BENZAMIDE COMPOUND AND PREPARATION METHOD, USE, AND PHARMACEUTICAL COMPOSITION THEREOF

Abstract

The present invention relates to a benzamide compound and a preparation method, use and pharmaceutical composition thereof. The benzamide compound represented by formula (I) is a STAT3 inhibitor, and can be used to prevent and/or treat a disease related to STAT3 activity, such as a tumor, autoimmune disease, renal disease, cardiovascular disease, inflammation, metabolic/endocrine dysfunction, and neurological disease.

##STR00001##

Claims

1. A compound represented by Formula (I), or a stereoisomer, a geometric isomer, a tautomer or a pharmaceutically acceptable salt thereof: ##STR00077## wherein, R.sup.1 is selected from hydrogen, cyano, difluoromethyl, trifluoromethyl, halogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy; R.sub.2 is selected from 6- to 10-membered aryl or 5- to 10-membered heteroaryl; wherein the 6- to 10-membered aryl or 5- to 10-membered heteroaryl is optionally substituted by m Ra; or the 6- to 10-membered aryl or 5- to 10-membered heteroaryl is phenyl fused to 4- to 6-membered cycloalkene or 4- to 6-membered heterocycloalkene or 5- to 6-membered heteroaryl fused to the same; each Ra is independently selected from the following groups: cyano, difluoromethyl, trifluoromethyl, halogen, C.sub.1-3 alkyl, C.sub.3-7 cycloalkyl, C.sub.1-3 alkoxy; m is 0, 1, 2, 3, 4 or 5; R.sub.3, R.sub.4, R.sub.5, R.sub.6 are each independently selected from hydrogen, cyano, difluoromethyl, trifluoromethyl, halogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy.

2. The compound according to claim 1, or a stereoisomer, a geometric isomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is selected from hydrogen, cyano, difluoromethyl, trifluoromethyl, chlorine, methyl, ethyl, n-propyl, isopropyl, methoxy or ethoxy.

3. The compound according to claim 1, or a stereoisomer, a geometric isomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R.sub.2 is selected from: ##STR00078## each Ra is independently selected from cyano, difluoromethyl, trifluoromethyl, halogen, C.sub.1-3 alkyl, C.sub.3-7 cycloalkyl, C.sub.1-3 alkoxy; m is 0, 1, 2, 3, 4, or 5.

4. The compound according to claim 3, or a stereoisomer, a geometric isomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R.sub.2 is selected from: ##STR00079## Ra is selected from cyano, difluoromethyl, trifluoromethyl, halogen, C.sub.1-3 alkyl, C.sub.3-7 cycloalkyl or C.sub.1-3 alkoxy.

5. The compound according to claim 4, or a stereoisomer, a geometric isomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein Ra is selected from the following groups: chlorine, methyl, ethyl, cyclopropyl, methoxy or ethoxy.

6. The compound according to claim 1, or a stereoisomer, a geometric isomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R.sub.3, R.sub.4, R.sub.5, R.sub.6 are each independently selected from hydrogen, cyano, difluoromethyl, trifluoromethyl, fluorine, chlorine, methyl, ethyl, methoxy.

7. The compound according to claim 6, or a stereoisomer, a geometric isomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R.sub.3 is selected from methyl, R.sub.4, R.sub.5 and R.sub.6 are selected from hydrogen.

8. The compound according to claim 1, or a stereoisomer, a geometric isomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein, the compound is selected from: ##STR00080## ##STR00081## ##STR00082## ##STR00083##

9. A pharmaceutical composition comprising at least one compound according to claim 1, or a stereoisomer, a geometric isomer, a tautomer or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier and/or excipient.

10. The pharmaceutical composition according to claim 9, wherein the pharmaceutical composition further comprises other active pharmaceutical ingredient in addition to the compound, or a stereoisomer, a geometric isomer, a tautomer or a pharmaceutically acceptable salt thereof.

11. A method for preventing and/or treating STAT3-mediated diseases in a subject, comprising administering the compound according to claim 1, or a stereoisomer, a geometric isomer, a tautomer or a pharmaceutically acceptable salt thereof to the subject in need thereof.

12. Method according to claim 11, wherein the STAT3-mediated diseases include tumors, autoimmune diseases, renal diseases, cardiovascular diseases, inflammation, metabolic/endocrine dysfunction or neurological diseases.

13. The compound according to claim 2, or a stereoisomer, a geometric isomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R.sub.3, R.sub.4, R.sub.5, R.sub.6 are each independently selected from hydrogen, cyano, difluoromethyl, trifluoromethyl, fluorine, chlorine, methyl, ethyl, methoxy.

14. The compound according to claim 3, or a stereoisomer, a geometric isomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R.sub.3, R.sub.4, R.sub.5, R.sub.6 are each independently selected from hydrogen, cyano, difluoromethyl, trifluoromethyl, fluorine, chlorine, methyl, ethyl, methoxy.

15. The compound according to claim 1, or a stereoisomer, a geometric isomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R.sub.3, R.sub.4, R.sub.5, R.sub.6 are each independently selected from hydrogen, cyano, difluoromethyl, trifluoromethyl, fluorine, chlorine, methyl, ethyl, methoxy.

16. The compound according to claim 13, or a stereoisomer, a geometric isomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R.sub.3 is selected from methyl, R.sub.4, R.sub.5 and R.sub.6 are selected from hydrogen.

17. The compound according to claim 14, or a stereoisomer, a geometric isomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R.sub.3 is selected from methyl, R.sub.4, R.sub.5 and R.sub.6 are selected from hydrogen.

18. A pharmaceutical composition comprising at least one compound according to claim 8, or a stereoisomer, a geometric isomer, a tautomer or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier and/or excipient.

19. The pharmaceutical composition according to claim 18, wherein the pharmaceutical composition further comprises other active pharmaceutical ingredient in addition to the compound, or a stereoisomer, a geometric isomer, a tautomer or a pharmaceutically acceptable salt thereof.

Description

DESCRIPTION OF FIGURES

[0085] FIG. 1 shows the effects of Examples 12, 23, 33 and 34 on the expression of p-STAT3 of human prostate cancer cell DU145, which shows the inhibitory effects of Examples 12, 23, 33 and 34 on the expression of p-STAT3 of human prostate cancer cell DU145.

[0086] FIG. 2 is a tumor growth curve, which shows the inhibitory effect of Example 1 on the growth of xenograft tumor formed by subcutaneous xenotransplantation of human prostate cancer DU145 in nude mice.

[0087] FIG. 3 is a tumor growth curve, which shows the inhibitory effect of Examples 12 and 33 on the growth of xenograft tumor formed by subcutaneous xenotransplantation of human prostate cancer DU145 in nude mice.

SPECIFIC MODES FOR CARRYING OUT THE INVENTION

[0088] The followings are specific examples of the present invention, which further describe the technical solution of the present invention, but the protection scope of the present invention is not limited to these examples. Any change or equivalent substitution that does not depart from the present invention is included in the protection scope of the present invention.

[0089] In the following examples, molecule with single chiral center exists in the form of racemic mixture unless structural formula or chemical name is specified otherwise. Molecules with two or more chiral centers exist in form of diastereomer racemic mixture unless structural formula or chemical name is specified otherwise. Single enantiomer/diastereomer can be obtained by methods known to those skilled in the art.

[0090] Preparation Method

[0091] The compounds of the present invention can be synthesized according to the synthetic scheme in the present invention and/or techniques well known in the art. For example, the compounds provided by the invention can be prepared according to the following general synthetic method.

[0092] In a general synthesis method, the compound represented by formula (I) is synthesized according to method-1.

Method-1

[0093] ##STR00015##

[0094] Specifically, in method-1, the benzamide compound of the present invention can be synthesized by 2-step reaction. For example, compound C was obtained from compounds A and B as starting materials via condensation reaction; and the benzamide compound of the present invention was obtained from the compound C via sulfonylation reaction.

[0095] In another general synthesis method, the compound represented by formula (I) is synthesized according to method-2.

Method-2

[0096] ##STR00016##

[0097] Specifically, in the general synthesis method-2, the benzamide compound of the present invention can be synthesized by three steps. For example, compound E was obtained from compound D as starting material via sulfonylation reaction, and then compound F was obtained from the compound E via hydrolysis with sodium hydroxide. The benzamide compound of the present invention was obtained by the reaction of the compound F with pyridine-3-methylamine or substituted pyridine-3-methylamine.

[0098] The compounds of the present invention can be synthesized according to one or more synthetic schemes and/or techniques well known in the art. Those skilled in the art should realize that the synthetic method of some embodiments described in detail in the present invention can be easily applied to other embodiments. In some embodiments, the compound described herein can be prepared by appropriate combinations of synthetic methods known in the art. Many starting materials and other reagents can be purchased from commercial suppliers, such as Alfa aesar (China) chemical co., LTD., or easily prepared by synthetic methods commonly used in the art.

[0099] NMR spectra were recorded on instruments operated at 400 MHz or 500 MHz. .sup.1H NMR spectra were obtained in solution form (reported as ppm), using CDCl.sub.3 (7.26 ppm) or DMSO-d.sub.6 (2.50 ppm) or internal standard tetramethylsilane (0.00 ppm) as reference standard. When reporting peak multiplicity, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad peak), dd (double-doublet), dt (double-triplet). The given coupling constant is measured in Hertz (Hz).

[0100] (R)- and (S)-isomers of non-restrictive exemplary compounds, if present, can be separated by methods known to those skilled in the art, if needed, such as can be separated by, for example, crystallization through forming diastereomeric salts or complexes; can be separated by, for example, crystallization or chromatography through forming diastereomeric derivatives; can be separated by allowing one enantiomer to selectively react with an enantiomer-specific reagent, then separating the modified and unmodified enantiomers; or can be separated through chromatographic separation in chiral environment such as chiral chromatographic column. Selectively, specific enantiomers can be prepared by asymmetric synthesis using optically-active reagents, substrates, catalysts or solvents, or prepared by converting one enantiomer into another one through asymmetric conversion.

[0101] In the following preparative methods and examples, “Me” refers to methyl, “Et” refers to ethyl, “PE” refers to petroleum ether, “EtOAc” refers to ethyl acetate, “MeOH” refers to methanol, “DMSO-d.sub.6” refers to deuterated dimethyl sulfoxide, “DCM” refers to methylene chloride, “DMAP” refers to 4-dimethylaminopyridine, “HATU” refers to O-(7-azabenzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, “rt” refers to room temperature, “mL” refers to milliliters, “mmol” refers to millimoles, “μM” refers to micromoles, “nM” refers to nanomoles, and “° C.” refers to degrees Celsius.

Example 1: Preparation of 4-methyl-3-((4-methylphenyl) sulfonamido)-N-(pyridin-3-ylmethyl) benzamide

[0102] ##STR00017##

Step 1: Preparation of 3-amino-4-methyl-N-(pyridin-3-ylmethyl) benzamide

[0103] ##STR00018##

[0104] A reaction mixture of 3-amino-4-methylbenzoic acid (3.02 g, 20 mmol), pyridin-3-ylmethylamine (3.24 g, 30 mmol), HATU (9.12 g, 24 mmol) and triethylamine (6.07 g, 60 mmol) in DCM (150 mL) was stirred overnight. Water (100 mL) was added and the resulting suspension was stirred vigorously for 10 minutes. The resulting yellow solid was collected by suction filtration, washed with water (50 mL×2) and DCM (30 mL×3), and dried to obtain a yellow solid (4.02 g, yield 83%).

[0105] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.79 (t, J=6.0 Hz, 1H), 8.53 (d, J=1.8 Hz, 1H), 8.44 (dd, J=4.8, 1.6 Hz, 1H), 7.69 (dt, J=7.8, 1.9 Hz, 1H), 7.34 (ddd, J=7.8, 4.8, 0.8 Hz, 1H), 7.11 (s, 1H), 7.02-6.94 (m, 2H), 4.99 (s, 2H), 4.44 (d, J=6.0 Hz, 2H), 2.08 (s, 3H).

Step 2: Preparation of 4-methyl-3-((4-methylphenyl)sulfonamido)-N-(pyridin-3-ylmethyl) benzamide

[0106] ##STR00019##

[0107] A mixture of 3-amino-4-methyl-N-(pyridin-3-ylmethyl) benzamide (121 mg, 0.5 mmol), p-toluenesulfonyl chloride (111 mg, 0.6 mmol), pyridine (59 mg, 0.75 mmol) and DMAP (12 mg, 0.1 mmol) in DCM (10 mL) was stirred overnight at room temperature. Water (50 mL) was added, and the resulting mixture was extracted with DCM (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saline (30 mL), dried with anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative thin layer chromatography (silica gel, DCM/MEOH=15:1) to obtain a yellow foamy solid (132 mg, yield 63%).

[0108] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.64 (s, 1H), 9.02 (t, J=5.9 Hz, 1H), 8.53 (d, J=1.8 Hz, 1H), 8.46 (dd, J=4.8, 1.6 Hz, 1H), 7.70 (dt, J=7.8, 1.9 Hz, 1H), 7.66-7.57 (m, 2H), 7.52 (d, J=8.3 Hz, 2H), 7.39-7.36 (m, 1H), 7.33 (d, J=8.1 Hz, 2H), 7.21 (d, J=7.7 Hz, 1H), 4.45 (d, J=5.8 Hz, 2H), 2.35 (s, 3H), 1.95 (s, 3H).

Example 2: 3-((4-methylphenyl)sulfonamido)-N-(pyridin-3-ylmethyl)benzamide

[0109] ##STR00020##

Step 1: Preparation of 3-amino-N-(pyridin-3-ylmethyl)benzamide

[0110] ##STR00021##

[0111] According to the method of step 1 in Example 1, the title compound was synthesized from 3-aminobenzoic acid.

[0112] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.85 (t, J=5.9 Hz, 1H), 8.53 (d, J=1.2 Hz, 1H), 8.45 (dd, J=4.5, 1.1 Hz, 1H), 7.74-7.67 (m, 1H), 7.36 (ddd, J=7.7, 4.7, 0.4 Hz, 1H), 7.08 (t, J=7.8 Hz, 1H), 7.05 (t, J=2.0 Hz, 1H), 7.00-6.96 (m, 1H), 6.69 (ddd, J=7.9, 2.3, 1.0 Hz, 1H), 5.31 (br s, 2H), 4.44 (d, J=5.9 Hz, 2H).

[0113] MS (ESI+) m/z 228.0 [M+H]+.

Step 2: Preparation of 3-((4-methylphenyl)sulfonamido)-N-(pyridin-3-ylmethyl) benzamide

[0114] ##STR00022##

[0115] According to the method of step 2 in Example 1, the title compound was synthesized from 3-amino-N-(pyridin-3-ylmethyl) benzamide.

[0116] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.39 (s, 1H), 9.05 (t, J=5.7 Hz, 1H), 8.61-8.39 (m, 2H), 7.78-7.59 (m, 4H), 7.52 (dd, J=7.7, 1.1 Hz, 1H), 7.45-7.29 (m, 4H), 7.28-7.21 (m, 1H), 4.45 (d, J=5.7 Hz, 2H), 2.32 (s, 3H).

Example 3: 4-fluoro-3-((4-methylphenyl) sulfonamido)-N-(pyridin-3-ylmethyl) benzamide

[0117] ##STR00023##

Step 1: Preparation of 3-amino-4-fluoro-N-(pyridin-3-ylmethyl) benzamide

[0118] ##STR00024##

[0119] According to the method of step 1 in Example 1, the title compound was synthesized from 3-amino-4-fluorobenzoic acid.

[0120] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.90 (t, J=5.7 Hz, 1H), 8.53 (s, 1H), 8.46 (d, J=4.6 Hz, 1H), 7.70 (dt, J=7.8, 1.8 Hz, 1H), 7.35 (dd, J=7.8, 4.7 Hz, 1H), 7.32-7.26 (m, 1H), 7.10-7.01 (m, 2H), 5.34 (br s, 2H), 4.44 (d, J=5.9 Hz, 2H).

[0121] MS (ESI+) m/z 245.9 [M+H]+.

Step 2: Preparation of 4-fluoro-3-((4-methylphenyl)sulfonamido)-N-(pyridin-3-ylmethyl)benzamide

[0122] ##STR00025##

[0123] According to the synthesis method of step 2 in Example 1, the title compound was synthesized from 3-amino-4-fluoro-N-(pyridin-3-ylmethyl) benzamide.

[0124] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.26 (s, 1H), 9.12 (t, J=5.9 Hz, 1H), 8.54 (s, 1H), 8.47 (d, J=4.0 Hz, 1H), 7.86 (dd, J=7.7, 2.2 Hz, 1H), 7.75-7.67 (m, 2H), 7.60 (d, J=8.3 Hz, 2H), 7.40-7.31 (m, 3H), 7.26 (dd, J=10.0, 8.6 Hz, 1H), 4.46 (d, J=5.8 Hz, 2H), 2.35 (s, 3H).

Example 4: 4-chloro-3-((4-methylphenyl)sulfonamido)-N-(pyridin-3-ylmethyl) benzamide

[0125] ##STR00026##

Step 1: Preparation of 3-amino-4-chloro-N-(pyridin-3-ylmethyl)benzamide

[0126] ##STR00027##

[0127] According to the method of step 1 in Example 1, the title compound was synthesized from 3-amino-4-chlorobenzoic acid.

[0128] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.95 (t, J=5.9 Hz, 1H), 8.53 (d, J=1.7 Hz, 1H), 8.45 (dd, J=4.8, 1.6 Hz, 1H), 7.74-7.65 (m, 1H), 7.35 (ddd, J=7.8, 4.8, 0.7 Hz, 1H), 7.29 (d, J=2.1 Hz, 1H), 7.27 (d, J=8.3 Hz, 1H), 7.02 (dd, J=8.3, 2.1 Hz, 1H), 5.53 (br s, 2H), 4.45 (d, J=5.9 Hz, 2H).

[0129] MS (ESI+) m/z 261.9 [M+H]+.

Step 2: Preparation of 4-chloro-3-((4-methylphenyl)sulfonamido)-N-(pyridin-3-ylmethyl)benzamide

[0130] ##STR00028##

[0131] According to the method of step 2 in Example 1, the title compound was synthesized from 4-chloro-3-((4-methylphenyl) sulfonamido) benzoic acid.

[0132] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.08 (s, 1H), 9.18 (t, J=5.8 Hz, 1H), 8.54 (d, J=1.6 Hz, 1H), 8.47 (dd, J=4.7, 1.4 Hz, 1H), 7.85 (d, J=2.1 Hz, 1H), 7.75-7.66 (m, 2H), 7.59 (d, J=8.3 Hz, 2H), 7.51 (d, J=8.4 Hz, 1H), 7.40-7.31 (m, 3H), 4.47 (d, J=5.8 Hz, 2H), 2.36 (s, 3H).

Example 5: Preparation of 4-methoxy-3-((4-methylphenyl)sulfonamido)-N-(pyridin-3-ylmethyl)benzamide

[0133] ##STR00029##

Step 1: Preparation of 3-amino-4-methoxy-N-(pyridin-3-ylmethyl)benzamide

[0134] ##STR00030##

[0135] According to the method of step 1 in Example 1, the title compound was synthesized from 3-amino-4-methoxybenzoic acid.

[0136] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.75 (t, J=5.9 Hz, 1H), 8.52 (d, J=1.8 Hz, 1H), 8.44 (dd, J=4.7, 1.5 Hz, 1H), 7.73-7.65 (m, 1H), 7.38-7.31 (m, 1H), 7.17 (d, J=2.2 Hz, 1H), 7.11 (dd, J=8.3, 2.2 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 4.85 (s, 2H), 4.43 (d, J=5.9 Hz, 2H), 3.80 (s, 3H).

Step 2: Preparation of 4-methoxy-3-((4-methylphenyl)sulfonamido)-N-(pyridin-3-ylmethyl)benzamide

[0137] ##STR00031##

[0138] According to the method of step 2 in Example 1, the title compound was synthesized from 3-amino-4-methoxy-N-(pyridin-3-ylmethyl) benzamide.

[0139] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.52 (s, 1H), 8.97 (t, J=5.8 Hz, 1H), 8.53 (d, J=2.0 Hz, 1H), 8.46 (dd, J=4.8, 1.5 Hz, 1H), 7.82 (d, J=2.2 Hz, 1H), 7.74-7.66 (m, 2H), 7.57 (d, J=8.3 Hz, 2H), 7.36 (dd, J=7.8, 4.8 Hz, 1H), 7.31 (d, J=8.3 Hz, 2H), 6.96 (d, J=8.7 Hz, 1H), 4.45 (d, J=5.9 Hz, 2H), 3.52 (s, 3H), 2.34 (s, 3H).

Example 6: 4-ethyl-3-((4-methylphenyl)sulfonamido)-N-(pyridin-3-ylmethyl)benzamide

[0140] ##STR00032##

Step 1: Preparation of 3-amino-4-ethyl-N-(pyridin-3-ylmethyl)benzamide

[0141] ##STR00033##

[0142] According to the method of step 1 in Example 1, the title compound was synthesized from 3-amino-4-ethylbenzoic acid.

[0143] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.81 (t, J=6.0 Hz, 1H), 8.52 (d, J=1.7 Hz, 1H), 8.45 (dd, J=4.7, 1.5 Hz, 1H), 7.73-7.65 (m, 1H), 7.39-7.31 (m, 1H), 7.11 (d, J=1.6 Hz, 1H), 7.04-6.95 (m, 2H), 5.03 (s, 2H), 4.44 (d, J=6.0 Hz, 2H), 2.46 (q, J=7.5 Hz, 2H), 1.12 (t, J=7.5 Hz, 3H).

Step 2: Preparation of 4-ethyl-3-((4-methylphenyl)sulfonamido)-N-(pyridin-3-ylmethyl)benzamide

[0144] ##STR00034##

[0145] According to the synthesis method of step 2 in Example 1, the title compound was synthesized from 3-amino-4-ethyl-N-(pyridin-3-ylmethyl) benzamide.

[0146] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.64 (s, 1H), 9.00 (t, J=5.9 Hz, 1H), 8.52 (d, J=2.0 Hz, 1H), 8.46 (dd, J=4.8, 1.6 Hz, 1H), 7.71-7.64 (m, 2H), 7.57-7.51 (m, 3H), 7.39-7.31 (m, 3H), 7.27 (d, J=8.1 Hz, 1H), 4.45 (d, J=5.9 Hz, 2H), 2.44 (q, J=7.5 Hz, 2H), 2.35 (s, 3H), 0.92 (t, J=7.5 Hz, 3H).

Example 7: 3-methyl-5-((4-methylphenyl)sulfonamido)-N-(pyridin-3-ylmethyl)benzamide

[0147] ##STR00035##

Step 1: Preparation of 3-amino-5-methyl-N-(pyridin-3-ylmethyl)benzamide

[0148] ##STR00036##

[0149] According to the method of step 1 in Example 1, the title compound was synthesized from 3-amino-5-methylbenzoic acid.

[0150] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.81 (t, J=6.0 Hz, 1H), 8.53 (d, J=1.7 Hz, 1H), 8.45 (dd, J=4.8, 1.6 Hz, 1H), 7.70 (ddd, J=7.9, 2.1, 1.7 Hz, 1H), 7.36 (ddd, J=7.8, 4.8, 0.8 Hz, 1H), 6.86 (t, J=1.7 Hz, 1H), 6.84-6.81 (m, 1H), 6.58-6.48 (m, 1H), 5.29 (br s, 2H), 4.43 (d, J=6.0 Hz, 2H), 2.20 (s, 3H).

[0151] MS (ESI+) m/z 242.2 [M+H]+.

Step 2: Preparation of 3-methyl-5-((4-methylphenyl)sulfonamido)-N-(pyridin ylmethyl)benzamide

[0152] ##STR00037##

[0153] According to the method of step 2 in Example 1, the title compound was synthesized from 3-amino-5-methyl-N-(pyridin-3-ylmethyl) benzamide.

[0154] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.32 (s, 1H), 8.99 (t, J=5.9 Hz, 1H), 8.52 (d, J=1.8 Hz, 1H), 8.46 (dd, J=4.7, 1.6 Hz, 1H), 7.73-7.59 (m, 3H), 7.41 (t, J=1.6 Hz, 1H), 7.38-7.30 (m, 4H), 7.10-7.05 (m, 1H), 4.43 (d, J=5.9 Hz, 2H), 2.32 (s, 3H), 2.24 (s, 3H).

[0155] MS (ESI+) m/z 396.3 [M+H]+.

Example 8: 3-methoxy-5-((4-methylphenyl)sulfonamido)-N-(pyridin-3-ylmethyl)benzamide

[0156] ##STR00038##

Step 1: Preparation of 3-amino-5-methoxy-N-(pyridin-3-ylmethyl)benzamide

[0157] ##STR00039##

[0158] According to the method of step 1 in Example 1, the title compound was synthesized from 3-amino-5-methoxybenzoic acid.

[0159] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.84 (t, J=6.0 Hz, 1H), 8.53 (d, J=1.2 Hz, 1H), 8.45 (dd, J=4.6, 1.2 Hz, 1H), 7.70 (ddd, J=7.9, 2.1, 1.7 Hz, 1H), 7.36 (ddd, J=7.8, 4.8, 0.7 Hz, 1H), 6.71-6.63 (m, 1H), 6.58 (dd, J=2.3, 1.5 Hz, 1H), 6.28 (t, J=2.1 Hz, 1H), 5.33 (s, 2H), 4.44 (d, J=5.9 Hz, 2H), 3.70 (s, 3H).

Step 2: Preparation of 3-methoxy-5-((4-methylphenyl)sulfonamido)-N-(pyridin ylmethyl)benzamide

[0160] ##STR00040##

[0161] According to the method of step 2 in Example 1, the title compound was synthesized from 3-amino-5-methoxy-N-(pyridin-3-ylmethyl) benzamide.

[0162] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.44 (s, 1H), 9.22 (t, J=5.3 Hz, 1H), 8.78 (s, 1H), 8.72 (d, J=5.3 Hz, 1H), 8.26 (d, J=6.1 Hz, 1H), 7.90-7.79 (m, 1H), 7.73-7.61 (m, 2H), 7.35 (d, J=7.9 Hz, 2H), 7.26-7.18 (m, 1H), 7.15 (s, 1H), 6.83 (t, J=2.1 Hz, 1H), 4.56 (d, J=5.7 Hz, 2H), 3.73 (s, 3H), 2.33 (s, 3H).

Example 9: 3-fluoro-5-((4-methylphenyl)sulfonamido)-N-(pyridin-3-ylmethyl)benzamide

[0163] ##STR00041##

Step 1: Preparation of 3-amino-5-fluoro-N-(pyridin-3-ylmethyl)benzamide

[0164] ##STR00042##

[0165] According to the method of step 1 in Example 1, the title compound was synthesized from 3-amino-5-fluorobenzoic acid.

[0166] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.93 (t, J=5.9 Hz, 1H), 8.53 (d, J=1.8 Hz, 1H), 8.46 (dd, J=4.8, 1.6 Hz, 1H), 7.76-7.65 (m, 1H), 7.36 (ddd, J=7.9, 4.8, 0.7 Hz, 1H), 6.92-6.84 (m, 1H), 6.74 (ddd, J=9.8, 2.3, 1.5 Hz, 1H), 6.45 (dt, J=11.4, 2.2 Hz, 1H), 5.64 (br s, 2H), 4.44 (d, J=5.9 Hz, 2H).

[0167] MS (ESI+) m/z 246.2 [M+H]+.

Step 2: Preparation of 3-fluoro-5-((4-methylphenyl)sulfonamido)-N-(pyridin-3-ylmethyl)benzamide

[0168] ##STR00043##

[0169] According to the method of step 2 in Example 1, the title compound was synthesized from 3-amino-5-fluoro-N-(pyridin-3-ylmethyl) benzamide.

[0170] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.82 (s, 1H), 9.42 (t, J=4.7 Hz, 1H), 8.87 (s, 1H), 8.80 (d, J=5.5 Hz, 1H), 8.44 (d, J=8.0 Hz, 1H), 8.03-7.91 (m, 1H), 7.77-7.64 (m, 2H), 7.47 (dd, J=10.9, 1.5 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 7.11 (dt, J=10.4, 2.1 Hz, 1H), 4.60 (d, J=5.7 Hz, 2H), 2.34 (s, 3H).

[0171] MS (ESI+) m/z 400.3 [M+H]+.

Example 10: 3-chloro-5-((4-methylphenyl)sulfonamido)-N-(pyridin-3-ylmethyl)benzamide

[0172] ##STR00044##

Step 1: Preparation of 3-amino-5-chloro-N-(pyridin-3-ylmethyl)benzamide

[0173] ##STR00045##

[0174] According to the method of step 1 in Example 1, the title compound was synthesized from 3-amino-5-chlorobenzoic acid.

[0175] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.98 (t, J=5.9 Hz, 1H), 8.53 (d, J=1.4 Hz, 1H), 8.46 (d, J=4.6 Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.36 (dd, J=7.8, 4.8 Hz, 1H), 7.04-6.96 (m, 2H), 6.72 (t, J=1.9 Hz, 1H), 5.64 (br s, 2H), 4.44 (d, J=5.9 Hz, 2H).

[0176] MS (ESI+) m/z 262.2 [M+H]+.

Step 2: Preparation of 3-chloro-5-((4-methylphenyl)sulfonamido)-N-(pyridin-3-ylmethyl)benzamide

[0177] ##STR00046##

[0178] According to the method of step 2 in Example 1, the title compound was synthesized from 3-amino-5-chloro-N-(pyridin-3-ylmethyl) benzamide.

[0179] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.77 (s, 1H), 9.31 (t, J=5.8 Hz, 1H), 8.76 (d, J=1.4 Hz, 1H), 8.70 (dd, J=5.3, 1.0 Hz, 1H), 8.21 (d, J=8.0 Hz, 1H), 7.78 (dd, J=7.9, 5.4 Hz, 1H), 7.71-7.66 (m, 2H), 7.65 (t, J=1.7 Hz, 1H), 7.59 (dd, J=2.0, 1.5 Hz, 1H), 7.38 (dd, J=8.5, 0.5 Hz, 2H), 7.29 (t, J=2.0 Hz, 1H), 4.55 (d, J=5.7 Hz, 2H), 2.34 (s, 3H).

[0180] MS (ESI+) m/z 416.3 [M+H]+.

Example 11: 2-methyl-5-((4-methylphenyl)sulfonamido)-N-(pyridin-3-ylmethyl)benzamide

[0181] ##STR00047##

Step 1: Preparation of 5-amino-2-methyl-N-(pyridin-3-ylmethyl)benzamide

[0182] ##STR00048##

[0183] According to the method of step 1 in Example 1, the title compound was synthesized from 5-amino-2-methylbenzoic acid.

[0184] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.70 (t, J=6.0 Hz, 1H), 8.55 (d, J=1.8 Hz, 1H), 8.46 (dd, J=4.7, 1.4 Hz, 1H), 7.76-7.68 (m, 1H), 7.37 (ddd, J=7.9, 4.8, 0.7 Hz, 1H), 6.86 (d, J=8.1 Hz, 1H), 6.58 (d, J=2.4 Hz, 1H), 6.53 (dd, J=8.1, 2.5 Hz, 1H), 5.03 (s, 2H), 4.41 (d, J=6.0 Hz, 2H), 2.12 (s, 3H).

[0185] MS (ESI+) m/z 242.2 [M+H]+.

Step 2: Preparation of 2-methyl-5-((4-methylphenyl)sulfonamido)-N-(pyridin-3-ylmethyl)benzamide

[0186] ##STR00049##

[0187] According to the method of step 1 in Example 1, the title compound was synthesized from 5-amino-2-methyl-N-(pyridin-3-ylmethyl) benzamide.

[0188] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.24 (s, 1H), 8.82 (t, J=6.0 Hz, 1H), 8.56-8.51 (m, 1H), 8.48 (dd, J=4.8, 1.6 Hz, 1H), 7.73-7.67 (m, 1H), 7.67-7.60 (m, 2H), 7.38 (ddd, J=7.8, 4.8, 0.7 Hz, 1H), 7.36-7.31 (m, 2H), 7.11-7.02 (m, 3H), 4.42 (d, J=6.0 Hz, 2H), 2.33 (s, 3H), 2.16 (s, 3H).

[0189] MS (ESI+) m/z 396.3 [M+H]+.

Example 12: 3-((4-ethylphenyl)sulfonamido)-4-methyl-N-(pyridin-3-ylmethyl)benzamide

[0190] ##STR00050##

[0191] According to the method of step 2 in Example 1, the title compound was synthesized from 3-amino-4-methyl-N-(pyridin-3-ylmethyl) benzamide and p-ethylbenzenesulfonyl chloride.

[0192] .sup.1H NMR (400 MHz) δ 9.65 (s, 1H), 9.04 (t, J=6.0 Hz, 1H), 8.53 (d, J=2.0 Hz, 1H), 8.46 (dd, J=4.8, 1.6 Hz, 1H), 7.70 (dt, J=7.9, 2.0 Hz, 1H), 7.65-7.60 (m, 2H), 7.58-7.53 (m, 2H), 7.40-7.33 (m, 3H), 7.21 (d, J=8.0 Hz, 1H), 4.45 (d, J=6.0 Hz, 2H), 2.65 (d, J=7.6 Hz, 2H), 1.95 (s, 3H), 1.16 (t, J=7.6 Hz, 3H).

Example 13: 3-((4-methoxyphenyl)sulfonamido)-4-methyl-N-(pyridin-3-ylmethyl)benzamide

[0193] ##STR00051##

[0194] According to the method of step 2 in Example 1, the title compound was synthesized from 3-amino-4-methyl-N-(pyridin-3-ylmethyl) benzamide and 4-methoxybenzenesulfonyl chloride.

[0195] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.55 (s, 1H), 9.02 (t, J=5.9 Hz, 1H), 8.53 (s, 1H), 8.46 (d, J=4.2 Hz, 1H), 7.69 (d, J=7.9 Hz, 1H), 7.66-7.59 (m, 2H), 7.56 (d, J=8.9 Hz, 2H), 7.36 (dd, J=7.8, 4.8 Hz, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.05 (d, J=8.9 Hz, 2H), 4.45 (d, J=5.8 Hz, 2H), 3.80 (s, 3H), 1.97 (s, 3H).

Example 14: 3-((3-methoxyphenyl)sulfonamido)-4-methyl-N-(pyridin-3-ylmethyl)benzamide

[0196] ##STR00052##

[0197] According to the method of step 2 in Example 1, the title compound was synthesized from 3-amino-4-methyl-N-(pyridin-3-ylmethyl) benzamide and 3-methoxybenzenesulfonyl chloride.

[0198] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.72 (s, 1H), 9.03 (t, J=5.9 Hz, 1H), 8.53 (d, J=1.8 Hz, 1H), 8.46 (dd, J=4.8, 1.6 Hz, 1H), 7.69 (dt, J=7.9, 1.9 Hz, 1H), 7.64 (dd, J=7.8, 1.8 Hz, 1H), 7.61 (d, J=1.7 Hz, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.36 (ddd, J=7.8, 4.7, 0.6 Hz, 1H), 7.26-7.17 (m, 3H), 7.15-7.10 (m, 1H), 4.45 (d, J=5.9 Hz, 2H), 3.73 (s, 3H), 1.99 (s, 3H).

[0199] MS (ESI+) m/z 412.3 [M+H]+.

Example 15: 3-((4-ethoxyphenyl)sulfonamido)-4-methyl-N-(pyridin-3-ylmethyl)benzamide

[0200] ##STR00053##

[0201] According to the method of step 2 in Example 1, the title compound was synthesized from 3-amino-4-methyl-N-(pyridin-3-ylmethyl) benzamide and 4-ethoxybenzenesulfonyl chloride.

[0202] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.57 (s, 1H), 9.04 (t, J=5.8 Hz, 1H), 8.53 (d, J=1.4 Hz, 1H), 8.46 (dd, J=4.6, 1.2 Hz, 1H), 7.69 (dt, J=7.9, 1.9 Hz, 1H), 7.66-7.58 (m, 2H), 7.54 (d, J=8.9 Hz, 2H), 7.40-7.32 (m, 1H), 7.21 (d, J=7.9 Hz, 1H), 7.03 (d, J=9.0 Hz, 2H), 4.45 (d, J=5.9 Hz, 2H), 4.07 (q, J=7.0 Hz, 2H), 1.96 (s, 3H), 1.32 (t, J=7.0 Hz, 3H).

Example 16: 3-((3,4-dimethylphenyl)sulfonamido)-4-methyl-N-(pyridin-3-ylmethyl)benzamide

[0203] ##STR00054##

[0204] According to the method of step 2 in Example 1, the title compound was synthesized from 3-amino-4-methyl-N-(pyridin-3-ylmethyl) benzamide and 3,4-dimethylbenzenesulfonyl chloride.

[0205] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.58 (s, 1H), 9.02 (t, J=5.9 Hz, 1H), 8.52 (d, J=1.2 Hz, 1H), 8.46 (dd, J=4.7, 1.1 Hz, 1H), 7.69 (dt, J=7.8, 1.8 Hz, 1H), 7.65-7.58 (m, 2H), 7.42 (s, 1H), 7.39-7.33 (m, 2H), 7.29 (d, J=8.0 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 4.45 (d, J=5.8 Hz, 2H), 2.26 (s, 3H), 2.22 (s, 3H), 1.99 (s, 3H).

Example 17: 3-((2,4-dimethylphenyl)sulfonamido)-4-methyl-N-(pyridin ylmethyl)benzamide

[0206] ##STR00055##

[0207] According to the method of step 2 in Example 1, the title compound was synthesized from 3-amino-4-methyl-N-(pyridin-3-ylmethyl) benzamide and 2,4-dimethylbenzenesulfonyl chloride.

[0208] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.66 (s, 1H), 9.00 (t, J=5.9 Hz, 1H), 8.52 (d, J=0.8 Hz, 1H), 8.49 (t, J=4.8, 0.8 Hz, 1H), 7.68 (dt, J=7.7, 1.7 Hz, 1H), 7.65-7.57 (m, 2H), 7.51 (d, J=8.1 Hz, 1H), 7.36 (dd, J=7.8, 4.8 Hz, 1H), 7.26-7.17 (m, 2H), 7.08 (d, J=8.0 Hz, 1H), 4.44 (d, J=5.8 Hz, 2H), 2.50 (s, 3H), 2.30 (s, 3H), 2.01 (s, 3H).

Example 18: 4-methyl-N-(pyridin-3-ylmethyl)-3-((4-(trifluoromethyl)phenyl) sulfonamido)benzamide

[0209] ##STR00056##

[0210] According to the method of step 2 in Example 1, the title compound was synthesized from 3-amino-4-methyl-N-(pyridin-3-ylmethyl) benzamide and 4-trifluoromethylbenzenesulfonyl chloride.

[0211] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.04 (s, 1H), 9.05 (s, 1H), 8.53 (d, J=1.8 Hz, 1H), 8.46 (dd, J=4.8, 1.5 Hz, 1H), 7.96 (d, J=8.3 Hz, 2H), 7.86 (d, J=8.2 Hz, 2H), 7.72-7.64 (m, 2H), 7.61 (d, J=1.8 Hz, 1H), 7.35 (ddd, J=7.9, 4.8, 0.7 Hz, 1H), 7.26 (d, J=8.1 Hz, 1H), 4.46 (d, J=5.9 Hz, 2H), 1.96 (s, 3H).

Example 19: 4-methyl-N-(pyridin-3-ylmethyl)-3-((3-(trifluoromethyl)phenyl) sulfonamido)benzamide

[0212] ##STR00057##

[0213] According to the method of step 2 in Example 1, the title compound was synthesized from 3-amino-4-methyl-N-(pyridin-3-ylmethyl) benzamide and 3-trifluoromethylbenzenesulfonyl chloride.

[0214] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.06 (s, 1H), 9.27 (t, J=5.5 Hz, 1H), 8.84 (d, J=1.4 Hz, 1H), 8.79 (d, J=5.4 Hz, 1H), 8.39 (d, J=7.8 Hz, 1H), 8.07 (d, J=7.8 Hz, 1H), 8.00-7.90 (m, 2H), 7.89-7.80 (m, 2H), 7.73 (dd, J=8.0, 1.8 Hz, 1H), 7.54 (d, J=1.7 Hz, 1H), 7.28 (d, J=8.1 Hz, 1H), 4.60 (d, J=5.8 Hz, 2H), 1.98 (s, 3H).

[0215] MS (ESI+) m/z 450.3 [M+H]+.

Example 20: 3-((4-fluorophenyl)sulfonamido)-4-methyl-N-(pyridin-3-ylmethyl)benzamide

[0216] ##STR00058##

[0217] According to the method of step 2 in Example 1, the title compound was synthesized from 3-amino-4-methyl-N-(pyridin-3-ylmethyl) benzamide and 4-fluorobenzenesulfonyl chloride.

[0218] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.78 (s, 1H), 9.03 (t, J=5.9 Hz, 1H), 8.53 (s, 1H), 8.46 (d, J=3.8 Hz, 1H), 7.72-7.62 (m, 3H), 7.64 (dd, J=7.9, 1.8 Hz, 1H), 7.58 (d, J=1.8 Hz, 1H), 7.43-7.33 (m, 3H), 7.24 (d, J=8.1 Hz, 1H), 4.45 (d, J=5.9 Hz, 2H), 1.98 (s, 3H).

Example 21: 3-((4-chlorophenyl)sulfonamido)-4-methyl-N-(pyridin-3-ylmethyl)benzamide

[0219] ##STR00059##

[0220] According to the method of step 2 in Example 1, the title compound was synthesized from 3-amino-4-methyl-N-(pyridin-3-ylmethyl) benzamide and 4-chlorobenzenesulfonyl chloride.

[0221] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.86 (s, 1H), 9.04 (t, J=5.9 Hz, 1H), 8.53 (d, J=1.9 Hz, 1H), 8.46 (dd, J=4.8, 1.6 Hz, 1H), 7.69 (dt, J=7.8, 1.9 Hz, 1H), 7.67-7.62 (m, 5H), 7.60 (d, J=1.7 Hz, 1H), 7.39-7.33 (m, 1H), 7.25 (d, J=8.0 Hz, 1H), 4.46 (d, J=5.8 Hz, 2H), 1.98 (s, 3H).

Example 22: 3-((4-isopropylphenyl)sulfonamido)-4-methyl-N-(pyridin-3-ylmethyl)benzamide

[0222] ##STR00060##

[0223] According to the method of step 2 in Example 1, the title compound was synthesized from 3-amino-4-methyl-N-(pyridin-3-ylmethyl) benzamide and 4-isopropylbenzenesulfonyl chloride.

[0224] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.63 (s, 1H), 9.02 (t, J=5.9 Hz, 1H), 8.53 (d, J=1.8 Hz, 1H), 8.46 (dd, J=4.8, 1.6 Hz, 1H), 7.69 (dt, J=7.8, 1.9 Hz, 1H), 7.65-7.59 (m, 2H), 7.56 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H), 7.38-7.33 (m, 1H), 7.21 (d, J=8.5 Hz, 1H), 4.45 (d, J=5.9 Hz, 2H), 3.01-2.88 (m, 1H), 1.94 (s, 3H), 1.18 (d, J=6.9 Hz, 6H).

Example 23: 3-((4-cyclopropylphenyl)sulfonamido)-4-methyl-N-(pyridin-3-ylmethyl)benzamide

[0225] ##STR00061##

[0226] According to the method of step 2 in Example 1, the title compound was synthesized from 3-amino-4-methyl-N-(pyridin-3-ylmethyl) benzamide and 4-cyclopropylbenzenesulfonyl chloride.

[0227] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.61 (s, 1H), 9.02 (t, J=5.9 Hz, 1H), 8.53 (d, J=1.6 Hz, 1H), 8.46 (dd, J=4.7, 1.4 Hz, 1H), 7.69 (dt, J=7.9, 2.1 Hz, 1H), 7.66-7.57 (m, 2H), 7.49 (d, J=8.5 Hz, 2H), 7.39-7.33 (m, 1H), 7.23-7.18 (m, 3H), 4.45 (d, J=5.9 Hz, 2H), 2.03-1.96 (m, 1H), 1.95 (s, 3H), 1.10-0.94 (m, 2H), 0.78-0.65 (m, 2H).

Example 24: 4-methyl-3-((4-n-propylphenyl) sulfonamido)-N-(pyridin-3-ylmethyl) benzamide

[0228] ##STR00062##

[0229] According to the method of step 2 in Example 1, the title compound was synthesized from 3-amino-4-methyl-N-(pyridin-3-ylmethyl) benzamide and 4-n-propylbenzenesulfonyl chloride.

[0230] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.63 (s, 1H), 9.02 (t, J=5.9 Hz, 1H), 8.53 (d, J=1.8 Hz, 1H), 8.46 (dd, J=4.8, 1.5 Hz, 1H), 7.69 (dt, J=7.7, 1.7 Hz, 1H), 7.65-7.59 (m, 2H), 7.53 (d, J=8.3 Hz, 2H), 7.39-7.31 (m, 3H), 7.21 (d, J=7.9 Hz, 1H), 4.45 (d, J=5.8 Hz, 2H), 2.60 (t, J=7.5 Hz, 2H), 1.92 (s, 3H), 1.66-1.49 (m, 2H), 0.85 (t, J=7.3 Hz, 3H).

Example 25: 3-((2,3-dihydro-1H-indene)-5-sulfonamido)-4-methyl-N-(pyridin ylmethyl)benzamide

[0231] ##STR00063##

[0232] According to the method of step 2 in Example 1, the title compound was synthesized from 3-amino-4-methyl-N-(pyridin-3-ylmethyl) benzamide and 2,3-dihydro-1H-indene-5-sulfonyl chloride.

[0233] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.59 (s, 1H), 9.02 (t, J=5.9 Hz, 1H), 8.52 (d, J=1.6 Hz, 1H), 8.46 (dd, J=4.7, 1.5 Hz, 1H), 7.75-7.65 (m, 1H), 7.64-7.58 (m, 2H), 7.51-7.46 (m, 1H), 7.44-7.39 (m, 1H), 7.38-7.32 (m, 2H), 7.21 (dd, J=8.4, 0.4 Hz, 1H), 4.45 (d, J=5.9 Hz, 2H), 2.98-2.76 (m, 4H), 2.09-1.92 (m, 5H).

Example 26: 3-(benzo[d][1,3]dioxole-5-sulfonamido)-4-methyl-N-(pyridin-3-ylmethyl)benzamide

[0234] ##STR00064##

[0235] According to the method of step 2 in Example 1, the title compound was synthesized from 3-amino-4-methyl-N-(pyridin-3-ylmethyl) benzamide and benzo[d][1,3] dioxole-5-sulfonyl chloride.

[0236] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.60 (s, 1H), 9.03 (t, J=5.9 Hz, 1H), 8.53 (s, 1H), 8.46 (d, J=3.9 Hz, 1H), 7.73-7.67 (m, 1H), 7.63 (dd, J=7.8, 1.8 Hz, 1H), 7.60 (d, J=1.8 Hz, 1H), 7.39-7.32 (m, 1H), 7.24 (d, J=7.9 Hz, 1H), 7.15 (dd, J=8.2, 1.9 Hz, 1H), 7.10 (d, J=1.8 Hz, 1H), 7.02 (d, J=8.2 Hz, 1H), 6.15 (s, 2H), 4.46 (d, J=5.9 Hz, 2H), 2.03 (s, 3H).

Example 27: 3-((2,3-dihydrobenzofuran)-5-sulfonamido)-4-methyl-N-(pyridin-3-ylmethyl)benzamide

[0237] ##STR00065##

[0238] According to the method of step 2 in Example 1, the title compound was synthesized from 3-amino-4-methyl-N-(pyridin-3-ylmethyl) benzamide and 2,3-dihydrobenzofuran-5-sulfonyl chloride.

[0239] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.52 (s, 1H), 9.16 (t, J=5.1 Hz, 1H), 8.78 (s, 1H), 8.73 (d, J=4.2 Hz, 1H), 8.27 (d, J=5.3 Hz, 1H), 7.85 (s, 1H), 7.64 (dd, J=4.1, 2.3 Hz, 2H), 7.49 (d, J=1.8 Hz, 1H), 7.38 (dd, J=8.4, 2.1 Hz, 1H), 7.24 (dd, J=8.4, 0.6 Hz, 1H), 6.85 (d, J=8.4 Hz, 1H), 4.61 (t, J=8.8 Hz, 2H), 4.58 (d, J=5.6 Hz, 2H), 3.18 (dd, J=8.8 Hz, 2H), 2.01 (s, 3H).

[0240] MS (ESI+) m/z 424.3 [M+H]+.

Example 28: 3-((2,3-dihydrobenzo[b][1,4]dioxine)-6-sulfonamido)-4-methyl-N-(pyridin-3-ylmethyl)benzamide

[0241] ##STR00066##

[0242] According to the method of step 2 in Example 1, the title compound was synthesized from 3-amino-4-methyl-N-(pyridin-3-ylmethyl) benzamide and (2,3-dihydrobenzo[b][1,4]dioxin)-6-sulfonyl chloride.

[0243] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.61 (s, 1H), 9.21 (t, J=5.6 Hz, 1H), 8.83 (s, 1H), 8.77 (d, J=5.4 Hz, 1H), 8.37 (d, J=7.7 Hz, 1H), 7.95-7.86 (m, 1H), 7.66 (dd, J=7.9, 1.6 Hz, 1H), 7.63 (d, J=1.7 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 7.11-7.06 (m, 2H), 6.98 (d, J=9.0 Hz, 1H), 4.60 (d, J=5.7 Hz, 2H), 4.38-4.23 (m, 4H), 2.01 (s, 3H).

[0244] MS (ESI+) m/z 440.3 [M+H]+.

Example 29: 4-methyl-3-(naphthalene-2-sulfonamido)-N-(pyridin-3-ylmethyl)benzamide

[0245] ##STR00067##

[0246] According to the method of step 2 in Example 1, the title compound was synthesized from 3-amino-4-methyl-N-(pyridin-3-ylmethyl) benzamide and naphthalene sulfonyl chloride.

[0247] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.85 (s, 1H), 9.01 (t, J=5.9 Hz, 1H), 8.51 (d, J=1.6 Hz, 1H), 8.46 (dd, J=4.7, 1.4 Hz, 1H), 8.28 (d, J=1.6 Hz, 1H), 8.13-8.00 (m, 3H), 7.77-7.58 (m, 6H), 7.36-7.31 (m, 1H), 7.18 (d, J=8.1 Hz, 1H), 4.43 (d, J=5.8 Hz, 2H), 1.94 (s, 3H).

Example 30: 4-methyl-3-((5-methylthiophene)-2-sulfonamido)-N-(pyridin-3-ylmethyl)benzamide

[0248] ##STR00068##

[0249] According to the method of step 2 in Example 1, the title compound was synthesized from 3-amino-4-methyl-N-(pyridin-3-ylmethyl) benzamide and 5-methylthiophene-2-sulfonyl chloride.

[0250] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.87 (s, 1H), 9.21 (t, J=5.7 Hz, 1H), 8.81 (d, J=1.4 Hz, 1H), 8.76 (d, J=5.4 Hz, 1H), 8.34 (d, J=8.0 Hz, 1H), 7.90 (dd, J=7.9, 5.5 Hz, 1H), 7.73-7.67 (m, 2H), 7.31-7.25 (m, 1H), 7.19 (d, J=3.7 Hz, 1H), 6.84 (dd, J=3.7, 1.1 Hz, 1H), 4.60 (d, J=5.7 Hz, 2H), 2.46 (s, 3H), 2.03 (s, 3H).

[0251] MS (ESI+) m/z 402.3 [M+H]+.

Example 31: 3-((5-chlorothiophene)-2-sulfonamido)-4-methyl-N-(pyridin-3-ylmethyl)benzamide

[0252] ##STR00069##

[0253] According to the method of step 2 in Example 1, the title compound was synthesized from 3-amino-4-methyl-N-(pyridin-3-ylmethyl) benzamide and 5-chlorothiophene-2-sulfonyl chloride.

[0254] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.13 (s, 1H), 9.08 (t, J=5.8 Hz, 1H), 8.54 (s, 1H), 8.47 (d, J=3.1 Hz, 1H), 7.73-7.67 (m, 2H), 7.64 (d, J=1.8 Hz, 1H), 7.36 (dd, J=7.8, 4.7 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.29 (d, J=4.1 Hz, 1H), 7.23 (d, J=4.1 Hz, 1H), 4.47 (d, J=5.9 Hz, 2H), 2.08 (s, 3H).

Example 32: 3-((6-methoxypyridine)-3-sulfonamido)-4-methyl-N-(pyridin-3-ylmethyl)benzamide

[0255] ##STR00070##

[0256] According to the method of step 2 in Example 1, the title compound was synthesized from 3-amino-4-methyl-N-(pyridin-3-ylmethyl) benzamide and 6-methoxypyridine-3-sulfonyl chloride.

[0257] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.87 (s, 1H), 9.22 (t, J=5.5 Hz, 1H), 8.82 (s, 1H), 8.76 (d, J=4.0 Hz, 1H), 8.43-8.32 (m, 2H), 8.00-7.83 (m, 2H), 7.70 (d, J=7.9 Hz, 1H), 7.61 (d, J=1.7 Hz, 1H), 7.28 (d, J=8.1 Hz, 1H), 6.99 (dd, J=8.8, 0.4 Hz, 1H), 4.59 (d, J=5.7 Hz, 2H), 3.90 (s, 3H), 2.04 (s, 3H).

[0258] MS (ESI+) m/z 413.3 [M+H]+.

Example 33: 4-methyl-3-((4-methylphenyl)sulfonamido)-N-((6-methylpyridin-3-yl)methyl)benzamide

[0259] ##STR00071##

Step 1: Preparation of methyl 4-methyl-3-((4-methylphenyl)sulfonamido) benzoate

[0260] ##STR00072##

[0261] A mixture of 3-amino-4-methyl benzoic acid (1.65 g, 10 mmol), p-toluenesulfonyl chloride (2.8 g, 12 mmol), pyridine (1.19 g, 15 mmol) and DMAP (0.122 g, 1 mmol) in DCM (40 mL) was stirred at rt overnight. The reaction mixture was diluted with water (100 mL) and acidified to pH=3-4 with dilute hydrochloric acid. The mixture was extracted with dichloromethane (50 mL×3). The combined organic layers were washed with water (100 mL×2) and saline (100 mL), dried with anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, PE/EtOAc=3:1) to obtain the product as yellow oil (2.82 g, yield 88%).

[0262] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.73 (s, 1H), 7.70-7.63 (m, 2H), 7.55 (d, J=8.0H, 2H), 7.36 (d, J=8.0 Hz, 2H), 7.28 (d, J=7.7 Hz, 1H), 3.81 (s, 3H), 2.36 (s, 3H), 2.03 (s, 3H).

[0263] MS (ESI+) m/z 319.8 [M+H]+.

Step 2: Preparation of 4-methyl-3-((4-methylphenyl)sulfonamido)benzoic acid

[0264] ##STR00073##

[0265] The mixture of methyl 4-methyl-3-((4-methylphenyl) sulfonamido) benzoate (2.71 g, 8.5 mmol) and sodium hydroxide (1.36 g, 34 mmol, 4 eq.) in methanol (51 mL) and water (17 mL) was refluxed for 7 hours. The resulting mixture was evaporated to dryness under reduced pressure, and the reaction mixture was diluted with water (100 mL), acidified to pH=2 with concentrated hydrochloric acid, and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with water (100 mL×2) and saline (100 mL), dried with anhydrous sodium sulfate, filtered, and concentrated until solid began to precipitate in the solution. The resulting suspension was left still for 1 hour, and the solid was collected by suction filtration and dried to afford a light yellow solid (2.1 g, yield 81%).

[0266] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.89 (br s, 1H), 9.69 (br s, 1H), 7.66 (dd, J=7.8, 1.6 Hz, 1H), 7.63 (d, J=1.5 Hz, 1H), 7.55 (d, J=8.2 Hz, 2H), 7.36 (d, J=8.1 Hz, 2H), 7.25 (d, J=7.9 Hz, 1H), 2.36 (s, 3H), 2.05 (s, 3H).

[0267] MS (ESI+) m/z 305.8 [M+H]+.

Step 3: Preparation of 4-methyl-3-((4-methylphenyl)sulfonamido)-N-((6-methylpyridin-3-yl)methyl)benzamide

[0268] ##STR00074##

[0269] The reaction mixture of 4-methyl-3-((4-methylphenyl) sulfonamido) benzoic acid (0.153 g, 0.5 mmol), 6-methylpyridin-3-ylmethylamine (0.080 g, 0.65 mmol), HATU (0.285 g, 0.75 mmol) and triethylamine (0.152 g, 1.5 mmol) in DCM (10 mL) was stirred overnight. Water (50 mL) was added, and the resulting mixture was extracted with DCM (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saline (30 mL), dried with anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative thin layer chromatography (silica gel, DCM/MeOH=15:1) to obtain a yellow foamy solid (126 mg, yield 62%).

[0270] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.63 (s, 1H), 8.97 (t, J=5.9 Hz, 1H), 8.38 (d, J=2.1 Hz, 1H), 7.64-7.55 (m, 3H), 7.55-7.49 (m, 2H), 7.33 (d, J=8.0 Hz, 2H), 7.20 (d, J=7.8 Hz, 2H), 4.40 (d, J=5.8 Hz, 2H), 2.44 (s, 3H), 2.35 (s, 3H), 1.95 (s, 3H).

Example 34: N-((6-methoxypyridin-3-yl)methyl)-4-methyl-3-((4-methylphenyl) sulfonamido)benzamide

[0271] ##STR00075##

[0272] The title compound was synthesized from 4-methyl-3-((4-methylphenyl) sulfonamido) benzoic acid and 6-methoxypyridin-3-ylmethylamine according to the method of Example 33.

[0273] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.63 (s, 1H), 8.93 (t, J=5.9 Hz, 1H), 8.10 (d, J=2.1 Hz, 1H), 7.69-7.56 (m, 3H), 7.52 (d, J=8.3 Hz, 2H), 7.33 (d, J=8.0 Hz, 2H), 7.20 (d, J=8.0 Hz, 1H), 6.79 (dd, J=8.8, 0.4 Hz, 1H), 4.36 (d, J=5.8 Hz, 2H), 3.83 (s, 3H), 2.35 (s, 3H), 1.94 (s, 3H).

Example 35: 4-methyl-3-((4-methylphenyl) sulfonamido)-N-((6-(trifluoromethyl) pyridin-3-yl)methyl)benzamide

[0274] ##STR00076##

[0275] According to the method of Example 34, the title compound was synthesized from 4-methyl-3-((4-methylphenyl) sulfonamido) benzoic acid and 6-trifluoromethylpyridin-3-ylmethylamine.

[0276] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.65 (s, 1H), 9.11 (t, J=5.8 Hz, 1H), 8.71 (d, J=1.4 Hz, 1H), 7.97 (dd, J=8.1, 1.5 Hz, 1H), 7.88 (d, J=8.1 Hz, 1H), 7.67-7.58 (m, 2H), 7.52 (d, J=8.3 Hz, 2H), 7.33 (d, J=8.1 Hz, 2H), 7.22 (d, J=8.6 Hz, 1H), 4.55 (d, J=5.8 Hz, 2H), 2.35 (s, 3H), 1.96 (s, 3H).

Evaluation of Pharmacological Activity

Experimental Example 1: MTT Assay was Used to Determine the Survival Rate of Tumor Cells

[0277] DU145 cells (human prostate cancer cells) in logarithmic growth phase were digested with 0.25% trypsin-EDTA to prepare single cell suspension, which was inoculated into 96-well plate overnight according to 1500 cells/well/100 μL, and fresh medium containing different concentrations of compounds to be tested and corresponding solvent control was added, and 100 μL (DMSO final concentration <0.1%) was added to each well, and the 96-well plate was further cultured at 37° C. for 72 h. 20 μL of freshly prepared PBS solution containing 5 mg/mL MTT was added to each well, and the 96-well plate was further cultured for 4 h. After the supernatant was discarded, 180 μL of DMSO was added to each well to dissolve the MTT formazan precipitate. After the 96-well plate was shaked and mixed by a micro oscillator, the optical density (OD) at the detection wavelength of 570 nm was measured. With DMSO-treated tumor cells as the control group, the inhibition rate on the growth of tumor cells of the compound to be tested was calculated from the following formula, and the IC.sub.50 was calculated according to the median-effect equation.

Inhibition rate (%)=(average OD value of control group-average OD value of dosing group)/average OD value of control group×100%

[0278] The results are shown in table 1. The experimental results showed that all the examples showed antiproliferative activity against human prostate cancer DU145, and their IC.sub.50 values were all less than 10 μM.

TABLE-US-00001 TABLE 1 Antiproliferative activity against human prostate cancer cell DU145 Example IC.sub.50 (μM) 1 0.12 ± 0.03 2  0.7 ± 0.15 3 0.79 ± 0.13 4  0.8 ± 0.12 6 0.86 ± 0.08 7 0.34 ± 0.01 9  0.9 ± 0.02 10 0.34 ± 0.01 11  2.0 ± 0.03 12 0.04 ± 0.01 13 0.18 ± 0.08 14  2.5 ± 0.02 15 0.86 ± 0.06 16 0.97 ± 0.03 17  0.5 ± 0.04 20 3.47 ± 1.22 21 0.93 ± 0.05 22   1 ± 0.16 23  0.05 ± 0.008 25  0.9 ± 0.04 26 0.61 ± 0.14 27  1.2 ± 0.01 28 0.42 ± 0.01 29   1 ± 0.07 30  1.2 ± 0.03 32  0.4 ± 0.02 33 0.008 ± 0.001 34 0.006 ± 0.002 35  0.2 ± 0.07

Experimental Example 2: Luciferase Double Reporter Gene Experiment

[0279] The luciferase plasmids STAT3-TA-Luc and pGMLR-TK were transiently co-transfected into DU145 cells by Lipofectamine 3000. After staying overnight, different concentrations of compounds to be tested were added and cultured for 24 hours. The supernatant was discarded, and the residue was washed twice with PBS, and then 20 μL of lysis solution was added to shake and lyse for 5 min. The supernatant was transferred to a 96-well Costar whiteplate, and 70 μL of Dual-Glo luciferase substrate solution was added, and the relative fluorescence intensity of firefly luciferase was detected, and then 70 μL of Stop-Glo substrate solution was added, and the relative fluorescence intensity of sea kidney luciferase was detected, the normalized value was obtained, and the inhibition rate and IC.sub.50 value were calculated.

[0280] The results are shown in table 2. The experimental results showed that Examples 1, 6, 9, 12, 13, 17, 20, 23, 30, 33, 34 and 35 showed obvious STAT3 transcription inhibition activity in the STAT3 specific luciferase double reporter gene experiment of human prostate cancer cell DU145.

TABLE-US-00002 TABLE 2 Experimental results of luciferase double reporter gene on human prostate cancer cell DU145 with high STAT3 expression Example IC.sub.50 (μM) 1  7 ± 1.3 6 9.7 ± 1.3  9 6.2 ± 0.3  12 .sup. 1 ± 0.35 13 10 ± 2.1  17 8.2 ± 0.02 20 15 ± 1.4  23 .sup. 1 ± 0.19 30 17.5 ± 0.3  33 0.5 ± 0.12 34 0.8 ± 0.27 35 .sup. 8 ± 0.43

Experimental Example 3: The Expression of p-STAT3 was Detected by Western Blotting

[0281] DU145 cells treated for 16 h with different concentrations of examples 12, 23, 33 and 34 and DU145 cells in control group were collected and washed twice with pre-cooled PBS. After appropriate amount of RIPA lysate (50 mM Tris-HCl, 1 mM EDTA, 1% Triton X-100, 150 mM NaCl, 0.1% SDS, 1 mM NaF, Na.sub.3VO.sub.4, protease inhibitor, pH 7.4) was added to lyse for 1 h on ice, the reaction mixture was centrifuged at 4° C., 12,000 rpm for 20 min, and then the supernatant was collected for protein quantification and boiled for denaturation. Equal amount of protein was taken for 10% SDS-PAGE electrophoresis. The specific antibodies of p-STAT3 (Tyr705) and STAT3 were used as primary antibody, which was incubated overnight at 4° C. The corresponding HRP-labeled secondary antibody was used, incubated at room temperature for 2 h, and washed. ECL chemiluminescence substrate reaction solution was added to develop in gel imaging system, and the image was saved. (3-actin was used as internal reference.

[0282] The results are shown in FIG. 1.

Experimental Example 4: Study on the Efficacy of Xenotransplantation in Nude Mice

[0283] Tumor cells of human prostate cancer DU145 were collected under aseptic conditions, and the cell density was adjusted to 1×10.sup.6 cells/mL with sterilized normal saline, and then 0.2 mL of which was inoculated subcutaneously in the axillary back of nude mice. When the tumor grew to 1 cm in diameter, it was taken out under aseptic conditions, cut into tumor blocks with the size of 1 mm×1 mm, and inoculated subcutaneously in the axillary back of nude mice. Two weeks later, after the tumor grew to 100˜300 mm.sup.3, the animals were randomly divided into groups and began to be administered (recorded as day 0). The compound to be tested is administered orally. The animals were weighed twice a week and the length and width of tumor were measured with vernier caliper. After the experiment, the nude mice were dislocated and killed, and the tumor tissues were stripped, weighed and photographed. Finally, the tumor inhibition rate was calculated, and the anti-tumor effect was evaluated by the tumor inhibition rate. The results are shown in tables 3 and 4 and FIGS. 2 and 3.

[0284] The tumor volume is calculated according to the following formula:

[0285] Tumor volume=(a×b.sup.2)/2, where a and b represent the length and width of tumor respectively.

[0286] The tumor growth inhibition percentage is calculated according to the following formula: tumor growth inhibition (%)=(1−T/C)×100, T is the tumor volume of group of the compound to be tested, and C is the tumor volume of the solvent control group.

[0287] The results are shown in tables 3 and 4, and FIGS. 2 and 3.

TABLE-US-00003 TABLE 3 The inhibitory effect of Example 1 on the growth of xenograft tumor formed by subcutaneous xenotransplantation of human prostate cancer DU145 in nude mice Tumor growth Dose inhibition Example (mg/kg × times) (%) 1 10 × 7 58.8*** 20 × 7 62.7*** 40 × 7 73.5*** ***p < 0.001

TABLE-US-00004 TABLE 4 The inhibitory effect of Examples 12 and 33 on the growth of xenograft tumor formed by subcutaneous xenotransplantation of human prostate cancer DU145 in nude mice Tumor growth Dose inhibition Example (mg/kg × times) (%) 12 20 × 14 40.4 40 × 11 79.7*** 33 20 × 6  63.0** 40 × 5  80.0** ***p < 0.001; **p < 0.01

Summary of Pharmacological Activities:

[0288] All the examples showed antiproliferative activity against human prostate cancer DU145, and their IC.sub.50 values were all less than 10 μM m. Examples 1, 6, 9, 12, 13, 17, 20, 23, 30, 33, 34 and 35 showed obvious STAT3 transcription inhibition activity in the STAT3 specific luciferase double reporter gene experiment of human prostate cancer cell DU145. Example 1 showed obvious inhibitory activity on STAT3 phosphorylation of human prostate cancer DU145 at 1 μM concentration, Examples 12 and 23 showed obvious inhibitory activity on STAT3 phosphorylation of human prostate cancer DU145 at 0.5 μM concentration, and Examples 33 and 34 showed obvious inhibitory activity on STAT3 phosphorylation of human prostate cancer DU145 at 0.1 μM concentration. Among them, Examples 1, 12 and 33 have significant inhibitory effects on the growth of xenograft tumor formed by subcutaneous xenotransplantation of human prostate cancer DU145 in nude mice.