ArylSulfonamide-based matrix metalloprotease inhibitors

Abstract

The present invention provides a compound of formula (I): ##STR00001##
said compound is inhibitor of MMP-2, and/or MMP-8, and/or MMP-9, and/or MMP-12 and/or MMP-13, and thus can be employed for the treatment of a disorder or disease characterized by abnormal activity of MMP-2, and/or MMP-8, and/or MMP-9, and/or MMP-12 and/or MMP-13. Accordingly, the compound of formula (I) can be used in treatment of disorders or diseases mediated by MMP-2, and/or MMP-8, and/or MMP-9, and/or MMP-12, and/or MMP-13. Finally, the present invention also provides a pharmaceutical composition.

Claims

1. A compound selected from 2-Chloro-5-(4-pyrrol-1-yl-benzoyl)-benzenesulfonamide; 2-Chloro-5-(4-thiophen-2-yl-benzoyl)-benzenesulfonamide; 2-Chloro-5-(4-thiophen-3-yl-benzoyl)-benzenesulfonamide; 2-Chloro-5-(4-pyridin-3-yl-benzoyl)-benzenesulfonamide; 2-Chloro-5-(4-pyridin-4-yl-benzoyl)-benzenesulfonamide; 2-Chloro-5-[4-(2-chloro-pyridin-4-yl)-benzoyl]-benzenesulfonamide; 2-Chloro-5-(3-ethyl-1H-indazole-6-carbonyl)-benzenesulfonamide; 2-Chloro-5-(3-methyl-1H-indazole-6-carbonyl)-benzenesulfonamide; 2-Chloro-5-(3-isopropyl-1H-indazole-6-carbonyl)-benzenesulfonamide; 5-(1-Benzyl-3-ethyl-1H-indazole-6-carbonyl)-2-chloro-benzenesulfonamide; and 2-Chloro-5-[3-(2-cyclopentyl-ethyl)-1H-indazole-6-carbonyl]-benzenesulfonamide; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 selected from 2-Chloro-5-(4-thiophen-3-yl-benzol)-benzenesulfonamide and 2-Chloro-5-(3-ethyl-1H-indazole-6-carbonyl)-benzenesulfonamide; or a pharmaceutically acceptable salt thereof.

3. A method of inhibiting activity of MMP-2, and/or MMP-8, and/or MMP-9, and/or MMP-12 and/or MMP-13 in a subject, comprising: administering to the subject a therapeutically effective amount of the compound according to claim 1.

4. A method of treating a disorder or a disease in a subject mediated by MMP-2, and/or MMP-8, and/or MMP-9, and/or MMP-12 and/or MMP-13, comprising: administering to the subject a therapeutically effective amount of the compound according to claim 1.

5. The method of claim 4, wherein the disorder or the disease is selected from the group consisting of Alport syndrome, asthma, rhinitis, chronic obstructive pulmonary diseases (COPD), arthritis, atherosclerosis and restenosis, cancer invasion and metastasis, diseases involving tissue destruction, loosening of hip joint replacements, periodontal disease, fibrotic disease, infarction and heart disease, liver and renal fibrosis, endometriosis, diseases related to the weakening of the extracellular matrix, heart failure, aortic aneurysms, CNS related diseases, Alzheimer's disease and Multiple Sclerosis (MS), hematological disorders.

6. A pharmaceutical composition, comprising: a therapeutically effective amount of the compound of claim 1 and one or more pharmaceutically acceptable carriers.

7. A pharmaceutical composition, comprising: a therapeutically effective amount of the compound according to claim 1 and one or more therapeutically active agents selected from 1) AT.sub.1 receptor antagonists selected from the group consisting of abitesartan, benzyllosartan, candesartan, elisartan, embusartan, enoltasosartan, eprosartan, fonsartan, forasartan, glycyllosartan, irbesartan, isoteoline, losartan, milfasartan, olmesartan, opomisartan, pratosartan, ripisartan, saprisartan, saralasin, sarmesin, tasosartan, telmisartan, valsartan, zolasartan; Kissei KRH-94, Lusofarmaco LR-B/057, Lusofarmaco LR-B/081, Lusofarmaco LR B/087, Searle SC-52458, Sankyo CS-866, Takeda TAK-536, Uriach UR-7247, A-81282, A-81988, BIBR-363, BIBS39, BIBS-222, BMS-180560, BMS-184698, CGP-38560A, CGP-48369, CGP-49870, CGP-63170, CI-996, CV-11194, DA-2079, DE-3489, DMP-811, DuP-167, DuP-532, GA-0056, E-4177, EMD-66397, EMD-73495, EXP-063, EXP-929, EXP-3174, EXP-6155, EXP-6803, EXP-7711, EXP-9270, FK-739, HN-65021, HR-720, ICI-D6888, ICI-D7155, ICI-D8731, KR1-1177, KT3-671, KW-3433, L-158809, L-158978, L-159282, L-159689, L-159874, L-161177, L-162154, L-162234, L-162441, L-163007, L-163017, LY-235656, LY-285434, LY-301875, LY-302289, LY-315995, ME-3221, PD-123177, PD-123319, PD-150304, RG-13647, RWJ-38970, RWJ-46458, S-8307, S-8308, SL-91.0102, U-96849, U-97018, UP-269-6, UP-275-22, WAY-126227, WK-1492.2K, WK-1360, X-6803, XH-148, XR-510, YM-358, YM-31472, ZD-6888, ZD-7155 and ZD-8731 which are all known per se, or any physiologically compatible salts, solvates, prodrugs or esters thereof; 2) non-selective alpha-adrenoceptor antagonists, tolazoline or phenoxybenzamine; 3) selective alpha-adrenoceptor antagonists, doxazosin, prazosin, terazosin or urapidil; beta-adrenoceptor antagonists, acebutolol, alprenolol, atenolol, betaxolol, bisoprolol, bupranolol, carazolol, carteolol, celiprolol, mepindolol, metipranolol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol and timolol; 4) mixed antagonists of alpha- and beta-adrenoceptors, carvedilol or labetolol; ganglion blockers, reserpine or guanethidine; 5) alpha2-adrenoceptor agonists, centrally acting alpha2-adrenoceptor agonists, clonidine, guanfacine, guanabenz methyldopa and moxonidine; 6) rennin inhibitors, alskiren; 7) ACE inhibitors, benazepril, captopril, cilazapril, enalapril, fosinopril, imidapril, lisinopril, moexipril, quinapril, perindopril, ramipril, spirapril or trandolapril; 8) mixed or selective endothelin receptor antagonists atrasentan, bosentan, clazosentan, darusentan, sitaxsentan, tezosentan, BMS-193884 or J-104132; direct vasodilators, diazoxide, dihydralazine, hydralazine or minoxidil; 9) mixed ACE/NEP dual inhibitors, omapatrilat; ECE inhibitors, FR-901533; PD-069185; CGS-26303; CGS-34043; CGS-35066; CGS-30084; CGS-35066; SM-19712; Ro0677447; 10) selective NEP inhibitors; 11) vasopressin antagonists; 12) aldosterone receptor antagonists, eplerenone; 13) aldosterone inhibitors; 14) angiotensin vaccine; 15) urotensin II receptor antagonists; and 16) an antiinflammatory agent and an antirheumatic agent.

8. A pharmaceutical composition, comprising: a therapeutically effective amount of the compound according to claim 1 and one or more therapeutically active agents selected from aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds which induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platin compounds; compounds targeting/decreasing a protein or lipid kinase activity and further anti-angiogenic compounds; compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase; gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematologic malignancies; compounds which target, decrease or inhibit the activity of Flt-3; Hsp90 inhibitors 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics; temozolomide (TEMODAL®); kinesin spindle protein inhibitors, SB715992 or SB743921 from GlaxoSmithKline, or pentamidine/chlorpromazine from CombinatoRx; MEK inhibitors ARRY142886 from Array PioPharma, AZD6244 from AstraZeneca, PD181461 from Pfizer and leucovorin.

9. A method of treating a disorder or a disease in a subject mediated by MMP-2, and/or MMP-8, and/or MMP-9, and/or MMP-12 and/or MMP-13, comprising: administering to the subject a therapeutically effective amount of the compound according to claim 2.

10. The method of claim 9, wherein the disorder or the disease is selected from the group consisting of Alport syndrome, asthma, rhinitis, chronic obstructive pulmonary diseases (COPD), arthritis, atherosclerosis and restenosis, cancer invasion and metastasis, diseases involving tissue destruction, loosening of hip joint replacements, periodontal disease, fibrotic disease, infarction and heart disease, liver and renal fibrosis, endometriosis, diseases related to the weakening of the extracellular matrix, heart failure, aortic aneurysms, CNS related disease, Alzheimer's disease and Multiple Sclerosis (MS), hematological disorders.

11. A pharmaceutical composition, comprising: a therapeutically effective amount of the compound of claim 2 and one or more pharmaceutically acceptable carriers.

12. A pharmaceutical composition, comprising: a therapeutically effective amount of the compound according to claim 2 and one or more therapeutically active agents selected from 1) AT.sub.1 receptor antagonists selected from the group consisting of abitesartan, benzyllosartan, candesartan, elisartan, embusartan, enoltasosartan, eprosartan, fonsartan, forasartan, glycyllosartan, irbesartan, isoteoline, losartan, milfasartan, olmesartan, opomisartan, pratosartan, ripisartan, saprisartan, saralasin, sarmesin, tasosartan, telmisartan, valsartan, zolasartan; Kissei KRH-94, Lusofarmaco LR-B/057, Lusofarmaco LR-B/081, Lusofarmaco LR B/087, Searle SC-52458, Sankyo CS-866, Takeda TAK-536, Uriach UR-7247, A-81282, A-81988, BIBR-363, BIBS39, BIBS-222, BMS-180560, BMS-184698, CGP-38560A, CGP-48369, CGP-49870, CGP-63170, CI-996, CV-11194, DA-2079, DE-3489, DMP-811, DuP-167, DuP-532, GA-0056, E-4177, EMD-66397, EMD-73495, EXP-063, EXP-929, EXP-3174, EXP-6155, EXP-6803, EXP-7711, EXP-9270, FK-739, HN-65021, HR-720, ICI-D6888, ICI-D7155, ICI-D8731, KR1-1177, KT3-671, KW-3433, L-158809, L-158978, L-159282, L-159689, L-159874, L-161177, L-162154, L-162234, L-162441, L-163007, L-163017, LY-235656, LY-285434, LY-301875, LY-302289, LY-315995, ME-3221, PD-123177, PD-123319, PD-150304, RG-13647, RWJ-38970, RWJ-46458, S-8307, S-8308, SL-91.0102, U-96849, U-97018, UP-269-6, UP-275-22, WAY-126227, WK-1492.2K, WK-1360, X-6803, XH-148, XR-510, YM-358, YM-31472, ZD-6888, ZD-7155 and ZD-8731 which are all known per se, or any physiologically compatible salts, solvates, prodrugs or esters thereof; 2) non-selective alpha-adrenoceptor antagonists, tolazoline or phenoxybenzamine; 3) selective alpha-adrenoceptor antagonists, doxazosin, prazosin, terazosin or urapidil; beta-adrenoceptor antagonists, acebutolol, alprenolol, atenolol, betaxolol, bisoprolol, bupranolol, carazolol, carteolol, celiprolol, mepindolol, metipranolol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol and timolol; 4) mixed antagonists of alpha- and beta-adrenoceptors, carvedilol or labetolol; ganglion blockers, reserpine or guanethidine; 5) alpha2-adrenoceptor agonists, centrally acting alpha2-adrenoceptor agonists, clonidine, guanfacine, guanabenz methyldopa and moxonidine; 6) rennin inhibitors, alskiren; 7) ACE inhibitors, benazepril, captopril, cilazapril, enalapril, fosinopril, imidapril, lisinopril, moexipril, quinapril, perindopril, ramipril, spirapril or trandolapril; 8) mixed or selective endothelin receptor antagonists atrasentan, bosentan, clazosentan, darusentan, sitaxsentan, tezosentan, BMS-193884 or J-104132; direct vasodilators, diazoxide, dihydralazine, hydralazine or minoxidil; 9) mixed ACE/NEP dual inhibitors, omapatrilat; ECE inhibitors, FR-901533; PD-069185; CGS-26303; CGS-34043; CGS-35066; CGS-30084; CGS-35066; SM-19712; Ro0677447; 10) selective NEP inhibitors; 11) vasopressin antagonists; 12) aldosterone receptor antagonists, eplerenone; 13) aldosterone inhibitors; 14) angiotensin vaccine; 15) urotensin II receptor antagonists; and 16) an antiinflammatory agent and an antirheumatic agent.

13. A pharmaceutical composition, comprising: a therapeutically effective amount of the compound according to claim 2 and one or more therapeutically active agents selected from aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds which induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platin compounds; compounds targeting/decreasing a protein or lipid kinase activity and further anti-angiogenic compounds; compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase; gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematologic malignancies; compounds which target, decrease or inhibit the activity of Flt-3; Hsp90 inhibitors 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics; temozolomide (TEMODAL®); kinesin spindle protein inhibitors, SB715992 or SB743921 from GlaxoSmithKline, or pentamidine/chlorpromazine from CombinatoRx; MEK inhibitors ARRY142886 from Array PioPharma, AZD6244 from AstraZeneca, PD181461 from Pfizer and leucovorin.

14. The method of claim 4, wherein the disorder or the disease is selected from Alport syndrome, asthma, rhinitis, chronic obstructive pulmonary diseases (COPD), arthritis, atherosclerosis, cancer metastasis, loosening of hip joint replacements, periodontal disease, and fibrotic disease of the lung.

15. The method of claim 9, wherein the disorder or the disease is selected from Alport syndrome, asthma, rhinitis, chronic obstructive pulmonary diseases (COPD), arthritis, atherosclerosis, cancer metastasis, loosening of hip joint replacements, periodontal disease, and fibrotic disease of the lung.

Description

EXAMPLES

(1) The present invention will now be illustrated by reference to the following examples which set forth particularly advantageous embodiments. However, it should be noted that these embodiments are illustrative and are not to be construed as restricting the invention in any way.

Example 1: 3-(4-Methoxy-benzoyl)-benzenesulfonamide

(2) ##STR00010##

3-(4-Methoxy-benzoyl)-benzenesulfonyl chloride

(3) Under a nitrogen atmosphere, aluminum chloride (7.5 g, 56.5 mmol) is slurried in dichloromethane (150 mL) then 3-chlorosulfonyl-benzoyl chloride (7.5 g, 31.4 mmol) is added and allowed to stir at ambient temperature for 10 minutes. Anisole (4.06 g, 37.65 mmol) is added. The reaction is allowed to stir at ambient temperature for 18 hours. The reaction mixture is poured over ice-cold 6 N HCl and extracted with dichloromethane to give a purple oil. Purification by silica gel chromatography (10% ethyl acetate in hexanes) yielded 4 g (41% yield) of the title compound as a yellow powder. .sup.1H NMR (CDCl.sub.3): δ 8.5 (t, 1H, J=1.7 Hz), 8.25 (m, 1H), 8.1 (m, 1H), 7.7-7.9 (m, 3H), 7.0 (d, 2H, J=6.9 Hz), 3.9 (s, 3H).

3-(4-Methoxy-benzoyl)-benzenesulfonamide

(4) 3-(4-Methoxy-benzoyl)-benzenesulfonyl chloride is dissolved in dichloromethane (10 ml) and treated with 1.7 mL of a 2 M solution of ammonia in methanol. The reaction is stirred at ambient temperature for 2 hours and quenched with 1N HCl. The organic phase is separated and evaporated under reduced pressure to give the crude sulfonamide. Purification by silica gel chromatography (gradient of ethyl acetate in hexanes 5-25%) yielded 100 mg (50% yield) of the title compound. .sup.1H NMR (CDCl.sub.3, 300 MHz): δ 8.3 (t, 1H, J=1.6 Hz), 8.1 (m, 1H), 7.95 (m, 1H), 7.8 (d, 2H, J=6.98 Hz), 7.65 (t, 1H, J=7.8 Hz), 7.0 (d, 2H, J=6.98 Hz), 4.95 (s, 2H), 3.9 (s, 3H). MP: 119-122° C. LCMS Elution time 0.81 MS (m/z): 291 (M+1). CHN Calc C, 57.72, H, 4.50, N, 4.81. Found C, 57.65, H, 4.33, N, 4.69.

Example 2: 2-fluoro-5-(4-methoxy-benzoyl)-benzenesulfonamide

3-Chlorosulfonyl-4-fluoro benzoic acid

(5) ##STR00011##

(6) 4-Fluoro-benzoic acid (8 g, 57 mmol) is added carefully to chlorosulfonic acid (58 g, 498 mmol) then sodium chloride (10 g, 169 mmol) is added in small portions. After complete addition, the reaction is heated at 160° C. for 5 h. The reaction mixture is cooled down and poured into ice-water. A white solid precipitate is collected and redissolved in ethyl acetate. The organic layer is washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and the solvent is removed in vacuo. The residue is triturated with hexane to give 7 g (51% yield) of the title compound as a white solid. .sup.1H NMR (CDCl.sub.3): δ 8.78 (m, 1H), 8.52 (m, 1H), 7.5 (t, 1H). MS (m/z): 308 (M−1).

3-Chlorosulfonyl-4-fluoro benzoyl chloride

(7) ##STR00012##

(8) To a suspension of 3-chlorosulfonyl-4-fluoro benzoic acid (2.5 g, 10 mmol) in methylene chloride at 0° C. is added oxalyl chloride (1.33 g, 11 mmol), followed by the addition of 1 drop of N,N,-dimethylformamide. The reaction mixture is warmed up to room temperature and stirred for an additional 4 h. The solvent is removed, and the residue is dried under vacuum for 1 hr to obtain the title compound as an oil, which is used for the next step without further purification.

2-Fluoro-5-(4-methoxy-benzoyl)-benzenesulfonyl chloride

(9) ##STR00013##

(10) To a suspension of aluminium chloride (2.1 g, 15.7 mmol) in methylene chloride (50 mL) is added 3-chlorosulfonyl-4-fluoro benzoyl chloride (10.5 mmol). The reaction mixture is stirred at room temperature for 10 minutes then anisole (1.36 g, 12.5 mmol) is added. After the mixture is stirred at room temperature for 16 h, the reaction is quenched with 6 N HCl, and extracted with methylene chloride three times. The combined organic layers are washed with a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (ethyl acetate/hexane: 1:9) followed by recrystallization (methylene chloride-hexane) provides 1.8 g (54% yield) of the title compound as a white solid. .sup.1H NMR (CDCl.sub.3): δ 8.41 (m, 1H), 8.20 (m, 1H), 7.82 (d, J=15 Hz, 2H), 7.50 (t, 1H), 7.08 (d, J=15 Hz, 2H), 3.95 (s, 3H).

2-Fluoro-5-(4-methoxy-benzoyl)-benzenesulfonamide

(11) ##STR00014##

(12) To a solution of 2-fluoro-5-(4-methoxy-benzoyl)-benzenesulfonyl chloride (0.45 g, 1.0 mmol) in methylene chloride is added aqueous ammonium solution (1 mL). The reaction mixture is stirred for 10 min at room temperature. The solvent is removed and the residue is redissolved in ethyl acetate and extracted with water. The organic layers are washed with a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. The residue is recrystallized with methylene chloride-hexane to give 100 mg (32% yield) of the title compound as pale yellow solid. .sup.1H NMR (CDCl.sub.3): δ 8.40 (m, 1H), 8.05 (m, 1H), 7.80 (d, J=8 Hz, 2H), 7.32 (t, 1H), 7.00 (d, J=8 Hz, 2H), 5.15 (s, 1H), 3.90 (s, 3 H). Analytics calculated for C.sub.14H.sub.12FNO.sub.4S: C, 54.36; H, 3.91; N, 4.53. Found: C, 53.89; H, 3.50; N, 4.50.

Example 3: 2-Chloro-5-(4-methoxy-benzoyl)-benzenesulfonamide

(13) ##STR00015##

2-Chloro-5-(4-methoxy-benzoyl)-benzenesulfonamide

(14) Under nitrogen, aluminum chloride (1.95 g, 14.6 mmol) is slurried in dichloromethane (50 mL) then 4-chloro-3-sulfamoyl benzoyl chloride is added and allowed to stir at ambient temperature for 30 minutes. Anisole (683 mg, 6.3 mmol) is added in 2 mL methylene chloride. The reaction is allowed to stir at ambient temperature for 18 hours. The reaction mixture is poured over ice-cold 6 N HCl and extracted with dichloromethane to give a colorless oil. Purification by silica gel chromatography (gradient of ethyl acetate in hexanes 5-25%) yielded a white foam which is crystallized three times from ether to afford the title compound. .sup.1H NMR (MeOD) δ 3.9 (s, 3H), 7.1 (d, 2H, J=8.84 Hz), 7.7-8.0 (m, 4H), 8.4 (d, 1H, J=1.96 Hz). MS (m/z): 326 (M+1). CHN Calc C, 51.62, H, 3.71, N, 4.3. Found C, 51.70, H, 3.76, N, 4.22. M.P. 156-158° C.

Example 4: 2,3-Difluoro-5-(4-methoxy-benzoyl)-benzenesulfonamide

(15) ##STR00016##

(16) 2,3-Difluoro-5-(4-methoxy-benzoyl)-benzenesulfonamide is prepared as described above for 2-fluoro-5-(4-methoxy-benzoyl)-benzenesulfonamide. .sup.1H NMR (CDCl.sub.3): δ 8.0 (m, 1H), 7.88 (m, 1H), 7.80 (d, J=15 Hz, 2H), 7.00 (d, J=15 Hz, 2H), 5.30 (s, 2H), 3.92 (s, 3H). Analytics calculated for C.sub.14H.sub.11F.sub.2NO.sub.4S: C, 51.38; H, 3.39; N, 4.28. Found: C, 51.98; H, 3.76; N, 3.86. MS (m/z): 326 (M−1).

Example 5: 5-(4-Methoxy-benzoyl)-2-nitro-benzenesulfonamide

(17) ##STR00017##

2-Amino-5-(4-methoxy-benzoyl)-benzenesulfinamide

(18) To a solution of 2-fluoro-5-(4-methoxy-benzoyl)-benzenesulfonamide (0.25 g, 0.81 mmol) dissolved in dioxane (3 mL) is added aqueous ammonia solution (1 mL). The reaction mixture is heated at 100° C. for 6 h in sealed tube and then cooled to room temperature and concentrated in vacuo. The residue is partitioned between water and ethyl acetate, and the aqueous phase is extracted with ethyl acetate three times. The combined organic extracts are washed with a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo to provide 0.2 g (81%) of the title compound as a pale yellow solid. .sup.1H NMR (DMSO): δ 8.05 (d, J=2 Hz, 1H), 7.70 (m, 3H), 7.40 (s, 2H), 7.05 (d, J=9 Hz, 2H), 6.92 (d, J=9 Hz, 1H), 3.88 (s, 3H).

5-(4-Methoxy-benzoyl)-2-nitro-benzenesulfonamide

(19) To a solution of 2-amino-5-(4-methoxy-benzoyl)-benzenesulfinamide (0.15 g, 0.49 mmol) dissolved in acetic acid (2 mL) is added NaBO.sub.3.water (0.215 g, 2.16 mmol). The reaction mixture is heated at 50° C. for 7 h and then cooled to room temperature. Sodium hydroxide (solid) is added to neutralize the mixture, and the solution is then extracted with methylene chloride three times. The combined organic extracts are washed with a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. The resulting residue is dissolved in dioxane, followed by the addition of 1 N of sodium hydroxide solution (2 mL). After stirring at 50° C. for 1 h, the mixture is cooled to room temperature and concentrated in vacuo. The residue is partitioned between water and methylene chloride, and the aqueous phase is extracted with methylene chloride three times. The combined organic extracts are washed with a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (50% ethyl acetate-hexane) followed by recrystallization (methylene chloride-hexane) provides 0.038 g (28%) of the title compound as a pale yellow solid. .sup.1H NMR (CDCl.sub.3): δ 8.50 (d, J=1 Hz, 1H), 8.05 (m, 2H), 7.80 (d, J=8 Hz, 2H), 7.00 (d, J=8 Hz, 2H), 5.50 (s, 1H), 3.90 (s, 3H). Analytics calculated for C.sub.14H.sub.12N.sub.2O.sub.6S: C, 50.00; H, 3.60; N, 8.33. Found: C, 49.99; H, 3.41; N, 7.96. MS (m/z): 335 (M−1).

Example 6: 5-(4-Methoxy-benzoyl)-2-methyl-benzenesulfonamide

(20) ##STR00018##

3-Chlorosulfonyl-4-methyl-benzoic acid

(21) Sodium chloride (8 g, 138 mmol) is added to chlorosulfonic acid (30 mL, 451 mmol) and in small portions 4-methyl-benzoic acid (4 g, 29 mmol) is added to the stirred mixture. After complete addition, the reaction is heated at 122° C. for 16 h. The reaction mixture is cooled and poured into ice-water. The organic material is extracted with ethyl acetate. The organic layer is washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and the solvent is removed in vacuo. The residue is used as is in the next step.

4-Methyl-3-sulfamoyl-benzoic acid

(22) A solution of ammonia in methanol (40 mL, 2 M) is added to the crude 3-chlorosulfonyl-4-methyl-benzoic acid and the solution stirred at room temperature for 16 hours. The volume is reduced by 50% by heating under reduced pressure, the solution is filtered to remove the precipitate and the precipitate washed with additional methanol. The sulphonamide precipitate is used directly in the next step.

4-methyl-3-sulfamoyl-benzoyl chloride

(23) 4-Methyl-3-sulfamoyl-benzoic acid (2 g, 10 mmol) is added to thionyl chloride (15 mL) and heated at reflux for 3 hours. Hexanes are added to the cooled solution and an oil forms. The hexanes are decanted and the oil is dissolved in methylene chloride and washed with hexanes. The solvent is removed under reduced pressure and the crude oil used in the next step.

5-(4-Methoxy-benzoyl)-2-methyl-benzenesulfonamide

(24) To a suspension of aluminium chloride (906 mg, 6.8 mmol) in methylene chloride (20 mL) is added 4-methyl-3-sulfamoyl-benzoyl chloride (1.1 g, 4.7 mmol) and anisole (1.1 g, 10.2 mmol). After the mixture is stirred at room temperature for 16 h, the reaction is quenched with 6 N HCl, and extracted with methylene chloride three times. The combined organic layers are washed with a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. On standing, crystals form and trituration with diethyl ether and ethyl acetate provides 0.84 g (58% yield) of the title compound as a white solid. MS (m/z): 306 (M+1).

Example 7: 5-(4-Methoxy-benzoyl)-2-methylsulfanyl-benzenesulfonamide

(25) ##STR00019##

(26) To a solution of 2-fluoro-5-(4-methoxy-benzoyl)-benzenesulfonamide (0.15 g, 0.48 mmol) dissolved in dioxane (3 mL) is added sodium thiomethoxide (0.041 g, 0.57 mmol). The reaction mixture is heated at 90° C. for 4 h and then cooled to room temperature and concentrated in vacuo. The residue is partitioned between water and methylene chloride, and the aqueous phase is extracted with methylene chloride three times. The combined organic extracts are washed with a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (50% ethyl acetate-hexane) gives 0.11 g (68%) of the title compound as a white solid. .sup.1H NMR (CDCl.sub.3): δ 8.4 (d, J=2 Hz, 1H), 7.90 (dd, J=8, 2 Hz, 1H), 7.80 (d, J=9 Hz, 2H), 7.50 (d, J=8 Hz, 1H), 7.00 (d, J=9 Hz, 2H), 5.20 (s, 2H), 3.90 (s, 3H), 2.65 (s, 3H). Analytics calculated for C.sub.15H.sub.15NO.sub.4S.sub.2: C, 53.04; H, 4.48; N, 4.15. Found: C, 52.67; H, 4.57; N, 4.08. MS (m/z): 336 (M−1).

Example 8: 2-Methanesulfinyl-5-(4-methoxy-benzoyl)-benzenesulfonamide

(27) ##STR00020##

(28) To a solution of 5-(4-methoxy-benzoyl)-2-methylsulfanyl-benzenesulfonamide (0.06 g, 0.18 mmol) dissolved in methylene chloride (3 mL) at 0° C. is added m-chloroperoxybenzoic acid (0.061 g, 0.36 mmol). The reaction mixture is stirred at room temperature for 30 minutes Then, the reaction is quenched with saturated sodium sulfite and sodium bicarbonate solution. The aqueous layer is extracted with methylene chloride three times. The combined organic extracts are washed with a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (75% ethyl acetate-hexane) followed by recrystallization (methylene chloride-hexane) provides 0.022 g (35%) of the title compound as a pale yellow solid. .sup.1H NMR (CDCl.sub.3): δ 8.35 (d, J=8 Hz, 1H), 8.10 (dd, J=8, 1 Hz, 1H), 7.80 (d, J=9 Hz, 2H), 7.00 (d, J=9 Hz, 2H), 5.60 (s, 2H), 3.95 (s, 3H), 3.00 (s, 3H). Analytics calculated for C.sub.15H.sub.15NO.sub.5S.sub.2: C, 50.98; H, 4.28; N, 3.96. Found: C, 50.17; H, 4.46; N, 3.40. MS (m/z): 352 (M−1).

Example 9: 2-Methanesulfonyl-5-(4-methoxy-benzoyl)-benzenesulfonamide

(29) ##STR00021##

(30) To a solution of 5-(4-methoxy-benzoyl)-2-methylsulfanyl-benzenesulfonamide (0.12 g, 0.36 mmol) dissolved in methylene chloride (3 mL) at 0° C. is added m-chloroperoxybenzoic acid (0.153 g, 0.90 mmol). The reaction mixture is stirred at room temperature for 2 h. Then, the reaction is quenched with saturated sodium sulfite and sodium bicarbonate solution. The aqueous layer is extracted with methylene chloride three times. The combined organic extracts are washed with a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (75% ethyl acetate-hexane) followed by recrystallization (methylene chloride-hexane) provides 0.038 g (28%) of the title compound as a pale yellow solid. .sup.1H NMR (CDCl.sub.3): δ 8.55 (d, J=1 Hz, 1H), 8.40 (d, J=8 Hz, 1H), 8.10 (dd, J=8, 1 Hz, 1H), 7.80 (d, J=8 Hz, 2H), 7.00 (d, J=8 Hz, 2H), 5.80 (s, 2H), 3.95 (s, 3H), 3.44 (s, 3H). Analytics calculated for C.sub.15H.sub.15NO.sub.6S.sub.2: C, 48.77; H, 4.09; N, 3.79. Found: C, 48.51; H, 4.16; N, 3.40. MS (m/z): 368 (M−1).

Example 10: 2-Chloro-5-(4-methoxy-benzoyl)-N-phenethyl-benzenesulfonamide

(31) ##STR00022##

2-Chloro-5-(4-methoxy-benzoyl)-benzenesulfonyl chloride

(32) The title compound is prepared as described above for 2-fluoro-5-(4-methoxy-benzoyl)-benzenesulfonyl chloride, starting with 4-chloro-benzoic acid.

2-Chloro-5-(4-methoxy-benzoyl)-N-phenethyl-benzenesulfonamide

(33) 2-Chloro-5-(4-methoxy-benzoyl)-benzenesulfonyl chloride (0.2 g, 5.79 mmol) is dissolved in methylene chloride (10 mL). Phenethylamine (0.077 g, 6.36 mmol) is added, followed by the addition of triethylamine (0.146 g, 14.5 mmol). The reaction mixture is stirred for 2 h at room temperature. Water is added, and the mixture extracted with methylene chloride. The solvent is removed and the mixture is purified by flash column chromatography, using 50% of ethyl acetate-hexane as an eluent. The product is obtained as a colorless oil (0.13 g, 52% yield). .sup.1H NMR (CDCl.sub.3): δ 8.4 (m, 1H), 7.90 (m, 1H), 7.50 (d, J=8 Hz, 2H), 7.28 (m, 3H), 7.00 (d, J=8 Hz, 2H), 7.17 (m, 2H), 4.97 (m, 1H), 3.91 (s, 3H), 3.20 (m, 2H), 2.80 (m, 2H). Analytics calculated for C.sub.22H.sub.20ClNO.sub.4S: C, 61.46; H, 4.69; N, 3.26. Found: C, 61.20; H, 4.95; N, 3.10. MS (m/z): 430.0 (M+1).

Example 11: 2-Chloro-N-[2-(4-fluoro-phenyl)-ethyl]-5-(4-methoxy-benzoyl)-benzenesulfonamide

(34) ##STR00023##

(35) The title compound is prepared as described for 2-chloro-5-(4-methoxy-benzoyl)-N-phenethyl-benzenesulfonamide, except using 4-fluoro-phenethylamine. .sup.1H NMR (CDCl.sub.3): δ 8.4 (m, 1H), 7.90 (m, 1H), 7.80 (d, J=8 Hz, 2H), 7.60 (m, 1H), 7.08 (m, J=8 Hz, 2H), 7.00 (m, 3H), 4.97 (m, 1H), 3.91 (s, 3H), 3.20 (m, 2H), 2.80 (m, 2H). Analytics calculated for C.sub.22H.sub.19ClFNO.sub.4S: C, 58.99; H, 4.28; N, 3.13. Found: C, 58.58; H, 4.33; N, 3.12. MS (m/z): 448.0 (M+1).sup.−.

Example 12: 2-Chloro-5-(3-hydroxy-4-methoxy-benzoyl)-benzenesulfonamide

(36) ##STR00024##

5-Bromo-2-methoxy-phenol

(37) To a solution of 5-bromo-2-methoxy-benzaldehyde (8 g, 4.67 mmol) dissolved in methylene chloride (24 mL) at 0° C. is slowly added a solution of m-chloroperoxybenzoic acid (10.90 g, 5.60 mmol) in methylene chloride (80 mL). The reaction mixture is slowly warmed up to room temperature and stirred for 72 h. The white solid is filtered off and the filtrate is stirred for 2 h with 2 M sodium sulfite (32 mL). The organic layer is concentrated in vacuo then the residue is dissolved in diethyl ether and washed with 1 M sodium sulfite and a half-saturated sodium bicarbonate solution. The organic phase is extracted with 2 M sodium hydroxide. The combined basic extract is acidified to pH 3-4 with concentrated HCl, and extracted with diethyl ether. The combined organic extracts are washed with a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo to provide 3.5 g (37%) of the title compound as a brown solid. .sup.1H NMR (CDCl.sub.3): δ 7.10 (d, J=2 Hz, 1H), 7.00 (dd, J=8, 2 Hz, 1H), 6.70 (d, J=8 Hz, 1H), 3.95 (s, 3H).

(5-Bromo-2-methoxy-phenoxy)-tert-butyl-dimethyl-silane

(38) To a solution of 5-bromo-2-methoxy-phenol (3.5 g, 17.2 mmol) dissolved in methylene chloride (50 mL) are added triethylamine (2.08 g, 20.6 mmol) and 4-dimethylaminopyridine (0.15 g, 0.86 mmol). Then tert-butyldimethylsilyl chloride is added slowly and the reaction mixture is stirred at room temperature for 16 h. The reaction is quenched with 10% of citric acid, and then the organic layer is washed with saturated sodium bicarbonate solution, a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (15% ethyl acetate-hexane) provides 5.6 g (100%) of the title compound as a colorless oil. .sup.1H NMR (CDCl.sub.3): δ 6.82 (m, 2H), 6.58 (d, J=9 Hz, 1H), 3.74 (s, 3H), 0.95 (s, 9H), 0.05 (s, 6H).

5-{[3-(tert-butyl-dimethyl-silanyloxy)-4-methoxy-phenyl]-hydroxy-methyl}-2-chloro-benzenesulfonamide

(39) To a solution of (5-bromo-2-methoxy-phenoxy)-tert-butyl-dimethyl-silane (2 g, 6.32 mmol) dissolved in tetrahydrofuran (25 mL) at −78° C. under nitrogen is dropwisely added 1.7 M of tert-butyllithium (8.06 mL, 12.6 mmol). The reaction mixture is stirred at −78° C. for 5 minutes Then, the solution of 2-chloro-5-formyl-benzenesulfonamide (0.462 g, 2.11 mmol) in tetrahydrofuran (5 mL) is added slowly. The reaction mixture is warmed up to room temperature and stirred for 24 h. The reaction is quenched with 1 N of HCl, and extracted with ethyl acetate three times. The combined organic extracts are washed with a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (50% ethyl acetate-hexane) provides 0.57 g (59%) of the title compound as a brown oil. .sup.1H NMR (CDCl.sub.3): δ 8.00 (m, 1H), 7.40 (m, 2H), 6.70 (d, 3H), 5.70 (s, 1H), 5.00 (m, 2H), 3.70 (s, 3H), 0.90 (s, 9H), 0.05 (s, 6H).

5-[3-(tert-Butyl-dimethyl-silanyloxy)-4-methoxy-benzoyl]-2-chloro-benzenesulfonamide

(40) To a solution of 5-{[3-(tert-butyl-dimethyl-silanyloxy)-4-methoxy-phenyl]-hydroxy-methyl}-2-chloro-benzenesulfonamide (0.57 g, 1.24 mmol) dissolved in acetone (100 mL) is added Jones reagent (3 M, 0.4 mL), and the reaction mixture is stirred at room temperature for 15 minutes The reaction is quenched with water, and the aqueous layer is extracted with methylene chloride three times. The combined organic extracts are washed with saturated sodium bicarbonate solution, a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. Recrystallization from methylene chloride/hexane provides 0.28 g (50%) of the title compound as a grey solid. .sup.1H NMR (CDCl.sub.3): δ 8.23 (d, J=2 Hz, 1H), 7.80 (dd, J=8, 2 Hz, 1H), 7.50 (d, J=8 Hz, 1H), 7.20 (m, 2H), 6.70 (d, J=8 Hz, 1H), 5.00 (s, 2H), 3.70 (s, 3H), 0.90 (s, 9H), 0.05 (s, 6H).

2-Chloro-5-(3-hydroxy-4-methoxy-benzoyl)-benzenesulfonamide

(41) To a solution of 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-methoxy-benzoyl]-2-chloro-benzenesulfonamide (0.28 g, 0.61 mmol) dissolved in tetrahydrofuran (20 mL) is added 1 M tetrabutylammonium fluoride (1.23 mL, 1.22 mmol) in tetrahydrofuran. The reaction mixture is stirred at room temperature for 30 minutes The reaction is quenched with 1 N of HCl, and extracted with ethyl acetate three times. The combined organic extracts are washed with a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. Recrystallization from ethyl acetate/methylene chloride provides 0.11 g (49%) of the title compound as a brown solid. .sup.1H NMR (DMSO): S 9.60 (s, 1H), 8.20 (d, J=2 Hz, 1H), 7.80 (m, 4H), 7.20 (m, 2H), 7.10 (d, J=8 Hz, 1H), 3.90 (s, 3H). Analytics calculated for C.sub.14H.sub.12ClNO.sub.5S: C, 49.20; H, 3.54; N, 4.10. Found: C, 49.90; H, 3.30; N, 5.06. MS (m/z): 342 (M+1).

Example 13: 2-Chloro-5-[4-(2-hydroxy-ethoxy)-benzoyl]-benzenesulfonamide

(42) ##STR00025##

[2-(4-Bromo-phenoxy)-ethoxy]-tert-butyl-dimethyl-silane

(43) 2-(4-Bromo-phenoxy)-ethanol (5 g, 23 mmol) is dissolved in dichloromethane (40 mL). Triethylamine (2.8 g, 28 mmol) and 4-dimethylaminopyridine (140 mg, 1.15 mmol) were then added followed by tert-butyldimethylsilyl chloride (3.65 g, 24.3 mmol) as a solution in dichloromethane (10 mL). The reaction is allowed to stir at ambient temperature for 18 hours. The reaction mixture is washed with 10% aqueous citric acid, the organic layer is separated and concentrated in vacuo to afford 7.5 g (98% yield) of the title compound. .sup.1H NMR (CDCl.sub.3) δ 0.05 (s, 6H), 0.85 (s, 9H), 3.85-3.94 (m, 4H), 6.72 (d, 2H, J=6.90 Hz), 7.28 (d, 2H, J=6.90 Hz).

5-{4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-benzoyl}-2-chloro-benzenesulfonamide

(44) [2-(4-Bromo-phenoxy)-ethoxy]-tert-butyl-dimethyl-silane (7.3 g, 22.12 mmol) is dissolved in tetrahydrofuran (120 mL) and cooled to −78° C. The solution is treated with a solution of n-butyllithium (1.6 M in hexanes, 13.8 mL, 22.12 mmol) and stirred 30 minutes after which a solution of 4-chloro-N-methoxy-N-methyl-3-sulfamoyl-benzamide (2.05 g, 7.37 mmol) in tetrahydrofuran (20 mL) is added. The reaction is allowed to stir for 18 hours while warming to ambient temperature. The reaction is quenched with a saturated solution of ammonium chloride and extracted twice with ether. The organic phase is separated and concentrated in vacuo. The residue is purified by column chromatography (gradient of ethyl acetate in hexanes 10-50%) affording 1.84 g (53% yield) of the title compound. MS (m/z): 470.2 (M+1).

2-Chloro-5-[4-(2-hydroxy-ethoxy)-benzoyl]-benzenesulfonamide

(45) 5-{4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-benzoyl}-2-chloro-benzenesulfonamide (1.84 g, 3.92 mmol) is dissolved in tetrahydrofuran (50 mL), and treated with a solution of tetrabutylammonium fluoride reagent (1 M in tetrahydrofuran, 2.2 mmol). The reaction is allowed to stir for 1 hour. The reaction is diluted with water and extracted with ether. The organic phase is separated and concentrated in vacuo affording 1.39 g (100% yield) of the title compound. .sup.1H NMR (DMSO) δ 3.75 (t, 2H, J=4.55 Hz), 4.12 (t, 2H, J=4.80 Hz), 4.95 (s, 2H), 7.12 (d, 2H, J=8.84 Hz), 7.76-7.90 (m, 4H), 8.24 (d, 1H, J=2.02). MS (m/z): 354 (M−1).

Example 14: 2-Chloro-5-(4-butoxy-benzoyl)-benzenesulfonamide

(46) ##STR00026##

2-Chloro-5-[hydroxy-(4-butoxy-phenyl)-methyl]-benzenesulfonamide

(47) 1-Bromo-4-butoxy-benzene (625 mg, 2.73 mmol) is dissolved in tetrahydrofuran (2 mL) and cooled to −78° C. The solution is treated with a solution of n-butyllithium (1.6 M in hexanes, 1.7 mL, 2.73 mmol) which resulted in precipitation of the aryllithium. The suspension is allowed to warm to ambient temperature and is added via canula to a solution of 2-chloro-5-formyl-benzenesulfonamide (200 mg, 0.91 mmol) in tetrahydrofuran (2 mL) at −78° C. The reaction is allowed to warm to ambient temperature, at which point it is quenched with a saturated solution of ammonium chloride. The tetrahydrofuran is removed in vacuo and the residue is diluted with water and extracted with ethyl acetate. The organic phase is separated and concentrated in vacuo. The residue is used without further purification.

2-Chloro-5-(4-butoxy-benzoyl)-benzenesulfonamide

(48) 2-Chloro-5-[hydroxy-(4-butoxy-phenyl)-methyl]-benzenesulfonamide is dissolved in acetone (10 mL), and treated with a solution of Jones reagent (3 M in water, 0.91 mmol). The reaction is allowed to stir for 30 minutes. The reaction is diluted with water and extracted with dichloromethane. The organic phase is separated and concentrated in vacuo. The residue is purified by silica gel chromatography (gradient of ethyl acetate in hexanes 10-50%) affording 74 mg of the title compound. .sup.1H NMR (CDCl.sub.3) δ 0.95 (t, 3H, J=7.31 Hz), 1.50 (m, 2H), 1.80 (m, 2H), 4.05 (t, 2H, J=6.48 Hz), 5.15 (s, 2H), 6.95 (d, 2H, J=9.04 Hz), 7.65 (d, 1H, J=8.22), 7.80 (d, 2H, J=9.04 Hz), 7.90 (dd, h, J=1.88, 7.91), 8.45 (d, 1H, J=1.88). MS (m/z): 368 (M+1). CHN Calc C, 55.51, H, 4.93, N, 3.81. Found C, 55.47, H, 4.84, N, 3.63.

Example 15: 2-Chloro-5-(4-isobutoxy-benzoyl)-benzenesulfonamide

(49) ##STR00027##

1-Bromo-4-isobutoxy-benzene

(50) 4-Bromo-phenol (2 g, 11.6 mmol) is dissolved in acetone (40 mL). Potassium carbonate (8 g, 38.4 mmol) is then added followed by isobutyl bromide (4 g, 29.2 mmol). The reaction is heated to reflux for four days, refilling solvent as necessary. The reaction mixture is diluted with water and extracted with ether, the organic layer is separated and concentrated in vacuo. The residue is dissolved in hexane dried with magnesium sulfate, and filtered through a plug of silica gel. The solvent is removed in vacuo to afford 1.6 g (60% yield) of the title compound as a colorless non-viscous oil. .sup.1H NMR (CDCl.sub.3) δ 1.01 (d, 6H, J=6.56 Hz), 2.05-2.08 (m, 1H), 3.67 (d, 2H, J=6.57 Hz), 6.77 (d, 2H, J=9.09 Hz), 7.36 (d, 2H, J=9.09 Hz).

2-Chloro-5-(4-isobutoxy-benzoyl)-benzenesulfonamide

(51) 1-Bromo-4-isobutoxy-benzene (625 mg, 2.73 mmol) is dissolved in tetrahydrofuran (2 mL) and cooled to −78° C. The solution is treated with a solution of n-butyllithium (1.6 M in hexanes, 1.7 mL, 2.73 mmol) and stirred 30 minutes after which a solution of 4-chloro-N-methoxy-N-methyl-3-sulfamoyl-benzamide (250 mg, 0.91 mmol) in tetrahydrofuran (2 mL) is added. The reaction is allowed to stir for 18 hours while warming to ambient temperature. The reaction is quenched with a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic phase is separated and concentrated in vacuo. The residue is purified by column chromatography (gradient of ethyl acetate in hexanes 10-50%) affording 120 mg (37% yield) of the title compound. .sup.1H NMR (DMSO) δ 1.00 (d, 6H, J=6.56 Hz), 2.01-2.10 (m, 1H), 3.88 (d, 2H, J=6.57 Hz), 7.11 (d, 2H, J=8.85 Hz), 7.76 (d, 2H, J=8.85 Hz), 7.81-7.84 (m, 3H), 7.89 (dd, 1H, J=2.02, 8.08), 8.24 (d, 1H, J=2.02). MS (m/z): 366 (M−1). CHN Calc C, 55.51, H, 4.93, N, 3.81. Found C, 55.38, H, 4.74, N, 3.77.

Example 16: 2-Chloro-5-[4-(3-methyl-butoxy)-benzoyl]-benzenesulfonamide

(52) ##STR00028##

2-Chloro-5-{hydroxy-[4-(3-methyl-butoxy)-phenyl]-methyl}-benzenesulfonamide

(53) 1-Bromo-4-(3-methyl-butoxy)-benzene (665 mg, 2.73 mmol) is dissolved in tetrahydrofuran (2 mL) and cooled to −78° C. The solution is treated with a solution of n-butyllithium (1.6 M in hexanes, 1.7 mL, 2.73 mmol) which resulted in precipitation of the aryllithium. The suspension is allowed to warm to ambient temperature and is added via canula to a solution of 2-chloro-5-formyl-benzenesulfonamide (200 mg, 0.91 mmol) in tetrahydrofuran (2 mL) at −78° C. The reaction is allowed to warm to ambient temperature, at which point it is quenched with a saturated solution of ammonium chloride. The tetrahydrofuran is removed in vacuo and the residue is diluted with water and extracted with ethyl acetate. The organic phase is separated and concentrated in vacuo. The residue is used without further purification.

2-Chloro-5-[4-(3-methyl-butoxy)-benzoyl]-benzenesulfonamide

(54) 2-Chloro-5-{hydroxy-[4-(3-methyl-butoxy)-phenyl]-methyl}-benzenesulfonamide is dissolved in acetone (10 mL), and treated with a solution of Jones reagent (3 M in water, 0.91 mmol). The reaction is allowed to stir for 30 minutes. The reaction is diluted with water and extracted with dichloromethane. The organic phase is separated and concentrated in vacuo. The residue is purified by silica gel chromatography (gradient of ethyl acetate in hexanes 25-75%) followed by recrystallization from ether affording 25 mg of the title compound. .sup.1H NMR (DMSO) δ 0.93 (s, 3H), 0.95 (s, 3H), 1.64-1.82 (m, 3H), 4.13 (t, 2H, J=6.41 Hz), 7.12 (d, 2H, J=8.67 Hz), 7.75-7.91 (m, 4H), 8.24 (d, 1H, J=1.89). MS (m/z): 380 (M−1). CHN Calc C, 56.62, H, 5.28, N, 3.67. Found C, 56.54, H, 5.04, N, 3.73.

Example 17: 2-Chloro-5-[4-(3-phenyl-propoxy)-benzoyl]-benzenesulfonamide

(55) ##STR00029##

2-Chloro-N-dimethylaminomethylene-5-(4-hydroxy-benzoyl)-benzenesulfonamide

(56) A solution of N,N,-dimethylformamide dimethyl acetal (1.2 g, 10.1 mmol) in acetonitrile (10 mL) is slowly added to a solution of 2-chloro-5-(4-hydroxy-benzoyl)-benzenesulfonamide (2.61 g, 8.4 mmol) in acetonitrile (10 mL). The reaction is allowed to stir for 5 hours at ambient temperature. Volatiles were removed in vacuo. The residue is partitioned between ethyl acetate and water, the organic layer is separated and the solvent is removed in vacuo, affording 2.5 g (81% yield) of the title compound which is carried on directly in the next step.

2-Chloro-5-[4-(3-phenyl-propoxy)-benzoyl]-benzenesulfonamide

(57) 2-Chloro-N-dimethylaminomethylene-5-(4-hydroxy-benzoyl)-benzenesulfonamide (250 mg, 0.68 mmol) is dissolved in N,N,-dimethylformamide (5 mL). Potassium carbonate (235 mg, 1.7 mmol) is then added followed by (3-bromo-propyl)-benzene (135 mg, 0.68 mmol). The reaction is heated to 65° C. for 18 hours. The reaction mixture is diluted with water and extracted with ethyl acetate, the organic layer is separated and concentrated in vacuo. The crude ether is purified by column chromatography (gradient of ethyl acetate in hexanes 25-75%). The residue is dissolved in ethanol (3 mL), treated with concentrated HCl (40 μl) and heated to reflux for 2.5 hours after which the reaction is allowed to cool to ambient temperature overnight. The volatiles were removed in vacuo and the crude sulfonamide is purified by column chromatography (gradient of ethyl acetate in hexanes 20-70%) affording 10 mg of the title compound. .sup.1H NMR (DMSO) δ 2.02-2.11 (m, 2H), 2.76 (t, 2H, J=7.16 Hz), 4.10 (t, 2H, J=6.41 Hz), 7.10 (d, 2H, J=8.67 Hz), 7.17-7.32 (m, 5H), 7.75-7.91 (m, 6H), 8.24 (d, 1H, J=1.88 Hz). MS (m/z): 430 (M+1).

Example 18: 2-Chloro-5-(4-pentyloxy-benzoyl)-benzenesulfonamide

(58) ##STR00030##

2-Chloro-5-[(4-pentyloxy-phenyl)-hydroxy-methyl]-benzenesulfonamide

(59) 1-Bromo-4-pentyloxy-benzene (656 mg, 2.73 mmol) is dissolved in tetrahydrofuran (2 mL) and cooled to −78° C. The solution is treated with a solution of n-butyllithium (1.6 M in hexanes, 1.7 mL, 2.73 mmol) which resulted in precipitation of the aryllithium. The suspension is allowed to warm to ambient temperature and is added via canula to a solution of 2-chloro-5-formyl-benzenesulfonamide (200 mg, 0.91 mmol) in tetrahydrofuran (2 mL) at −78° C. The reaction is allowed to warm to ambient temperature, at which point it is quenched with a saturated solution of ammonium chloride. The tetrahydrofuran is removed in vacuo and the residue is diluted with water and extracted with ethyl acetate. The organic phase is separated and concentrated in vacuo. The residue is used without further purification.

2-Chloro-5-(4-pentyloxy-benzoyl)-benzenesulfonamide

(60) 2-Chloro-5-[(4-pentyloxy-phenyl)-hydroxy-methyl]-benzenesulfonamide is dissolved in acetone (10 mL), and treated with a solution of Jones reagent (3 M in water, 0.91 mmol). The reaction is allowed to stir for 30 minutes. The reaction is diluted with water and extracted with dichloromethane. The organic phase is separated and concentrated in vacuo. The residue is purified by silica gel chromatography (gradient of ethyl acetate in hexanes 25-75%) followed by recrystallization from ether affording 15 mg of the title compound. .sup.1H NMR (DMSO) δ 0.90 (t, 3H, J=6.79 Hz), 1.31-1.46 (m, 4H), 1.70-1.79 (m, 2H), 4.09 (t, 2H, J=6.49 Hz), 7.10 (d, 2H, J=9.04 Hz), 7.75-7.90 (m, 4H), 8.24 (d, 1H, J=1.89). MS (m/z): 382 (M+1).

Example 19: 2-Chloro-5-(4-hexyloxy-benzoyl)-benzenesulfonamide

(61) ##STR00031##

2-Chloro-5-[(4-hexyloxy-phenyl)-hydroxy-methyl]-benzenesulfonamide

(62) 1-Bromo-4-hexyloxy-benzene (695 mg, 2.73 mmol) is dissolved in tetrahydrofuran (2 mL) and cooled to −78° C. The solution is treated with a solution of n-butyllithium (1.6 M in hexanes, 1.7 mL, 2.73 mmol) which resulted in precipitation of the aryllithium. The suspension is allowed to warm to ambient temperature and is added via canula to a solution of 2-chloro-5-formyl-benzenesulfonamide (200 mg, 0.91 mmol) in tetrahydrofuran (2 mL) at −78° C. The reaction is allowed to warm to ambient temperature, at which point it is quenched with a saturated solution of ammonium chloride. The tetrahydrofuran is removed in vacuo and the residue is diluted with water and extracted with ethyl acetate. The organic phase is separated and concentrated in vacuo. The residue is used without further purification.

2-Chloro-5-(4-hexyloxy-benzoyl)-benzenesulfonamide

(63) 2-Chloro-5-[(4-hexyloxy-phenyl)-hydroxy-methyl]-benzenesulfonamide is dissolved in acetone (10 mL), and treated with a solution of Jones reagent (3 M in water, 0.91 mmol). The reaction is allowed to stir for 30 minutes. The reaction is diluted with water and extracted with dichloromethane. The organic phase is separated and concentrated in vacuo. The residue is purified by silica gel chromatography (gradient of ethyl acetate in hexanes 25-75%) followed by recrystallization from ether affording 30 mg of the title compound. .sup.1H NMR (DMSO) δ 0.88 (t, 3H, J=6.78 Hz), 1.28-1.45 (m, 6H), 1.70-1.79 (m, 2H), 4.09 (t, 2H, J=6.4 Hz), 7.10 (d, 2H, J=9.04 Hz), 7.75-7.90 (m, 4H), 8.24 (d, 1H, J=1.89). MS (m/z): 396 (M+1).

Example 20: 2-Chloro-5-(4-trifluoromethoxy-benzoyl)-benzenesulfonamide

(64) ##STR00032##

2-Chloro-5-[hydroxy-(4-trifluoromethoxy-phenyl)-methyl]-benzenesulfonamide

(65) 1-Bromo-4-trifluoromethoxy-benzene (660 mg, 2.73 mmol) is dissolved in tetrahydrofuran (2.5 mL) and cooled to −78° C. The solution is treated with a solution of n-butyllithium (1.6 M in hexanes, 1.7 mL, 2.73 mmol) which resulted in precipitation of the aryllithium. The suspension is allowed to warm to ambient temperature and is added via canula to a solution of 2-chloro-5-formyl-benzenesulfonamide (200 mg, 0.91 mmol) in tetrahydrofuran (2.5 mL) at −78° C. The reaction is allowed to warm to ambient temperature, at which point it is quenched with a saturated solution of ammonium chloride. The tetrahydrofuran is removed in vacuo and the residue is diluted with water and extracted with ethyl acetate. The organic phase is separated and concentrated in vacuo. The residue is used without further purification.

2-Chloro-5-(4-trifluoromethoxy-benzoyl)-benzenesulfonamide

(66) 2-Chloro-5-[hydroxy-(4-trifluoromethoxy-phenyl)-methyl]-benzenesulfonamide is dissolved in acetone (10 mL), and treated with a solution of Jones reagent (3 M in water, 0.91 mmol). The reaction is allowed to stir for 30 minutes. The reaction is diluted with water and extracted with dichloromethane. The organic phase is separated and concentrated in vacuo. The residue is purified by silica gel chromatography (gradient of ethyl acetate in hexanes 10-50%) affording 92 mg of the title compound. .sup.1H NMR (CDCl.sub.3) δ 5.20 (s, 2H), 7.35 (d, 2H, J=8.3 Hz), 7.70 (d, 1H, J=8.3), 7.84 (d, 2H, J=8.7 Hz), 7.95 (dd, 1h, J=1.9, 8.3), 8.48 (d, 1H, J=1.9). MS (m/z): 378 (M−1). CHN Calc C, 44.28, H, 2.39, N, 3.69. Found C, 43.97, H, 2.22, N, 3.60.

Example 21: 2-Chloro-5-(4-phenylethynyl-benzoyl)-benzenesulfonamide

(67) ##STR00033##

(68) To a degassed solution of 5-(4-bromo-benzoyl)-2-chloro-benzenesulfonamide (500 mg, 1.33 mmol), phenylacetylene (204 mg, 2.00 mmol), copper iodide (15 mg), triphenylphosphine (9 mg, 0.033 mmol) and triethylamine (0.278 mL, 2 mmol) in tetrahydrofuran (4 mL) is added dichlorobis(triphenylphosphine)-palladium (47 mg, 0.067 mmol). The reaction mixture is allowed to stir at room temperature for 18 hours then poured into water (25 mL) and extracted twice with ethyl acetate. The organic fractions are combined, washed twice with a saturated sodium chloride solution, dried with magnesium sulfate, filtered and concentrated in vacuo. The resulting residue is purified via silica gel chromatography (20-50% ethyl acetate in hexanes) to yield the title compound as a white solid. MS (m/z): 394 (M−1).

Example 22: 4-(4-Chloro-3-sulfamoyl-benzoyl)-N-(2-pyridin-2-yl-ethyl)-benzamide

(69) ##STR00034##

4-(4-Chloro-3-sulfamoyl-benzoyl)-N-(2-pyridin-2-yl-ethyl)-benzamide

(70) 4-(4-Chloro-3-sulfamoyl-benzoyl)-benzoic acid (50 mg, 0.15 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (57 mg, 0.30 mmol), 1-hydroxy-7-azabenzotriazole (41 mg, 0.30 mmol) were dissolved in dichloromethane (5 mL), then triethylamine (61 mg, 0.60 mmol) is added followed by 2-pyridin-2-yl-ethylamine (23 mg, 0.19 mL) and the reaction is allowed to stir at ambient temperature overnight. The reaction is then quenched with trifluoroacetic acid (1 mmol) and loaded directly onto a silica gel column, chromatography (gradient of ethyl acetate in hexanes 10-100%) followed by crystallization from ether afforded 20 mg of the title compound. .sup.1H NMR (DMSO) δ 3.02 (t, 2H, J=7.57 Hz), 3.63-3.68 (m, 2H), 7.22-7.25 (m, 1H), 7.30 (d, 1H, J=7.83 Hz), 7.70-7.74 (m, 1H), 7.83-7.87 (m, 5H), 7.92-7.99 (m, 3H), 8.31 (d, 1H, J=2.02), 8.51-8.53 (m, 1H), 8.85-8.82 (m, 1H). MS (m/z): 442 (M−1). CHN Calc C, 56.82, H, 4.09, N, 9.47. Found C, 55.65, H, 3.90, N, 9.22 (+0.5 water).

Example 23: 2-Chloro-5-(4-pyrrolidin-1-yl-benzoyl)-benzenesulfonamide

(71) ##STR00035##

1-(4-Bromo-phenyl)-pyrrolidine

(72) A oven-dried 50 mL of round bottom flask is charged with Pd.sub.2(dba).sub.3 (116 mg, 0.13 mmol), BINAP (158 mg, 0.25 mmol), and sodium tert-butoxide (916 mg, 9.54 mmol). The flask is evacuated and backfilled with argon. Degassed toluene (5 mL), 1-iodo-4-bromobenzene (1.8 g, 6.36 mmol), pyrrolidine (542 mg, 7.63 mmol) are then added. The mixture is heated at 80° C. until the starting aryl iodide is completed consumed judged by LC-MS analysis. The mixture is diluted with ethyl acetate, filtered through Celite, and concentrated in vacuo. The crude product is purified by flash chromatography to give 1.1 g of product as light brown solid. .sup.1H NMR (400 MHz, CDCl.sub.3): δ 2.00 (t, 4H, J=4 Hz), 3.24 (t, 4H, J=4 Hz), 6.42 (d, 2H, J=8 Hz), 7.29 (d, 2H, J=8 Hz).

2-Chloro-5-(4-pyrrolidin-1-yl-benzoyl)-benzenesulfonamide

(73) Following method C, 1-(4-bromo-phenyl)-pyrrolidine is converted into the title compound. .sup.1H NMR (400 MHz, CDCl.sub.3): δ 2.06 (t, 4H, J=8 Hz), 3.40 (t, 4H, J=8 Hz), 5.19 (s, 2H), 6.55 (d, 2H, J=6 Hz), 7.63 (d, 1H, J=8 Hz), 7.72 (d, 2H, J=8 Hz), 7.86 (d, 1H, J=8 Hz), 8.41 (s, 1H). MS (m/z): 365 (M+1).

Example 24: 2-Chloro-5-[4-(2,5-dihydro-pyrrol-1-yl)-benzoyl]-benzenesulfonamide

(74) ##STR00036##

(75) Following method B, 2-chloro-5-((4-diallylamino-phenyl)-hydroxy-methyl)-benzenesulfonamide is synthesized from the appropriate aryl iodide.

2-Chloro-5-{[4-(2,5-dihydro-pyrrol-1-yl)-phenyl]-hydroxy-methyl}-benzenesulfonamide

(76) A solution of 100 mg of 2-chloro-5-((4-diallylamino-phenyl)-hydroxy-methyl)-benzenesulfonamide (0.25 mmol, 1 equivalent) in 5 mL of chloroform is degassed with argon for 5 minutes, then 5 mg of Grubb's catalyst (0.005 mmol, 2% mmol) is added. The reaction mixture is stirred at room temperature for 1 h, then diluted with dichloromethane, filtered through Celite, and a pad of silica gel, then concentrated in vacuo to give 70 mg of the title compound which is carried forward without further purification.

2-Chloro-5-[4-(2,5-dihydro-pyrrol-1-yl)-benzoyl]-benzenesulfonamide

(77) Following method B the title compound is prepared from 2-chloro-5-{[4-(2,5-dihydro-pyrrol-1-yl)-phenyl]-hydroxy-methyl}-benzenesulfonamide. .sup.1H NMR (400 MHz, CDCl.sub.3): δ 0.92 (s, 4H), 5.28 (m, 2H), 6.42 (s, 2H), 7.180 (t, 1H, J=2 Hz), 7.55-7.7 (m, 3H), 7.85-8.05 (m, 2H). MS (m/z): 361 (M−1).

Example 25: 2-Chloro-5-(4-piperidin-1-yl-benzoyl)-benzenesulfonamide

(78) ##STR00037##

(79) A solution of 300 mg of 4-chloro-3-sulfamoyl-benzoyl chloride (1.186 mmol, 1 equivalent) in 20 mL of dichloromethane is stirred at room temperature as 2.37 mL of diethyl aluminum chloride (1.0 M in hexane) is added drop-wise. The reaction is stirred at room temperature for 10 minutes, then 229 mg of 1-phenyl piperidine is added. The reaction is stirred at room temperature for 30 minutes. The reaction mixture is poured onto ice-2 N HCl and extracted with dichloromethane. The aqueous layer is then basified with 2 N sodium hydroxide and extracted with dichloromethane. The combined organic extracts are washed with water, dried over sodium sulfate, and concentrated in vacuo. After purification by flash chromatography, 180 mg of product is obtained. .sup.1H NMR (400 MHz, CDCl.sub.3): δ 1.69 (s, 6H), 3.18 (m, 1H), 3.42 (s, 3H), 5.18 (s, 2H), 6.86 (d, 2H, J=8 Hz), 7.62 (d, 1H, J=8 Hz), 7.70 (d, 2H, J=8 Hz), 7.87 (d, 1H, J=8 Hz), 8.42 (s, 1H). MS (m/z): 379 (M+1). Analytics calculated for C.sub.18H.sub.19ClN2O.sub.3S: C, 57.06; H, 5.05; N, 7.39. Found: C, 56.88; H, 5.04; N, 7.13.

Example 26: 2-Chloro-5-[4-(3-methyl-piperidin-1-yl)-benzoyl]-benzenesulfonamide

(80) ##STR00038##

Preparation of 1-(4-bromo-phenyl)-3-methyl-piperidine

(81) 1-(4-Bromo-phenyl)-3-methyl-piperidine is prepared from 0.25 mL of 3-methylpiperidine according to the procedure described in example 25. MS (m/z): 255 (M+1).

(82) A solution of 0.821 g of 1-(4-bromo-phenyl)-3-methyl-piperidine in tetrahydrofuran is cooled to −78° C. and treated with 0.3 g of 4-chloro-N-methoxy-N-methyl-3-sulfamoyl-benzamide. The mixture is stirred for 10 min and treated slowly with 4.31 mL of a solution of tert-butyl lithium (1.5 M) in tetrahydrofuran (3 mL). The orange solution is stirred at −78° C. for 15 min then at 0° C. for 1 hour. The reaction mixture is quenched with saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (2×50 mL). The organics are washed with water, a saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is loaded on Celite and purified by silica gel chromatography (1:1 hexanes/ethyl acetate) to give 2-chloro-5-[4-(3-methyl-piperidin-1-yl)-benzoyl]-benzenesulfonamide as a light yellow syrup. MS (m/z): 393 (M+1). HPLC Reverse Phase (Nucleosil 100-5 C18, gradient 10.fwdarw.100% CH.sub.3CN in 5 min) room temperature=5.40 minutes.

Example 27: 2-Chloro-5-[4-(4-phenyl-piperidin-1-yl)-benzoyl]-benzenesulfonamide

(83) ##STR00039##

(84) A solution of 0.227 g of 1-(4-bromo-phenyl)-4-phenyl-piperidine in tetrahydrofuran (5 mL) is cooled to −78° C. and treated with 2 portions of 0.29 mL each of tert-butyllithium (1.5 M in pentane). After 20 min at −78° C. the reaction mixture is treated with 0.1 g of 4-chloro-N-methoxy-N-methyl-3-sulfamoyl-benzamide in tetrahydrofuran (5 mL) and stirred for another 1.5 h. The temperature is then increased slowly to 0° C. and after completion the reaction is quenched by addition of 2 mL of saturated aqueous ammonium chloride and extracted with diethyl ether. The organics are washed with water, dried over magnesium sulfate, concentrated to 0.27 g of crude product which is purified by silica gel chromatography (1:1 hexanes/ethyl acetate) to give 2-chloro-5-[4-(4-phenyl-piperidin-1-yl)-benzoyl]-benzenesulfonamide as a powder. MS (m/z): (M−1) 453; Rf 0.65 (1:1 hexanes/ethyl acetate)

Example 28: 2-Chloro-5-[4-(4-methyl-piperazin-1-yl)-benzoyl]-benzenesulfonamide

(85) ##STR00040##

(86) A solution of 0.275 g of 1-(4-bromo-phenyl)-4-methyl-piperazine in tetrahydrofuran (90 mL) is cooled to −78° C. and treated with 1.44 mL of tert-butyllithium (1.5 M in pentane). After 15 min at −78° C. the reaction mixture is treated with 0.1 g of 4-chloro-N-methoxy-N-methyl-3-sulfamoyl-benzamide in tetrahydrofuran (3 mL). The temperature is then increased slowly to 0° C. and after completion the reaction is quenched by addition of 2 mL of saturated aqueous ammonium chloride and extracted with diethyl ether. The organics are washed with water, dried (magnesium sulfate) and concentrated to give 0.32 g of crude product which is purified by silica gel chromatography (95:5 methylene chloride/methanol) to give 2-chloro-5-[4-(4-methyl-piperazin-1-yl)-benzoyl]-benzenesulfonamide as a tan powder. MS (m/z): 394 (M+1); Rf 0.06 (95:5 methylene chloride/methanol).

Example 29: 2-Chloro-5-(indane-5-carbonyl)-benzenesulfonamide

(87) ##STR00041##

2-Chloro-5-(indane-5-carbonyl)-benzenesulfonamide

(88) Under nitrogen, aluminum chloride (315 mg, 2.4 mmol) is slurried in dichloromethane (20 mL) then 3-chlorosulfonyl-benzoyl chloride (200 mg, 0.79 mmol) is added and the reaction is allowed to stir at ambient temperature for 10 minutes. Indan (100 mg, 0.79 mmol) is added. The reaction is allowed to stir at ambient temperature for 18 hours. The reaction mixture is poured over ice-water and extracted with dichloromethane. The organic layer is concentrated to give 265 mg of the title compound (100% yield). .sup.1H NMR (CDCl.sub.3, 300 MHz): δ 8.47 (d, 1H, J=2.19 Hz), 7.93 (dd, 1H, J=2.19, 8.33 Hz), 7.67 (d, 1H, J=8.11), 7.64 (s, 1H), 7.53 (d, 1H, J=7.89 Hz), 7.33 (d, 1H, J=7.89 Hz), 5.17 (s, 2H), 2.98 (m, 4H), 2.15 (m, 2H). M.P.: 164-166° C. MS (m/z): 336 (M+1).

Example 30: 2-Chloro-5-(1H-pyrrole-3-carbonyl)-benzenesulfonamide

(89) ##STR00042##

1-Benzenesulfonyl-1H-pyrrole

(90) To a well-agitated suspension of sodium hydroxide (4.46 g, 111 mmol) in methylene chloride (26 mL) at 0° C. is added pyrrole (2.5 g, 0.37 mmol), and the reaction mixture is stirred for 10 min, following which a solution of benzenesulfonyl chloride (7.86 g, 0.44 mmol) in methylene chloride (5.15 mL) is slowly added, allowed to warm to room temperature and stirred overnight. The reaction is quenched by pouring into water (100 mL). The organic layer is separated, and the aqueous layer is extracted with methylene chloride three times. The combined organic extracts are water, dried with sodium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (10% ethyl acetate-hexane) provides 4.6 g (60%) of the title compound as a white solid. .sup.1H NMR (CDCl.sub.3): δ 7.80 (m, 2H), 7.50 (m, 3H), 7.25 (m, 2H), 6.30 (m, 2H).

5-(1-Benzenesulfonyl-1H-pyrrole-3-carbonyl)-2-chloro-benzenesulfonamide

(91) To a suspension of aluminum chloride (1.89 g, 14 mmol) in methylene chloride (10 mL) is added 4-chloro-3-sulfamoyl-benzoyl chloride (2 g, 7.9 mmol). The reaction mixture is stirred at room temperature for 10 minutes then a solution of 1-benzenesulfonyl-1H-pyrrole (1.13 g, 5.45 mmol) in methylene chloride (3.3 mL) is added. After stirring at room temperature overnight, the reaction is quenched with 6 N HCl and extracted with ethyl acetate three times. The combined organic layers are washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated in vacuo. Purification by silica gel chromatography (ethyl acetate/hexane: 2:8) provides 0.6 g (26%) of the title compound as a yellow solid. .sup.1H NMR (DMSO): δ 8.30 (s, 1H), 8.15 (m, 2H), 8.05 (m, 2H), 7.80 (m, 4H), 7.70 (m, 2H), 7.40 (m, 1H), 6.70 (m, 1H).

2-Chloro-5-(1H-pyrrole-3-carbonyl)-benzenesulfonamide

(92) 5-(1-Benzenesulfonyl-1H-pyrrole-3-carbonyl)-2-chloro-benzenesulfonamide (0.1 g, 0.23 mmol) is dissolved in 3 mL of 2:1 (v:v) mixture of methanol and 5 N aqueous sodium hydroxide and heated at reflux for 20 minutes then the reaction mixture is allowed to cool down and the organic solvent is removed in vacuo. The aqueous solution is acidified with 5 N HCl to pH 3, thoroughly extracted with ethyl acetate, then the combined organic extracts are washed with water, a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. Recrystallization from ethyl acetate/methylene chloride provides 43 mg (66%) of the title compound as a white solid. .sup.1H NMR (DMSO): δ 11.70 (s, 1H), 8.70 (m, 1H), 8.00 (m, 1H), 7.80 (m, 3H), 7.50 (m, 1H), 7.00 (m, 1H), 6.60 (m, 1H). MS (m/z): 285 (M+1) Analytics calculated For C.sub.11H.sub.9N.sub.2ClO.sub.3S: C, 46.40; H, 3.19; N, 9.84. Found: C, 45.84; H, 2.90; N, 9.41.

Example 31: 2-Chloro-5-(thiophene-2-carbonyl)-benzenesulfonamide

(93) ##STR00043##

2-Chloro-5-(thiophene-2-carbonyl)-benzenesulfonamide

(94) To a solution of thiophene (0.27 g, 3.20 mmol) dissolved in tetrahydrofuran (10 mL) at −78° C. under nitrogen is dropwisely added 1.6 M of n-butyllithium (2 mL, 3.40 mmol). The reaction mixture is stirred at −78° C. for 1 h then a solution 4-chloro-N-methoxy-N-methyl-3-sulfamoyl-benzamide (0.3 g, 1.08 mmol) in tetrahydrofuran (2 mL) is added slowly and the reaction mixture is allowed to warm to room temperature and stirred for 1 h. The reaction is quenched with saturated ammonium chloride and extracted with ethyl acetate three times. The combined organic extracts are washed with a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (50% ethyl acetate-hexane) provides 0.059 g (18%) of the title compound as a yellow solid. .sup.1H NMR (DMSO): δ 8.33 (d, J=2 Hz, 1H), 8.15 (dd, J=4, 1 Hz, 1H), 8.05 (dd, J=8, 4 Hz, 1H), 7.85 (m, 4H), 7.35 (m, 1H). Analytics calculated for C.sub.11H.sub.8NClO.sub.3S.sub.2: C, 43.78; H, 2.67; N, 4.64. Found: C, 43.70; H, 2.61; N, 4.61. MS (m/z): 300.0 (M−1).

Example 32: 2-Chloro-5-(2-methyl-3H-benzoimidazole-5-carbonyl)-benzenesulfonamide

(95) ##STR00044##

(96) A solution of 0.303 g of 6-bromo-2-methyl-1H-benzoimidazole in tetrahydrofuran (20 mL) is cooled to −50° C. and treated with 2.7 mL of tert-butyllithium (1.5 M in pentane). After 2 h at −50° C. the reaction mixture is treated with 0.12 g of 4-chloro-N-methoxy-N-methyl-3-sulfamoyl-benzamide in tetrahydrofuran (10 mL). After 3 h the mixture is quenched with saturated aqueous ammonium chloride, taken up in ethyl acetate, and washed with saturated aqueous sodium chloride. The organics are dried (magnesium sulfate), concentrated and purified by silica gel chromatography (98:2 methylene chloride/methanol) to give 2-chloro-5-(2-methyl-3H-benzoimidazole-5-carbonyl)-benzenesulfonamide. MS (m/z): 348 (M−1); Rf 0.30 (9:1 methylene chloride/methanol).

Example 33: 5-(9H-Carbazole-2-carbonyl)-2-chloro-benzenesulfonamide

(97) ##STR00045##

(98) A mixture of 0.5 g of 5-(9-acetyl-9H-carbazole-2-carbonyl)-2-chloro-benzenesulfonamide and 20 mL of potassium hydroxide solution (10% in water) is heated at reflux overnight and is allowed to cool to room temperature. The reaction mixture is extracted with ethyl acetate, washed with water then a saturated sodium chloride solution, and dried over sodium sulfate. After concentration the residue is loaded on Celite and purified by silica gel chromatography (1:1 hexanes/ethyl acetate) to give 5-(9H-carbazole-2-carbonyl)-2-chloro-benzenesulfonamide as dark orange crystals. MS (m/z): 385 (M+1).

Preparation of 5-(9-acetyl-9H-carbazole-2-carbonyl)-2-chloro-benzenesulfonamide

(99) To a solution of 1 g of 1-carbazol-9-yl-ethanone and 2.43 g of 4-chloro-3-sulfamoyl-benzoyl chloride in methylene chloride (20 mL) is added 2.55 g of aluminum chloride. The mixture is stirred at 50° C. overnight. The solution is then cooled at −78° C., quenched with a 6 N HCl solution and allowed to warm up to room temperature. Methylene chloride is added to dissolve the precipitate and the solution is extracted, washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue is loaded on Celite and purified by silica gel chromatography (1:1 hexanes/ethyl acetate) to afford 5-(9-acetyl-9H-carbazole-2-carbonyl)-2-chloro-benzenesulfonamide as yellow foam. MS (m/z): 427 (M+1). HPLC Reverse Phase (Nucleosil 100-5 C18, gradient 10.fwdarw.100% CH.sub.3CN in 5 min) room temperature=5.35 minutes.

Example 34 and Example 35: 8-(4-Chloro-3-sulfamoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester and 7-(4-chloro-3-sulfamoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester

(100) ##STR00046##

(101) A mixture of 5-benzenesulfonyl-8-(4-chloro-3-sulfamoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester and 5-benzenesulfonyl-7-(4-chloro-3-sulfamoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester (1 g) is dissolved in 5 mL of tetrahydrofuran-methanol-water (10:10:1) and treated with 0.344 g of potassium carbonate. The reaction mixture is heated at 140° C. for 15 min (microwave irradiation), filtered and concentrated. The residue is purified on reverse phase HPLC to give pure 8-(4-chloro-3-sulfamoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester MS (m/z): 462 (M+1); and 7-(4-chloro-3-sulfamoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester MS (m/z): 462 (M+1); both as yellow syrups. Both isomers are separated by HPLC (Chiracel OD-H 250-4.6 mm, flow 1 ml/Min, UV 235 nM, gradient hexane-ethanol 70-30). The retention times are 6.91 min for 8-(4-chloro-3-sulfamoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester and 10.20 min for 7-(4-chloro-3-sulfamoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester.

Preparation of 5-benzenesulfonyl-8-(4-chloro-3-sulfamoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester and 5-benzenesulfonyl-7-(4-chloro-3-sulfamoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester

(102) Step 1

(103) A solution of 3 g of 1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester in methylene chloride (50 mL) is treated with 0.982 g of sodium hydroxide and stirred and room temperature overnight. Benzenesulfonylchloride (6.30 mL) is added to the reaction and stirred at room temperature overnight. The reaction mixture is diluted with water (250 mL) and extracted with methylene chloride. The organics are combined, washed with water then a saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue is loaded on Celite and purified by silica gel chromatography (1:1 hexanes/ethyl acetate) to give 5-benzenesulfonyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester as a yellow powder. MS (m/z): 385 (M+1).

(104) Step 2

(105) The mixture of regioisomers 5-benzenesulfonyl-8-(4-chloro-3-sulfamoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester and 5-benzenesulfonyl-7-(4-chloro-3-sulfamoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester is prepared from 0.5 g of 5-benzenesulfonyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester according to the procedure described in example 102. MS (m/z): 603 (M+1).

Example 36: 2-Chloro-5-(1-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carbonyl)-enzenesulfonamide

(106) ##STR00047##

2,3-Piperidinedione 3-(3-bromophenyl) hydrazone

(107) 3-Carbethoxy-2-piperidone (4.7 g, 27.4 mmol) is stirred with potassium hydroxide (1.64 g) in water (56 mL) and kept at 30° C. on an oil bath overnight. 3-Bromoaniline (4.99 g, 29 mmol) is treated with water (50 mL) and concentrated HCl (10 mL) and cooled to 0° C. Sodium nitrite (2.46 g, 35 mmol) in water (9 mL) is added dropwise to the above solution at 0° C. and stirred for an additional 20 minutes. Urea is added to decompose the excess nitrous acid, and the diazotized solution is neutralized with 10% aqueous sodium carbonate solution (45-50 mL). The resulting solution is filtered into the solution of previously hydrolyzed 3-carbethoxy-2-piperidone (2-piperidone-3-carboxylic acid) at 0° C. After a few minutes, glacial acetic acid is added to bring the pH of the solution to 3-4. The reaction mixture is stirred at 0° C. for 5-6 h, and the yellow precipitate which resulted is filtered, washed with water, and dried to get the title compound (2.5 g, 32% yield).

7-Bromo-2,3,4,9-tetrahydro-pyrido[3,4-b]indol-1-one

(108) A solution of 2,3-piperidinedione 3-(3-bromophenyl) hydrazone (2.5 g, 22.3 mmol) in formic acid (40 mL) is refluxed for 1 h then cooled to room temperature. The reaction mixture is neutralized with sodium carbonate to basic condition. The resulting precipitate is filtered and collected. Recrystallization with ethanol provides 1.0 g (56%) of the title compound as a yellow solid.

7-Trimethylstannanyl-2,3,4,9-tetrahydro-pyrido[3,4-b]indol-1-one

(109) 7-Bromo-2,3,4,9-tetrahydro-pyrido[3,4-b]indol-1-one (0.42 g, 1.59 mmol) and hexamethylditin (0.64 g, 1.96 mmol) are dissolved in deoxygenated toluene (16 mL) under a nitrogen atmosphere. Palladium tetrakis(triphenylphosphine) (0.118 g, 0.11 mmol) is added, and the mixture is heated at reflux for 7 h. The reaction mixture is partitioned between pH 7 buffer and ethyl acetate, and the aqueous layer is extracted with ethyl acetate three times. The combined organics are dried over magnesium sulfate and concentrated in vacuo. The title compound is obtained as the yellow oil, which is used in the next step without further purification.

2-Chloro-5-(1-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carbonyl)-enzenesulfonamide

(110) 7-Trimethylstannanyl-2,3,4,9-tetrahydro-pyrido[3,4-b]indol-1-one (0.66 g, 1.88 mmol) and 1,8-bis(dimethylamino) naphthalene (0.210 g, 0.94 mmol) in tetrahydrofuran (25 mL) is treated with 4-chloro-3-sulfamoyl-benzoyl chloride (0.48 g, 1.88 mmol). After a few minutes, allylpalladium chloride dimer (0.057 g, 0.15 mmol) is added. The reaction mixture is stirred for 5 min at room temperature and then refluxed for 2 h. After cooling to room temperature the reaction mixture is diluted with methylene chloride and washed with a saturated sodium chloride solution then concentrated in vacuo. Purification by silica gel chromatography (75% ethyl acetate-hexane) followed by recrystallization (ethanol-ethyl acetate) provides 0.014 g (1.8%) of the title compound as a pale yellow solid. .sup.1H NMR (DMSO): δ 12.00 (s, 1H), 8.30 (s, 1H), 8.00 (m, 1H), 7.90 (m, 6H), 7.60 (m, 1H), 3.40 (m, 2H), 3.00 (m, 2H). MS (m/z): 402.0 (M−1).

Example 37: 2-Chloro-5-[2-(2,2-dimethyl-propionyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-carbonyl]-benzenesulfinamide

(111) ##STR00048##

2,2-Dimethyl-1-(1,3,4,9-tetrahydro-pyrido[3,4-b]indol-2-yl)-propan-1-one

(112) To a solution of 2,3,4,9-tetrahydro-1H-pyrido[3,4-b] indole (2 g, 11.6 mmol) dissolved in methylene chloride (20 mL) is added 2,2-dimethyl-propionyl chloride (1.42 mL, 11.6 mmol) followed by the addition of triethylamine (1.61 mL, 11.6 mmol). The reaction mixture is stirred at room temperature for 30 minutes The reaction is quenched with water and extracted with methylene chloride three times. The combined organic extracts are washed with saturated sodium bicarbonate, a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo to give 2.8 g (94%) of the title compound as a grey solid.

1-(9-Benzenesulfonyl-1,3,4,9-tetrahydro-pyrido[3,4-b] indol-2-yl)-2,2-dimethyl-propan-1-one

(113) To a well-agitated suspension of sodium hydroxide (0.81 g, 20.2 mmol) in methylene chloride (10 mL) is added 2,2-dimethyl-1-(1,3,4,9-tetrahydro-pyrido[3,4-b]indol-2-yl)-propan-1-one (2.3 g, 8.98 mmol). The reaction mixture is stirred for 15 min, and then benzenesulfonyl chloride (1.89 g, 10.7 mmol) is added. The solution is stirred at room temperature for 1 h. The reaction is diluted with methylene chloride, washed with water then a saturated sodium chloride solution, dried with sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography (50% ethyl acetate-hexane) provides 2.0 g (56.2%) of the title compound as a white solid.

5-[9-Benzenesulfonyl-2-(2,2-dimethyl-propionyl)-2,3,4,9-tetrahydro-1H-pyrido [3,4-b]indole-6-carbonyl]-2-chloro-benzenesulfinamide and 5-[9-Benzenesulfonyl-2-(2,2-dimethyl-propionyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carbonyl]-2-chloro-benzenesulfinamide

(114) To a suspension of aluminum chloride (0.338 g, 2.54 mmol) in methylene chloride (10 mL) is added 4-chloro-3-sulfamoyl-benzoyl chloride (0.36 g, 1.41 mmol). The reaction mixture is stirred at room temperature for 15 min then 1-(9-benzenesulfonyl-1,3,4,9-tetrahydro-pyrido [3,4-b] indol-2-yl)-2,2-dimethyl-propan-1-one is added. After the mixture is stirred at room temperature overnight, the reaction is quenched with 6 N HCl and extracted with methylene chloride three times. The combined organic layers are washed with a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (ethyl acetate/hexane: 2:8) provides 0.12 g (13.8%) of the two title compounds as a yellow solid.

2-Chloro-5-[2-(2,2-dimethyl-propionyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-carbonyl]-benzenesulfinamide

(115) 5-[9-Benzenesulfonyl-2-(2,2-dimethyl-propionyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-carbonyl]-2-chloro-benzenesulfinamide and its isomer (0.12 g, 0.195 mmol) are dissolved in 3 mL of 2:1 (v:v) mixture of methanol and 5 N aqueous sodium hydroxide then heated at reflux for 20 minutes The reaction mixture is allowed to cool to room temperature and the methanol is removed in vacuo. The aqueous solution is acidified with 5 N HCl to pH 3 and then thoroughly extracted with ethyl acetate, the combined organic extracts are washed with water then a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. Purification via preparative HPLC provides 0.014 g (15%) of the title compound as a yellow solid. .sup.1H NMR (DMSO): δ 11.40 (s, 1H), 8.30 (s, 1H), 7.90 (m, 2H), 7.80 (m, 3H), 7.50-7.60 (m, 2H), 4.74 (s, 2H), 4.00 (m, 2H), 2.80 (m, 2H). MS (m/z): 472.1 (M−1).

Example 38: 2-Chloro-5-(1-methyl-2-oxo-2,3,4,9-tetrahydro-1H-indeno[2,1-b]pyridine-7-carbonyl)-benzenesulfonamide

(116) ##STR00049##

3-Methylamino-propionic acid methyl ester

(117) Methyl acrylate (10 g, 116 mmol) is dissolved in methanol (20 mL) and cooled to −20° C. Methylamine (2 M in tetrahydrofuran, 90 mL, 180 mmol) is added via addition funnel and the reaction is allowed to stir at −20° C. for 2 hours. Solvents were then removed in vacuo and the residue is distilled under reduced pressure (45° C. at 5 torr) to afford the title compound as a colorless liquid (3.5 g, 28% yield). .sup.1H NMR (CDCl.sub.3) δ 2.44 (s, 3H), 2.52 (t, 2H, J=6.31 Hz), 2.86 (t, 2H, J=6.31 Hz), 3.69 (s, 3H).

1-Methyl-1,3,4,9-tetrahydro-indeno[2,1-b]pyridin-2-one

(118) 3-Methylamino-propionic acid methyl ester (1.5 g, 13.64 mmol) is added to a solution of 2-indanone (1.7 g, 12.86 mmol) in toluene (20 mL) and the reaction is brought to reflux for 2.5 hours. Toluene is removed in vacuo and the residue is dissolved in ethylene glycol (17 mL) and the resulting solution is heated to reflux for 8 hours. The reaction is allowed to cool to ambient temperature, is poured over water and extracted with dichloromethane. The organic phase is dried over magnesium sulfate and concentrated in vacuo to afford the crude title compound as a brown oil. The crude product is purified by silica gel chromatography (gradient of ethyl acetate in hexanes 10-100%) affording 720 mg (28% yield) of the title compound. .sup.1H NMR (CDCl.sub.3) δ 2.70-2.80 (m, 4H), 3.23 (s, 3H), 3.5 (s, 2H), 7.07-7.15 (m, 2H), 7.24-7.33 (m, 1H), 7.38 (d, 1H, J=7.07). MS (m/z): 199.2 (M+1).

2-Chloro-5-(1-methyl-2-oxo-2,3,4,9-tetrahydro-1H-indeno[2,1-b]pyridine-7-carbonyl)-benzenesulfonamide

(119) Under nitrogen, aluminum chloride (2.0 g, 15.06 mmol) is slurried in dichloromethane (100 mL) then 4-chloro-3-sulfamoyl-benzoyl chloride (1.28 g, 5.02 mmol) is added and allowed to stir at ambient temperature for 30 minutes. To this mixture 1-methyl-1,3,4,9-tetrahydro-indeno[2,1-b]pyridin-2-one (1.0 g, 5.02 mmol) is added in 13 mL dichloromethane. The reaction is allowed to stir at ambient temperature for 1 hour. The reaction mixture is poured over ice-water (300 mL) and extracted with dichloromethane, organic separated and concentrated to give crude title compound. Recrystallization from warm methanol afforded the title compound as a yellow powder (1.1 g, 53% yield). .sup.1H NMR (MeOD) δ 2.77-2.83 (m, 4H), 3.28 (s, 3H), 3.59 (s, 2H), 5.17 (s, 2H), 7.19 (d, 1H, J=7.83 Hz), 7.68-7.73 (m, 2H), 7.86 (s, 1H), 7.94 (dd, 1H, J=2.27, 8.33 Hz), 8.46 (d, 1H, J=2.02 Hz). MS (m/z): 417 (M+1). M.P. 259-260° C.

Example 39: 2-Chloro-5-(1-ethyl-2-oxo-2,3,4,9-tetrahydro-1H-indeno[2,1-b]pyridine-7-carbonyl)-benzenesulfonamide

(120) ##STR00050##

3-Ethylamino-propionic acid methyl ester

(121) Methyl acrylate (5.22 g, 60.6 mmol) is dissolved in methanol (20 mL) and cooled to −20° C. Ethylamine (2 M in tetrahydrofuran, 47 mL, 94 mmol) is added via addition funnel and the reaction is allowed to stir at −20° C. for 2 hours. Solvents were then removed in vacuo and the residue is distilled under reduced pressure to afford the title compound as a colorless liquid (2.41 g, 30% yield). .sup.1H NMR (CDCl.sub.3) δ 1.11 (t, 3H, J=7.02 Hz), 2.53 (t, 2H, J=6.58 Hz), 2.66 (q, 2H, J=7.02 Hz), 2.89 (t, 2H, J=6.58 Hz), 3.69 (s, 3H).

1-Ethyl-1,3,4,9-tetrahydro-indeno[2,1-b]pyridin-2-one

(122) 3-Ethylamino-propionic acid methyl ester (2.41 g, 18.4 mmol) is added to a solution of 2-indanone (2.3 g, 17.33 mmol) in toluene (27 mL), and the reaction is brought to reflux for 2 hours. Toluene is removed in vacuo and the residue is dissolved in ethylene glycol (23 mL) and the resulting solution is heated to reflux for 8 hours. The reaction is allowed to cool to ambient temperature and is poured over water and extracted with dichloromethane. The organic phase is dried over magnesium sulfate and concentrated in vacuo to afford the crude title compound. The crude product is purified by silica gel chromatography (gradient of ethyl acetate in hexanes 10-100%) affording 1 g (27% yield) of the title compound. MS (m/z): 213.3 (M+1).

2-Chloro-5-(1-ethyl-2-oxo-2,3,4,9-tetrahydro-1H-indeno[2,1-b]pyridine-7-carbonyl)-benzenesulfonamide

(123) Under nitrogen, aluminum chloride (0.7 g, 4.9 mmol) is slurried in dichloromethane (15 mL) then 4-chloro-3-sulfamoyl-benzoyl chloride (287 mg, 1.13 mmol) is added and allowed to stir at ambient temperature for 30 minutes. Then 1-ethyl-1,3,4,9-tetrahydro-indeno[2,1-b]pyridin-2-one (240 mg, 1.13 mmol) is added in 4 mL dichloromethane. The reaction is allowed to stir at ambient temperature for 1.5 hours. The reaction mixture is poured over ice-water and extracted with dichloromethane, the organic layer is separated and concentrated to give crude title compound as a brown oil. Recrystallization from warm dichloromethane afforded the title compound as a yellow powder (125 mg, 26% yield). .sup.1H NMR (MeOD) δ 1.26 (t, 2H, J=7.01 Hz), 2.76-2.83 (m, 4H), 3.6 (s, 2H), 3.77 (q, 2H, J=7.01), 5.19 (s, 2H), 7.19 (d, 1H, J=8.11 Hz), 7.68-7.73 (m, 2H), 7.86 (d, 1H, J=1.09), 7.94 (dd, 1H, J=2.19, 8.11 Hz), 8.46 (d, 1H, J=1.97 Hz). MS (m/z): 431 (M+1).

Example 40: 2-Chloro-5-[4-(2,5-dimethyl-pyrrol-1-yl)-3-fluoro-benzoyl]-benzenesulfonamide

(124) ##STR00051##

(125) Following method B, 2-chloro-5-((4-(2,5-dimethyl-pyrrol-1-yl)-3-fluoro-phenyl)-hydroxy-methyl)-benzenesulfonamide is synthesized from the corresponding aryl bromide. In the next step, a solution of 100 mg of 2-chloro-5-((4-(2,5-dimethyl-pyrrol-1-yl)-3-fluoro-phenyl)-hydroxy-methyl)-benzenesulfonamide (0.24 mmol, 1 equivalent), 43 mg of 4-methylmorpholine N-oxide, and 122 mg of 4 Å molecular sieves in 5 mL of dichloromethane is stirred at room temperature as 5 mg of tetrapropylammonium perruthenate is added. The reaction is stirred at room temperature for 1 h, then filtered through a pad of silica gel, eluted with ethyl acetate and concentrated in vacuo. After purification by flash chromatography, 45 mg of product is obtained. .sup.1H NMR (400 MHz, CDCl.sub.3): δ 2.05 (s, 6H), 5.20 (s, 2H), 6.0 (s, 2H), 7.40 (t, 1H, J=8 Hz), 7.65-7.75 (m, 3H), 8.05 (dd, 1H, J=8 Hz), 8.55 (d, 1H, J=2 Hz). MS (m/z): 407 (M+1).

Example 41: 2-Chloro-5-(1H-indole-6-carbonyl)-benzenesulfonamide

(126) ##STR00052##

(127) A dispersion of potassium hydride in oil (33.15 mmol) is washed with hexanes under argon then tetrahydrofuran (310 mL) is added at 0° C. and the resulting suspension is treated by dropwise addition of 6.77 g of 6-bromoindole in tetrahydrofuran (61 mL). The reaction mixture is stirred at 0° C. for 15 min to give a yellow solution. A solution of 44.2 mL of tert-butyllithium (1.5 M in pentane) is added slowly at −78° C. while maintaining the temperature below −75° C. to produce a yellow suspension. After 15 min a solution of 3.08 g of 4-chloro-N-methoxy-N-methyl-3-sulfamoyl-benzamide in tetrahydrofuran (61 mL) is added and the temperature is allowed to increase slowly to 0° C. The reaction mixture is quenched by addition of 62 mL of saturated aqueous ammonium chloride and extracted with ethyl ether. The organics were washed with water, dried over magnesium sulfate and concentrated to 9.65 g of a brown oil which is chromatographed on silica gel (1:1 hexanes/ethyl acetate) to give 2-chloro-5-(1H-indole-6-carbonyl)-benzenesulfonamide as a yellow foam. MS (m/z): 333 (M−1); Rf 0.37 (1:1 hexanes/ethyl acetate).

Example 42: 2-Fluoro-5-(1H-indole-6-carbonyl)-benzenesulfonamide

(128) ##STR00053##

(129) A solution of 0.997 g of 6-bromoindole in tetrahydrofuran (20 mL) is cooled to −50° C. and treated by slow addition of 8.79 mL of tert-butyllithium (1.5 M in pentane). After 2 h at −50° C. the reaction mixture is treated with 0.4 g of 4-fluoro-N-methoxy-N-methyl-3-sulfamoyl-benzamide in tetrahydrofuran (10 mL), stirred for an additional 3 h at −50° C. and quenched by addition of 2 mL of saturated aqueous ammonium chloride. The reaction mixture is taken up in ethyl acetate, washed with a saturated sodium chloride solution and dried (magnesium sulfate). After concentration in vacuo the residue is purified by silica gel chromatography (1:1 hexanes/ethyl acetate) to give 2-fluoro-5-(1H-indole-6-carbonyl)-benzenesulfonamide as an amorphous solid. MS (m/z): 317 (M−1); Rf 0.32 (1:1 hexanes/ethyl acetate).

Example 43: 5-(1H-Indole-6-carbonyl)-2-methyl-benzenesulfonamide

(130) ##STR00054##

(131) 5-(1H-Indole-6-carbonyl)-2-methyl-benzenesulfonamide is prepared from 4 g of N-methoxy-4,N-dimethyl-3-sulfamoyl-benzamide according to the procedure described in Method C. MS (m/z): 313 (M−1); Rf 0.28 (1:1 hexanes/ethyl acetate).

Preparation of N-methoxy-4,N-dimethyl-3-sulfamoyl-benzamide

(132) A mixture of 3.63 g of 4-methyl-3-sulfamoyl-benzoic acid, 1.92 g of N,O-dimethylhydroxylamine hydrochloride, and 5.02 mL of triethylamine in methylene chloride (120 mL) is treated with 8.32 g of benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate. The reaction mixture is stirred overnight at room temperature, washed sequentially with saturated aqueous sodium bicarbonate, water and a saturated sodium chloride solution, dried (magnesium sulfate) and concentrated in vacuo. The crude material is purified by silica gel chromatography (1:2 hexanes/ethyl acetate) to give N-methoxy-4,N-dimethyl-3-sulfamoyl-benzamide as a white powder. MS (m/z): 257 (M−1); Rf 0.25 (1:2 hexanes/ethyl acetate).

Example 44: 3-(1H-Indole-6-carbonyl)-benzenesulfonamide

(133) ##STR00055##

(134) 3-(1H-Indole-6-carbonyl)-benzenesulfonamide is prepared from 2.95 g of N-methoxy-N-methyl-3-sulfamoyl-benzamide according to the procedure described in method C. MS (m/z): 299 (M−1); Rf 0.25 (1:1 hexanes/ethyl acetate).

Preparation of N-methoxy-N-methyl-3-sulfamoyl-benzamide

(135) N-Methoxy-N-methyl-3-sulfamoyl-benzamide is prepared from 3.14 g of 3-sulfamoyl-benzoic acid according to the procedure described in method C. MS (m/z): 243 (M−1); Rf 0.21 (1:2 hexanes/ethyl acetate).

Preparation of 4-fluoro-N-methoxy-N-methyl-3-sulfamoyl-benzamide

(136) 4-Fluoro-N-methoxy-N-methyl-3-sulfamoyl-benzamide is prepared from 0.5 g of 4-fluoro-3-sulfamoyl-benzoic acid according to the procedure described in method C. MS (m/z): 261 (M−1); Rf 0.45 (9:1 methylene chloride/methanol).

Example 45: 2-chloro-5-(3-phenyl-1H-indole-6-carbonyl)-benzenesulfonamide

(137) ##STR00056##

Method for the Preparation of 5-[3-bromo-1-(tert-butyldimethylsilyl)-1H-indole-6-carbonyl]-2-chloro-N-(tert-butyldimethylsilyl)-benzenesulfonamide

(138) Step 1:

(139) A solution of 3.89 g of 2-chloro-5-(1H-indole-6-carbonyl)-benzenesulfonamide in tetrahydrofuran (370 mL) is cooled to −78° C. and treated by dropwise addition of n-butyllithium in hexane (1.6 M, 24.4 mL). After 15 min at −78° C. the orange solution is treated by addition of 3.47 g of tert-butyldimethylchlorosilane in tetrahydrofuran (50 mL) and the temperature is allowed to increase slowly to 0° C. After 1.5 h at 0° C. the reaction mixture is treated with water at 0° C. and extracted with diethyl ether. The organic phase is washed with a saturated sodium chloride solution, dried (magnesium sulfate) and concentrated to an oil which is triturated under sonication in diisopropylether to give 5-[1-(tert-butyldimethylsilyl)-1H-indole-6-carbonyl]-2-chloro-N-(tert-butyldimethylsilyl)-benzenesulfonamide as a white powder. MS (m/z): 563 (M+1), Rf 0.60 (2:1 hexanes/ethyl acetate).

(140) Step 2:

(141) A solution of 1.7 g of 5-[1-(tert-butyldimethylsilyl)-1H-indole-6-carbonyl]-2-chloro-N-(tert-butyldimethylsilyl)-benzenesulfonamide in tetrahydrofuran (110 mL) at −78° C. is treated with 0.564 g of N-bromosuccinimide. After 6 h at −78° C. the temperature is allowed to reach room temperature. The reaction mixture is taken up in diethyl ether, washed with water and dried (magnesium sulfate). The solvent is evaporated and the residue is triturated under sonication with diisopropylether to give 5-[3-bromo-1-(tert-butyldimethylsilyl)-1H-indole-6-carbonyl]-2-chloro-N-(tert-butyldimethylsilyl)-benzenesulfonamide as a tan powder. MS (m/z): 643 (M+1); Rf 0.90 (95:5 methylene chloride/methanol).

2-chloro-5-(3-phenyl-1H-indole-6-carbonyl)-benzenesulfonamide

(142) To a mixture of 0.1 g of 5-[3-bromo-1-(tert-butyl-dimethyl-silyl)-1H-indole-6-carbonyl]-2-chloro-N-(tert-butyl-dimethyl-silyl)-benzenesulfonamide, 0.039 g of phenylboronic acid and 0.025 g of 1,1′-bis(diphenylphosphino)-ferrocenedichloropalladium(II)-dichloromethane complex in dimethoxyethane (3.6 mL) is added 0.099 g of tri-potassium phosphate in water (1.2 mL). The solution is heated to 130° C. for 5 minutes (microwave irradiation). The reaction mixture is extracted with ethyl acetate. The organic phase is washed with water, dried (magnesium sulfate) and concentrated to 0.094 g of crude product. Purification via flash chromatography on silica gel (98:2 methylene chloride/methanol) afforded 2-chloro-5-(3-phenyl-1H-indole-6-carbonyl)-benzenesulfonamide as a tan powder. MS (m/z): 409 (M−1); Rf 0.22 (95:5:0.5 methylene chloride/methanol/ammonium hydroxide).

(143) Likewise the following compounds are prepared from 5-[3-bromo-1-(tert-butyl-dimethyl-silyl)-1H-indole-6-carbonyl]-2-chloro-N-(tert-butyl-dimethyl-silyl)-benzenesulfonamide.

2-Chloro-5-[3-(4-methoxy-phenyl)-1H-indole-6-carbonyl]-benzenesulfonamide

(144) MS (m/z): 439 (M−1); Rf 0.22 (95:5 methylene chloride/methanol).

2-Chloro-5-[3-(4-fluoro-phenyl)-1H-indole-6-carbonyl]-benzenesulfonamide

(145) MS (m/z): 427 (M−1); Rf 0.16 (3:1 methylene chloride/diethyl ether).

5-[3-(3-Acetyl-phenyl)-1H-indole-6-carbonyl]-2-chloro-benzenesulfonamide

(146) MS (m/z): 452 (M−1); Rf 0.18 (3:1 methylene chloride/diethyl ether).

5-[3-(4-Acetyl-phenyl)-1H-indole-6-carbonyl]-2-chloro-benzenesulfonamide

(147) MS (m/z): 451 (M−1); Rf 0.16 (3:1 methylene chloride/diethyl ether).

2-Chloro-5-[3-(3-methanesulfonyl-phenyl)-1H-indole-6-carbonyl]-benzenesulfonamide

(148) MS (m/z): 487 (M−1); Rf 0.11 (1:1 methylene chloride/diethyl ether).

2-Chloro-5-[3-(4-methanesulfonyl-phenyl)-1H-indole-6-carbonyl]-benzenesulfonamide

(149) MS (m/z): 487 (M−1); Rf 0.09 (2:1 methylene chloride/diethyl ether).

2-Chloro-5-[3-(4-ethanesulfonyl-phenyl)-1H-indole-6-carbonyl]-benzenesulfonamide

(150) MS (m/z): 501 (M−1); Rf 0.12 (3:1 methylene chloride/diethyl ether).

5-(3-Biphenyl-4-yl-1H-indole-6-carbonyl)-2-chloro-benzenesulfonamide

(151) MS (m/z): 485 (M−1); Rf 0.19 (95:5:0.5 methylene chloride/methanol/ammonium hydroxide).

2-Chloro-5-(3-thiophen-3-yl-1H-indole-6-carbonyl)-benzenesulfonamide

(152) MS (m/z): 415 (M−1); Rf 0.23 (3:1 methylene chloride/diethyl ether).

5-[3-(5-Acetyl-thiophen-2-yl)-1H-indole-6-carbonyl]-2-chloro-benzenesulfonamide

(153) MS (m/z): 451 (M−1); Rf 0.16 (3:1 methylene chloride/diethyl ether).

5-(1H, 1′H-[3,5]Biindolyl-6-carbonyl)-2-chloro-benzenesulfonamide

(154) MS (m/z): 447 (M−1); Rf 0.22 (3:1 methylene chloride/diethyl ether).

2-Chloro-5-(3-pyridin-3-yl-1H-indole-6-carbonyl)-benzenesulfonamide

(155) MS (m/z): 410 (M−1); Rf 0.23 (90:10:1 methylene chloride/methanol/ammonium hydroxide).

2-Chloro-5-(3-pyrimidin-5-yl-1H-indole-6-carbonyl)-benzenesulfonamide

(156) MS (m/z): 411 (M−1); Rf 0.08 (95:5:0.5 methylene chloride/methanol/ammonium hydroxide).

2-Chloro-5-{3-[4-(morpholine-4-carbonyl)-phenyl]-1H-indole-6-carbonyl}-benzenesulfonamide

(157) MS (m/z): 522 (M−1); Rf 0.12 (95:5 methylene chloride/methanol).

2-Chloro-5-[3-(3,5-dimethyl-isoxazol-4-yl)-1H-indole-6-carbonyl]-benzenesulfonamide

(158) MS (m/z): 428 (M−1); Rf 0.13 (3:1 methylene chloride/diethyl ether).

2-Chloro-5-[3-(5-chloro-2-methoxy-pyridin-4-yl)-1H-indole-6-carbonyl]-benzenesulfonamide

(159) MS (m/z): 474 (M−1); Rf 0.21 (3:1 methylene chloride/diethyl ether).

2-Chloro-5-(3-pyridin-4-yl-1H-indole-6-carbonyl)-benzenesulfonamide

(160) MS (m/z): 410 (M−1); Rf 0.26 (90:10:1 methylene chloride/methanol/ammonium hydroxide).

2-Chloro-5-[3-(2-chloro-pyridin-4-yl)-1H-indole-6-carbonyl]-benzenesulfonamide

(161) MS (m/z): 444 (M−1); Rf 0.08 (95:5:0.5 methylene chloride/methanol/ammonium hydroxide).

Example 46: 2-Chloro-5-[3-(2-methyl-pyridin-4-yl)-1H-indole-6-carbonyl]-benzenesulfonamide

(162) ##STR00057##

(163) To a mixture of 0.1 g of 5-[3-bromo-1-(tert-butyl-dimethyl-silyl)-1H-indole-6-carbonyl]-2-chloro-N-(tert-butyl-dimethyl-silyl)-benzenesulfonamide, 0.095 g of crude (2-methyl-4-pyridinyl)-boronic acid and 0.025 g of 1,1′-bis(diphenylphosphino)-ferrocenedichloropalladium(II)-dichloromethane complex in dimethoxyethane (3.6 mL) is added 0.099 g of tri-potassium phosphate in water (1.2 mL). The solution is heated to 130° C. for 5 minutes (microwave irradiation). The reaction mixture is extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and concentrated to 0.071 g of crude product. Purification via flash chromatography on silica gel (95:5:0.5 methylene chloride/methanol/ammonium hydroxide) afforded 2-chloro-5-[3-(2-methyl-pyridin-4-yl)-1H-indole-6-carbonyl]-benzenesulfonamide as a tan powder. MS (m/z): 424 (M−1); Rf 0.06 (95:5:0.5 methylene chloride/methanol/ammonium hydroxide).

Preparation of (2-methyl-4-pyridinyl)-boronic acid

(164) Step 1:

(165) A suspension of 10 g of 4-bromopyridine hydrochloride in tetrahydrofuran (180 mL) is treated at −78° C. with 48.2 mL of methylmagnesium chloride (3 M in tetrahydrofuran). After 25 min at −78° C. the reaction mixture is treated by slow addition of a solution of 7.69 mL of phenyl chloroformate in tetrahydrofuran (20 mL) resulting in an increase of the reaction temperature to room temperature. The reaction mixture is stirred at room temperature for 10 min and then treated by addition of a saturated aqueous solution of ammonium chloride (84 mL) at 0° C. followed by diethyl ether. The organic phase is washed with water, 2 N aqueous HCl, water and a saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo to 17.1 g of carbamate as an orange oil. This material is taken up in toluene (200 mL) and treated with a solution of 15.64 g of o-chloranil in acetic acid (117 mL). After 26 h at room temperature the resulting solution is treated with 30% aqueous sodium hydroxide. The resulting emulsion is filtered through Celite. Phases are separated and extracted with toluene. The organics are washed with water and extracted with 2 N HCl. Acidic extracts are washed with diethyl ether, treated with 30% aqueous sodium hydroxide at 0° C. and extracted with methylene chloride. The organic extracts are dried (magnesium sulfate), concentrated and purified by silica gel chromatography (1:1 methylene chloride/diethyl ether) to give 4-bromo-2-methyl-pyridine as an oil. MS (m/z): 174 (M+1); Rf 0.31 (1:1 methylene chloride/diethyl ether).

(166) Step 2:

(167) A solution of 4.7 mL of n-butyllithium (1.6 M in hexane) in diethyl ether (20 mL) is cooled to −78° C. and treated with a solution of 1.07 g of 4-bromo-2-methyl-pyridine in diethyl ether (10 mL) previously dried over molecular sieves at 40° C. overnight. After 20 min at −78° C. the resulting orange suspension is treated with 1.87 mL of triisopropylborate and the temperature is allowed to increase to room temperature over a 2 h period. After an additional 2 h the reaction mixture is treated with water. The organic phase is extracted with 0.5 N sodium hydroxide. Extracts are washed with diethyl ether and acidified with 2 N HCl to pH 6.

(168) The resulting suspension is concentrated under vacuum to give a paste containing (2-methyl-4-pyridinyl)-boronic acid which is used without further purification for the Suzuki coupling. MS (m/z): 136 (M−1).

(169) Likewise the following compounds are prepared from 5-[3-bromo-1-(tert-butyl-dimethyl-silyl)-1H-indole-6-carbonyl]-2-chloro-N-(tert-butyl-dimethyl-silyl)-benzenesulfonamide and the corresponding boronic acids

2-Chloro-5-[3-(2-ethyl-pyridin-4-yl)-1H-indole-6-carbonyl]-benzenesulfonamide

(170) MS (m/z): 438 (M−1); Rf 0.10 (95:5:0.5 methylene chloride/methanol/ammonium hydroxide).

Preparation of (2-ethyl-4-pyridinyl)-boronic acid

(171) (2-Ethyl-4-pyridinyl)-boronic acid is prepared from 5 g of 4-bromopyridine hydrochloride according to the procedure described in example 46, step 1 and step 2. MS (m/z): 150 (M−1).

2-Chloro-5-[3-(2-cyclopropyl-pyridin-4-yl)-1H-indole-6-carbonyl]-benzenesulfonamide

(172) MS (m/z): 450 (M−1); Rf 0.13 (95:5:0.5 methylene chloride/methanol/ammonium hydroxide).

(2-cyclopropyl-4-pyridinyl)-boronic acid

(173) (2-Cyclopropyl-4-pyridinyl)-boronic acid is prepared from 5 g of 4-bromopyridine hydrochloride according to the procedure described in example 46, step 1 and step 2. MS (m/z): 162 (M−1).

2-Chloro-5-{3-[2-(3-methoxy-propyl)-pyridin-4-yl]-1H-indole-6-carbonyl}-benzenesulfonamide

(174) MS (m/z): 482 (M−1); Rf 0.07 (95:5:0.5 methylene chloride/methanol/ammonium hydroxide).

[2-(3-methoxy-propyl)-4-pyridinyl]-boronic acid

(175) [2-(3-Methoxy-propyl)-4-pyridinyl]-boronic acid is prepared from 1.35 g of 4-bromopyridine hydrochloride according to the procedure described in example 46, step 1 and step 2. MS (m/z): 196 (M+1).

2-Chloro-5-{3-[2-(3-morpholin-4-yl-propyl)-pyridin-4-yl]-1H-indole-6-carbonyl}-benzenesulfonamide

(176) MS (m/z): 539 (M+1); Rf 0.15 (90:10:1 ethyl acetate/methanol/ammonium hydroxide).

[2-(3-morpholin-4-yl-propyl)-4-pyridinyl]-boronic acid

(177) [2-(3-morpholin-4-yl-propyl)-4-pyridinyl]-boronic acid is prepared from 5.36 g of 4-bromopyridine hydrochloride according to the procedure described in example 46, step 1 and step 2. MS (m/z): 251 (M+1).

2-Chloro-5-{3-[2-(2-dimethylamino-ethoxy)-pyridin-4-yl]-1H-indole-6-carbonyl}-benzenesulfonamide

(178) MS (m/z): 497 (M−1); Rf 0.2 (90:10:1 ethyl acetate/methanol/ammonium hydroxide).

Example 47: Preparation of [2-(2-dimethylamino-ethoxy)-4-pyridinyl]-boronic acid

(179) Step 1:

(180) A mixture of 5.55 g of sodium and 26.9 mL of 2-dimethylaminoethanol in tetrahydrofuran (180 mL) is heated to reflux for 20 hours. The reaction mixture is cooled to room temperature, treated with 4 g of 4-amino-2-chloropyridine and heated to 140° C. for 20 min (microwave irradiation). The reaction mixture is treated with concentrated HCl to pH 8 at 0° C., saturated with sodium chloride and extracted with diethyl ether. The organics are dried (magnesium sulfate) and concentrated to 11.9 g of crude product which is purified by silica gel chromatography (90:10:1 ethyl acetate/methanol/ammonium hydroxide) to give 2-(2-dimethylamino-ethoxy)-pyridin-4-ylamine as tan crystals. MS (m/z): 182 (M+1); Rf 0.1 (90:10:1 ethyl acetate/methanol/ammonium hydroxide).

(181) Step 2:

(182) A mixture of 1.2 g of 2-(2-dimethylamino-ethoxy)-pyridin-4-ylamine, 0.749 g of sodium bromide and 1.16 g of copper sulfate is cooled to 0° C. and treated with 12 mL of 9 M sulfuric acid with stirring. The resulting dark suspension is treated at 0° C. with a solution of 0.503 g of sodium nitrite in water (0.8 mL) and stirred at 0° C. for 1.5 h and at room temperature for 1.5 h. The reaction mixture is pored onto ice-water, brought to basic pH with 30% sodium hydroxide, and extracted with methylene chloride. The organics are dried (magnesium sulfate), concentrated and purified by silica gel chromatography (7:3 ethyl acetate/methanol) to give [2-(4-bromo-pyridin-2-yloxy)-ethyl]-dimethyl-amine as an oil. MS (m/z): 245 (M+1); Rf 0.25 (7:3 ethyl acetate/methanol).

(183) Step 3:

(184) [2-(2-Dimethylamino-ethoxy)-4-pyridinyl]-boronic acid is prepared from 0.713 g of [2-(4-bromo-pyridin-2-yloxy)-ethyl]-dimethyl-amine according to the procedure described in Example 6 step 2. MS (m/z): 211 (M+1).

(185) The following compound can be prepared with similar steps.

2-Chloro-5-{3-[2-(2-morpholin-4-yl-ethoxy)-pyridin-4-yl]-1H-indole-6-carbonyl}-benzenesulfonamide

(186) MS (m/z): 539 (M−1); Rf 0.38 (90:10:1 ethyl acetate/methanol/ammonium hydroxide).

Preparation of [2-(2-morpholin-4-yl-ethoxy)-4-pyridinyl]-boronic acid

(187) [2-(2-Morpholin-4-yl-ethoxy)-4-pyridinyl]-boronic acid is prepared from N-(2-hydroxyethyl)-morpholine according to the procedure described for the preparation of [2-(2-dimethylamino-ethoxy)-4-pyridinyl]-boronic acid. MS (m/z): 253 (M+1).

Example 48: 2-Methyl-5-[3-(2-methyl-pyridin-4-yl)-1H-indole-6-carbonyl]-benzenesulfonamide

(188) ##STR00058##

(189) 2-Methyl-5-[3-(2-methyl-pyridin-4-yl)-1H-indole-6-carbonyl]-benzenesulfonamide is prepared from 0.25 g of 5-[3-bromo-1-(tert-butyl-dimethyl-silyl)-1H-indole-6-carbonyl]-N-(tert-butyl-dimethyl-silyl)-2-methyl-benzenesulfonamide according to the procedure described in Example 6 (microwave irradiation at 150° C. for 5 min). MS (m/z): 404 (M−1); Rf 0.19 (90:10:1 methylene chloride/methanol/ammonium hydroxide).

Preparation of 5-[3-bromo-1-(tert-butyl-dimethyl-silyl)-1H-indole-6-carbonyl]-N-(tert-butyl-dimethyl-silyl)-2-methyl-benzenesulfonamide

(190) Step 1:

(191) 5-[1-(tert-Butyldimethylsilyl)-1H-indole-6-carbonyl]-N-(tert-butyldimethylsilyl)-2-methyl-benzenesulfonamide is prepared from 3.09 g of 5-(1H-indole-6-carbonyl)-2-methyl-benzenesulfonamide according to the procedure described in Example 5, step 1. MS (m/z): 543 (M+1); Rf 0.75 (2:1 hexanes/ethyl acetate).

(192) Step 2:

(193) 5-[3-Bromo-1-(tert-butyldimethylsilyl)-1H-indole-6-carbonyl]-N-(tert-butyldimethylsilyl)-2-methyl-benzenesulfonamide is prepared from 3.21 g of 5-[1-(tert-butyldimethylsilyl)-1H-indole-6-carbonyl]-N-(tert-butyldimethylsilyl)-2-methyl-benzenesulfonamide according to the procedure described in Example 5, step 2. MS (m/z): 622 (M+1); Rf 0.77 (95:5 methylene chloride/methanol).

Example 49: 3-[3-(2-Methyl-pyridin-4-yl)-1H-indole-6-carbonyl]-benzenesulfonamide

(194) ##STR00059##

(195) 3-[3-(2-Methyl-pyridin-4-yl)-1H-indole-6-carbonyl]-benzenesulfonamide is prepared from 0.25 g of 5-[3-bromo-1-(tert-butyl-dimethyl-silyl)-1H-indole-6-carbonyl]-N-(tert-butyl-dimethyl-silyl)-benzenesulfonamide according to the procedure described in Example 6 (microwave irradiation at 150° C. for 5 min). MS (m/z): 390 (M−1); Rf 0.19 (90:10:1 methylene chloride/methanol/ammonium hydroxide)

Preparation of 5-[3-bromo-1-(tert-butyl-dimethyl-silyl)-1H-indole-6-carbonyl]-N-(tert-butyl-dimethyl-silyl)-benzenesulfonamide

(196) Step 1:

(197) 5-[1-(tert-Butyldimethylsilyl)-1H-indole-6-carbonyl]-N-(tert-butyldimethylsilyl)-benzenesulfonamide is prepared from 1.857 g of 3-(1H-indole-6-carbonyl)-benzenesulfonamide according to the procedure described in example 45, step 1. MS (m/z): 529 (M+1); Rf 0.66 (2:1 hexanes/ethyl acetate).

(198) Step 2:

(199) 5-[3-Bromo-1-(tert-butyldimethylsilyl)-1H-indole-6-carbonyl]-N-(tert-butyldimethylsilyl)-benzenesulfonamide is prepared from 1.14 g of 5-[1-(tert-butyldimethylsilyl)-1H-indole-6-carbonyl]-N-(tert-butyldimethylsilyl)-benzenesulfonamide according to the procedure described in example 45, step 2. MS (m/z): 607 (M+1); Rf 0.78 (95:5 methylene chloride/methanol).

(200) Likewise the following compounds are prepared from 5-[3-bromo-1-(tert-butyl-dimethyl-silyl)-1H-indole-6-carbonyl]-N-(tert-butyl-dimethyl-silyl)-benzenesulfonamide and the corresponding boronic acids.

3-{3-[2-(3-Methoxy-propyl)-pyridin-4-yl]-1H-indole-6-carbonyl}-benzenesulfonamide

(201) MS (m/z): 450 (M+1); Rf 0.22 (90:10:1 methylene chloride/methanol/ammonium hydroxide).

3-{3-[2-(3-Methoxy-propyl)-pyridin-4-yl]-1H-indole-6-carbonyl}-benzenesulfonamide

(202) MS (m/z): 505 (M+1); Rf 0.10 (90:10:1 methylene chloride/methanol/ammonium hydroxide).

Example 50

(203) The following compounds were prepared following method A using aluminum trichloride or other suitable aluminum reagents and the appropriate substituted phenyl moiety as illustrated by the following procedure.

5-Benzoyl-2-chloro-benzenesulfonamide

(204) To a well stirred solution of 4-chloro-3-sulfamoyl-benzoyl chloride (0.5 g, 1.97 mmol) in 5 mL methylene chloride is added aluminum chloride (0.485 g, 1.85 mmol). After 30 min, benzene (1 mL, 5.72 mmol) is added and the reaction is stirred for 2 h at room temperature. The reaction mixture is then poured over ice, acidified with 6 N HCl and extracted three times with diethyl ether. The organic layers were combined, dried with magnesium sulfate, filtered and concentrated in vacuo. The resulting residue is purified via silica gel chromatography to yield 40 mg (69%) of the title compound as a tan solid. MS (m/z): 294 (M−1). Analytics calculated for C.sub.13H.sub.10ClNO.sub.3S: C, 52.8; H, 3.41; N, 4.74. Found: C, 52.62; H, 3.21; N, 4.72.

2-Chloro-5-(4′-ethyl-biphenyl-4-carbonyl)-benzenesulfonamide

(205) ##STR00060##

(206) MS (m/z): 310 (M−1). Analytics calculated for C.sub.13H.sub.10ClNO.sub.4S: C, 50.09; H, 3.23; N, 4.49. Found: C, 49.91; H, 3.18; N, 4.44.

2-Chloro-5-(4′-allyloxy-benzoyl)-benzenesulfonamide

(207) ##STR00061##

(208) MS (M−1) 350.

5-(4-Bromo-benzoyl)-2-chloro-benzenesulfonamide

(209) ##STR00062##

(210) MS (m/z): 448 (M−1). Analytics calculated for C.sub.13H.sub.9BrClNO.sub.3S: C, 41.68; H, 2.42; N, 3.74. Found: C, 41.69; H, 1.99; N, 3.56.

5-(4-tert-Butyl-benzoyl)-2-chloro-benzenesulfonamide

(211) ##STR00063##

(212) MS (m/z): 352 (M+1).

2-Chloro-5-(4-cyclopropyl-benzoyl)-benzenesulfonamide

(213) ##STR00064##

(214) MS (m/z): 334 (M−1). Analytics calculated for C.sub.16H.sub.14ClNO.sub.3S: C, 57.23; H, 4.2; N, 4.17. Found: C, 56.69; H, 4.13; N, 4.01.

2-Chloro-5-(4-cyclopentyl-benzoyl)-benzenesulfonamide

(215) ##STR00065##

(216) MS (m/z): 364 (M+1). Analytics calculated for C.sub.18H.sub.18ClNO.sub.3S: C, 59.42; H, 4.99; N, 3.85. Found: C, 59.28; H, 4.76; N, 3.83.

2-Chloro-5-(4-cyclohexyl-benzoyl)-benzenesulfonamide

(217) ##STR00066##

(218) .sup.1H NMR (400 MHz, DMSO): δ 1.3-1.8 (m, 10H), 2.6-2.7 (br, 1H), 7.4 (d, 2H, J=8 Hz), 7.70 (d, 2H, J=8 Hz), 7.80 (m, 3H), 7.88-7.92 (m, 1H), 8.28 (d, 1H, J=2 Hz). MS (m/z): 376 (M−1). Analytics calculated for C.sub.19H.sub.20ClNO.sub.3S: C, 60.39; H, 5.33; N, 3.71. Found: C, 60.53; H, 5.08; N, 3.46.

2-Chloro-5-(4-cyano-benzoyl)-benzenesulfonamide

(219) ##STR00067##

(220) .sup.1H NMR (400 MHz, CDCl.sub.3): δ5.3 (br, 2H), 7.75 (d, 1H, J=8 Hz), 7.8-7.9 (m, 41), 7.97 (m, 1H), 8.45 (d, 1H, J=2 Hz). MS (m/z): 319 (M−1).

5-(2-Bromo-4-methyl-benzoyl)-2-chloro-benzenesulfonamide

(221) ##STR00068##

(222) MS (m/z): 386 (M−1). Analytics calculated for C.sub.14H.sub.11BrClNO.sub.3S: C, 43.26; H, 2.85; N, 3.6. Found: C, 43.19; H, 2.83; N, 3.60.

5-(4-Bromo-2-methyl-benzoyl)-2-chloro-benzenesulfonamide

(223) ##STR00069##

(224) MS (m/z): 386 (M−1). Analytics calculated for C.sub.14H.sub.11BrClNO.sub.3S: C, 43.26; H, 2.85; N, 3.6. Found: C, 43.07; H, 2.86; N, 3.60.

2-Chloro-5-(2-fluoro-4-methoxy-benzoyl)-benzenesulfonamide

(225) ##STR00070##

2-Chloro-5-(3-fluoro-4-hydroxy-benzoyl)-benzenesulfonamide

(226) ##STR00071##

(227) MS (m/z): 330 (M+1). Analytics calculated for C.sub.13H.sub.9ClFNO.sub.4S: C, 47.35; H, 2.75; N, 4.25. Found: C, 47.47; H, 2.67; N, 4.07. M.P. 206-208° C.

2-Chloro-5-(2,4-dimethoxy-benzoyl)-benzenesulfonamide

(228) ##STR00072##

(229) MS (m/z): 356 (M+1). Analytics calculated for C.sub.15H.sub.14ClNO.sub.5S: C, 50.64; H, 3.97; N, 3.94. Found: C, 50.49; H, 3.72; N, 3.91.

2-Chloro-5-(2-fluoro-4-hydroxy-benzoyl)-benzenesulfonamide

(230) ##STR00073##

(231) MS (m/z): 330 (M+1). Analytics calculated for C.sub.13H.sub.9ClFNO.sub.4S: C, 47.35; H, 2.75; N, 4.25. Found: C, 47.36; H, 2.65; N, 3.99. M.P. 183-185° C.

5-(Biphenyl-4-carbonyl)-2-chloro-benzenesulfonamide

(232) ##STR00074##

2-Chloro-5-(4′-methyl-biphenyl-4-carbonyl)-benzenesulfonamide

(233) ##STR00075##

(234) MS (m/z): 384 (M−1). Analytics calculated for C.sub.20H.sub.16ClNO.sub.3S: C, 62.25; H, 4.18; N, 3.63. Found: C, 61.92; H, 3.91; N, 3.54.

2-Chloro-5-(2′-fluoro-biphenyl-4-carbonyl)-benzenesulfonamide

(235) ##STR00076##

(236) MS (m/z): 388 (M−1). Analytics calculated for C.sub.19H.sub.13ClNO.sub.3S: C, 58.54; H, 3.36; N, 3.59. Found: C, 58.31; H, 3.50; N, 3.52.

2-Chloro-5-(4′-fluoro-biphenyl-4-carbonyl)-benzenesulfonamide

(237) ##STR00077##

(238) MS (m/z): 388 (M−1). Analytics calculated for C.sub.19H.sub.13ClNO.sub.3S: C, 58.54; H, 3.36; N, 3.59. Found: C, 57.7; H, 3.23; N, 3.46.

2-Chloro-5-(4′-chloro-biphenyl-4-carbonyl)-benzenesulfonamide

(239) ##STR00078##

(240) MS (m/z): 405 (M−1). Analytics calculated for C.sub.19H.sub.13Cl.sub.2NO.sub.3S: C, 56.17; H, 3.22; N, 3.45. Found: C, 55.99; H, 2.92; N, 3.41.

5-(3′-Bromo-biphenyl-4-carbonyl)-2-chloro-benzenesulfonamide

(241) ##STR00079##

(242) MS (m/z): 448 (M−1). Analytics calculated for C.sub.19H.sub.13BrClNO.sub.3S: C, 50.63; H, 2.91; N, 3.11. Found: C, 50.58; H, 2.89; N, 2.86.

5-(4-Azepan-1-yl-benzoyl)-2-chloro-benzenesulfonamide

(243) ##STR00080##

(244) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 1.57 (br, 4H), 1.80 (br, 4H), 3.55 (t, 4H, J=4 Hz), 5.18 (s, 2H), 6.90 (d, 2H, J=8 Hz), 7.66 (d, 1H, J=8 Hz), 7.70 (d, 2H, J=8 Hz), 7.88 (d, 1H, J=8 Hz), 8.43 (s, 1H). MS (m/z): 393 (M+1). Analytics calculated for C.sub.19H.sub.21ClN2O.sub.3S: C, 58.08; H, 5.39; N, 7.13. Found: C, 58.10; H, 5.21; N, 6.89.

2-Chloro-5-(naphthalene-2-carbonyl)-benzenesulfonamide

(245) ##STR00081##

(246) MS (m/z): (M−1) 344.

2-Chloro-5-(2,3-dihydro-1H-indole-5-carbonyl)-benzenesulfonamide

(247) ##STR00082##

(248) MS (m/z): 335 (M−1). Analytics calculated for C.sub.15H.sub.13ClN2O.sub.3S: C, 53.49; H, 3.89; N, 8.32. Found: C, 53.50; H, 4.08; N, 7.34. M.P. 55-56.

2-Chloro-5-(1H-indole-3-carbonyl)-benzenesulfonamide

(249) ##STR00083##

(250) MS (m/z): 333 (M−1). Analytics calculated for C.sub.15H.sub.11ClN2O.sub.3S: C, 53.82; H, 3.31; N, 8.37. Found: C, 53.84; H, 3.22; N, 8.31.

Example 51

(251) The following analogs were prepared by method B unless otherwise noted.

2-Chloro-5-(3-methyl-benzoyl)-benzenesulfonamide

(252) ##STR00084##

(253) MS (m/z): 308 (M−1). Analytics calculated for C.sub.14H.sub.12ClNO.sub.3S: C, 54.28; H, 3.9; N, 4.52. Found: C, 54.31; H, 3.67; N, 4.41.

2-Chloro-5-(4-trimethylsilanylethynyl-benzoyl)-benzenesulfonamide

(254) ##STR00085##

(255) MS (m/z): 390 (M−1). Analytics calculated for C.sub.18H.sub.18ClNO.sub.3SSi: C, 55.16; H, 4.63; N, 3.57. Found: C, 55.11; H, 4.43; N, 3.44. M.P. 206-208° C.

2-Chloro-5-(4-pyrrol-1-yl-benzoyl)-benzenesulfonamide

(256) ##STR00086##

(257) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 5.18 (s, 2H), 6.40 (t, 2H), 7.15 (t, 2H), 7.50 (d, 2H, J=8 Hz), 7.7 (d, 1H, J=8 Hz), 7.87 (d, 2H, J=8 Hz), 7.98 (dd, 1H), 8.50 (d, 1H, J=2 Hz). MS (m/z): 359 (M−1). Analytics calculated for C.sub.17H.sub.13ClN.sub.2O.sub.3S: C, 56.59; H, 3.63; N, 7.76. Found: C, 56.64; H, 3.85; N, 7.36.

2-Chloro-5-(1H-indole-5-carbonyl)-benzenesulfonamide

(258) ##STR00087##

(259) MS (m/z): 335 (M+1). Analytics calculated for C.sub.15H.sub.11ClN.sub.2O.sub.3S: C, 53.82; H, 3.31; N, 8.37. Found: C, 52.39; H, 3.04; N, 7.64. M.P. 65-66° C.

Example 52

(260) The following analogs were prepared by Method C unless otherwise noted.

5-(4-Butyl-benzoyl)-2-chloro-benzenesulfonamide

(261) ##STR00088##

(262) MS (m/z): 350 (M−1). Analytics calculated for C.sub.17H.sub.18ClNO.sub.3S: C, 58.03; H, 5.16; N, 3.98. Found: C, 58.06; H, 4.86; N, 3.73.

2-Chloro-5-(4-diethylamino-benzoyl)-benzenesulfonamide

(263) ##STR00089##

(264) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 1.25 (t, 6H, J=2 Hz), 3.45 (q, 4H, J=2 Hz, J=1 Hz), 5.17 (s, 2H), 6.65 (d, 2H, J=8 Hz), 7.64 (d, 1H, J=8 Hz), 7.72 (d, 2H, J=8 Hz), 7.86 (d, 1H, J=8 Hz), 8.41 (s, 1H). MS (m/z): 367 (M+1).

2-Chloro-5-(4-diallylamino-benzoyl)-benzenesulfonamide

(265) ##STR00090##

(266) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 4.02 (br, 4H), 5.20 (m, 6H), 5.85 (m, 2H), 6.7 (d, 2H, J=9 Hz), 7.6-7.7 (m, 3H), 7.85 (dd, 1H, J=2 Hz), 8.4 (d, 1H, J=2 Hz). MS (m/z): 391 (M+1)

5-[4-(4-Benzyl-piperidin-1-yl)-benzoyl]-2-chloro-benzenesulfonamide

(267) HPLC Reverse Phase (Nucleosil 100-5 C18, gradient 10.fwdarw.100% CH.sub.3CN in 5 min) room temperature=5.55 minutes. MS (m/z): 470 (M+1).

2-Chloro-5-(4-morpholin-4-yl-benzoyl)-benzenesulfonamide

(268) ##STR00091##

(269) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 3.36 (t, 4H, J=4 Hz), 3.87 (t, 4H, J=4 Hz), 5.18 (s, 2H), 6.90 (d, 2H, J=8 Hz), 7.66 (d, 1H, J=8 Hz), 7.75 (d, 2H, J=8 Hz), 7.90 (d, 1H, J=8 Hz), 8.43 (s, 1H). MS (m/z): 381 (M+1).

2-Chloro-5-[4-(2-oxo-azetidin-1-yl)-benzoyl]-benzenesulfonamide

(270) HPLC Reverse Phase (Nucleosil 100-5 C18, gradient 10.fwdarw.100% CH.sub.3CN in 5 min) room temperature=5.17 minutes. MS (m/z): 365 (M+1).

Preparation of 4-benzyl-1-(4-bromo-phenyl)-piperidine

(271) A mixture of 1-bromo-4-iodo benzene (0.500 g), 4-benzylpiperidine (0.25 mL), sodium-tert-butylate (0.238 g), tris(dibenzylideneacetone)dipalladium (0.016 g) and 2,2′-bis/diphenylphosphino)-1,1′-binapthyl racemate (0.018 g) is dissolved in tetrahydrofuran and stirred at room temperature overnight. The reaction mixture is concentrated and the resulting residue is loaded on Celite and purified by silica gel chromatography (4:1 hexanes/ethyl acetate) to give 4-benzyl-1-(4-bromo-phenyl)-piperidine as a light yellow syrup. MS (m/z): 331 (M+1).

5-(3H-Benzoimidazole-5-carbonyl)-2-chloro-benzenesulfonamide

(272) The title compound is prepared by analogous methods starting from 6-bromo-1H-benzoimidazole. MS (m/z): (M−1) 334; Rf 0.17 (9:1 methylene chloride/methanol).

2-Chloro-5-(1-methyl-1H-indole-5-carbonyl)-benzenesulfonamide

(273) ##STR00092##

(274) MS (m/z): 347 (M−1). Analytics calculated for C.sub.16H.sub.13ClN.sub.2O.sub.3S: C, 55.09; H, 3.76; N, 10.16. Found: C, 54.85; H, 3.58; N, 7.65.

2-Chloro-5-[1-(3-methyl-butyl)-1H-indole-5-carbonyl]-benzenesulfonamide

(275) ##STR00093##

(276) MS (m/z): 403 (M−1). Analytics calculated for C.sub.20H.sub.21ClN.sub.2O.sub.3S: C, 59.33; H, 5.23; N, 8.76. Found: C, 59.04; H, 5.10; N, 6.91.

Typical Procedure for the Formation of 4-(4-chloro-3-sulfamoyl-benzoyl)-N-alkyl-benzamides

4-(4-Chloro-3-sulfamoyl-benzoyl)-benzoic acid

(277) ##STR00094##

(278) A mixture of 500 mg of 2-chloro-5-(4-methyl-benzoyl)-benzenesulfonamide (1.61 mmol, 1 equivalent) in pyridine/water (80/20 mL) is refluxed as 5 g of potassium permanganate is added in portions. After the additions are completed, the reaction is refluxed for 3 h. The reaction is cooled to room temperature, filtered and the filtrate is concentrated in vacuo. The residue is acidified with 1 N HCl, extracted with ethyl acetate and the combined organic extracts are washed with a saturated sodium chloride solution, dried over sodium sulfate, and concentrated in vacuo to give 450 mg of the title compound as white solid. MS (m/z): 338 (M−1).

Example 53: 4-(4-Chloro-3-sulfamoyl-benzoyl)-N-propyl-benzamide

(279) ##STR00095##

(280) A suspension of 1.2 g of 4-(4-chloro-3-sulfamoyl-benzoyl)-benzoic acid (3.54 mmol, 1 equivalent) in 20 mL of dichloromethane is stirred at room temperature as 898 mg of oxalyl chloride (7.08 mmol, 2 equivalents) is added drop-wise followed by the addition of 2 drops of N,N,-dimethylformamide. The reaction mixture is stirred at room temperature for 2 h and then concentrated in vacuo. The resulting acid chloride is used directly in the next step reaction without further purification.

(281) To a stirred solution of 200 mg of acid chloride (0.56 mmol, 1 equivalent) in 10 mL of dichloromethane is added 132 mg of propylamine. The reaction is stirred at room temperature for 18 h. The reaction is acidified with 1 N HCl and extracted with dichloromethane. The combined organic extracts are dried over sodium sulfate and concentrated in vacuo. After purification by flash chromatography, 120 mg of product is obtained as white crystals (yield 56%). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 1.0 (t, 3H, J=7 Hz), 1.7 (q, 2H, J=7 Hz), 3.4 (t, 2H, J=2 Hz), 7.75-8.43 (m, 7H). MS (m/z): 387 (M+1). Analytics calculated for C.sub.17H.sub.17ClN.sub.2O.sub.4S: C, 53.61; H, 4.50; N, 7.36. Found: C, 53.28; H, 4.42; N, 7.34.

(282) The following compounds were prepared in an analogous manner.

4-(4-Chloro-3-sulfamoyl-benzoyl)-N-phenyl-benzamide

(283) ##STR00096##

(284) .sup.1H NMR (400 MHz, DMSO): δ 7.10 (t, 1H, J=8 Hz), 7.35 (t, 2H, J=8 Hz), 7.75-7.98 (m, 6H), 8.08 (d, 2H, J=8 Hz), 8.31 (d, 1H, J=2 Hz). MS (m/z): 415 (M+1). Analytics calculated for C.sub.21H.sub.17ClN.sub.2O.sub.4S: C, 57.90; H, 3.64; N, 6.75. Found: C, 57.89; H, 3.42; N, 6.63.

N-Benzyl-4-(4-chloro-3-sulfamoyl-benzoyl)-benzamide

(285) ##STR00097##

(286) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 4.61 (br, 2H), 7.2-7.4 (m, 5H), 7.75-8.05 (m, 4H), 8.42 (m, 1H). MS (m/z): 427 (M−1). Analytics calculated for C.sub.21H.sub.17ClN.sub.2O.sub.4S: C, 58.81; H, 4.00; N, 6.53. Found: C, 58.53; H, 4.02; N, 6.43.

4-(4-Chloro-3-sulfamoyl-benzoyl)-N-(4-phenyl-butyl)-benzamide

(287) ##STR00098##

(288) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 1.70 (m, 4H), 2.75 (t, 2H, J=6.5 Hz), 3.55 (t, 2H), 5.27 (s, 2H), 6.22 (s, 1H), 7.15 (m 4H), 7.70-7.89 (m, 7H). MS (m/z): 471 (M+1). Analytics calculated for C.sub.24H.sub.23ClN.sub.2O.sub.4S: C, 61.21; H, 4.92; N, 5.95. Found: C, 61.53; H, 5.28; N, 5.91.

N-tert-Butyl-4-(4-chloro-3-sulfamoyl-benzoyl)-benzamide

(289) ##STR00099##

(290) .sup.1H NMR (400 MHz, MeOD): δ 1.48 (s, 9H), 7.75-7.98 (m, 6H), 8.42 (d, 1H, J=2 Hz). MS (m/z): 395 (M+1).

2-Chloro-5-[4-(pyrrolidine-1-carbonyl)-benzoyl]-benzenesulfonamide

(291) ##STR00100##

(292) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 1.88-2.05 (m, 4H), 3.40 (t, 2H, J=6.5 Hz), 3.55 (br, 1H), 3.65 (t, 2H, J=6.5 Hz), 5.31 (s, 2H), 7.58-7.99 (m, 6H), 8.48 (d, 1H, J=2 Hz). MS (m/z): 393 (M+1). Analytics calculated for C.sub.18H.sub.17ClN.sub.2O.sub.4S: C, 55.03; H, 4.36; N, 7.13. Found: C, 55.24; H, 4.29; N, 7.45.

4-(4-Chloro-3-sulfamoyl-benzoyl)-N-phenethyl-benzamide

(293) ##STR00101##

(294) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 3.00 (t, 2H), 3.83 (t, 2H), 5.22 (s, 2H), 6.27 (br, 11H), 7.2-7.35 (m, 5H), 7.72-8.0 (m, 6H), 8.45 (s, 1H). MS (m/z): 443 (M+1). Analytics calculated for C.sub.22H.sub.19ClN2O.sub.4S: C, 59.66; H, 4.32; N, 6.32. Found: C, 60.00; H, 4.71; N, 6.13.

Typical Procedure for Suzuki Couplings of 5-(4-bromo-benzoyl)-2-chloro-benzenesulfonamide

2-Chloro-5-(3′-nitro-biphenyl-4-carbonyl)-benzenesulfonamide

(295) ##STR00102##

(296) A mixture of 220 mg of 5-(4-bromo-benzoyl)-2-chloro-benzenesulfonamide (0.587 mmol, 1 equivalent), 196 mg of 3-nitrobenzene boronic acid (1.174 mmol, 2 equivalent), 556 mg of Ba(OH).sub.2 (1.761 mmol, 3 equivalent), and 14 mg of Pd(PPh.sub.3).sub.4 in degassed dioxane/water (30 mL/10 mL) is refluxed for 18 h. The reaction is quenched with 1 N HCl and extracted with ethyl acetate. The combined organic extracts are dried over sodium sulfate, and concentrated in vacuo. After purification by flash chromatography, 50 mg of the title compound is obtained as white solid. .sup.1H NMR (400 MHz, CDCl.sub.3): δ 5.2 (br, 2H), 6.18 (br, 1H), 7.02 (d, 2H, J=8 Hz), 7.12-7.45 (m, 5H), 7.6-7.8 (m, 3H), 7.90 (dd, 1H), 8.41 (s, 1H). MS (m/z): 387 (M+1).

(297) The following compounds were made by analogous procedures

2-Chloro-5-(4-naphthalen-2-yl-benzoyl)-benzenesulfonamide

(298) ##STR00103##

(299) MS (m/z): 420 (M−1). Analytics calculated for C.sub.23H.sub.16ClNO.sub.3S: C, 65.48; H, 3.82; N, 3.32. Found: C, 65.19; H, 3.97; N, 3.19. M.P. 193-195° C.

2-Chloro-5-(4-thiophen-2-yl-benzoyl)-benzenesulfonamide

(300) ##STR00104##

(301) MS (m/z): 376 (M−1). M.P. 146-148° C.

2-Chloro-5-(4-thiophen-3-yl-benzoyl)-benzenesulfonamide

(302) ##STR00105##

(303) MS (m/z): 376 (M−1).sup.−. Analytics calculated for C.sub.17H.sub.12ClN.sub.3S.sub.2: C, 54.04; H, 3.2; N, 3.71. Found: C, 54.12; H, 3.09; N, 3.52.

2-Chloro-5-(4-pyridin-3-yl-benzoyl)-benzenesulfonamide

(304) ##STR00106##

(305) MS (m/z): 371 (M−1). Analytics calculated for C.sub.18H.sub.13ClN2O.sub.3S: C, 57.99; H, 3.51; N, 7.51. Found: C, 58.41; H, 3.49; N, 7.07. M.P. 190-192° C.

2-Chloro-5-(4-pyridin-4-yl-benzoyl)-benzenesulfonamide

(306) ##STR00107##

(307) MS (m/z): 371 (M−1).

2-Chloro-5-[4-(2-chloro-pyridin-4-yl)-benzoyl]-benzenesulfonamide

(308) ##STR00108##

(309) MS (m/z): 406 (M−1). Analytics calculated for C.sub.18H.sub.12Cl.sub.2N2O.sub.3S: C, 53.08; H, 2.97; N, 6.88. Found: C, 52.72; H, 3.10; N, 6.97. M.P. 218-220° C.

2-Chloro-5-(3′-methyl-biphenyl-4-carbonyl)-benzenesulfonamide

(310) ##STR00109##

(311) MS (m/z): 384 (M−1). Analytics calculated for C.sub.20H.sub.16ClNO.sub.3S: C, 62.25; H, 4.18; N, 3.63. Found: C, 62.28; H, 3.98; N, 3.45. M.P. 176-178° C.

2-Chloro-5-(4′-trifluoromethyl-biphenyl-4-carbonyl)-benzenesulfonamide

(312) ##STR00110##

(313) MS (m/z): 438 (M−1). Analytics calculated for C.sub.20H.sub.13ClF.sub.3NO.sub.3S: C, 54.62; H, 2.98; N, 3.18. Found: C, 54.63; H, 2.56; N, 3.00. M.P. 117-119° C.

2-Chloro-5-(4′-ethyl-biphenyl-4-carbonyl)-benzenesulfonamide

(314) ##STR00111##

(315) MS (m/z): 398 (M−1). Analytics calculated for C.sub.21H.sub.18ClNO.sub.3S: C, 63.07; H, 4.54; N, 3.5. Found: C, 63.14; H, 4.35; N, 3.42.

5-(3′-Amino-biphenyl-4-carbonyl)-2-chloro-benzenesulfonamide

(316) ##STR00112##

(317) MS (m/z): 385 (M−1). Analytics calculated for C.sub.19H.sub.15ClN2O.sub.3S: C, 58.99; H, 3.91; N, 7.24. Found: C, 59.30; H, 3.78; N, 7.33. M.P. 228-230° C.

N-[4′-(4-Chloro-3-sulfamoyl-benzoyl)-biphenyl-3-yl]-acetamide

(318) ##STR00113##

(319) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 2.23 (s, 3H), 5.2 (s, 2H), 7.38-8.0 (m, 10H), 8.5 (s, 1H). MS (m/z): 429 (M+1). Analytics calculated for C.sub.21H.sub.17ClN.sub.2O.sub.4S: C, 58.81; H, 4.00; N, 6.53. Found: C, 58.99; H, 3.90; N, 6.19.

2-Chloro-5-(3′-hydroxymethyl-biphenyl-4-carbonyl)-benzenesulfonic acid

(320) ##STR00114##

(321) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 4.81 (s, 2H), 5.17 (s, 2H), 7.40-7.90 (m, 9H), 8.01 (d, 1H, J=8 Hz), 8.53 (s, 1H). MS (m/z): 400 (M−1).

2-Chloro-5-(4′-formyl-biphenyl-4-carbonyl)-benzenesulfonamide

(322) ##STR00115##

(323) MS (m/z): 398 (M−1).

4′-(4-Chloro-3-sulfamoyl-benzoyl)-biphenyl-4-carboxylic acid

(324) ##STR00116##

(325) MS (m/z): 414 (M−1). Analytics calculated for C.sub.20H.sub.14ClNO.sub.5S: C, 57.76; H, 3.39; N, 3.37. Found: C, 57.45; H, 3.05; N, 3.25.

4′-(4-Chloro-3-sulfamoyl-benzoyl)-biphenyl-4-carboxylic acid methyl ester

(326) ##STR00117##

(327) MS (m/z): 428 (M−1). Analytics calculated for C.sub.21H.sub.16ClNO.sub.5S.sub.2: C, 58.67; H, 3.75; N, 3.26. Found: C, 58.29; H, 3.72; N, 3.20.

5-(3′-Benzyloxy-biphenyl-4-carbonyl)-2-chloro-benzenesulfonamide

(328) ##STR00118##

(329) MS (m/z): 476 (M−1).

2-Chloro-5-(2′-methyl-biphenyl-4-carbonyl)-benzenesulfonamide

(330) ##STR00119##

(331) MS (m/z): 384 (M−1). Analytics calculated for C.sub.20H.sub.16ClNO.sub.3S: C, 62.25; H, 4.18; N, 3.63. Found: C, 62.64; H, 4.18; N, 3.63. M.P. 98-100° C.

2-Chloro-5-(3′-trifluoromethyl-biphenyl-4-carbonyl)-benzenesulfonamide

(332) ##STR00120##

(333) MS (m/z): 438 (M−1). Analytics calculated for C.sub.20H.sub.13ClF.sub.3NO.sub.3S: C, 54.62; H, 2.98; N, 3.18. Found: C, 55.27; H, 2.97; N, 2.84. M.P. 75-77° C.

(334) The following two examples were also synthesized via palladium mediated cross coupling.

2-Chloro-5-(4-ethynyl-benzoyl)-benzenesulfonamide

(335) ##STR00121##

(336) MS (m/z): 318 (M−1). Analytics calculated for C.sub.15H.sub.10ClNO.sub.3S: C, 56.34; H, 3.15; N, 4.38. Found: C, 56.19; H, 2.88; N, 4.24. M.P. 147-149° C.

2-Chloro-5-(4-phenylamino-benzoyl)-benzenesulfonamide

(337) ##STR00122##

(338) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 5.2 (br, 2H), 6.18 (br, 1H), 7.02 (d, 2H, J=8 Hz), 7.12-7.45 (m, 5H), 7.6-7.8 (m, 3H), 7.90 (dd, 1H), 8.41 (s, 1H). MS (m/z): 387 (M+1).

Example 54: General Synthesis of Indazole Analogs

(339) ##STR00123##
A Typical Procedure for Acylation-Fries Rearrangement

(340) To a solution of 3-bromophenol (1.0 equivalent) in methylene chloride (5 vol) is added aluminum chloride (1.5 equivalent) followed by acid chloride (1.0 equivalent). The mixture is heated to reflux for 2-3 h, cooled to room temperature, and the mixture is poured slowly into a beaker containing ice and 2 N HCl and extracted with methylene chloride. The combined organic extracts are dried over sodium sulfate, filtered, and concentrated to a crude solid, which is purified by flash chromatography.

(341) General Procedure for Mesylate Formation

(342) To a solution of phenol (1.0 equivalent) in dichloromethane (5 vol) is added triethylamine (2.0 equivalent). The resulting solution is cooled to 0° C. and methylsulfonyl chloride (1.1 equivalent) is added drop-wise. The reaction is stirred at room temperature for (30 minutes to 18 h), poured into 1 N HCl and extracted with dichloromethane. The combined organic extracts are dried over sodium sulfate, filtered, and concentrated to give the crude product, which is purified by flash chromatography.

(343) General Procedure for Indazole Formation

(344) The mesylate (1.0 equivalent) is combined with the HCl salt of the benzyl hydrazine (1.5 equivalent) and sodium acetate (3.0 equivalent) in xylenes (6 vol). The mixture is heated to reflux in a Dean-Stark apparatus until completion. The reaction is cooled to room temperature, poured into 1 N HCl and extracted with toluene. The combined organic extracts are dried over sodium sulfate and concentrated to afford the crude indazole which is purified by flash chromatography.

(345) General Procedure for N-Debenzylation

(346) Benzyl-indazole is dissolved in dimethylsulfoxide and potassium tert-butoxide (1 M solution in tetrahydrofuran) is added at room temperature. Oxygen is then bubbled into the solution for 5 minutes. The reaction is allowed to stir at room temperature for 18 h. The reaction is quenched with aqueous saturated ammonium chloride then extracted three times with ethyl acetate. The combined organic extracts are dried over sodium sulfate, and concentrated. Purification by flash chromatography provides the deprotected indazole.

Example 55: 2-Chloro-5-(3-ethyl-1H-indazole-6-carbonyl)-benzenesulfonamide

(347) ##STR00124##

(348) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 1.45 (t, 3H, J=8 Hz), 3.06 (q, 2H, J=8 Hz), 5.24 (2H), 7.57 (d, 1H, J=0.16 Hz), 7.71 (d, 1H, J=0.16 Hz), 7.86-7.82 (m, 4H), 8.52 (s, 1H).

(349) MS (m/z): 364 (M+1).

Example 56: 2-Chloro-5-(3-methyl-1H-indazole-6-carbonyl)-benzenesulfonamide

(350) ##STR00125##

(351) .sup.1H NMR (400 MHz, MeOD). δ 2.61 (s, 3H), 7.54 (m, 1H), 7.78 (1H), 7.88 (1H), 7.98 (1H), 8.48 (1s, 1H). MS (m/z): 350 (M+1).

Example 57: 2-Chloro-5-(3-isopropyl-1H-indazole-6-carbonyl)-benzenesulfonamide

(352) ##STR00126##

(353) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 1.48 (d, 6H, J=8 Hz), 3.47 (m, 1H), 5.24 (m, 2H), 7.55 (d, 1H, J=4 Hz), 7.71 (d, 1H, J=4 Hz), 7.86-7.89 (m, 2H), 8.01 (d, 1H, J=4 Hz), 8.52 (s, 1H). MS (m/z): 378 (M+1).

Example 58: 5-(1-Benzyl-3-ethyl-1H-indazole-6-carbonyl)-2-chloro-benzenesulfonamide

(354) ##STR00127##

(355) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 1.35 (t, 3H, J=7.7 Hz), 3.06 (q, 2H, J=7.7 Hz), 5.15 (m, 2H), 5.58 (2H), 7.19 (d, 2H, J=8 Hz), 7.28-7.86 (m, 8H), 8.48 (d, 1H, J=4 Hz). MS (m/z): 454.1 (M+1).

Example 59: 2-Chloro-5-[3-(2-cyclopentyl-ethyl)-1H-indazole-6-carbonyl]-benzenesulfonamide

(356) ##STR00128##

(357) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 1.25 (m, 2H), 1.5-1.7 (m, 6H), 1.85 (m, 5H), 3.03 (t, 2H), 5.34 (s, 2H), 7.56 (d, 1H, J=4 Hz), 7.70 (d, 1H), 7.83 (m, 2H), 8.0 (1H), 8.5 (s, 1H). MS (m/z): 432 (M+1).

(358) Table 1 below shows the inhibitory activity (IC.sub.50 values) of representative compounds to MMP02 and MMP13.

(359) TABLE-US-00001 TABLE 1 MMP- MMP- Ex- 02 13 ample IC.sub.50 IC.sub.50 MW MW # IUPAC Name (μM) (μM) (Calc′d) (Found)  1 3-(4-Methoxy- 1.92 2.49 291.33 290 benzoyl)- (M − 1) benzenesulfonamide  2 2-Fluoro-5-(4- 2.41 1.59 309.32 308 methoxy-benzoyl)- (M − 1) benzenesulfonamide  3 2-Chloro-5-(4- 5.18 2.02 325.77 326 methoxy-benzoyl)- (M + 1) benzenesulfonamide  4 2,3-Difluoro-5-(4- 4.68 5.73 327.31 326 methoxy-benzoyl)- (M − 1) benzenesulfonamide  5 5-(4-Methoxy- 1.06 1.39 336.33 335 benzoyl)-2-nitro- (M − 1) benzenesulfonamide  6 5-(4-Methoxy- 2.78 4.51 305.36 306 benzoyl)-2-methyl- (M + 1) benzenesulfonamide  7 5-(4-Methoxy- 2.36 3.72 337.42 336 benzoyl)-2- (M − 1) methylsulfanyl- benzenesulfonamide  8 2-Methanesulfinyl- 4.48 10.74 353.42 352 5-(4-methoxy- (M − 1) benzoyl)- benzenesulfonamide  9 2-Methanesulfonyl- 2.93 11.35 369.42 368 5-(4-methoxy- (M − 1) benzoyl)- benzenesulfonamide 10 3-[3-(2-Methyl- 3.4 0.03 391.45 390 pyridin-4-yl)-1H- (M − 1) indole-6-carbonyl]- benzenesulfonamide 11 3-{3-[2-(3- 3.95 0.075 449.53 450 Methoxy-propyl)- (M + 1) pyridin-4-yl]-1H- indole-6-carbonyl}- benzenesulfonamide 12 2-Chloro-5-(4- 9.13 3.04 429.93 430.0 methoxy-benzoyl)- (M + 1) N-phenethyl- benzenesulfonamide 13 2-Chloro-N-[2-(4- 8.8 6.9 447.92 448.0 fluoro-phenyl)- (M + 1) ethyl]-5-(4- methoxy-benzoyl)- benzenesulfonamide 14 3-{3-[2-(3- 0.8 0.01 504.61 505 Morpholin-4-yl- (M + 1) propyl)-pyridin-4-yl]- 1H-indole-6- carbonyl}- benzenesulfonamide 15 2-Chloro-5-(4- 5.16 10 311.75 310 hydroxy-benzoyl)- (M − 1) benzenesulfonamide 16 2-Chloro-5-[4-(2- 5.94 4.9 341.77 342 hydroxy-ethoxy)- (M + 1) benzoyl]- benzenesulfonamide 17 2-Chloro-5-[4-(2- 2.30 3.71 355.8 354 hydroxy-ethoxy)- (M − 1) benzoyl]- benzenesulfonamide 19 2-Chloro-5-(4- 1.58 1.22 367.85 366 isobutoxy-benzoyl)- (M − 1) benzenesulfonamide 20 2-Chloro-5-(4′- 11 13.6 351.81 350 allyloxy-benzoyl)- (M − 1) benzenesulfonamide 21 2-Chloro-5-[4-(3- 4.73 0.86 381.88 380 methyl-butoxy)- (M − 1) benzoyl]- benzenesulfonamide 22 2-Chloro-5-[4-(3- 14 2.05 429.93 430 phenyl-propoxy)- (M + 1) benzoyl]- benzenesulfonamide 23 2-Chloro-5-(4- 4.15 0.95 381.88 382 pentyloxy-benzoyl)- (M + 1) benzenesulfonamide 24 2-Chloro-5-(4- 9.16 2.1 395.91 396 hexyloxy-benzoyl)- (M + 1) benzenesulfonamide 26 2-Chloro-5-(3- 17.2 10.53 309.77 308 methyl-benzoyl)- (M − 1) benzenesulfonamide 27 2-Chloro-5-(4- 7.46 9.64 379.74 378 trifluoromethoxy- (M − 1) benzoyl)- benzenesulfonamide 30 2-Chloro-5-(4- 1.23 1.69 335.81 334 cyclopropyl- (M − 1) benzoyl)- benzenesulfonamide 31 2-Chloro-5-(4- 10.44 12.41 363.87 370 cyclopentyl- (M − 1) benzoyl)- benzenesulfonamide 32 2-Chloro-5-(4- 8.3 10.02 377.89 376 cyclohexyl- (M − 1) benzoyl)- benzenesulfonamide 33 2-Chloro-5-(4- >30 2.59 391.95 390 trimethylsilanylethynyl- (M − 1) benzoyl)- benzenesulfonamide 34 2-Chloro-5-(4-ethynyl- 2.51 4.71 319.77 318 benzoyl)- (M − 1) benzenesulfonamide 35 2-Chloro-5-(4- 6.89 0.84 395.87 394 phenylethynyl- (M − 1) benzoyl)- benzenesulfonamide 37 4-(4-Chloro-3- 22.8 8.9 414.87 415 sulfamoyl-benzoyl)-N- (M + 1) phenyl-benzamide 38 N-Benzyl-4-(4-chloro- 14.54 8.58 428.9 427 3-sulfamoyl-benzoyl)- (M − 1) benzamide 40 4-(4-Chloro-3- >30 7.06 470.98 471 sulfamoyl-benzoyl)-N- (M + 1) (4-phenyl-butyl)- benzamide 41 2-Chloro-5-(4- >9 7.52 421.91 420 naphthalen-2-yl- (M − 1) benzoyl)- benzenesulfonamide 42 2-Chloro-5-(4- 0.51 1.5 377.87 376 thiophen-2-yl-benzoyl)- (M − 1) benzenesulfonamide 43 2-Chloro-5-(4- 0.30 0.38 377.87 376 thiophen-3-yl-benzoyl)- (M − 1) benzenesulfonamide 44 2-Chloro-5-(4-pyridin- 0.62 0.56 372.83 371 3-yl-benzoyl)- (M − 1) benzenesulfonamide 45 2-Chloro-5-(4-pyridin- 0.053 0.08 372.83 371 4-yl-benzoyl)- (M − 1) benzenesulfonamide 46 2-Chloro-5-[4-(2- 0.15 0.21 407.28 406 chloro-pyridin-4-yl)- (M − 1) benzoyl]- benzenesulfonamide 47 2-Chloro-5-(4-cyano- 17.3 11.1 320.76 319 benzoyl)- (M − 1) benzenesulfonamide 48 5-(2-Bromo-4-methyl- >30 25.3 388.67 386 benzoyl)-2-chloro- (M − 1) benzenesulfonamide 49 5-(4-Bromo-2-methyl- >30 24.8 388.67 386 benzoyl)-2-chloro- (M − 1) benzenesulfonamide 50 2-Chloro-5-(2-fluoro-4- 24.3 21.3 343.76 342 methoxy-benzoyl)- (M − 1) benzenesulfonamide 51 2-Chloro-5-(3-fluoro-4- 14.6 18.7 329.74 330 hydroxy-benzoyl)- (M + 1) benzenesulfonamide 52 2-Chloro-5-(2,4- 29.1 21.3 355.8 356 dimethoxy-benzoyl)- (M + 1) benzenesulfonamide 53 5-Benzoyl-2-chloro- >30 >30 295.75 294 benzenesulfonamide (M − 1) 54 2-Chloro-5-(3-fluoro-4- 23.4 27.1 329.74 330 hydroxy-benzoyl)- (M + 1) benzenesulfonamide 55 2-Chloro-5-(4-hydroxy- 25.5 27.5 313.74 312 benzoyl)- (M − 1) benzenesulfonamide 56 N-tert-Butyl-4-(4- >30 26.7 394.88 395 chloro-3-sulfamoyl- (M + 1) benzoyl)-benzamide 57 2-Chloro-5-[4- >30 21.2 392.86 393 (pyrrolidine-1- (M + 1) carbonyl)-benzoyl]- benzenesulfonamide 58 4-(4-Chloro-3- >30 24.2 442.92 443 sulfamoyl-benzoyl)-N- (M + 1) phenethyl-benzamide 59 5-(Biphenyl-4- 1.16 2.63 371.85 370 carbonyl)-2-chloro- (M − 1) benzenesulfonamide 60 2-Chloro-5-(3′-methyl- 6.31 5.44 385.87 384 biphenyl-4-carbonyl)- (M − 1) benzenesulfonamide 61 2-Chloro-5-(4′-methyl- 1.1 1.02 385.87 384 biphenyl-4-carbonyl)- (M − 1) benzenesulfonamide 62 2-Chloro-5-(4′- 2.21 0.83 439.84 438 trifluoromethyl- (M − 1) biphenyl-4-carbonyl)- benzenesulfonamide 63 2-Chloro-5-(4′-ethyl- 2.05 0.38 399.9 398 biphenyl-4-carbonyl)- (M − 1) benzenesulfonamide 64 2-Chloro-5-(2′-fluoro- 4.05 7.55 389.84 388 biphenyl-4-carbonyl)- (M − 1) benzenesulfonamide 65 2-Chloro-5-(4′-fluoro- 1.18 1.61 389.84 388 biphenyl-4-carbonyl)- (M − 1) benzenesulfonamide 66 2-Chloro-5-(4′-chloro- 0.72 0.63 406.29 405 biphenyl-4-carbonyl)- (M − 1) benzenesulfonamide 67 5-(3′-Bromo-biphenyl- 10.2 5.29 450.74 488 4-carbonyl)-2-chloro- (M − 1) benzenesulfonamide 68 2-Chloro-5-(3′-nitro- 3.44 3.15 416.84 387 biphenyl-4-carbonyl)- (M + 1) benzenesulfonamide 69 5-(3′-Amino-biphenyl- 1.37 2.41 386.86 385 4-carbonyl)-2-chloro- (M − 1) benzenesulfonamide 70 N-[4′-(4-Chloro-3- 11.43 4.01 428.9 429 sulfamoyl-benzoyl)- (M + 1) biphenyl-3-yl]- acetamide 71 2-Chloro-5-(3′- 1.09 1.4 402.86 400 hydroxymethyl- (M − 1) biphenyl-4-carbonyl)- benzenesulfonic acid 72 2-Chloro-5-(4′-formyl- 0.18 0.13 399.86 398 biphenyl-4-carbonyl)- (M − 1) benzenesulfonamide 73 4′-(4-Chloro-3- 0.98 0.61 415.86 414 sulfamoyl-benzoyl)- (M − 1) biphenyl-4-carboxylic acid 74 4′-(4-Chloro-3- 0 93 0.24 429.88 428 sulfamoyl-benzoyl)- (M − 1) biphenyl-4-carboxylic acid methyl ester 78 2-Chloro-5-(4- 0.27 0.35 338.82 339 dimethylamino- (M + 1) benzoyl)- benzenesulfonamide 79 2-Chloro-5-(4- 5.72 10.42 366.87 367 diethylamino-benzoyl)- (M + 1) benzenesulfonamide 80 2-Chloro-5-(4- 0.055 0.113 364.85 365 pyrrolidin-1-yl- (M + 1) benzoyl)- benzenesulfonamide 81 2-Chloro-5-[4-(2,5- 1.31 1.01 362.84 361 dihydro-pyrrol-1-yl)- (M − 1) benzoyl]- benzenesulfonamide 82 2-Chloro-5-(4-pyrrol-1- 1.15 0.86 360.82 359 yl-benzoyl)- (M − 1) benzenesulfonamide 83 2-Chloro-5-(4- 0.87 1.77 378.88 379 piperidin-1-yl-benzoyl)- (M + 1) benzenesulfonamide 84 2-Chloro-5-[4-(3- 1.35 7.54 392.91 393 methyl-piperidin-1-yl)- (M + 1) benzoyl]- benzenesulfonamide 85 2-Chloro-5-[4-(4- 2.05 0.57 454.98 453 phenyl-piperidin-1-yl)- (M − 1) benzoyl]- benzenesulfonamide 86 5-[4-(4-Benzyl- >30 7.67 469.01 470 piperidin-1-yl)- (M + 1) benzoyl]-2-chloro- benzenesulfonamide 87 2-Chloro-5-[4-(4- 1.74 1.19 393.9 394 methyl-piperazin-1-yl)- (M + 1) benzoyl]- benzenesulfonamide 88 2-Chloro-5-(4- 0.96 1.84 380.85 381 morpholin-4-yl- (M + 1) benzoyl)- benzenesulfonamide 89 2-Chloro-5-[4-(2-oxo- 2.06 3.34 364.81 365 azetidin-1-yl)-benzoyl]- (M + 1) benzenesulfonamide 90 5-(4-Azepan-1-yl- 13.8 10.8 392.91 393 benzoyl)-2-chloro- (M + 1) benzenesulfonamide 91 2-Chloro-5-(4- >30 22.5 474.92 391 methoxy-benzoyl)-N- (M + 1) [2-(4-nitro-phenyl)- ethyl]- benzenesulfonamide 92 2-Chloro-5-(4- 22.8 20.7 386.86 387 phenylamino-benzoyl)- (M + 1) benzenesulfonamide 93 2-Chloro-5- 26.5 13.71 345.81 344 (naphthalene-2- (M − 1) carbonyl)- benzenesulfonamide 94 2-Chloro-5-(indane-5- 23.5 22.6 335.81 336 carbonyl)- (M + 1) benzenesulfonamide 95 2-Chloro-5-(1H- 3.97 6.21 284.72 285 pyrrole-3-carbonyl)- (M + 1) benzenesulfonamide 96 2-Chloro-5-(thiophene- 10 14.7 301.77 300.0 2-carbonyl)- (M − 1) benzenesulfonamide 97 5-(3H-Benzoimidazole- 1.21 0.63 335.77 334 5-carbonyl)-2-chloro- (M − 1) benzenesulfonamide 98 2-Chloro-5-(2-methyl- 2.25 8.31 349.8 348 3H-benzoimidazole-5- (M − 1) carbonyl)- benzenesulfonamide 99 2-Chloro-5-(3-ethyl- 0.27 0.25 363.83 364 1H-indazole-6- (M + 1) carbonyl)- benzenesulfonamide 100  2-Chloro-5-(3-methyl- 0.26 0.25 349.8 350 1H-indazole-6- (M + 1) carbonyl)- benzenesulfonamide 101  2-Chloro-5-(3- 6.35 3.65 377.85 378 isopropyl-1H-indazole- (M + 1) 6-carbonyl)- benzenesulfonamide 102  5-(9H-Carbazole-2- 1.01 2.71 384.84 385 carbonyl)-2-chloro- (M + 1) benzenesulfonamide 103  7-(4-Chloro-3- 0.85 0.36 461.93 462 sulfamoyl-benzoyl)- (M + 1) 1,3,4,5-tetrahydro- pyrido[4,3-b]indole-2- carboxylic acid ethyl ester 104  8-(4-Chloro-3- 21.45 1.9 461.93 462 sulfamoyl-benzoyl)- (M + 1) 1,3,4,5-tetrahydro- pyrido[4,3-b]indole-2- carboxylic acid ethyl ester 105  2-Chloro-5-(1-oxo- 8 9 403.85 402.0 2,3,4,9-tetrahydro-1H- (M − 1) beta-carboline-7- carbonyl)- benzenesulfonamide 106  2-Chloro-5-[2-(2,2- >2.7 0.95 473.98 472.1 dimethyl-propionyl)- (M − 1) 2,3,4,9-tetrahydro-1H- beta-carboline-6- carbonyl]- benzenesulfonamide 109  2-Chloro-5-[4-(2,5- 21.8 19.9 406.87 407 dimethyl-pyrrol-1-yl)-3- (M + 1) fluoro-benzoyl]- benzenesulfonamide 110  2-Chloro-5-(2,3- 12.0 16.1 336.8 335 dihydro-1H-indole-5- (M − 1) carbonyl)- benzenesulfonamide 111  5-(1-Benzyl-3-ethyl- >30 25.3 453.95 454 1H-indazole-6- (M + 1) carbonyl)-2-chloro- benzenesulfonamide 112  2-Chloro-5-[3-(2- 2.95 0.129 431.94 432 cyclopentyl-ethyl)-1H- (M + 1) indazole-6-carbonyl]- benzenesulfonamide 113  2-Chloro-5-(1H-indole- 8.94 3.08 334.78 333 3-carbonyl)- (M − 1) benzenesulfonamide 114  2-Chloro-5-(1-methyl- 3.31 3.13 348.81 347 1H-indole-5-carbonyl)- (M − 1) benzenesulfonamide 116  2-Chloro-5-(1H-indole- 15.4 15.3 334.78 335 5-carbonyl)- (M + 1) benzenesulfonamide 117  2-Chloro-5-[1-(3- 26.7 23.0 404.92 403 methyl-butyl)-1H- (M − 1) indole-5-carbonyl]- benzenesulfonamide 118  2-Chloro-5-(3-phenyl- 2.00 1.03 410.88 409 1H-indole-6-carbonyl)- (M − 1) benzenesulfonamide 119  2-Chloro-5-[3-(4- 24 6.04 440.91 439 methoxy-phenyl)-1H- (M − 1) indole-6-carbonyl]- benzenesulfonamide 120  2-Chloro-5-[3-(4- 1.9 0.95 428.87 427 fluoro-phenyl)-1H- (M − 1) indole-6-carbonyl]- benzenesulfonamide 121  5-[3-(3-Acetyl-phenyl)- 3.9 0.59 452.92 452 1H-indole-6-carbonyl]- (M − 1) 2-chloro- benzenesulfonamide 122  5-[3-(4-Acetyl-phenyl)- 12.5 1.45 452.92 451 1H-indole-6-carbonyl]- (M − 1) 2-chloro- benzenesulfonamide 123  2-Chloro-5-[3-(3- 5.02 0.39 488.97 487 methanesulfonyl- (M − 1) phenyl)-1H-indole-6- carbonyl]- benzenesulfonamide 124  2-Chloro-5-[3-(4- 19.7 0.54 488.97 487 methanesulfonyl- (M − 1) phenyl)-1H-indole-6- carbonyl]- benzenesulfonamide 125  2-Chloro-5-[3-(4- >30 1.01 503 501 ethanesulfonyl- (M − 1) phenyl)-1H-indole-6- carbonyl]- benzenesulfonamide 126  5-(3-Biphenyl-4-yl-1H- 22.8 10 486.98 485 indole-6-carbonyl)-2- (M − 1) chloro- benzenesulfonamide 127  2-Chloro-5-(3- 4.6 1.6 416.91 415 thiophen-3-yl-1H- (M − 1) indole-6-carbonyl)- benzenesulfonamide 128  5-[3-(5-Acetyl- 6.9 0.16 458.95 451 thiophen-2-yl)-1H- (M − 1) indole-6-carbonyl]-2- chloro- benzenesulfonamide 129  5-(1H,1′H- 2.95 1.65 449.92 447 [3,5′]Biindolyl-6- (M − 1) carbonyl)-2-chloro- benzenesulfonamide 130  2-Chloro-5-(3-pyridin- 2.62 0.24 411.87 410 3-yl-1H-indole-6- (M − 1) carbonyl)- benzenesulfonamide 131  2-Chloro-5-(3- 4 0.195 412.86 411 pyrimidin-5-yl-1H- (M − 1) indole-6-carbonyl)- benzenesulfonamide 132  2-Chloro-5-{3-[4- 16 0.73 524 522 (morpholine-4- (M − 1) carbonyl)-phenyl]-1H- indole-6-carbonyl}- benzenesulfonamide 133  2-Chloro-5-[3-(3,5- 23 0.30 429.89 428 dimethyl-isoxazol-4- (M − 1) yl)-1H-indole-6- carbonyl]- benzenesulfonamide 134  2-Chloro-5-[3-(5- 23 0.10 476.34 474 chloro-2-methoxy- (M − 1) pyridin-4-yl)-1H-indole- 6-carbonyl]- benzenesulfonamide 135  2-Chloro-5-(3-pyridin- 1.05 0.09 411.87 410 4-yl-1H-indole-6- (M − 1) carbonyl)- benzenesulfonamide 136  2-Chloro-5-[3-(2- 18 0.25 446.31 444 chloro-pyridin-4-yl)-1H- (M − 1) indole-6-carbonyl]- benzenesulfonamide 137  2-Chloro-5-[3-(2- 3.45 0.041 425.9 424 methyl-pyridin-4-yl)- (M − 1) 1H-indole-6-carbonyl]- benzenesulfonamide 138  2-Chloro-5-[3-(2-ethyl- 3.55 0.06 439.92 438 pyridin-4-yl)-1H-indole- (M − 1) 6-carbonyl]- benzenesulfonamide 139  2-Chloro-5-[3-(2- 4.15 0.068 451.94 450 cyclopropyl-pyridin-4- (M − 1) yl)-1H-indole-6- carbonyl]- benzenesulfonamide 141  2-Chloro-5-{3-[2-(3- 1.1 0.02 539.06 539 morpholin-4-yl-propyl)- (M + 1) pyridin-4-yl]-1H-indole- 6-carbonyl}- benzenesulfonamide 142  2-Chloro-5-{3-[2-(2- 0.2 0.017 498.99 497 dimethylamino- (M − 1) ethoxy)-pyridin-4-yl]- 1H-indole-6-carbonyl}- benzenesulfonamide 143  2-Chloro-5-{3-[2-(2- 2.85 0.15 541.03 539 morpholin-4-yl- (M − 1) ethoxy)-pyridin-4-yl]- 1H-indole-6-carbonyl}- benzenesulfonamide 144  2-Fluoro-5-(1H-indole- 0.39 0.3 318.33 317 6-carbonyl)- (M − 1) benzenesulfonamide 145  5-(1H-Indole-6- 0.20 0.1 314.37 313 carbonyl)-2-methyl- (M − 1) benzenesulfonamide 146  3-(1H-Indole-6- 0.24 0.2 300.34 299 carbonyl)- (M − 1) benzenesulfonamide 147  2-Methyl-5-[3-(2- 2.4 0.02 405.48 404 methyl-pyridin-4-yl)- (M − 1) 1H-indole-6-carbonyl]- benzenesulfonamide

Other Embodiments

(360) Other embodiments will be evident to those of skill in the art. It should be understood that the foregoing detailed description is provided for clarity only and is merely exemplary. The spirit and scope of the present invention are not limited to the above examples, but are encompassed by the following claims.