8.3 Hz, 2H), 6.40 (s, 1H), 6.35-6.32 (m, 1H), 5.78 (s, 1H), 4.55 (s, 2H), 2.09 (s, 3H). 153 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.12 (s, 1H), 9.63 (s, 1H), 7.45 (s, 1H), 7.34-7.30 (m, 3 H), 7.25-7.19 (m, 2H), 6.13 (s, 1H), 2.20 (s, 9H), 1.98 (s, 3H), 1.00 (s, 9H), 0.20 (s, 6H). 156 .sup.1H NMR (300 MHz, DMSO) δ 12.25 (s, 1H), 8.85 (s, 1H), 8.75 (d, J = 2.4 Hz, 1H), 8.14 (dd, J = 8.4, 2.4 Hz, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.17 (s, 1H), 7.10 (s, 1H), 6.58 (d, J = 2.5 Hz, 1H), 6.52 (dd, J = 8.5, 2.7 Hz, 1H), 6.12 (s, 1H), 2.14 (s, 3H). 157 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.11 (s, 1H), 9.62 (s, 1H), 9.21 (s, 1H), 7.50 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 7.9 Hz, 3H), 6.80 (d, J = 8.0 Hz, 2H), 6.07 (s, 1H), 4.08 (q, J = 6.6 Hz, 2H), 2.19 (s, 3H), 1.23 (t, J = 6.5 Hz, 3H). 158 .sup.1H NMR (300 MHz, MeOD) δ 7.39 (dd, J = 12.3, 1.9 Hz, 1H), 7.31 (d, J = 8.5 Hz, 2H), 7.04 (s, 1H), 7.00 (dd, J = 8.5, 2.4 Hz, 1H), 6.94 (t, J = 8.7 Hz, 1H), 6.14 (s, 1H), 2.87 (s, 3H), 2.26 (s, 3H). 159 .sup.1H NMR (300 MHz, Chloroform-d) δ 7.85 (d, J = 7.9 Hz, 2H), 7.35 (s, 1H), 7.23 (s, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.88 (d, J = 7.9 Hz, 2H), 6.76 (s, 1H), 6.13 (s, 1H), 3.78 (s, 3H), 2.21 (s, 3H). 160 .sup.1H NMR (300 MHz, MeOD) δ 7.38 (dd, J = 12.3, 2.1 Hz, 1H), 7.29 (d, J = 8.3 Hz, 1H), 7.12 (d, J = 8.5 Hz, 1H), 6.94 (t, J = 8.7 Hz, 1H), 6.70 (d, J = 2.8 Hz, 1H), 6.62 (dd, J = 8.5, 2.9 Hz, 1H), 5.85 (s, 1H), 2.63 (q, J = 7.5 Hz, 2H), 1.21 (t, J = 7.5 Hz, 3H). 161 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.18 (s, 1H), 10.04 (s, 1H), 9.26 (s, 1H), 7.49 (d, J = 12.5 Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.22-7.09 (m, 3H), 6.97 (t, J = 8.7 Hz, 1H), 6.14 (s, 1H), 3.62 (s, 3H), 2.19 (s, 3H). 162 .sup.1H NMR (300 MHz, DMSO) δ 9.18 (s, 1H), 7.71 (s, 1H), 7.58 (s, 1H), 7.49-7.44 (m, 1H), 7.30 (d, J = 8.6 Hz, 1H), 6.97 (t, J = 8.7 Hz, 1H), 6.59-6.51 (m, 2H), 6.06 (s, 1H). 163 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.28 (s, 1H), 9.69 (s, 1H), 8.70 (s, 1H), 8.26 (s, 1H), 7.96 (t, J = 8.3 Hz, 1H), 7.53 (d, J = 8.6 Hz, 2H), 7.01 (dd, J = 8.8, 3.3 Hz, 1H), 6.82 (d, J = 8.5 Hz, 2H), 6.06 (s, 1H). 164 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 11.87 (s, 1H), 9.57 (s, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.19 (d, J = 8.5 Hz, 1H), 6.80 (d, J = 3.1 Hz, 2H), 6.76 (s, 1H), 6.44 (d, J = 2.4 Hz, 1H), 6.38 (dd, J = 8.6, 2.6 Hz, 1H), 5.82 (s, 1H), 4.85 (s, 1H), 3.67-3.52 (m, 4H), 3.08 (t, J = 6.8 Hz, 2H), 2.47 (s, 2H), 2.45-2.36 (m, 4H), 2.14 (s, 3H). 165 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.53 (s, 1H), 9.73 (s, 1H), 7.99 (s, 1H), 7.83 (s, 1H), 7.53 (d, J = 8.6 Hz, 2H), 7.46 (d, J = 6.8 Hz, 2H), 6.82 (d, J = 8.6 Hz, 2H), 6.31 (s, 1H), 2.26 (s, 3H). 166 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.06 (s, 1H), 9.65 (s, 1H), 7.49 (d, J = 8.7 Hz, 2H), 7.04 (s, 1H), 6.79 (d, J = 8.9 Hz, 3H), 6.70 (dd, J = 8.7, 2.8 Hz, 1H), 6.01 (s, 1H), 3.56 (q, J = 4.3 Hz, 4H), 2.97 (dt, J = 19.4, 5.1 Hz, 4H), 2.20 (s, 3H), 2.03 (s, 3H). 167 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.61 (d, J = 8.7 Hz, 2H), 7.48-7.33 (m, 6H), 7.05 (d, J = 9.0 Hz, 3H), 6.73 (d, J = 2.6 Hz, 1H), 6.66 (dd, J = 8.7, 2.8 Hz, 1H), 6.04 (s, 1H), 5.14 (s, 2H), 2.97-2.87 (m, 4H), 2.87-2.78 (m, 4H), 2.20 (s, 3H). 168 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 11.64 (s, 1H), 9.50 (s, 1H), 8.96 (s, 1H), 7.41 (d, J = 8.6 Hz, 2H), 6.77-6.69 (m, 2H), 6.67-6.57 (m, 1H), 6.45 (s, 2H), 5.33 (s, 1H), 2.10 (s, 6H). 169 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.08 (s, 1H), 9.63 (s, 1H), 8.82 (s, 2H), 7.49 (d, J = 8.6 Hz, 2H), 7.09 (s, 1H), 6.80 (d, J = 8.6 Hz, 3H), 6.73 (dd, J = 8.8, 2.9 Hz, 1H), 6.03 (s, 1H), 3.33 (s, 4H), 3.17 (d, J = 4.2 Hz, 4H), 2.21 (s, 3H). 170 .sup.1H NMR (300 MHz, DMSO) δ 12.48 (s, 1H), 9.66 (s, 1H), 8.33 (d, 2H), 7.87 (d, J = 8.6 Hz, 2H), 7.81 (s, 1H), 7.74 (d, J = 7.7 Hz, 2H), 7.39 (d, J = 8.8 Hz, 1H), 7.28 (s, 1H), 7.13 (s, 1H), 6.31 (s, 1H), 1.99 (s, 3H). 171 .sup.1H NMR (300 MHz, DMSO) δ 8.51 (s, 1H), 8.33 (s, 1H), 7.87 (d, J = 8.7 Hz, 2H), 7.81 (s, 1H), 7.74 (d, J = 8.7 Hz, 2H), 7.30 (d, J = 7.7 Hz, 1H), 7.13 (s, 1H), 7.08 (d, J = 8.8 Hz, 2H), 6.33 (s, 1H), 2.87 (s, 3H). 172 .sup.1H NMR (300 MHz, DMSO) δ 12.48 (s, 1H), 9.20 (s, 1H), 8.32 (s, 1H), 7.81- 7.68 (m, 7H), 7.13 (s, 1H), 6.62-6.51 (m, 2H), 6.23 (s, 1H). 173 .sup.1H NMR (300 MHz, DMSO) δ 8.92 (s, 1H), 8.32 (s, 1H), 7.84 (d, J = 8.7 Hz, 2H), 7.80 (s, 1H), 7.72 (d, J = 8.6 Hz, 2H), 7.48 (s, 1H), 7.12 (s, 1H), 6.98- 6.96 (m, 2H), 6.30 (s, 1H). 174 .sup.1H NMR (300 MHz, DMSO) δ 12.66 (s, 1H), 9.87 (s, 1H), 8.93 (s, 1H), 8.33 (s, 1H), 7.82-7.76 (m, 6H), 7.61 (s, 1H), 7.30 (d, J = 9.0 Hz, 1H), 7.13 (s, 1H), 6.49 (s, 1H), 2.01 (s, 3H). 175 .sup.1H NMR (300 MHz, DMSO) δ 8.40 (s, 1H), 7.98 (d, J = 8.6 Hz, 2H), 7.87 (s, 1H), 7.82 (d, J = 8.6 Hz, 2H), 7.15 (s, 1H), 7.01 (t, J = 9.2 Hz, 1H), 6.92 (d, J = 14 Hz, 1H), 6.81 (d, J = 9.4 Hz, 1H), 6.73 (s, 1H), 176 .sup.1H NMR (300 MHz, DMSO) δ 12.50 (s, 1H), 9.21 (s, 1H), 8.32 (s, 1H), 7.81- 7.75 (m, 5H), 7.25 (s, 1H), 7.13 (s, 1H), 6.81 (s, 1H), 6.69 (d, J = 8.8 Hz, 1H), 6.35 (s, 1H). 177 .sup.1H NMR (300 MHz, DMSO) δ 12.61 (s, 1H), 9.70 (s, 1H), 8.33 (s, 1H), 7.84- 7.76 (m, 5H), 7.31 (s, 1H), 7.13 (s, 1H), 7.06 (s, 1H), 6.98 (d, J = 8.3 Hz, 1H), 6.42 (s, 1H), 2.59 (q, J = 7.4 Hz, 2H), 1.97 (s, 3H), 1.15 (t, J = 7.4 Hz, 3H). 178 .sup.1H NMR (300 MHz, DMSO) δ 9.78 (s, 1H), 8.41 (s, 1H), 8.00 (d, J = 8.5 Hz, 2H), 7.88-7.81 (m, 4H), 7.15 (s, 1H), 6.90 (d, J = 11.5 Hz, 1H), 6.75 (s, 1H), 2.11 (s, 3H), 2.07 (s, 3H). 180 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.47 (s, 1H), 9.79 (s, 1H), 8.55 (d, J = 2.5 Hz, 1H), 7.96-7.74 (m, 5H), 7.60 (s, 1H), 7.39-7.24 (m, 3H), 6.57 (t, J = 2.1 Hz, 1H), 6.31 (s, 1H), 3.87 (t, J = 6.3 Hz, 2H), 2.77 (t, J = 6.3 Hz, 2H), 2.23 (s, 3H). 181 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.92 (s, 1H), 9.62 (s, 1H), 8.55 (d, J = 2.5 Hz, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.84 (d, J = 8.9 Hz, 2H), 7.77 (d, J = 1.7 Hz, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.35 (d, J = 2.4 Hz, 2H), 7.29 (dd, J = 8.6, 2.5 Hz, 1H), 6.60-6.54 (m, 1H), 6.32 (s, 1H), 4.00 (d, J = 12.8 Hz, 12H), 2.23 (s, 3H). 182 .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.40 (dd, J = 12.4, 1.7 Hz, 1H), 7.37-7.18 (m, 4H), 6.95 (t, J = 8.7 Hz, 1H), 6.13 (s, 1H), 3.12 (s, 2H), 2.38 (s, 6H), 2.28 (s, 3H). 183 .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.40 (dd, J = 12.2, 2.0 Hz, 1H), 7.36-7.22 (m, 4H), 6.95 (t, J = 8.7 Hz, 1H), 6.12 (s, 1H), 3.73 (t, J = 4.7 Hz, 4H), 2.78 (t, J = 7.0 Hz, 2H), 2.64-2.50 (m, 6H), 2.27 (s, 3H). 184 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.54 (s, 1H), 9.25 (s, 1H), 8.24-8.04 (m, 1H), 7.79 (dd, J = 8.6, 5.4 Hz, 3H), 7.38-7.13 (m, 2H), 7.03-6.45 (m, 2H). 185 .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.40 (dd, J = 12.3, 2.1 Hz, 1H), 7.36-7.24 (m, 4H), 6.96 (t, J = 8.7 Hz, 1H), 6.13 (s, 1H), 3.20 (t, J = 6.5 Hz, 2H), 2.76 (t, J = 6.7 Hz, 2H), 2.71 (s, 6H), 2.27 (s, 3H). 187 .sup.1H NMR (300 MHz, DMSO-d 6) δ 12.51 (s, 1H), 9.18 (s, 1H), 8.56 (d, J = 2.3 Hz, 1H), 7.91 (d, J = 8.7 Hz, 2H), 7.84 (d, J = 8.4 Hz, 2H), 7.77 (s, 1H), 7.40 (s, 1H), 6.98-6.94 (m, 2H), 6.61-6.53 (m, 1H), 6.36 (s, 1H), 2.88 (s, 3H), 2.23 (s, 3H). 188 .sup.1H NMR (300 MHz, DMSO-d 6) δ 12.47 (s, 1H), 9.53 (s, 1H), 8.54 (d, J = 2.5 Hz, 1H), 7.90 (d, J = 8.6 Hz, 2H), 7.82 (d, J = 8.6 Hz, 2H), 7.76 (d, J = 1.7 Hz, 1H), 7.53 (s, 1H), 6.97 (d, J = 6.3 Hz, 3H), 6.56 (t, J = 2.2 Hz, 1H), 6.27 (s, 1H), 5.75 (s, 1H). 189 .sup.1H NMR (300 MHz, DMSO-d 6) δ 12.33 (s, 1H), 9.20 (s, 1H), 8.54 (d, J = 2.5 Hz, 1H), 7.90 (d, J = 8.5 Hz, 2H), 7.80 (d, J = 8.6 Hz, 2H), 7.76 (d, J = 1.7 Hz, 1H), 7.65 (s, 1H), 6.63-6.55 (m, 2H), 6.52 (dd, J = 8.8, 2.8 Hz, 1H), 6.20 (s, 1H). 190 .sup.1H NMR (300 MHz, DMSO) δ 12.52 (s, 1H), 9.17 (s, 1H), 7.79 (d, J = 7.6 Hz, 2H), 7.62 (s, 1H), 7.53 (d, J = 7.3 Hz, 2H), 7.37 (s, 1H), 6.97-6.94 (m, 2H), 6.32 (s, 1H), 2.88 (s, 3H), 2.22 (s, 3H). 191 .sup.1H NMR (300 MHz, DMSO) δ 11.38 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 2.5 Hz, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.29 (s, 1H), 7.21-7.08 (m, 2H), 6.96-6.94 (m, 2H), 6.25 (s, 1H), 5.71 (s, 1H), 2.87 (s, 3H), 2.24 (s, 3H). 192 .sup.1H NMR (300 MHz, DMSO-d 6) δ 12.33 (s, 1H), 9.20 (s, 1H), 8.54 (d, J = 2.5 Hz, 1H), 7.90 (d, J = 8.5 Hz, 2H), 7.80 (d, J = 8.6 Hz, 2H), 7.76 (d, J = 1.7 Hz, 1H), 7.65 (s, 1H), 6.63-6.55 (m, 2H), 6.52 (dd, J = 8.8, 2.8 Hz, 1H), 6.20 (s, 1H). 193 .sup.1H NMR (300 MHz, DMSO-d 6) δ 12.38 (s, 1H), 9.26 (s, 1H), 8.55 (d, J = 2.5 Hz, 1H), 7.91 (d, J = 8.6 Hz, 2H), 7.82 (d, J = 8.6 Hz, 2H), 7.77 (d, J = 1.6 Hz, 1H), 7.62 (d, J = 8.9 Hz, 1H), 7.32 (s, 1H), 6.82 (d, J = 2.7 Hz, 1H), 6.69 (dd, J = 8.9, 2.8 Hz, 1H), 6.56 (t, J = 2.1 Hz, 1H), 6.33 (s, 1H). 194 .sup.1H NMR (300 MHz, DMSO-d 6) δ 12.15 (s, 1H), 8.74 (s, 1H), 7.68 (d, J = 7.0 Hz, 2H), 7.40 (t, J = 7.4 Hz, 2H), 7.29 (t, J = 7.3 Hz, 1H), 6.98 (s, 1H), 6.57 (d, J = 2.8 Hz, 1H), 6.51 (dd, J = 8.5, 2.9 Hz, 1H), 6.05 (s, 1H), 2.16 (s, 3H). 195 .sup.1H NMR (300 MHz, DMSO-d 6) δ 12.41 (s, 1H), 9.63 (s, 1H), 7.70 (d, J = 7.5 Hz, 2H), 7.58 (s, 1H), 7.43 (t, J = 7.2 Hz, 2H), 7.33 (d, J = 7.5 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 6.26 (s, 1H), 2.21 (s, 3H), 1.99 (s, 3H). 196 .sup.1H NMR (300 MHz, DMSO-d 6) δ 12.48 (s, 1H), 9.17 (s, 1H), 7.71 (d, J = 7.6 Hz, 2H), 7.49-7.29 (m, 4H), 6.95 (d, J = 9.7 Hz, 2H), 6.31 (s, 1H), 2.87 (s, 3H), 2.23 (s, 3H). 197 .sup.1H NMR (300 MHz, DMSO-d 6) δ 12.31 (s, 1H), 9.15 (s, 1H), 7.64 (d, J = 8.4 Hz, 3H), 7.30 (s, 1H), 7.00 (d, J = 8.5 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 6.21 (s, 1H), 3.79 (s, 3H), 2.87 (s, 3H), 2.22 (s, 3H). 198 .sup.1H NMR (300 MHz, DMSO) δ 12.76 (s, 1H), 9.19 (s, 1H), 7.91 (s, 4H), 7.54 (m, 2H), 6.98-6.95 (m, 2H), 6.47 (s, 1H), 2.88 (s, 3H), 2.23 (s, 3H). 199 .sup.1H NMR (300 MHz, DMSO) δ 12.55 (s, 1H), 9.19 (s, 1H), 7.75-7.62 (m, 5H), 7.40 (s, 1H), 6.98-6.95 (m, 2H), 6.34 (s, 1H), 2.88 (s, 3H), 2.23 (s, 3H). 200 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.29 (s, 1H), 10.03 (s, 1H), 9.16 (s, 1H), 7.61 (s, 1H), 7.51 (dd, J = 12.5, 2.1 Hz, 1H), 7.40-7.27 (m, 2H), 7.05-6.89 (m, 3H), 6.22 (s, 1H), 2.87 (s, 3H), 2.22 (s, 3H). 201 .sup.1H NMR (300 MHz, DMSO-d 6) δ 12.19 (s, 1H), 9.62 (s, 1H), 7.56 (d, J = 8.4 Hz, 3H), 7.30 (s, 1H), 7.24 (d, J = 8.9 Hz, 1H), 7.18 (s, 1H), 6.99 (d, J = 8.5 Hz, 2H), 6.13 (s, 1H), 4.10 (q, J = 5.3 Hz, 4H), 3.74 (t, J = 4.8 Hz, 4H), 2.20 (s, 3H), 1.98 (s, 3H). 202 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.02 (s, 1H), 8.70 (s, 1H), 7.53 (d, J = 8.3 Hz, 2H), 7.34 (s, 1H), 6.97 (d, J = 8.5 Hz, 2H), 6.89 (s, 1H), 6.55 (d, J = 2.9 Hz, 1H), 6.50 (d, J = 8.6 Hz, 1H), 5.94 (s, 1H), 3.74 (dd, J = 5.9, 3.6 Hz, 4H), 3.14 (t, J = 4.9 Hz, 4H), 2.15 (s, 3H). 203 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.25 (s, 1H), 7.65 (s, 1H), 7.57 (d, J = 8.2 Hz, 2H), 7.28 (s, 1H), 7.04-6.89 (m, 4H), 6.18 (s, 1H), 3.74 (t, J = 4.2 Hz, 4H), 3.23-3.10 (m, 4H), 2.87 (s, 3H), 2.22 (s, 3H). 204 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.46 (s, 1H), 9.16 (s, 1H), 7.85-7.70 (m, 2H), 7.65 (s, 1H), 7.36 (s, 1H), 7.34-7.18 (m, 2H), 7.01-6.90 (m, 2H), 6.30 (s, 1H), 2.87 (s, 3H), 2.23 (s, 3H). 205 (300 MHz, DMSO-d.sub.6) δ 12.19 (s, 1H), 8.76 (s, 1H), 7.69 (s, 4H), 7.30 (s, 1H), 6.99 (s, 1H), 6.57 (s, 1H), 6.52 (d, J = 8.8 Hz, 1H), 6.03 (s, 1H), 3.86 (t, J = 7.0 Hz, 2H), 2.16 (s, 3H), 2.08 (p, J = 7.6 Hz, 3H) 206 (300 MHz, DMSO-d.sub.6)δ 12.22 (s, 1H) 8.94 (s, 2H), 8.78 (s, 1H), 7.67 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.2 Hz, 3H), 7.02 (s, 1H), 6.72-6.62 (m, 1H), 6.57 (d, J = 2.8 Hz, 1H), 6.52 (dd, J = 8.4, 2.8 Hz, 1H), 6.05 (s, 1H), 4.14 (s, 4H), 3.62 (t, J = 5.6 Hz, 2H), 2.40 (t, J = 6.2 Hz, 2H), 2.16 (s, 3H), 2.12-2.04 (m, 1H), 1.91-1.79 (m, 5H), 1.75 (s, 6H), 1.56 (d, J = 14.3 Hz, 1H), 1.24 (s, 1H), 0.97-0.72 (m, 1H). 207 (300 MHz, DMSO-d 6) δ 12.45 (s, 1H), 9.28 (s, 1H), 8.55 (s, 1H), 7.91 (d, J = 7.4 Hz, 2H), 7.83 (d, J = 8.6 Hz, 2H), 7.77 (d, J = 1.3 Hz, 1H), 7.57 (s, 1H), 7.24 (s, 1H), 7.16 (d, J = 7.8 Hz, 2H), 6.57 (t, J = 2.0 Hz, 1H), 6.29 (s, 1H), 3.63 (s, 3H), 2.21 (s, 3H). 208 (300 MHz, DMSO-d 6) δ 12.46 (s, 1H), 9.29 (s, 1H), 8.56 (s, 1H), 7.92 (d, J = 7.9 Hz, 2H), 7.84 (d, J = 8.5 Hz, 2H), 7.78 (d, J = 1.7 Hz, 1H), 7.57 (s, 1H), 7.26 (s, 1H), 7.17 (d, J = 9.8 Hz, 2H), 6.58 (t, J = 2.1 Hz, 1H), 6.30 (s, 1H), 3.64 (s, 3H), 2.22 (s, 3H). 209 (300 MHz, DMSO-d 6) δ 12.44 (s, 1H), 9.26 (s, 1H), 8.55 (d, J = 2.5 Hz, 1H), 7.90 (d, J = 8.6 Hz, 2H), 7.83 (d, J = 8.5 Hz, 2H), 7.77 (d, J = 1.7 Hz, 1H), 7.56 (s, 1H), 7.25 (s, 1H), 7.17 (d, J = 12.5 Hz, 2H), 6.57 (t, J = 2.1 Hz, 1H), 6.28 (s, 1H), 4.09 (q, J = 7.1 Hz, 2H), 2.21 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H). 210 (300 MHz, DMSO-d.sub.6) δ 12.37 (s, 1H), 9.72-9.56 (m, 1H), 7.72 (s, 4H), 7.58 (s, 1H), 7.32 (s, 1H), 7.29-7.20 (m, 2H), 6.24 (s, 1H), 3.90-3.82 (m, 2H), 2.22 (s, 3H), 2.13-2.04 (m, 9H), 1.99 (d, J = 2.0 Hz, 3H). 211 (300 MHz, DMSO-d.sub.6) δ 12.40 (s, 1H), 9.64 (s, 1H), 7.70 (d, J = 7.9 Hz, 2H), 7.59 (s, 1H), 7.39-7.21 (m, 5H), 6.25 (s, 1H), 4.11 (q, J = 5.2 Hz, 2H), 3.63 (d, J = 6.1 Hz, 2H), 3.18 (d, J = 5.2 Hz, 4H), 2.41 (t, J = 6.1 Hz, 3H), 2.22 (s, 3H), 2.00 (s, 3H), 1.87 (d, J = 5.4 Hz, 4H). 212 (500 MHz, Methanol-d.sub.4) δ 8.37 (d, J = 2.3 Hz, 1H), 7.86 (dd, J = 8.7, 2.5 Hz, 1H), 7.05 (d, J = 8.5 Hz, 1H), 6.75 (d, J = 8.6 Hz, 1H), 6.62 (d, J = 2.8 Hz, 1H), 6.56 (dd, J = 8.5, 2.9 Hz, 1H), 5.85 (s, 1H), 3.86 (s, 3H). 213 (300 MHz, DMSO-d 6) δ 12.45 (s, 1H), 9.17 (s, 1H), 8.54 (d, J = 2.4 Hz, 1H), 8.02 (d, J = 8.6 Hz, 1H), 7.64 (s, 1H), 7.38 (s, 1H), 7.00-6.86 (m, 3H), 6.30 (s, 1H), 3.88 (s, 3H), 2.87 (s, 3H), 2.22 (s, 3H). 214 (300 MHz, DMSO-d 6) δ 12.39 (s, 1H), 9.64 (s, 1H), 8.53 (d, J = 2.4 Hz, 1H), 8.02 (d, J = 8.7 Hz, 1H), 7.57 (s, 1H), 7.38-7.21 (m, 3H), 6.90 (d, J = 7.6 Hz, 1H), 6.24 (s, 1H), 3.88 (s, 3H), 2.21 (s, 3H), 1.99 (s, 3H). 215 (300 MHz, DMSO-d.sub.6) δ 12.08 (s, 1H), 9.19 (s, 1H), 9.07 (s, 1H), 8.77 (s, 1H), 7.72-7.65 (m, 2H), 7.37 (d, J = 8.6 Hz, 2H), 7.22 (s, 1H), 7.05-6.97 (m, 2H), 6.58 (dd, J = 5.8, 2.8 Hz, 2H), 6.52 (dt, J = 8.0, 3.7 Hz, 2H), 6.00 (s, 1H), 4.10 (d, J = 5.4 Hz, 1H), 3.66 (t, J = 4.5 Hz, 2H), 3.18 (d, J = 4.4 Hz, 3H), 3.09 (t, J = 4.5 Hz, 2H), 2.16 (s, 3H), 2.08 (s, 2H), 1.99 (s, 2H). 216 (300 MHz, DMSO-d 6) δ 12.26 (s, 1H), 8.85 (s, 1H), 8.81 (d, J = 1.7 Hz, 1H), 8.64 (d, J = 2.2 Hz, 1H), 8.28 (dd, J = 8.6, 2.2 Hz, 1H), 7.95 (d, J = 8.6 Hz, 1H), 7.85 (s, 1H), 7.16 (s, 2H), 6.60 (d, J = 2.1 Hz, 2H), 6.54 (dd, J = 8.6, 2.5 Hz, 1H), 6.15 (s, 1H), 2.17 (s, 3H). 217 (300 MHz, DMSO-d 6) δ 12.60 (s, 1H), 9.66 (s, 1H), 8.84 (s, 1H), 8.64 (d, J = 2.6 Hz, 1H), 8.30 (d, J = 9.8 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.85 (s, 1H), 7.39 (s, 1H), 7.34 (s, 1H), 7.27 (d, J = 8.2 Hz, 1H), 6.64-6.56 (m, 1H), 6.38 (s, 1H), 2.22 (s, 3H), 1.99 (s, 3H). 218 (300 MHz, DMSO-d 6) δ 12.60 (s, 1H), 9.20 (s, 1H), 8.85 (s, 1H), 8.64 (d, J = 2.6 Hz, 1H), 8.31 (d, J = 8.5 Hz, 1H), 7.98 (d, J = 8.5 Hz, 1H), 7.85 (s, 1H), 7.47 (s, 1H), 6.98-6.95 (m, 2H), 6.64-6.56 (m, 1H), 6.44 (s, 1H), 2.88 (s, 3H), 2.23 (s, 3H). 219 (500 MHz, DMSO-d.sub.6) δ 9.97 (s, 3H), 7.74 (d, J = 8.4 Hz, 4H), 7.63 (s, 4H), 7.29 (d, J = 8.6 Hz, 4H), 6.41 (s, 3H), 5.70 (s, 3H), 2.10 (s, 3H), 2.04 (s, 1H). 220 (500 MHz, DMSO-d 6) δ 12.10 (s, 1H), 8.69 (s, 1H), 7.51 (d, J = 8.3 Hz, 2H), 6.89 (s, 1H), 6.80 (d, J = 8.5 Hz, 2H), 6.69 (s, 1H), 6.54 (d, J = 2.7 Hz, 1H), 6.45 (dd, J = 8.5, 2.8 Hz, 1H), 2.94 (s, 6H), 2.16 (s, 3H). 221 (300 MHz, DMSO-d 6) δ 12.50 (s, 1H), 9.23 (s, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.81 (d, J = 6.9 Hz, 1H), 7.70 (s, 1H), 7.50 (s, 1H), 7.41-7.29 (m, 2H), 6.98 (d, J = 9.2 Hz, 2H), 6.29 (s, 1H), 2.88 (s, 3H), 2.22 (s, 3H). 222 (300 MHz, DMSO-d 6) δ 12.17 (s, 1H), 9.35 (s, 1H), 8.03-7.64 (m, 3H), 7.56- 6.90 (m, 6H), 6.21 (s, 1H), 3.64 (s, 3H), 2.21 (s, 3H). 223 (300 MHz, DMSO-d 6) δ 12.63 (d, J = 7.0 Hz, 1H), 12.21 (s, 1H), 9.32 (s, 1H), 7.95 (s, 1H), 7.80 (s, 1H), 7.69 (s, 1H), 7.43 (d, J = 42.1 Hz, 3H), 7.28-7.14 (m, 2H), 7.00 (s, 1H), 6.21 (s, 1H), 4.15-4.07 (m, 2H), 2.21 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H). 224 (300 MHz, DMSO-d 6) δ 12.63 (s, 1H), 12.18 (s, 1H), 9.34 (s, 1H), 7.94 (d, J = 7.4 Hz, 1H), 7.80 (d, J = 7.2 Hz, 1H), 7.69 (s, 1H), 7.34 (h, J = 6.7, 6.2 Hz, 3H), 7.24-7.17 (m, 2H), 6.22 (s, 1H), 3.34 (s, 3H), 2.21 (s, 3H). 225 (300 MHz, DMSO-d 6) δ 9.94 (s, 1H), 8.70 (d, J = 2.1 Hz, 1H), 8.24 (d, J = 8.7 Hz, 2H), 8.06 (d, J = 8.8 Hz, 2H), 7.85 (s, 1H), 7.15 (d, J = 6.6 Hz, 2H), 7.07 (d, J = 8.8 Hz, 1H), 6.67 (s, 1H), 6.63 (s, 1H), 3.07 (s, 3H), 2.71 (s, 3H), 2.15 (s, 3H). 226 (300 MHz, DMSO-d.sub.6) δ 12.42 (s, 1H), 9.86 (s, 1H), 7.90 (s, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.54 (s, 1H), 7.28 (dd, J = 8.9, 2.5 Hz, 1H), 7.02 (d, J = 8.6 Hz, 2H), 6.33 (s, 1H), 3.80 (s, 3H), 2.01 (s, 3H). 227 (300 MHz, DMSO-d 6) δ 12.32 (s, 1H), 8.80 (s, 1H), 8.56 (d, J = 2.5 Hz, 1H), 8.13 (s, 1H), 7.77 (q, J = 3.5 Hz, 2H), 7.63 (d, J = 7.7 Hz, 1H), 7.51 (t, J = 7.9 Hz, 1H), 7.22 (s, 1H), 7.05 (s, 1H), 6.61-6.56 (m, 2H), 6.53 (dd, J = 8.5, 2.8 Hz, 1H), 6.16 (s, 1H), 2.16 (s, 3H). 228 .sup.1H NMR (300 MHz, DMSO-d 6) δ 12.58 (s, 1H), 9.20 (s, 1H), 8.57 (d, J = 2.5 Hz, 1H), 8.18 (s, 1H), 7.78 (d, J = 1.5 Hz, 2H), 7.66 (d, J = 7.3 Hz, 1H), 7.55 (t, J = 7.9 Hz, 1H), 7.41 (s, 1H), 6.98 (d, J = 9.0 Hz, 2H), 6.62-6.54 (m, 1H), 6.45 (s, 1H), 2.88 (s, 3H), 2.24 (s, 3H). 229 (300 MHz, DMSO-d.sub.6) δ 9.55 (s, 1H), 8.56 (d, J = 2.6 Hz, 1H), 7.91 (d, J = 8.7 Hz, 1H), 7.84 (d, J = 8.6 Hz, 2H), 7.77 (s, 1H), 7.40-7.26 (m, 4H), 6.58 (t, J = 2.2 Hz, 1H), 6.30 (s, 1H), 2.22 (s, 3H), 1.09 (d, J = 6.8 Hz, 6H). 230 (500 MHz, DMSO-d.sub.6) δ 11.54 (s, 1H), 9.29 (s, 1H), 7.89-7.76 (m, 4H), 6.85 (d, J = 8.5 Hz, 1H), 6.68 (d, J = 2.7 Hz, 1H), 6.62 (dd, J = 8.4, 2.8 Hz, 1H), 4.11 (q, J = 5.3 Hz, 1H), 3.89 (t, J = 7.1 Hz, 2H), 3.18 (d, J = 5.2 Hz, 2H), 2.56 (d, J = 8.0 Hz, 3H), 2.14 (s, 3H), 2.09 (q, J = 7.6 Hz, 2H), 1.24 (s, 1H). 231 (300 MHz, DMSO-d.sub.6) δ 8.56 (d, J = 2.5 Hz, 1H), 7.99 (d, J = 8.5 Hz, 2H), 7.92-7.75 (m, 3H), 7.34 (s, 1H), 7.20 (qd, J = 13.8, 12.6, 7.3 Hz, 2H), 6.89 (s, 1H), 6.63-6.55 (m, 1H), 3.34 (d, J = 7.0 Hz, 1H), 2.31 (s, 1H), 2.24 (s, 3H), 1.99 (d, J = 1.1 Hz, 4H), 1.18 (t, J = 7.1 Hz, 1H). 232 (300 MHz, DMSO-d.sub.6) δ 12.71 (s, 1H), 9.28 (s, 1H), 8.57 (d, J = 2.5 Hz, 1H), 7.99 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 8.3 Hz, 2H), 7.79 (d, J = 1.7 Hz, 1H), 7.18 (s, 1H), 7.11 (d, J = 6.6 Hz, 2H), 6.59 (t, J = 2.1 Hz, 1H), 3.63 (s, 3H), 2.23 (s, 3H). 233 (300 MHz, DMSO-d.sub.6) δ 12.70 (s, 1H), 9.24 (s, 1H), 8.57 (d, J = 2.5 Hz, 1H), 7.99 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 8.4 Hz, 2H), 7.79 (d, J = 1.7 Hz, 1H), 7.19 (s, 1H), 7.11 (d, J = 7.9 Hz, 2H), 6.59 (t, J = 2.1 Hz, 1H), 4.09 (q, J = 7.1 Hz, 2H), 2.22 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H). 234 (300 MHz, Methanol-d.sub.4) δ 7.70-7.60 (m, 2H), 7.05-6.98 (m, 2H), 6.94 (d, J = 8.5 Hz, 1H), 6.65 (d, J = 2.8 Hz, 1H), 6.56 (dd, J = 8.6, 2.9 Hz, 1H), 3.84 (s, 3H), 2.25 (s, 3H). 235 (300 MHz, DMSO-d.sub.6) δ 12.82 (s, 1H), 9.18 (s, 1H), 8.57 (d, J = 2.6 Hz, 1H), 7.99 (d, J = 8.5 Hz, 2H), 7.84 (d, J = 8.5 Hz, 2H), 7.78 (d, J = 1.7 Hz, 1H), 7.24 (s, 1H), 6.98 (s, 1H), 6.92 (d, J = 7.4 Hz, 1H), 6.62-6.54 (m, 1H), 2.87 (s, 3H), 2.24 (s, 3H). 236 (300 MHz, DMSO-d.sub.6) δ 12.75 (s, 1H), 9.29 (s, 1H), 8.58 (s, 1H), 7.99 (d, J = 8.4 Hz, 2H), 7.90-7.75 (m, 3H), 7.16 (d, J = 11.0 Hz, 3H), 6.84 (s, 1H), 6.64- 6.53 (m, 1H), 3.63 (s, 3H), 2.23 (s, 3H). 237 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.44 (s, 1H), 8.80 (s, 1H), 7.86 (d, J = 8.0 Hz, 2H), 7.51 (s, 2H), 6.86 (s, 1H), 6.57 (d, J = 2.6 Hz, 1H), 6.47 (dd, J = 8.5, 2.8 Hz, 1H), 2.66-2.54 (m, 2H), 1.17-1.09 (m, 3H). 238 (300 MHz, DMSO-d.sub.6) δ 13.01 (s, 1H), 9.58 (s, 1H), 8.39 (s, 1H), 8.07 (d, J = 8.7 Hz, 2H), 7.87 (d, J = 8.7 Hz, 2H), 7.63 (s, 1H), 7.07 (d, J = 8.5 Hz, 1H), 6.72 (d, J = 2.7 Hz, 1H), 6.64 (dd, J = 8.5, 2.7 Hz, 1H), 5.99 (s, 1H), 2.14 (d, J = 9.1 Hz, 5H). 239 .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 10.07 (s, 1H), 8.48 (s, 1H), 8.22 (d, J = 8.9 Hz, 2H), 7.99 (d, J = 8.7 Hz, 2H), 7.68 (s, 1H), 7.58 (s, 1H), 7.51 (d, J = 8.6 Hz, 1H), 7.06-7.00 (m, 1H), 6.65 (s, 1H), 2.70 (s, 3H), 2.14 (s, 5H), 2.07 (s, 3H). 240 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.83 (s, 1H), 7.92 (t, J = 1.8 Hz, 1H), 7.70 (d, J = 7.7 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.10 (s, 2H), 6.58 (d, J = 2.8 Hz, 1H), 6.52 (dd, J = 8.5, 2.9 Hz, 1H), 6.11 (s, 1H), 2.15 (s, 3H). 241 (300 MHz, DMSO-d.sub.6) δ 11.16 (s, 1H), 9.33 (s, 1H), 8.97 (d, J = 2.4 Hz, 1H), 8.58 (dd, J = 4.7, 1.6 Hz, 1H), 8.16 (s, 1H), 8.06 (d, J = 8.3 Hz, 2H), 7.80 (d, J = 8.2 Hz, 2H), 7.55-7.49 (m, 1H), 6.97 (d, J = 2.2 Hz, 1H), 6.58 (d, J = 2.2 Hz, 1H), 6.35 (s, 1H), 2.40 (s, 3H). 242 .sup.1H NMR (500 MHz, Acetone-d.sub.6) δ 8.45 (d, J = 4.6 Hz, 1H), 7.86 (q, J = 8.9 Hz, 4H), 7.70 (d, J = 4.4 Hz, 1H), 7.34 (s, 1H), 6.69 (d, J = 2.9 Hz, 1H), 6.63 (dd, J = 8.6, 3.0 Hz, 1H), 6.54 (s, 1H), 6.14 (s, 1H), 2.24 (s, 3H). 243 .sup.1H NMR (300 MHz, Acetone-d.sub.6) δ 11.76 (s, 1H), 8.46 (d, J = 4.6 Hz, 1H), 8.12 (s, 1H), 7.89 (s, 4H), 7.72 (d, J = 4.3 Hz, 1H), 7.13 (dd, J = 11.9, 3.3 Hz, 2H), 6.89 (s, 1H), 6.41 (s, 1H), 2.32 (s, 3H). 244 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 11.53 (s, 1H), 8.73 (s, 1H), 7.65 (s, 1H), 7.46 (d, J = 8.2 Hz, 1H), 7.14 (dt, J = 23.9, 7.2 Hz, 2H), 6.77 (s, 1H), 6.55 (s, 1H), 6.47 (d, J = 9.1 Hz, 1H), 2.19 (s, 2H). 245 .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.07 (s, 1H), 7.77-7.59 (m, 2H), 7.20 (s, 2H), 7.02 (s, 1H), 6.59 (s, 1H), 6.53 (d, J = 8.7 Hz, 1H), 6.05 (s, 1H), 1.99 (s, 2H), 1.12 (t, J = 7.5 Hz, 3H). 246 .sup.1H NMR (300 MHz, Chloroform-d) δ 7.74 (q, J = 1.7 Hz, 1H), 7.58 (dt, J = 7.6, 1.5 Hz, 1H), 7.54-7.47 (m, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 7.06 (dd, J = 9.9, 8.9 Hz, 1H), 6.94 (dd, J = 6.3, 3.1 Hz, 1H), 6.83 (dt, J = 8.9, 3.5 Hz, 1H), 6.67-6.58 (m, 2H), 6.07 (s, 1H), 3.80 (s, 3H), 2.13 (s, 3H). 256 .sup.1H NMR (300 MHz, Chloroform-d) δ 8.08 (dd, J = 8.6, 5.0 Hz, 2H), 7.75 (dd, J = 8.7, 5.1 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.21 (t, J = 8.5 Hz, 2H), 7.12- 7.00 (m, 4H), 6.75 (s, 1H), 6.72-6.62 (m, 2H), 5.48 (s, 1H), 4.98 (s, 1H), 2.21 (s, 3H). 265 1H NMR (300 MHz, Methanol-d4) δ 8.01 (s, 2H), 7.66 (d, J = 3.1 Hz, 4H), 7.15 (d, J = 8.5 Hz, 1H), 6.67 (s, 1H), 6.62 (dd, J = 8.6, 2.8 Hz, 1H), 5.99 (s, 1H), 2.25 (s, 3H). 272 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.78 (s, 1H), 8.19 (s, 1H), 7.92 (s, 1H), 7.89 (s, 1H), 7.49 (d, J = 6.7 Hz, 2H), 7.39 (d, J = 7.7 Hz, 1H), 7.01 (s, 1H), 6.57 (s, 1H), 6.53 (d, J = 8.5 Hz, 1H), 6.14 (s, 1H), 3.88 (s, 3H), 2.17 (s, 3H). 273 .sup.1H NMR (500 MHz, Acetone-d.sub.6) δ 7.85 (d, J = 8.4 Hz, 2H), 7.63 (dd, J = 8.3, 1.8 Hz, 2H), 7.38 (d, J = 8.5 Hz, 1H), 7.16 (dd, J = 10.4, 8.9 Hz, 1H), 7.06 (dd, J = 6.4, 3.2 Hz, 1H), 6.93 (dt, J = 8.9, 3.5 Hz, 1H), 6.70 (d, J = 2.7 Hz, 1H), 6.64 (dd, J = 8.6, 2.8 Hz, 1H), 6.19 (s, 1H), 3.84 (s, 3H), 2.25 (s, 3H). 274 .sup.1H NMR (300 MHz, DMSO-d 6) δ 12.47 (s, 1H), 10.43 (s, 1H), 8.56 (d, J = 2.5 Hz, 1H), 8.42 (s, 1H), 7.92 (d, J = 8.5 Hz, 2H), 7.84 (d, J = 8.5 Hz, 2H), 7.77 (d, J = 1.7 Hz, 1H), 7.14 (s, 1H), 6.90 (d, J = 6.9 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 6.57 (t, J = 2.1 Hz, 1H), 6.24 (s, 1H), 4.49 (s, 2H). 275 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.17 (s, 1H), 10.41 (s, 1H), 9.66 (s, 1H), 8.33 (s, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.14 (s, 1H), 6.88 (d, J = 8.7 Hz, 1H), 6.81 (d, J = 8.5 Hz, 2H), 6.72 (d, J = 8.5 Hz, 1H), 6.01 (s, 1H), 4.49 (s, 2H). 276 .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.21 (s, 1H), 8.79 (s, 1H), 8.17 (s, 1H), 7.90 (s, 1H), 7.67 (d, J = 8.1 Hz, 2H), 7.60 (d, J = 8.1 Hz, 2H), 7.29 (s, 1H), 7.00 (s, 1H), 6.57 (d, J = 2.8 Hz, 1H), 6.52 (dd, J = 8.6, 2.9 Hz, 1H), 6.06 (s, 1H), 3.87 (s, 3H), 2.16 (s, 3H). 277 .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.85 (s, 1H), 7.70-7.54 (m, 4H), 7.05 (s, 1H), 6.58 (s, 1H), 6.52 (d, J = 8.6 Hz, 1H), 6.07 (s, 1H), 2.15 (s, 3H), 1.24 (s, 1H), 1.07 (s, 1H). 278 .sup.1H NMR (300 MHz, Acetone-d.sub.6) δ 7.75-7.68 (m, 2H), 7.61-7.54 (m, 2H), 7.30 (d, J = 8.5 Hz, 1H), 6.71 (d, J = 2.8 Hz, 1H), 6.68-6.58 (m, 2H), 6.12 (s, 1H), 2.24 (s, 3H). 279 .sup.1H NMR (300 MHz, Acetone-d.sub.6) δ 7.72 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.5 Hz, 1H), 6.74 (d, J = 2.8 Hz, 1H), 6.66 (dd, J = 8.5, 2.9 Hz, 1H), 6.59 (s, 1H), 6.08 (s, 1H), 2.65 (q, J = 7.5 Hz, 2H), 1.19 (t, J = 7.5 Hz, 3H). 280 .sup.1H NMR (300 MHz, Acetone-d.sub.6) δ 11.67 (s, 1H), 8.37 (s, 1H), 7.77-7.71 (m, 2H), 7.64-7.57 (m, 2H), 7.53 (d, J = 8.6 Hz, 1H), 7.38-7.34 (m, 1H), 7.33- 7.27 (m, 1H), 6.78 (s, 1H), 6.31 (s, 1H), 3.69 (s, 3H), 2.29 (s, 3H) 281 .sup.1H NMR (300 MHz, Acetone-d.sub.6) δ 8.39 (s, 1H), 7.79-7.70 (m, 2H), 7.65- 7.58 (m, 2H), 7.53 (d, J = 8.6 Hz, 1H), 7.36 (d, J = 2.5 Hz, 1H), 7.30 (dd, J = 8.8, 2.6 Hz, 1H), 6.80 (s, 1H), 6.31 (s, 1H), 3.69 (s, 3H), 2.29 (s, 3H). 282 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.45 (s, 1H), 9.01 (s, 1H), 7.65 (d, J = 5.3 Hz, 5H), 7.29 (s, 1H), 6.71 (d, J = 9.9 Hz, 1H), 6.24 (s, 1H), 2.14 (s, 3H). 283 .sup.1H NMR (300 MHz, Chloroform-d) δ 7.73-7.64 (m, 2H), 7.62-7.53 (m, 2H), 7.52-7.43 (m, 1H), 7.35 (d, J = 8.6 Hz, 1H), 7.20 (s, 1H), 7.10 (t, J = 9.3 Hz, 2H), 6.94 (dd, J = 6.4, 3.2 Hz, 1H), 6.86 (dt, J = 8.8, 3.5 Hz, 1H), 6.65 (s, 1H), 6.28 (s, 1H), 5.80 (s, 1H), 3.85 (s, 3H), 3.79 (s, 3H), 2.20 (d, J = 5.8 Hz, 3H). 284 1H NMR (300 MHz, Chloroform-d) δ 7.66 (d, J = 8.2 Hz, 2H), 7.51 (dd, J = 8.4, 1.6 Hz, 2H), 7.32 (d, J = 8.6 Hz, 1H), 7.15 (s, 1H), 7.13-7.04 (m, 2H), 6.91 (dd, J = 6.3, 3.1 Hz, 1H), 6.85 (dt, J = 8.9, 3.5 Hz, 1H), 6.75 (s, 1H), 6.26 (s, 1H), 5.83 (s, 1H), 3.83 (s, 3H), 3.78 (s, 3H), 2.14 (s, 3H). 285 .sup.1H NMR (300 MHz, DMSO-d 6)δ 12.24 (s, 1H), 9.26 (s, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.56 (s, 1H), 7.15 (t, J = 9.2 Hz, 3H), 6.99 (d, J = 8.4 Hz, 2H), 6.14 (s, 1H), 3.78 (s, 3H), 3.62 (s, 3H), 2.20 (s, 3H). 286 .sup.1H NMR (300 MHz, DMSO-d 6) δ 12.22 (s, 1H), 8.92 (s, 1H), 7.62 (d, J = 8.6 Hz, 3H), 7.51-7.32 (m, 5H), 7.19 (s, 1H), 7.07 (d, J = 8.4 Hz, 2H), 6.69 (d, J = 9.9 Hz, 1H), 6.12 (s, 1H), 5.15 (s, 2H), 2.14 (s, 3H). 287 .sup.1H NMR (300 MHz, DMSO-d 6)δ 12.24 (s, 1H), 9.26 (s, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.56 (s, 1H), 7.15 (t, J = 9.2 Hz, 3H), 6.99 (d, J = 8.4 Hz, 2H), 6.14 (s, 1H), 3.78 (s, 3H), 3.62 (s, 3H), 2.20 (s, 3H). 288 .sup.1H NMR (300 MHz, DMSO-d 6)δ 12.32 (s, 1H), 9.31 (s, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.56 (s, 1H), 7.15 (t, J = 9.2 Hz, 3H), 6.99 (d, J = 8.4 Hz, 2H), 6.40 (s, 1H), 3.63 (s, 3H), 3.24 (s, 3H), 2.20 (s, 3H). 289 .sup.1H NMR (300 MHz, DMSO-d 6)δ 12.33 (s, 1H), 9.32 (s, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.56 (s, 1H), 7.15 (t, J = 9.2 Hz, 3H), 6.99 (d, J = 8.4 Hz, 2H), 6.40 (s, 1H), 3.64 (s, 3H), 3.24 (s, 3H), 2.21 (s, 3H). 290 .sup.1H NMR (500 MHz, Acetone-d.sub.6) δ 8.41 (s, 1H), 7.73 (dd, J = 8.6, 2.0 Hz, 2H), 7.59 (dt, J = 8.6, 2.0 Hz, 2H), 7.52 (d, J = 8.6 Hz, 1H), 7.36 (s, 1H), 7.31 (d, J = 8.7 Hz, 1H), 6.81 (d, J = 5.3 Hz, 1H), 6.31 (d, J = 1.1 Hz, 1H), 3.69 (d, J = 1.1 Hz, 3H), 2.29 (s, 3H). 291 .sup.1H NMR (500 MHz, Acetone-d.sub.6) δ 8.43 (s, 1H), 7.75-7.70 (m, 2H), 7.58 (ddd, J = 8.4, 3.8, 2.2 Hz, 2H), 7.52 (d, J = 8.6 Hz, 1H), 7.36 (s, 1H), 7.32 (d, J = 8.7 Hz, 1H), 6.84 (s, 1H), 6.32 (s, 1H), 3.70 (d, J = 1.1 Hz, 3H), 2.28 (s, 3H). 292 .sup.1H NMR (300 MHz, Acetone-d.sub.6) δ 8.38 (s, 1H), 7.80-7.69 (m, 2H), 7.59 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 8.6 Hz, 1H), 7.40-7.27 (m, 2H), 6.31 (s, 1H), 3.69 (s, 3H), 2.29 (s, 3H). 293 .sup.1H NMR (300 MHz, Acetone-d.sub.6) δ 8.39 (s, 1H), 7.78-7.69 (m, 2H), 7.63- 7.55 (m, 2H), 7.50 (d, J = 8.6 Hz, 1H), 7.41-7.27 (m, 2H), 6.31 (s, 1H), 3.69 (s, 3H), 2.28 (s, 3H). 294 .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.38 (s, 1H), 9.28 (s, 1H), 8.18 (s, 1H), 7.91 (s, 1H), 7.65 (d, J = 29.7 Hz, 5H), 7.20 (d, J = 27.7 Hz, 3H), 6.25 (s, 1H), 3.88 (s, 3H), 3.64 (s, 3H), 2.21 (s, 3H). 295 .sup.1H NMR (500 MHz, Chloroform-d) δ 7.73 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 8.2 Hz, 2H), 7.15 (d, J = 8.5 Hz, 1H), 6.71 (s, 1H), 6.67 (d, J = 9.3 Hz, 1H), 6.07 (s, 1H), 2.21 (s, 4H). 296 .sup.1H NMR (500 MHz, Chloroform-d) δ 7.66 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.5 Hz, 1H), 7.06 (t, J = 32.9 Hz, 3H), 6.18 (s, 1H), 3.76 (s, 3H), 2.06 (d, J = 1.6 Hz, 5H). 297 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.22 (s, 1H), 10.05 (s, 1H), 9.26 (s, 1H), 7.50 (dd, J = 12.6, 2.1 Hz, 2H), 7.34 (d, J = 8.3 Hz, 1H), 7.15 (t, J = 10.6 Hz, 3H), 6.97 (t, J = 8.8 Hz, 1H), 6.14 (s, 1H), 3.62 (s, 3H), 2.49 (s, 8H), 2.19 (s, 3H). 298 .sup.1H NMR (300 MHz, DMSO-d 6) δ 12.45 (s, 1H), 9.28 (s, 1H), 7.74 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 8.2 Hz, 3H), 7.28 (s, 1H), 7.15 (d, J = 11.2 Hz, 2H), 6.26 (s, 1H), 3.63 (s, 3H), 2.20 (s, 3H). 299 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.45 (s, 1H), 9.28 (s, 1H), 7.74 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 8.2 Hz, 3H), 7.28 (s, 1H), 7.15 (d, J = 11.2 Hz, 2H), 6.26 (s, 1H), 3.63 (s, 3H), 2.20 (s, 3H).

[0413] Evaluation of Compounds

[0414] 1. Efficacy of Inhibiting TNIK Activity, In Vitro TNIK Kinase Assay Using qPCR

[0415] Kinase-tagged T7 phage strains were grown in parallel in an E. coli host derived from the BL21 strain. E. coli were grown to log-phase and infected with T7 phage from a frozen stock (multiplicity of infection=0.4) and incubated with shaking at 32° C. until (90-150 minutes). The lysates were centrifuged (6,000×g) and filtered (0.2 μm) to remove cell debris. The remaining kinases were produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays. The liganded beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and to reduce non-specific phage binding. Binding reactions were assembled by combining kinases, liganded affinity beads, and test compounds in 1× binding buffer (20% SeaBlock, 0.17×PBS, 0.05% Tween 20, 6 mM DTT). Test compounds were prepared as 40× stocks in 100% DMSO and directly diluted into the assay. All reactions were performed in polypropylene 384-well plates in a final volume of 0.04 ml.

[0416] The assay plates were incubated at room temperature with shaking for 1 hour and the affinity beads were washed with wash buffer (1×PBS, 0.05% Tween 20). The beads were then re-suspended in elution buffer (1×PBS, 0.05% Tween 20, 0.5 μM non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The kinase concentration in the eluates was measured by qPCR.

[0417] Results are shown in Tables 4 and 5 below.

TABLE-US-00004 TABLE 4 Compound No. TNIK activity at 1 μM (%) 2 2 3 2 5 47 6 36 9 47 12 1 13 15 14 1 15 36 16 8 17 34 18 19 19 9 20 36 21 22 22 2 23 5 24 0 25 5 27 8 30 33 31 6 32 1 33 0 34 1 35 14 36 6 37 5 38 1 39 0 40 0 41 13 42 8 43 1 44 5 45 4 46 2 47 44 48 28 49 0 50 2 51 1 52 7 53 0 54 1 55 1 56 2 57 17 58 0 59 0 60 17 61 5 62 1 67 21 68 36 70 14 71 34 73 0 74 1 75 4 76 3 77 3 79 4 80 1 81 0 82 2 83 3 85 0 86 1 87 4 88 0 89 0 90 7 91 20 92 0 93 37 94 1 96 16 98 4 99 12 100 8 101 3 102 2 103 5 108 5 109 0 110 7 111 0 112 20 113 6 114 4 115 4 116 7 117 3 118 2 119 2 121 36 122 9 123 34

TABLE-US-00005 TABLE 5 Compound No. Kd (nM) 12 29 24 14 29 25 34 95 39 6 40 9 49 19 58 11 59 16 62 8 73 14 81 3 88 16 89 21 94 12 111 20

[0418] As shown in Tables 4 and 5 above, the compounds of the present disclosure were very effective in inhibiting TNIK activity.

[0419] 2. Efficacy of Inhibiting TNIK Activity, In Vitro TNIK Kinase Assay Using ADP-Glo™ Kinase Assay System

[0420] The inhibitory properties of compounds were evaluated with TNIK kinase enzyme system and luminescent ADP-Glo Kinase Assay from Promega Corporation according to the manufacturer's protocol. The tested compounds were incubated with TNIK kinases. Reactions were performed in 10 μl kinase buffer supplemented with reaction mixture containing 2 μl ATP, 2 μl MBP protein and 2 μl TNIK at 37° C. for 30 min. The reactions' conditions are provided in Table 5. After kinase reaction, 5 μl reaction mixtures were transferred to 384 well assay plate (Greiner, solid white low-binding plates). Next, 5 μL of ADP-Glo Reagent was added to each well and incubated at 37° C. for 30 min. After 45 min, 10 μl Kinase Detection Reagent was added to each well and luminescence signal was detected with the SpectraMax M5c Microplate Reader (Molecular Devices, Menlo Park, Calif.) after 30 min at 37° C. incubation. The IC SO values were calculated using GraphPad Prism software (GraphPad Software Inc., La Jolla, Calif., USA) to determine kit performance. To the cut-off assay, the inhibitory activity of the compounds against TNIK kinase was expressed as the percentage of the kinase inhibitory activity for an indicated concentration of inhibitor. The IC.sub.50 of the compounds against TNIK kinase values were calculated a log-concentration-response curve fitted with a four-parameter logistic equation and expressed dose-response curve for % of inhibitory activity versus log of the compound concentration.

[0421] The reactions' conditions to be used in vitro TNIK kinase inhibitory assay are shown in Table 6.

TABLE-US-00006 TABLE 6 TNIK MBP kinase(ng/ substrate(μg/ reaction) reaction) ATP(μM) Other reagents 13 1 100 Kinase buffer (40 mM Tris (pH 7.5), 20 mM MgCl2, 0.1 mg/ml BSA)

[0422] Results of in vitro TNIK kinase assay (HTRF) are shown in Tables 7 and 8 below.

TABLE-US-00007 TABLE 7 Compound No. Inhibition at 1 μM(%) 33 97 36 85 58 98 74 88 77 87 80 89 81 100 85 92 86 93 96 69 97 66 109 97 110 95 114 100 115 98 116 96 117 94 119 100 126 94 127 100 129 61 132 64 133 63 135 72 136 79 138 100 139 89 140 94 141 92 142 98 143 73 144 89 146 100 147 89 148 61 149 59 150 87 151 92 152 94 153 50 154 85 155 100 156 72 157 98 158 99 160 99 161 95 164 50 165 63 169 82 170 78 171 81 172 83 173 83 174 89 175 91 176 92 177 80 178 97 180 99 181 96 182 98 183 93 185 73 188 89 189 89 190 100 191 82 192 90 193 100 194 94 195 88 196 78 197 96 198 96 199 99 200 89 201 88 202 90 203 87 204 76 205 98 206 95 207 100 208 100 209 99 210 90 212 76 213 74 214 66 215 97 216 100 217 98 218 97 219 56 220 78 221 91 222 60 223 88 224 64 226 97 227 91 228 90 229 97 231 74 234 71 237 99 240 96 241 78 242 97 243 96 244 92 245 90 246 80 265 93 272 84 273 92 274 87 275 93 276 99 277 99 278 99 279 99 280 96 281 98 282 99 283 91 284 86 285 88 286 91 287 54 288 73 289 72 290 91 291 93 292 90 293 88 294 92 295 88 296 53 297 91 298 88 299 95

TABLE-US-00008 TABLE 8 Compound No. IC.sub.50 (nM) 33 68 58 3 74 97 77 94 80 95 81 12 85 23 86 12 109 1 110 8 114 72 115 107 117 10 119 1 126 17 133 43 138 23 139 22 140 6 141 148 142 77 144 103 146 1 147 47 151 45 152 115 154 493 155 73 156 80 157 116 158 23 160 26 161 182 162 40 170 15 171 16 172 33 173 32 174 46 175 15 176 8 178 89 180 1 181 2 182 7 183 10 185 408 187 3 188 177 189 125 190 38 191 314 192 271 193 140 194 195 195 236 196 516 197 105 198 125 199 112 200 91 201 89 202 83 203 71 204 432 205 6 206 39 207 8 208 7 209 9 210 252 212 471 213 645 214 646 215 24 216 41 217 113 218 127 219 789 220 534 221 341 222 749 223 431 224 703 226 250 227 431 228 397 229 179 231 578 234 431 237 389 240 443 241 684 242 230 243 103 244 106 245 82 246 236 265 4 272 117 273 34 274 20 275 19 276 8 277 11 278 9 279 37 280 66 281 25 282 41 283 48 284 113 285 161 286 97 287 919 288 506 289 623 290 64 291 41 292 108 293 157 294 143 295 264 296 745 297 243 298 128 299 54

[0423] 3. Efficacy of Inhibiting Cancer Cells Using Colon Cancer Cell Lines

[0424] 1) Cell Culture

[0425] The human colon cancer cell line SW480 (Catalog No. CCL-228) and SW620 (Catalog No. CCL-227) were obtained from the American Type Culture Collection (ATCC), and maintained in DMEM (Thermo Fisher Scientific Inc., Waltham, Mass., USA) supplemented with 10% fetal bovine serum (FBS) (Thermo Fisher Scientific Inc., Waltham, Mass.), 100 U/ml penicillin, and 100 μg/ml streptomycin (Gibco, Gaithersburg, Md.). Cells were grown at 37° C. in 5% CO.sub.2 for confluence.

[0426] 2) Cell Viability Assay

[0427] Cell viability was measured using the Cell Counting Kit-8 (Dojindo Molecular Technologies). SW480 and SW620 cells (2.5×10.sup.4 cells/well) were seeded in 96-well plates and incubated for 24 h. After incubation, the cells were exposed to serially diluted compounds (0.1, 0.3, 1, 3, 10 and 30 μM) in 100 μl phenol free DMEM medium containing 0.1% FBS. After 48 h, CCK-8 reagent was added at 10 μl per well and incubated for 1 h at 37° C. Optical density was measured at 450 nm using a microplate reader (Bio-Rad Laboratories, Hercules, Calif.). The IC.sub.50 values were calculated using GraphPad Prism software (GraphPad Software Inc., La Jolla, Calif., USA) to determine kit performance. Experiments were performed in triplicate.

[0428] Results of cell viability assay using SW620 cell are shown in Table 9 below.

TABLE-US-00009 TABLE 9 Compound No SW620, IC.sub.50 (μM) 2 9.1 6 1.8 19 1.0 24 11.4 32 1.2 40 12.5 45 0.4 46 0.2 56 0.4 58 47.5 80 0.5 81 1.7 85 1.0 94 0.8 110 15.9 114 0.1 115 0.2 116 0.3 117 0.4 119 1.0 138 0.7 140 0.9 146 0.4 154 25.5 160 1.0 190 11.2 193 1.8 194 1.0 199 14.9 200 14.9 202 3.0 205 11.5 207 22.1 208 16.8 212 18.0 215 12.6 216 8.2 226 19.9 229 28.0 244 11.2 245 11.7 246 11.0 265 6.7 272 17.9 273 1.8 275 16.9 276 8.6 277 3.1 278 9.0 279 12.5 280 19.6 282 27.1 285 8.1 286 7.2 288 15.3 290 9.4 291 10.7 292 4.0 293 7.8 294 18.9 295 10.1 296 14.0 297 12.1 298 22.5 299 6.3

[0429] Results of cell viability assay using SW480 cell are shown in Table 10 below.

TABLE-US-00010 TABLE 10 Compound No. SW480, IC.sub.50 (μM) 2 2.6 6 2.9 18 18.7 19 1.0 24 8.2 32 5.4 40 16.6 45 0.9 46 0.6 56 18.9 80 1.5 81 5.7 85 8.2 94 13.5 110 1.5 114 1.3 115 0.7 116 9.1 117 8.2 119 4.4 127 3.1 138 2.8 140 5.5 146 1.3 160 10.0 190 8.1 193 11.5 194 10.6 199 12.9 202 5.4 205 13.4 206 13.4 207 11.3 208 11.0 212 8.9 215 4.0 216 10.9 229 19.6 244 5.9 245 11.4 246 9.5 265 37.3 272 18.6 273 6.8 276 10.1 277 6.4 278 7.4 279 19.9 280 21.9 282 11.5 283 28.1 285 13.1 286 6.4 290 8.3 291 9.1 292 2.3 293 4.6 294 4.2 295 5.2 296 8.7 297 7.6 298 7.7 299 3.0

[0430] 4. Efficacy of Inhibiting Wnt/β-Catenin Signaling

[0431] 1) Cell Culture

[0432] CHO-K1 (KCLB no. 10061) cells were cultured (37° C. 5% CO.sub.2) in RPMI medium (Gibco) containing 10% FBS (Gibco) and 1% penicillin/streptomycin (Gibco) of a T75 flask. The culture was washed with DPBS (Dulbecco's Phosphate-Beffered Saline, Gibco) and 2 ml of 0.05% trypsin-EDTA (trypsin-EDTA, Gibco) wad added and cultured for one minute. Next, cell suspension was centrifuged at 1,500 rpm for 2 minutes, and cell pellets was obtained for next steps.

[0433] 2) Reporter Gene Transfection

[0434] Cultured CHO-K1 cells were diluted with the cell culture medium to become 4×10.sup.4 cells/cm.sup.2 and then seeded into a culture plate. The plate was cultured overnight at 37 in a 5% CO.sub.2 condition. Next day, the transfection of reporter gene was performed as follows: 1.35 μg of reporter DNA (M50 Super 8XTOPFlash, no. 12456, Addgene) and lipofectamine 2000 (Lipofectamine 2000 Reagent, no. 11668, Invitrogen) were diluted in an Opti-MEM medium (Gibco) to make a solution for transfection according to the protocol of those reagents. The cell medium of the CHO-K1 cells attached by overnight culture was replaced with RPMI medium not containing FBS and penicillin/streptomycin. Then the cells were transfected with the solution and cultured (37° C., 5% CO.sub.2) for 5 hours. After that, the transfected cells were cultured overnight in RPMI medium containing 1% FBS and 1% penicillin/streptomycin to stabilize the transfected cells. The stabilized CHO-K1 cells were diluted with RPMI medium containing 1% FBS and seeded to be 2.5×10.sup.4 cells in a 96 well plate. The plate was cultured overnight to attach cells. The attached cells were used for evaluating reporter activity and cell toxicity next day.

[0435] 3) Addition of Test Compounds and Recombinant Wnt3a Protein

[0436] DMSO solutions of test compounds were diluted with the culture medium containing 1% FBS to make the solutions having 10 times concentration of the tested concentration. 0.1 volumes of those solutions were added to the transfected CHO-K1 cells, and cultured overnight at 37° C., 5% CO.sub.2. Next day, 40 μg/ml of recombinant Wnt3a protein (Mouse Recombinant Wnt3a, no. 1324-WN, R&D systems) was diluted to 200 ng/ml with RPMI medium containing 1% FBS. 0.1 volumes of the diluted Wnt3a protein solution were added to CHO-K1 cells containing test compounds. Next, the CHO-K1 cells were further cultivated (37° C., 5% CO.sub.2) for 7 hours.

[0437] 4) Determination of Luciferase Activity

[0438] Luciferase assay system (no. E1960, Promega) was used. The activity of luciferase in the cells was determined by the microplate reader (SpectraMax M5e Multi-Mod Microplate Reader, Molecular Devices). The luminescence values were normalized with respect to cell viability, and IC.sub.50 values of test compounds were calculated based on both the luminescence intensity of cells stimulated by Wnt3a without test compounds (100%) and the luminescence intensity of cells without test compounds and Wnt3a stimulus (0%).

[0439] 5) Cell Toxicity Evaluation of Test Compounds

[0440] DMSO solutions of test compounds were diluted with the culture medium containing 1% FBS to make the solutions having 10 times concentration of the tested concentration. 0.1 volumes of those solutions were added to the transfected CHO-K1 cells, and cultured overnight at 37° C., 5% CO.sub.2. Next day, 40 μg/ml of recombinant Wnt3a protein (Mouse Recombinant Wnt3a, no. 1324-WN, R&D systems) was diluted to 200 ng/ml with RPMI medium containing 1% FBS. 0.1 volumes of the diluted Wnt3a protein solution were added to CHO-K1 cells containing test compounds. Next, the CHO-K1 cells were further cultivated (37° C., 5% CO.sub.2) for 7 hours. After that, 10 μl of CCK-8 solution (Cell Counting Kit-8. Dojindo Molecular Technologies) was added and cultured (37° C., 5% CO.sub.2) for 1 hour. Cell viability in wells then was determined at 450 nm by the microplate reader (SpectraMax M5e Multi-Mod Microplate Reader, Molecular Devices). The determined cell viability was used for normalization of luciferase activity.

[0441] Results are shown in Tables 11 and 12 below.

TABLE-US-00011 TABLE 11 Compound No. Inhibition at 10 μM (%) 114 92 115 92 119 82 138 83 140 68 146 89 193 30 194 21 216 82 222 33

TABLE-US-00012 TABLE 12 Compound No. IC.sub.50 (μM) 81 3.1 114 1.5 115 1.9 119 2.8 138 2.1 140 7.0 146 1.0 216 6.1

[0442] 5. Mouse Xenograft Model Test

[0443] Test 5-1

[0444] Male nude mice grafted with SW620 cell which is colorectal carcinoma cell derived from human were used. Test compounds were administered several times and inhibitory effect of tumor by test compounds was evaluated.

[0445] The following groups were set up: 0 mg/kg dose of negative control group, 50 mg/kg dose of Compound 81 group, 75 mg/kg dose of Compound 58 group, 50 mg/kg dose of Compound 80 group, 75 mg/kg dose of Compound 110 group, 40 mg/kg dose of irinotocan group (positive control). The number of each group was six. Compound 81 was administered two times a day for 28 days, and other compounds were administered once a day for 28 days. The results are shown in FIG. 1.

[0446] The average tumor volume of 50 mg/kg dose of Compound 81 group showed significant difference in comparison to negative control at day 15, 18, 22, 25 and 29 after administration. The inhibitory rate of tumor growth was 72.3%, which means that the compound has a determinate effect of inhibiting tumor growth.

[0447] The average tumor volume of 75 mg/kg dose of Compound 58 group showed significant difference in comparison to negative control at day 15, 18, 22 and 25 after administration. The inhibitory rate of tumor growth was 58.5%, which means that the compound has a determinate effect of inhibiting tumor growth.

[0448] The average tumor volume of 50 mg/kg dose of Compound 80 group showed significant difference in comparison to negative control at day 15, 18, and 25 after administration. The inhibitory rate of tumor growth was 48.8%, which means that the compound has an effect of inhibiting tumor growth.

[0449] The average tumor volume of 75 mg/kg dose of Compound 110 group showed significant difference in comparison to negative control at day 15, 18, 22, 25 and 29 after administration. The inhibitory rate of tumor growth was 58.0%, which means that the compound has a determinate effect of inhibiting tumor growth.

[0450] The average tumor volume of 40 mg/kg dose of positive control (Irinotecan) group showed significant difference in comparison to negative control at day 15, 18, 22, 25 and 29 after administration. The inhibitory rate of tumor growth was 81.8%, which means that the compound has a determinate effect of inhibiting tumor growth.

[0451] In anti-cancer effect tests against colorectal carcinoma cell derived from human, SW620, 50 mg/kg dose of Compound 81, 75 mg/kg dose of Compound 58 and Compound 110 showed an effect of inhibiting growth of the tumor.

[0452] Test 5-2

[0453] The effect of inhibiting the growth of tumor after administering the compounds of the present invention was evaluated. Test compounds were repeated administered to male nude mice grafted with colorectal carcinoma cell, SW620, derived from human.

[0454] The following groups were set up: 0 mg/kg dose of negative control group, 100 mg/kg dose of Compound 81 group (oral administration), 100 mg/kg dose of Compound 81 group (intraperitoneal injection), 50, 100 and 160 mg/kg dose of Compound 138 group, 40 mg/kg dose of irinotecan group (positive control), a combined administration group of 100 mg/kg dose of Compound 81 and 40 mg/kg dose of irinotecan, and a combined administration group of 100 mg/kg dose of Compound 138 and 40 mg/kg dose of Irinotecan. The number of each group was six. Compounds 81 and 138 were administered two times a day for 15 days, and irinotecan was administered once a week for 15 days. The results are shown in FIGS. 2 and 3.

[0455] The average tumor volume of 100 mg/kg of oral administration of Compound 81 group showed significant difference in comparison to negative control. The inhibitory rate of tumor growth was 49.3%.

[0456] The average tumor volume of 100 mg/kg of intraperitoneal injection of Compound 81 group showed significant difference in comparison to negative control. The inhibitory rate of tumor growth was 53.2%.

[0457] The average tumor volumes of 50, 100 and 160 mg/kg dose of Compound 138 group showed significant difference in comparison to negative control. The inhibitory rates of tumor growth were 54.5, 64.7 and 57.8%.

[0458] The average tumor volume of 40 mg/kg of irinotecan group showed significant difference in comparison to negative control. The inhibitory rate of tumor growth was 69.0%.

[0459] The average tumor volume of the combined administration group of 100 mg/kg dose of Compound 81 and 40 mg/kg dose of irinotecan showed significant difference in comparison to negative control. The inhibitory rate of tumor growth was 78.8%.

[0460] The average tumor volume of the combined administration group of 100 mg/kg dose of Compound 138 and 40 mg/kg dose of irinotecan showed significant difference in comparison to negative control. The inhibitory rate of tumor growth was 78.0%.

[0461] In conclusion, in anti-cancer effect tests against colorectal carcinoma cell derived from human, SW620, Compound 81. Compound 138 and irinotecan clearly showed an effect of inhibiting growth of the tumor. And, the combined administration of irinotecan and Compound 81 or 138 showed a synergic inhibitory effect.

[0462] All mentioned documents are incorporated by reference as if herein written. When introducing elements of the present invention or the exemplary embodiment(s) thereof, the articles “a,” “an,” “the” and “said” are intended to mean that there are one or more of the elements. The terms “comprising,” “including” and “having” are intended to be inclusive and mean that there may be additional elements other than the listed elements. Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as limitations.