N-myristoyl transferase inhibitors

Abstract

The present invention relates to N-heterocyclic sulphonamide compounds, in particular pyrazole sulphonamide compounds, and their use as N-myristoyl transferase inhibitors.

Claims

1. A compound having the structure: ##STR00530## wherein n is 0, 1, 2, 3, 4, 5 or 6; E is independently selected from C and N; W is selected from a hydrocarbyl optionally substituted with R.sup.11, an optionally substituted aryl or heteroaryl group and a carbocyclyl optionally substituted with one or more of halogen, cyano, amino, hydroxy, C.sub.1-6 alkyl and C.sub.1-6 alkoxy groups; where M is selected from C and N; R.sup.3, R.sup.4 and R.sup.5 are independently selected from hydrogen, R.sup.12, hydrocarbyl optionally substituted with R.sup.12, and —(CH.sub.2).sub.l-heterocyclyl optionally substituted with R.sup.12; wherein R.sup.1 and R.sup.2 taken together with the atoms to which they are attached may form a heterocycle, optionally substituted with one or more R.sup.12; l is 0, 1, 2, 3, 4, 5 or 6; wherein each R.sup.11 and R.sup.12 is independently selected from halogen, trifluoromethyl, cyano, thio, nitro, oxo, ═NR.sup.13, —OR.sup.13, —SR.sup.13, —C(O)R.sup.13, —C(O)OR.sup.13, —OC(O)R.sup.13, —NR.sup.13COR.sup.14, —NR.sup.13CONR.sup.13.sub.2, —NR.sup.13COR.sup.14, —NR.sup.13CO.sub.2R.sup.14, —S(O)R.sup.13, —S(O).sub.2R.sup.13, —SONR.sup.13.sub.2, —NR.sup.13S(O).sub.2R.sup.14; —CSR.sup.13, —N(R.sup.13)R.sup.14, —C(O)N(R.sup.13)R.sup.14, —SO.sub.2N(R.sup.13)R.sup.14 and R.sup.15; wherein R.sup.13 and R.sup.14 are each independently selected from hydrogen or R.sup.15; wherein R.sup.15 is selected from hydrocarbyl, carbocyclyl and —(CH.sub.2).sub.m-heterocyclyl, and each R.sup.15 is optionally and independently substituted with one or more of halogen, cyano, amino, hydroxy, C.sub.1-6 alkyl and C.sub.1-6 alkoxy; ring D is an optionally substituted nitrogen containing 6 or 7 membered heterocycle, wherein each substitutable carbon or nitrogen in Ring D is optionally and independently substituted by one or more R.sup.7; R.sup.7 is independently selected from hydrogen, R.sup.20, hydrocarbyl optionally substituted with R.sup.20, and —(CH.sub.2).sub.v-heterocyclyl optionally substituted with R.sup.20; v is 0, 1, 2, 3, 4, 5 or 6; wherein each R.sup.20 is independently selected from halogen, trifluoromethyl, cyano, thio, nitro, oxo, ═NR.sup.21, —OR.sup.21, —SR.sup.21, —C(O)R.sup.21, —C(O)OR.sup.21, —OC(O)R.sup.21, —NR.sup.21COR.sup.22, —NR.sup.21CONR.sup.22.sub.2, —NR.sup.21COR.sup.22, —NR.sup.21CO.sub.2R.sup.22, —S(O)R.sup.21, —S(O).sub.2R.sup.21, —SONR.sup.21.sub.2, —NR.sup.21S(O).sub.2R.sup.22; —CSR.sup.21, N(R.sup.21)R.sup.22, —C(O)N(R.sup.21)R.sup.22, —SO.sub.2N(R.sup.21)R.sup.22 and R.sup.23; wherein R.sup.21 and R.sup.22 are each independently selected from hydrogen or R.sup.23; wherein R.sup.23 is selected from hydrocarbyl, carbocyclyl and —(CH.sub.2).sub.w-heterocyclyl, and each R.sup.23 is optionally and independently substituted with one or more of halogen, cyano, amino, hydroxy, C.sub.1-6 alkyl and C.sub.1-6 alkoxy; w is 0, 1, 2, 3, 4, 5 or 6; R.sup.8 is selected from the list of optional substituents represented by the group R.sup.4; m is 0, 1, 2, 3, 4, 5 or 6; p is 0, 1, 2, 3 or 4, wherein the values of R.sup.4 may be the same or different; q is 0, 1, 2, 3 or 4, wherein the values of R.sup.5 may be the same or different; and t is 0, 1, 2, 3, 4, 5 or 6, wherein the values of R.sup.7 may be the same or different; or a pharmaceutically acceptable salt thereof.

2. A compound as claimed in claim 1 wherein E is C.

3. A compound as claimed in claim 1 having the structure: ##STR00531## wherein R.sup.5a, R.sup.5b and R.sup.5c are independently selected from hydrogen, R.sup.12, hydrocarbyl optionally substituted with R.sup.12, and —(CH.sub.2).sub.l-heterocyclyl optionally substituted with R.sup.12; wherein R.sup.3a and R.sup.3b are independently selected from hydrogen, R.sup.12, hydrocarbyl optionally substituted with R.sup.12, and —(CH.sub.2).sub.l-heterocyclyl optionally substituted with R.sup.12.

4. A compound as claimed in claim 3 wherein R.sup.5a, R.sup.5b and R.sup.5c independently represent C.sub.1-6 alkyl.

5. A compound as claimed in claim 1 having the structure: ##STR00532##

6. A compound as claimed in claim 1 wherein W is C.sub.1-6 alkyl or cycloalkyl.

7. A compound as claimed in claim 1 wherein R.sup.4 is selected from hydrogen or C.sub.1-6 alkyl optionally substituted with halogen.

8. A compound as claimed in claim 1 selected from the group consisting of: ##STR00533## ##STR00534##

9. A compound as claimed in claim 1 wherein one or more of R.sup.3 and R.sup.5 taken together with the atoms to which they are attached form a carbocycle, optionally substituted with R.sup.12.

10. A compound as claimed in claim 1 wherein R.sup.4 is selected from hydrogen and C.sub.1-6 alkyl optionally substituted with fluoro.

11. A compound as claimed in claim 3 wherein R.sup.5a, R.sup.5b and R.sup.5c are independently selected from hydrogen, R.sup.12, C.sub.1-6 alkyl, alkenyl, alkynyl and haloalkyl, optionally substituted with R.sup.12.

12. A compound as claimed in claim 3 wherein R.sup.3a and R.sup.3b are independently selected from hydrogen, R.sup.12, C.sub.1-6 alkyl, alkenyl, alkynyl and haloalkyl, optionally substituted with R.sup.12.

Description

(1) The following Intermediates and Examples illustrate the preparation and properties of compounds according to the invention with reference to the following FIGURE:

(2) FIG. 1 shows a Kaplan Meier survival plot for DDD85646 in an acute model of trypanosomiasis infection

INTERMEDIATE 1

4-Bromo-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(3) Prototypical Procedure for Preparation of a Sulphonamide from an Amine and a Sulfonyl Chloride;

(4) 4-Bromobenzene sulfonyl chloride (5.0 g, 19.6 mmol) was added portionwise to a stirred solution of 4-amino-1,3,5-trimethyl-1H-pyrazole (2.45 g, 19.6 mmol) in pyridine (50 ml) at rt. The reaction was stirred for 24 h then concentrated to dryness in vacuo. The resulting residue was diluted with DCM (100 ml), washed with aqueous sodium hydroxide solution (0.5M, 100 ml), organic phase separated, dried (MgSO.sub.4), filtered and concentrated to dryness in vacuo. Trituration from Et.sub.2O and collection by vacuum filtration gave the title compound as a fine off-white solid (5.1 g, 14.8 mmol, 79%). δH (D-6 DMSO, 300K). m/z (ES.sup.+, 70V) 344.1 (MH.sup.+)

INTERMEDIATE 2 (DDD73234)

4-Bromo-2,6-dichloro-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(5) Prepared from 4-bromo-2,6-dichlorobenzenesulfonyl chloride (5.0 g, 15.4 mmol) and 4-amino-1,3,5-trimethyl-1H-pyrazole (1.93 g, 15.4 mmol) in pyridine (35 ml) according to the method of intermediate 1, to give the title compound as an orange solid (5.64 g, 13.7 mmol, 89%). δH (D-6 DMSO, 300K) 9.75 (1H, s), 8.00 (2H, s), 3.57 (3H, s), 1.93 (3H, s), 1.72 (3H, s). m/z (ES.sup.+, 70V) 413.9 (MH.sup.+).

INTERMEDIATE 3 (DDD86208)

4-Bromo-2-chloro-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(6) Prepared from 4-bromo-6-chlorobenzene sulfonyl chloride (5.0 g, 17.3 mmol) and 4-amino-1,3,5-trimethyl-1H-pyrazole (2.16 g, 17.3 mmol) in pyridine (35 ml) according to the method of intermediate 1, to give the title compound as an off-white solid (4.1 g, 10.8 mmol, 62%). δH (D-6 DMSO, 300K) 9.52 (1H, s), 8.05 (1H, d J 1.6 Hz), 7.72-7.63 (3H, m), 3.54 (3H, s), 1.89 (3H, s), 1.69 (3H, s). m/z (ES.sup.+, 70V) 379.9 (MH.sup.+).

INTERMEDIATE 4 (DDD88004)

4-Bromo-3,6-difluoro-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(7) Prepared from 2,5-difluoro-4-bromobenzenesulfonyl chloride (2 g, 6.9 mmol) and 4-amino-1,3,5-trimethyl-1H-pyrazole (858 mg, 6.9 mmol) in pyridine (30 ml) according to the method of intermediate 1, to give the title compound as a pale yellow solid (1.9 g, 5.0 mmol, 73%). δH (D-6 DMSO, 300K) 9.77 (1H, s), 8.12 (1H, dd, J 5.5 Hz 9.0 Hz), 7.55 (1H, dd J 6. Hz 7.5 Hz), 3.58 (3H, s), 1.92 (3H, s), 1.74 (3H, s). m/z (ES.sup.+, 70V) 380.0 (MH.sup.+).

INTERMEDIATE 5 (DDD73235)

6-Chloro-pyridine-3-sulfonic acid (1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

(8) Prepared from 6-chloropyridine-3-sulfonyl chloride (4.8 g, 22.7 mmol) and 4-amino-1,3,5-trimethyl-1H-pyrazole (2.84 g, 22.7 mmol) in pyridine (35 ml) according to the method of intermediate 1, to give the title compound as a white solid (5.13 g, 17.1 mmol, 75%). δH (D-6 DMSO, 300K) 9.51 (1H, s), 8.59 (1H, d J 2.3 Hz), 8.03 (1H, dd J 7.6 Hz 2.3 Hz), 7.77 (1H, d J 7.6 Hz), 3.58 (3H, s), 1.84 (3H, s), 1.63 (3H, s). m/z (ES.sup.+, 70V) 301.1 (MH.sup.+).

INTERMEDIATE 6

4-Bromo-N-(3,5-dimethyl-isoxazol-4-yl)-benzenesulfonamide

(9) Prepared from 4-bromobenzenesulfonyl chloride (4.56 g, 17.9 mmol) and 4-amino-3,5-dimethylisoxazole (2.02 g, 18.0 mmol) in pyridine (36 ml) according to the method of intermediate 1, to give the title compound as a white solid (5.15 g, 15.5 mmol, 87%). δH (CDCl.sub.3, 300K) 7.69 (2H, dd, J 6.9 Hz 1.7 Hz), 7.65 (2H, dd, J 6.9 Hz 1.7 Hz), 6.11 (1H, s), 2.12 (3H, s), 1.91 (3H, s). m/z (ES.sup.+, 70V) 333.0 (MH.sup.+).

INTERMEDIATE 7

4-Bromo-2,6-dichloro-N-(3,5-dimethyl-isoxazol-4-yl)-benzenesulfonamide

(10) Prepared from 4-bromo-2,6-dichlorobenzenesulfonyl chloride (1.00 g, 3.19 mmol) and 4-amino-3,5-dimethylisoxazole (0.346 g, 3.1 mmol) in pyridine (6 ml) according to the method of intermediate 1, to give the title compound as a tan solid (606 mg, 1.51 mmol, 49%). δH (CDCl.sub.3, 300K) 7.70 (2H, s), 6.66 (1H, s), 2.23 (3H, s), 2.05 (3H, s). m/z (ES.sup.+, 70V) 400.9 (MH.sup.+).

INTERMEDIATE 8

4-Bromo-N-(2-methyl-pyridin-3-yl)-benzenesulfonamide

(11) Prepared from 4-bromobenzenesulfonyl chloride (4.73 g, 18.5 mmol) and 2-methyl-3-aminopyridine (2.04 g, 18.9 mmol) in pyridine (36 ml) according to the method of intermediate 1, to give the title compound as a white solid (3.81 g, 11.6 mmol, 63%). δH (CDCl.sub.3, 300K) 8.36 (1H, dd J 4.8 Hz 1.5 Hz), 7.70 (1H, dd J 8.1 Hz 1.5 Hz), 7.63 (2H, dd J 6.6 Hz 2.3 Hz), 7.60 (2H, dd J 6.6 Hz 2.3 Hz), 7.17 (1H, dd J 8.1 Hz 4.8 Hz), 6.89 (1H, s), 2.25 (3H, s). m/z (ES.sup.+, 70V) 329.0 (MH.sup.+).

INTERMEDIATE 9

4-Bromo-2,6-dichloro-N-(2-methyl-pyridin-3-yl)-benzenesulfonamide

(12) Prepared from 4-bromo-2,6-dichlorobenzenesulfonyl chloride (1.00 g, 3.1 mmol) and 2-methyl-3-aminopyridine (0.33 g, 3.1 mmol) in pyridine (6 ml) according to the method of intermediate 1, to give the title compound as a yellow solid (0.80 g, 2.0 mmol, 65%). δH (CDCl.sub.3, 300K) 8.31 (1H, dd J 4.8 Hz 1.4 Hz), 7.65 (1H, d J 1.4 Hz), 7.64 (2H, s), 7.10 (2H, m), 2.52 (3H, s). m/z (ES.sup.+, 70V) 396.9 (MH.sup.+).

INTERMEDIATE 10

4-Bromo-2-fluoro-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(13) Prepared from 4-bromo-2-fluorobenzenesulfonyl chloride (0.75 g, 2.7 mmol) and 4-amino-1,3,5-trimethyl-1H-pyrazole (0.35 g, 2.8 mmol) in pyridine (4.5 ml) according to the method of intermediate 1, to give the title compound as an orange solid (0.59 g, 1.6 mmol, 60%). δH (D-6 DMSO, 300K) 9.60 (1H, s), 7.90 (1H, d J 9.4 Hz), 7.56 (1H, d J 8.2 Hz), 7.51 (1H, d J 7.7 Hz), 3.56 (3H, s), 1.89 (3H, s), 1.69 (3H, s). m/z (ES.sup.+, 70V) 364.0 (MH.sup.+).

INTERMEDIATE 11

4-(2-Chloro-pyridin-4-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(14) Prototypical Procedure for Suzuki Coupling of a Boronic Ester or Boronic Acid with an Aryl Halide;

(15) METHOD 1: A solution of the compound of intermediate 1 (1.5 g, 4.36 mmol), 2-chloropyridine-4-boronic acid (684 mg, 4.35 mmol), tribasic potassium phosphate (924 mg, 4.35 mmol) and Pd(dppf)Cl.sub.2.DCM (100 mg, 0.12 mmol) and water (1.5 ml) in oxygen-free DMF (8 ml) was heated in a microwave at 130° C. for 1 h. The reaction was concentrated to dryness in vacuo, diluted with DCM (100 ml), washed with saturated aqueous sodium hydrogencarbonate solution (2×25 ml), dried (MgSO.sub.4) and concentrated in vacuo to give a residual oil. Chromatography (SiO.sub.2, EtOAc) gave the title compound as a fine white solid (1.13 g, 2.66 mmol, 61%). δH (D-6 DMSO, 300K) 8.52 (1H, d J 5.2 Hz 7.88 (2H, d J 8.4 Hz), 7.74 (2H, d J 8.4 Hz), 7.58 (1H, s), 7.46 (1H, dd J 1.5 Hz 5.2 Hz), 6.36 (1H, s), 3.71 (3H, s), 2.12 (3H, s), 1.62 (3H, s). m/z (ES.sup.+, 70V) 377.1 (MH.sup.+).

INTERMEDIATE 12 (DDD86209)

2,6-Dichloro-4-(2-chloro-pyridin-4-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(16) Prepared from the sulphonamide of intermediate 2 (250 mg, 0.6 mmol), 2-chloropyridine-4-boronic acid (108 g, 0.67 mmol), tribasic potassium phosphate (145 mg, 0.68 mmol), Pd(dppf)Cl.sub.2.DCM (20 mg, 0.024 mmol) and water (0.3 ml) in oxygen-free DMF (2.5 ml) at 110° C. for 1 h according to the method of intermediate 11, to give the title compound as a white solid (212 mg, 0.47 mmol, 79%). δH (CDCl.sub.3, 300K) 8.38 (1H, dd J 0.5 Hz 5.2 Hz), 7.54 (2H, s), 7.37 (1H, dd J 1.6 Hz 5.2 Hz), 6.56 (1H, s), 3.65 (3H, s), 2.09 (3H, s), 1.69 (3H, s). m/z (ES.sup.+, 70V) 447.0 (MH.sup.+).

INTERMEDIATE 13

4-Bromomethyl-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(17) 4-Bromomethylbenzene sulfonyl chloride (3.72 g, 13.8 mmol) was added portionwise to a solution of 4-amino-1,3,5-trimethyl-1H-pyrazole (1.73 g, 13.8 mmol) and pyridine (1.5 ml) in DCM (100 ml) at rt. Concentration in vacuo gave a solid which was collected by vacuum filtration and washed with water (2×25 ml) then Et2O (100 ml) to give the title compound as a white solid (2.71 g, 7.59 mmol, 55%). δH (D-6 DMSO, 300K) 9.13 (1H, s), 7.64-7.55 (4H, m), 4.77 (2H, s), 3.55 (3H, s), 1.80 (3H, s), 1.54 (3H, s). m/z (ES.sup.+, 70V) 358.1 (MH.sup.+).

INTERMEDIATE 14

3′-Formyl-biphenyl-4-sulfonic acid (1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

(18) Prepared from the sulphonamide of intermediate 1 (1.54 g, 4.48 mmol), 3-formylphenylboronic acid (1.40 g, 10.0 mmol), tribasic potassium phosphate (1.98 g, 9.0 mmol), Pd(dppf)Cl.sub.2.DCM (100 mg, 0.12 mmol) and water (2 ml) in oxygen-free DMF (12 ml) at 130° C. for 1 h according to the method of intermediate 11, to give the title compound as a white solid (1.61 g, 4.36 mmol, 97%). δH (D-6 DMSO, 300K) 10.13 (1H, s), 9.19 (1H, s), 8.29 (1H, t J 1.6 Hz), 8.12-8.09 (1H, m), 8.0-7.96 (3H, m), 7.77-7.73 (3H, m), 3.56 (3H, s), 1.84 (3H, s), 1.61 (3H, s). m/z (ES.sup.+, 70V) 370.1 (MH.sup.+).

INTERMEDIATE 15

3,5-Dichloro-3′-formyl-biphenyl-4-sulfonic acid (1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

(19) Prepared from the sulphonamide of intermediate 2 (1.0 g, 2.43 mmol), 3-formylphenylboronic acid (440 mg, 2.91 mmol), tribasic potassium phosphate (620 mg, 2.91 mmol), Pd(dppf)Cl.sub.2.DCM (100 mg, 0.12 mmol) and water (0.5 ml) in oxygen-free DMF (6.0 ml) at 130° C. for 1 h according to the method of intermediate 11, to give the title compound as a white solid (870 mg, 2.0 mmol, 82%). δH (D-6 DMSO, 300K) 10.12 (1H, s), 9.68 (1H, s), 8.42 (1H, s), 8.21 (1H, d J 7.9 Hz), 8.07 (2H, s), 8.01 (1H, d J 7.5 Hz), 7.74 (1H dd J 7.5 Hz 7.9 Hz), 3.58 (3H, s), 1.50 (3H, s), 1.75 (3H, s). m/z (ES.sup.+, 70V) 439.2 (MH.sup.+).

INTERMEDIATE 16

3,5-Dichloro-4′-formyl-biphenyl-4-sulfonic acid (1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

(20) Prepared from the sulphonamide of intermediate 2 (1.0 g, 2.43 mmol), 4-formylphenylboronic acid (440 mg, 2.91 mmol), tribasic potassium phosphate (620 mg, 2.91 mmol), Pd(dppf)Cl.sub.2.DCM (100 mg, 0.12 mmol) and water (0.5 ml) in oxygen-free DMF (6.0 ml) at 130° C. for 1 h according to the method of intermediate 11, to give the title compound as a white solid (791 mg, 1.83 mmol, 75%). δH (D-6 DMSO, 300K) 10.12 (1H, s), 9.68 (1H, s), 8.31 (2H, d 7.1 Hz), 8.07 (2H, s), 8.01 (2H, d J 7.1 Hz), 3.58 (3H, s), 1.50 (3H, s), 1.75 (3H, s). m/z (ES.sup.+, 70V) 439.2 (MH.sup.+).

INTERMEDIATE 17

2′-Formyl-biphenyl-4-sulfonic acid (1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

(21) Prepared from the sulphonamide of intermediate 1 (1.0 g, 2.91 mmol), 2-formylphenyl boronic acid (524 mg, 3.49 mmol), tribasic potassium phosphate (740 mg, 3.49 mmol), Pd(dppf)Cl.sub.2.DCM (119 mg, 0.146 mmol) and water (2.0 ml) in oxygen-free DMF (10.0 ml) at 130 degC for 1 h according to the method of intermediate 10, to give the title compound as a white solid (700 mg, 1.90 mmol, 65%). δH (CDCl.sub.3, 300K) 9.93 (1H, s), 8.05 (1H, d J 7.7 Hz), 7.85 (2 h, d J 8.5 Hz), 7.68 (1H, dt J 1.5 Hz 7.6 Hz), 7.58 (1H, t J 1.5 Hz), 7.50 (1H, d J 8.5 Hz), 7.39 (1H, d J 7.7 Hz), 3.69 (3H, s), 2.12 (3H, s), 1.66 (3H, s). m/z (ES.sup.+, 70V) 370.1 (M+H.sup.+)

INTERMEDIATE 18 (DDD87766)

4-Bromo-N-methyl-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(22) Prototypical Procedure for N-Alkylation of a Sulphonamide with an Alkyl Halide;

(23) Sodium hydride (88 mg, 95% w/w, 3.48 mmol) was added portionwise to a solution of Intermediate 1 (1.0 g, 2.91 mmol) in DMF (10 ml) at 0° C. When effervescence had ceased, methyl iodide (217 μl, 3.48 mmol) was added dropwise and the reaction was allowed to warm to rt over 4 h. The reaction was concentrated to dryness in vacuo, diluted by addition of DCM (30 ml), washed with water (2×15 ml), dried (MgSO.sub.4) and concentrated in vacuo. The residue was triturated from Et.sub.2O and collected by vacuum filtration to give the title compound as a fine off-white solid (557 mg, 1.56, 54%). δH (D-6 DMSO, 300K) 9.67 (1H, s), 8.78 (1H, d J 5.7 Hz), 8.51 (1H, d J 8.6 Hz), 8.09 (1H, d J 5.8 Hz), 7.86 (1H, d J 5.6 Hz), 7.50 (1H, d J 5.7 Hz), 7.21 (2H, d J 8.4 Hz), 4.17 (2H, d J 8.4 Hz), 4.34 (1H, s), 4.18-4.14 (1H, m), 3.21 (1H, dd J 4.9 Hz 13.9 Hz) 2.98 (1H, dd J 9.3 Hz 13.9 Hz), 1.06 (3H, s), 0.99 (3H, s). m/z (ES.sup.+, 70V) 404.1 (MH.sup.+).

INTERMEDIATE 19 (DDD73490)

4-Bromo-2,6-dichloro-N-methyl-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(24) Was prepared from the sulphonamide of intermediate 2 (5.0 g, 12.2 mmol), sodium hydride (95% w/w, 380 mg, 15.2 mmol) according to the method of intermediate 18 to give the title compound as a brown solid (4.56 g, 10.7 mmol, 88%). δH (CDCl.sub.3, 300K) 7.60 (2H, s), 3.71 (3H, s), 3.40 (3H, s), 2.12 (3H, s), 1.84 (3H, s). m/z (ES.sup.+, 70V) 427.9 (MH.sup.+)

INTERMEDIATE 20

4-Bromo-2-methyl-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(25) Prepared from 4-bromo-2-methylbenzenesulfonyl chloride (0.736 g, 2.7 mmol) and 4-amino-1,3,5-trimethyl-1H-pyrazole (0.35 g, 2.8 mmol) in pyridine (4.5 ml) according to the method of intermediate 1, to give the title compound as an orange solid (906 m, 2.52 mmol, 93%). δH (D-6 DMSO, 300K) 9.24 (1H, s), 7.70 (1H, d, J 1.5 Hz), 7.54 (1H, dd, J 8.5 Hz 1.5 Hz), 7.48 (1H, d 8.5 Hz), 3.55 (3H, s), 2.57 (3H, s), 1.82 (3H, s), 1.59 (3H, s). m/z (ES.sup.+, 70V) 360.0 (MH.sup.+).

INTERMEDIATE 21 (DDD85593)

4-Bromo-2,6-dichloro-N-(3-hydroxy-propyl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(26) Prepared from the sulphonamide of intermediate 2 (230 mg, 0.56 mmol), 3-bromopropanol (500 mg, 3.6 mmol) and caesium carbonate (325 mg, 1.0 mmol) in DMF (1.5 ml) according to the method of intermediate 18, to give the title compound as a tan solid (211 mg, 0.45 mmol, 80%). δH (CDCl.sub.3, 300K) 7.58 (2H, s), 4.17-4.11 (2H, m), 3.86-3.75 (2H, m), 3.68 (3H, s), 2.09 (3H, s), 1.79 (3H, s), 1.76-1.69 (2H, m). m/z (ES.sup.+, 70V) 472.1 (MH.sup.+).

INTERMEDIATE 22

3′-Formyl-biphenyl-4-sulfonic acid methyl-(1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

(27) Prepared from Intermediate 18 (285 mg, 0.8 mmol), 3-formylphenylboronic acid (143 mg, 1.0 mmol), tribasic potassium phosphate (169 mg, 0.8 mmol), Pd(dppf)Cl.sub.2.DCM (33 mg, 0.04 mmol) and water (0.5 ml) in oxygen-free DMF (2 ml) at 130° C. for 1 h, according to the method of intermediate 11, to give the title compound as a white solid (170 mg, 0.4 mmol, 56%). δH (CDCl.sub.3, 300K) 10.12 (1H, s), 8.13 (1H, s), 7.94 (1H, d J 7.2 Hz), 7.88 (1H, d J 6.6 Hz), 7.83 (2H, d J 7.7 Hz), 7.76 (2H, d J 6.7 Hz), 7.65-7.70 (1H, m), 3.70 (3H, s), 3.22 (3H, s), 2.13 (3H, s), 1.59 (3H, s). m/z (ES.sup.+, 70V) 384.0 (MH.sup.+).

INTERMEDIATE 23A (DDD88198)

4-Bromo-2,6-dichloro-N-(3-isobutyl-1,5-dimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(28) Prepared from 4-bromo-2,6-dichlorobenzenesulfonyl chloride (0.68 g, 2.1 mmol) and 4-amino-1,5-dimethyl-3-isobutyl-1H-pyrazole (0.35 g, 2.1 mmol) in pyridine (5 ml) according to the method of intermediate 1, to give the title compound as a white solid (120 mg, 0.26 mmol, 12%). δH (D-6 DMSO, 300K) 7.65 (2H, s), 6.54 (1H, s), 3.70 (3H, s), 2.17 (3H, s), 1.96 (2H, d J 7.9 Hz), 1.74 (1H, m), 0.78 (6H, d J 6.6 Hz). m/z (ES.sup.+, 70V) 456.0 (MH.sup.+).

INTERMEDIATE 23B (DDD88197)

4-Bromo-2,6-dichloro-N-(5-isobutyl-1,3-dimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(29) Prepared from 4-bromo-2,6-dichlorobenzenesulfonyl chloride (0.35 g, 1.1 mmol) and 4-amino-1,3-dimethyl-5-isobutyl-1H-pyrazole (0.18 g, 1.1 mmol) in pyridine (4 ml) according to the method of intermediate 1, to give the title compound as an orange solid (118 mg, 0.26 mmol, 24%). δH (D-6 DMSO, 300K) 7.67 (2H, s), 6.69 (1H, s), 3.71 (3H, s), 2.45 (2H, d J 7.8 Hz), 1.90 (1H, m), 1.84 (3H, s), 0.91 (6H, d J 6.8 Hz). m/z (ES.sup.+, 70V) 456.0 (MH.sup.+).

INTERMEDIATE 24

5′-Formyl-3′-propoxy-biphenyl-4-sulfonic acid (1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

(30) Prepared from the sulphonamide of intermediate 1 (1.0 g, 2.91 mmol), 3-formyl-5 propoxyphenyl boronic acid (726 mg, 3.49 mmol), tribasic potassium phosphate (740 mg, 3.49 mmol), Pd(dppf)Cl.sub.2.DCM (119 mg, 0.146 mmol) and water (2.0 ml) in oxygen-free DMF (10.0 ml) at 130° C. for 1 h according to the method of intermediate 10, to give the title compound as a colourless solid (424 mg, 0.99 mmol, 34%). δH (CDCl.sub.3, 300K) 10.04 (1H, s), 7.82 (2H, d J 8.5 Hz), 7.67 (2H, d J 8.5 Hz), 7.67 (1H, t J 1.4 Hz), 7.43 (1H, s br), 7.39 (1H, t J 2.4 Hz), 5.81 (1H, s), 4.05 (2H, t J 6.6 Hz), 3.69 (3H, s), 2.10 (3H, s), 1.87 (2H, h), 1.61 (3H, s), 1.08 (3H, t J 7.5 Hz). m/z (ES.sup.+, 70V) 428.1 (M+H.sup.+).

INTERMEDIATE 25

5′-Formyl-3′-isopropoxy-biphenyl-4-sulfonic acid (1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

(31) Prepared from the sulphonamide of intermediate 1 (1.0 g, 2.91 mmol), 3-formyl-5 isopropoxyphenyl boronic acid (726 mg, 3.49 mmol), tribasic potassium phosphate (740 mg, 3.49 mmol), Pd(dppf)Cl.sub.2.DCM (119 mg, 0.146 mmol) and water (2.0 ml) in oxygen-free DMF (10.0 ml) at 130° C. for 1 h according to the method of intermediate 10, to give the title compound as a white solid (469 mg, 1.10 mmol, 38%). δH (CDCl.sub.3, 300K) 10.04 (1H, s), 7.82 (2H, d J 8.4 Hz), 7.71 (2H, d J 8.3 Hz), 7.65 (1H, s br), 7.41 (1H, s br), 7.37 (1H, t J 2.1 Hz), 5.88 (1H, s), 4.71 (1H, d J 6.1 Hz), 3.69 (3H, s), 2.10 (3H, s), 1.61 (3H, s), 1.40 (6H, d J 6.1 Hz). m/z (ES.sup.+, 70V) 428.2 (M+H.sup.+).

INTERMEDIATE 26

4-Bromo-N-(1,5-dimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(32) Prepared from 4-bromobenzenesulfonyl chloride (0.396 g, 1.55 mmol) and 4-amino-1,5-dimethyl-1H-pyrazole (0.172 g, 1.55 mmol) in pyridine (3 ml) according to the method of intermediate 1, to give the title compound as a yellow solid (0.362 g, 1.10 mmol, 71%). δH (D-6 DMSO, 300K) 9.43 (1H, s), 7.80 (2H, d J 8.7 Hz), 7.58 (2H, d J 8.7 Hz), 3.63 (3H, s), 1.89 (3H, s). m/z (ES.sup.+, 70V) 332.0 (MH.sup.+).

INTERMEDIATE 27

4-Bromo-2,6-dichloro-N-(1,5-dimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(33) Prepared from 4-bromo-2,6-dichlorobenzenesulfonyl chloride (500 mg, 1.54 mmol) and 4-amino-1,5-dimethyl-1H-pyrazole (172 mg, 1.55 mmol) in pyridine (3 ml) according to the method of intermediate 1, to give the title compound as a cream solid (392 mg, 0.99 mmol, 64%). δH (D-6 DMSO, 300K) 9.91 (1H, s), 7.97 (2H, s), 3.64 (3H, s), 2.04 (3H, s). m/z (ES.sup.+, 70V) 399.9 (MH.sup.+).

INTERMEDIATE 28

4-Bromo-N-(1,3-dimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(34) Prepared from 4-bromobenzenesulfonyl chloride (396 mg, 1.55 mmol) and 4-amino-1,3-dimethyl-1H-pyrazole (228 mg, 1.55 mmol) in pyridine (3 ml) according to the method of intermediate 1, to give the title compound as a white solid (469 mg, 1.42 mmol, 92%). δH (D-6 DMSO, 300K) 9.44 (1H, s), 7.79 (2H, d J 8.7 Hz), 7.57 (2H, d J 8.7 Hz), 7.39 (1H, s), 3.65 (3H, s), 1.70 (3H, s). m/z (ES.sup.+, 70V) 332.0 (MH.sup.+).

INTERMEDIATE 29

4-Bromo-2,6-dichloro-N-(1,3-dimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(35) Prepared from 4-bromo-2,6-dichlorobenzenesulfonyl chloride (500 mg, 1.54 mmol) and 4-amino-1,3-dimethyl-1H-pyrazole (228 mg, 1.55 mmol) in pyridine (3 ml) according to the method of intermediate 1, to give the title compound as a pale pink solid (501 mg, 1.26 mmol, 82%). δH (CDCl.sub.3, 300K) 7.65 (2H, s), 7.31 (1H, s), 6.77 (1H, s), 3.78 (3H, s), 2.04 (3H, s). m/z (ES.sup.+, 70V) 399.9 (MH.sup.+).

INTERMEDIATE 30

4-Bromo-N-(1-methyl-1H-pyrazol-4-yl)-benzenesulfonamide

(36) Prepared from 4-bromobenzenesulfonyl chloride (m396 g, 1.55 mmol) and 4-amino-1-methyl-1H-pyrazole (206 mg, 1.54 mmol) in pyridine (3 ml) according to the method of intermediate 1, to give the title compound as a white solid (424 mg, 1.34 mmol, 87%). δH (D-6 DMSO, 300K) 9.80 (1H, s), 7.79 (2H, d J 8.7 Hz), 7.61 (2H, d J 8.7 Hz), 7.48 (1H, s), 7.05 (1H, s), 3.71 (3H, s). m/z (ES.sup.+, 70V) 318.0 (MH.sup.+).

INTERMEDIATE 31

4-Bromo-2,6-dichloro-N-(1-methyl-1H-pyrazol-4-yl)-benzenesulfonamide

(37) Prepared from 4-bromo-2,6-dichlorobenzenesulfonyl chloride (500 mg, 1.54 mmol) and 4-amino-1-methyl-1H-pyrazole (206 mg, 1.54 mmol) in pyridine (3 ml) according to the method of intermediate 1, to give the title compound as a white solid (496 mg, 1.29 mmol, 84%). δH (D-6 DMSO, 300K) 7.64 (2H, s), 7.45 (1H, s), 7.18 (1H, s), 7.01 (1H, s), 3.85 (3H, s). m/z (ES.sup.+, 70V) 385.9 (MH.sup.+).

INTERMEDIATE 32

4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(38) Prototypical Procedure for Conversion of an Aryl Halide to an Aryl Boronic Ester;

(39) The sulphonamide of intermediate 1 (2.22 g, 7.5 mmol), bis-pinacolatodiboron (2.27 g, 8.97 mmol), potassium acetate (880 mg, 15.0 mmol) and Pd(dppf)Cl.sub.2.DCM (110 mg) in oxygen-free dioxane (10 ml) was heated to 120° C. for 1 h in a microwave. Concentration in vacuo, dilution with DCM (100 ml), washing with water (2×20 ml), drying (MgSO.sub.4) and concentration in vacuo gave a residue which was triturated with Et.sub.2O and collected by vacuum filtration to give the title compound as a pale red solid (1.97 g, 5.04 mmol, 67%). δH (D-6 DMSO, 300K) 9.18 (1H, s), 7.86 (2H, d J 7.7 Hz), 7.68 (2H, d J 7.7 Hz), 3.59 (3H, s), 1.82 (3H, s), 1.68 (3H, s), 1.36 (12H, s). m/z (ES.sup.+, 70V) 392.1 (MH.sup.+).

INTERMEDIATE 33

N-(2-Methyl-pyridin-3-yl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzenesulfonamide

(40) Prepared from the sulphonamide of intermediate 1 (720 mg, 2.91 mmol), bis-pinacolatodiboron (880 mg, 3.49 mmol), potassium acetate (342 mg) and Pd(dppf)Cl.sub.2.DCM (50 mg) in oxygen-free dioxane (4 ml) at 120° C. for 1 h according to the method of intermediate 32, to give the title compound as a tan coloured solid (497 mg, 1.33 mmol, 46%). δH (D-6 DMSO, 300K) 10.03 (1H, s), 8.30 (1H, d J 4.4 Hz), 7.86 (2H, d J 8.0 Hz), 7.71 (2H, d J 8.0 Hz), 7.40 (1H, d J 8.0 Hz), 7.20 (1H, dd J 4.4 Hz 8.0 Hz), 2.18 (3H, s), 1.35 (12H, s).

INTERMEDIATE 34

N-(3,5-Dimethyl-isoxazol-4-yl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzenesulfonamide

(41) Prepared from the sulphonamide of intermediate 6 (1.01 g, 3.06 mmol) and bis-pinacolatodiboron (851 mg, 3.35 mmol), potassium acetate (881 mg) and Pd(dppf)Cl.sub.2.DCM (72 mg) in oxygen-free dioxane (15 ml) at 120° C. for 2 h according to the method of intermediate 32, to give the title compound as a tan coloured solid (661 mg, 1.75 mmol, 57%). δH (CDCl.sub.3, 300K) 7.93 (2H, d J 8.3 Hz), 7.75 (2H, d J 8.3 Hz), 5.86 (1H, s), 2.06 (3H, s), 1.86 (3H, s), 1.38 (12H, s). m/z (ES.sup.+, 70V) 379.1 (MH.sup.+).

INTERMEDIATE 35

2,6-Dichloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(42) Prepared from the sulphonamide of intermediate 2 (1.0 g, 2.42 mmol) and bis-pinacolatodiboron (700 mg, 2.76 mmol), potassium acetate (750 mg) and Pd(dppf)Cl.sub.2.DCM (60 mg) in oxygen-free dioxane (12 ml) at 120° C. for 2 h according to the method of intermediate 32, to give the title compound as an orange-brown solid (1.0 g, 2.17 mmol, 90%). δH (CDCl.sub.3, 300K) 7.83 (2H, s), 6.70 (1H, s), 3.70 (3H, s), 2.14 (3H, s), 1.79 (3H, s), 1.35 (12H, s). m/z (ES.sup.+, 70V) 378.0 ([M minus pinacol]H.sup.+).

INTERMEDIATE 36

4-[3-(Tetrahydro-pyran-2-yloxy)-prop-1-ynyl]-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(43) Prototypical Procedure for Sonogashira Coupling of an Aryl Halide to an Alkyne;

(44) The sulphonamide of intermediate 1 (1.95 g, 6.76 mmol), tetrahydro-2-(2-propynyloxy)-2H-pyran (3.5 ml, 25.0 mmol), CuI (25 mg, 0.13 mmol) and Pd(PPh.sub.3).sub.4 (100 mg, 0.08 mmol), in DMF (15 ml) and NEt.sub.3 (10 ml) under argon, was heated at 110° C. for 1 h. The reaction was concentrated in vacuo, diluted with DCM (100 ml), washed with brine (2×25 ml), dried (MgSO4) and concentrated in vacuo to give a crude oil. Chromatography (SiO.sub.2, EtOAc) gave the title compound as a white solid (1.95 g, 4.83 mmol, 71%). (D-6 DMSO, 300K) 9.71 (1H, s), 8.15 (2H, d J 8.3 Hz), 7.91 (2H, d J 8.3 Hz), 4.88 (1H, s), 4.58 (1H, d J 16.5 Hz), 4.49 (1H, d J 16.5 Hz), 3.85-3.75 (1H, m), 3.61 (3H, s), 3.57-3.51 (1H, m), 1.95 (3H, s), 1.78-1.67 (2H, m), 1.75 (3H, s), 1.61-1.45 (4H, m br).

INTERMEDIATE 37

4-(3-Hydroxy-propyl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(45) The sulphonamide of intermediate 36 (2.0 g, 4.96 mmol) and palladium on charcoal (500 mg, 10% w/w) in methanol (40 ml) under hydrogen was stirred at rt for 24 h. The reaction was filtered through celite and the resulting clear solution was treated with 2M HCl in THF (5 ml) and stirred for a further 3 h. Concentration in vacuo and purification by chromatography (SiO.sub.2, EtOAc:MeOH 5:1) gave the title compound as a white powder (1.29 g, 3.99 mmol, 87%). δH (D-6 DMSO, 300K) 8.99 (1H, s), 7.52 (2H, d J 8.3 Hz), 7.38 (2H, d J 8.3 Hz), 4.55 (1H, s br), 3.55 (3H, s), 3.39 (2H, t J 6.4 Hz), 2.69 (2H, m), 1.80 (3H, s), 1.72 (2H, p J 6.4 Hz), 1.53 (3H, s). m/z (ES.sup.+, 70V) 324.1 (MH.sup.+).

INTERMEDIATE 38

2,6-Dichloro-4-[3-(tetrahydro-pyran-2-yloxy)-prop-1-ynyl]-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(46) Prepared from the sulphonamide of intermediate 2 (3.4 g, 8.23 mmol), tetrahydro-2-(2-propynyloxy)-2H-pyran (3.5 ml, 25.0 mmol), CuI (50 mg, 0.26 mmol) and Pd(PPh.sub.3).sub.4 (250 mg, 0.2 mmol), in DMF (25 ml) and NEt.sub.3 (10 ml) according to the method of intermediate 35, to give the title compound as a white solid (2.81 g, 5.97 mmol, 73%). δH (D-6 DMSO, 300K) 9.71 (1H, s), 7.79 (2H, s), 4.88 (1H, s), 4.58 (1H, d J 16.5 Hz), 4.49 (1H, d J 16.5 Hz), 3.85-3.75 (1H, m), 3.61 (3H, s), 3.57-3.51 (1H, m), 1.95 (3H, s), 1.78-1.67 (2H, m), 1.75 (3H, s), 1.61-1.45 (4H, m br).

INTERMEDIATE 39

4-Piperidin-3-yl-piperazine-1-carboxylic acid tert-butyl ester

(47) 1-Benzyl-3-piperidone hydrochloride (700 mg, 2.7 mmol), triethylamine (270 mg, 2.7 mmol) and 1-(tert-butoxycarbonyl)-piperizine (500 mg, 2.7 mmol) in DCM, was stirred at rt for 1 h, then heated to 50° C. for 40 min. Sodium triacetoxyborohydride (1.12 g, 5.3 mmol) was added and the reaction mixture allowed to cool, with stirring, over 12 h then concentrated to dryness in vacuo. The residue was partioned between DCM/water, the organics dried (MgSO4) and concentrated to dryness in vacuo. The resulting residue in EtOH (10 ml) was hydrogenated with 10% w/w palladium on carbon (200 mg) under hydrogen at rt for 18 h. The reaction was filtered through celite and concentrated to dryness in vacuo to give 3-piperazine-1-yl-piperidine as a pale yellow gum (700 mg, 2.6 mmol, 97%). δH (CDCl.sub.3, 300K) 3.43-3.37 (4H, m br), 3.21 (1H, d br, J 11.6 Hz), 3.01 (1H, d br, J 12.2 Hz), 2.59-2.47 (6H, m br), 2.45-2.38 (1H, m), 1.99-1.92 (1H, m br), 1.82-1.75 (1H, m), 1.58-1.48 (1H, m), 1.45 (9H, s), 1.42-1.33 (1H, m). m/z (ES.sup.+, 70V) 270.3 (MH.sup.+).

INTERMEDIATE 40 (DDD100805)

4-bromo-2,6-dichloro-N-(difluoromethyl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzenesulfonamide

(48) A well-stirred slurry containing the compound of intermediate 2 (3.0 g, 7.2 mmol), potassium carbonate (3.0 g, 21 mmol) and sodium chlorodifluoroacetate (3.3 g, 21 mmol) in acetonitrile (100 ml) was heated to 60° C. for 48 h. The resulting slurry was then concentrated in vacuo, diluted with DCM (100 ml) and water (100 ml), the organic phase separated, dried (MgSO.sub.4) and concentrated in vacuo. Trituration of the residue with diethyl ether gave a precipitate which was collected by vacuum filtration and dried to give the title compound as a fine white powder (2.05 g, 4.43 mmol, 62%). δH (CDCl.sub.3, 300K) 7.61 (2H, s), 7.34 (1H, dd J 59.4 Hz 61.2 Hz), 3.67 (3H, s), 2.01 (3H, s), 1.71 (3H, s). m/z (ES.sup.+, 70V) 464.1 (MH.sup.+).

INTERMEDIATE 41

4-Bromo-N-(3-isobutyl-1,5-dimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(49) Prepared from 4-bromobenzenesulfonyl chloride (8.41 g, 32.9 mmol) and the amine of intermediate 46 (5.23 g, 31.3 mmol) in pyridine (80 ml) according to the method of intermediate 1, to give the title compound as a pale yellow solid (9.57 g, 24.8 mmol, 79%). δH (CDCl.sub.3, 300K) 7.61 (4H, m), 5.74 (1H, bs), 3.69 (3H, s), 2.07 (3H, s), 1.78 (2H, d J 7.0 Hz), 1.69 (1H, m), 0.75 (6H, d J 6.5 Hz). m/z (ES.sup.+, 70V) 386.1 (MH.sup.+).

INTERMEDIATE 42

4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(3-isobutyl-1,5-dimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(50) Prepared from the sulphonamide of intermediate 41 (1.00 g, 2.59 mmol) and bis-pinacolatodiboron (780 mg, 3.07 mmol), potassium acetate (5601 mg, 5.70 mmol) and Pd(dppf)Cl.sub.2.DCM (80 mg) in oxygen-free dioxane (8 ml) at 120° C. for 40 min according to the method of intermediate 32, to give the title compound as a grey coloured solid (919 mg, 2.12 mmol, 82%). δH (D-6 DMSO, 300K) 323K, 50° C. 8.97 (1H, s), 7.82 (2H, d, J 8.2 Hz), 7.67 (2H, d J 8.2 Hz), 3.56 (3H, s), 1.90 (2H, d J 7.1 Hz), 1.75 (3H, s), 1.72 (1H, m), 1.32 (12H, s), 0.72 (6H, d J 6.6 Hz). m/z (ES.sup.+, 70V) 434.2 (MH.sup.+).

INTERMEDIATE 43

1,5-Dimethyl-3-(2-methylprop-1-enyl)-1H-pyrazole

(51) A suspension of isopropyltriphenylphosphonium iodide (5.23 g, 12.1 mmol) in THF (35 ml) at −20° C. was treated dropwise with a 1.6 M solution of butyllithium in hexanes (7.5 ml, 12 mmol). The mixture was stirred at −20° C. for 45 minutes before a solution of 1,5-dimethyl-1H-pyrazole-3-carboxaldehyde (1.20 g, 9.68 mmol) in THF (50 ml) was added. The thick suspension was allowed to warm to room temperature and stirred for 24 hours. The reaction mixture was treated with saturated aqueous ammonium chloride (150 ml) and the phases separated. The aqueous phase was back-extracted with ethyl acetate (3×50 ml) and the combined organic phases were dried (Na.sub.2SO.sub.4) and concentrated. The residue was extracted with petroleum ether (2×100 ml) and the combined extracts were concentrated to afford a yellow oil which was purified by chromatography (SiO.sub.2, 0-100% EtOAc-petroleum ether) to give the title compound as a colourless solid (1.56 g, 9.68 mmol). δH (CDCl.sub.3, 300K) 6.15 (1H, m), 6.01 (1H, s), 3.75 (3H, s), 2.26 (3H, s), 1.96 (3H, d J 0.8 Hz), 1.89 (3H, d J 1.2 Hz). m/z (ES.sup.+, 70V) 151.1 (MH.sup.+).

INTERMEDIATE 44

3-Isobutyl-1,5-dimethyl-1H-pyrazole

(52) A solution of the compound of intermediate 43 (1.56 g, 9.68 mmol) in methanol (50 ml) was purged with argon and treated with 10% palladium on carbon (0.291 g). The reaction vessel was purged with hydrogen and stirred at room temperature overnight. The reaction vessel was purged with argon and further 10% palladium on carbon (0.498 g) was added. The mixture stirred under hydrogen for a further 24 hours, then filtered through celite and concentrated. The residue was resuspended in petroleum ether 40-60 (100 ml), filtered and concentrated. The resulting residue was again suspended in petroleum ether (50 ml), re-filtered and concentrated to give the title compound (1.064 g, 6.99 mmol, 72%) as a pale yellow oil. δH (CDCl.sub.3, 300K) 5.78 (3H, s), 3.71 (3H, s), 2.40 (2H, d J 7.1 Hz), 2.22 (31-1, s), 1.87 (1H, m), 0.92 (6H, d J 6.6 Hz). m/z (ES.sup.+, 70V) 153.1 (MH.sup.+).

INTERMEDIATE 45

3-Isobutyl-1,5-dimethyl-4-nitro-1H-pyrazole

(53) The compound of intermediate 44 (1.049 g, 6.89 mmol) at 0° C. was treated with concentrated sulphuric acid (3.5 ml, 66 mmol). Nitric acid (90%, 2.8 ml, 67 mmol) was added dropwise at the same temperature. The cooling bath was removed and the mixture heated at 100° C. for 2 h. The mixture was then cooled, poured onto ice (150 ml), basified with aqueous sodium hydroxide (2M, 100 ml) and extracted with diethyl ether (3×100 ml). The combined organic extracts were washed with brine, dried (Na.sub.2SO.sub.4) and concentrated to give the title compound as a yellow oil (1.082 g, 5.49 mmol, 80%). δH (CDCl.sub.3, 300K) 3.79 (3H, s), 2.77 (2H, d J 7.1 Hz), 2.60 (3H, s), 2.04 (1H, m), 0.94 (6H, d J 6.7 Hz). m/z (ES.sup.+, 70V) 198.1 (MH.sup.+).

INTERMEDIATE 46

3-Isobutyl-1,5-dimethyl-1H-pyrazol-4-amine

(54) The compound of intermediate 45 (1.072 g, 5.44 mmol) in methanol (25 ml) under argon was treated with 10% palladium on carbon (0.174 g). The reaction vessel was purged with hydrogen and stirred at room temperature for 23 hours. The reaction mixture was filtered through a plug of celite and concentrated. The residue was dissolved in dichloromethane, re-filtered and concentrated to give the title compound as a red oil (0.886 g, 5.30 mmol, 97%). δH (CDCl.sub.3, 300K) 3.67 (3H, s), 2.48 (2H, br.s), 2.39 (2H, d J 7.2 Hz), 2.13 (3H, s), 1.92 (1H, m), 0.94 (6H, d J 6.7 Hz). m/z (ES.sup.+, 70V) 168.2 (MH.sup.+).

INTERMEDIATE 47

4-bromo-2,6-dichloro-N-(2,2,2-trifluoroethyl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzenesulfonamide

(55) The compound of intermediate 2 (200 mg, 0.48 mmol) and K.sub.2CO.sub.3 (127 mg, 0.96 mmol) in acetonitrile (2.0 mL) was, treated dropwise with 2,2,2-trifluoroethyl methanesulphonate (0.139 mL, 223 mg, 0.139 mmol) and the mixture heated in a microwave at 100° C. for 30 min. The mixture was then diluted with ethyl acetate (30.0 mL) and the organic layer washed with water (2×10 mL), brine (10 mL), dried over MgSO.sub.4 and concentrated in vacuo. The crude material was purified by column chromatography (SiO.sub.2, 6:4 Hexanes:EtOAc) to give the title compound as a colourless solid (217 mg, 0.44 mmol, 91%). δH (CDCl.sub.3, 300K) 7.58 (2H, s), 4.82-4.68 (1H, m), 3.97-3.68 (1H, m), 3.68 (3H, s), 2.17 (3H, s), 1.68 (3H, s). m/z (ES.sup.+, 70V) 496.2 (M+H.sup.+).

EXAMPLE DDD73498

6-(8-Amino-3,4-dihydro-1H-isoquinolin-2-yl)-pyridine-3-sulfonic acid (1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

(56) Prepared from the sulphonamide of intermediate 5 (1.33 gmg, 4.43 mmol) and 5-amino-1,2,3,4-tetrahydroisoquinoline (1.31 g, 8.8 mmol) in ethanol (0.75 ml), according to the method of example DDD86213, to give the title compound as a white powder (1.21 g, 2.94 mmol, 66%). δH (CDCl.sub.3, 300K) 8.41 (1H, d J 2.5 Hz), 7.64 (1H, dd J 2.5 Hz 9.1 Hz), 7.36 (1H, s), 7.03 (1H, t J 7.8 Hz), 6.69 (2H, t J 7.8 Hz), 6.58 (1H, d J 9.1 Hz), 4.70 (2H, s), 3.95 (2H, t J 6.0 Hz), 3.62 (3H, s), 2.72 (2H, t J 6.0 Hz), 2.01 (3H, s), 1.74 (3H, s). m/z (ES.sup.+, 70V) 413.2 (MH.sup.+).

EXAMPLE DDD85602

6-[2-(4-Methyl-piperazin-1-yl)-ethylamino]-pyridine-3-sulfonic acid (1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

(57) Prepared from the sulphonamide of intermediate 5 (225 mg, 0.75 mmol) and 4-(2-aminoethyl)-methylpiperazine (0.5 ml) in ethanol (0.75 ml), according to the method of example DDD86213, to give the title compound as a white powder (198 mg, 0.49 mmol, 65%). δH (D-6 DMSO, 300K) 8.77 (1H, s), 8.07 (1H, d J 2.4 Hz), 7.45 (1H, dd J 2.2 Hz 8.9 Hz), 7.28 (1H, s br), 6.54 (1H, d J 8.9 Hz), 3.57 (3H, s), 3.44-3.39 (2H, m), 2.41 (2H, t J 6.1 Hz), 2.41 (4H, s br), 2.36-2.31 (4H and 3H, s br), 2.16 (3H, s), 1.89 (3H, s), 1.67 (3H, s). m/z (ES.sup.+, 70V) 408.2 (MH.sup.+).

EXAMPLE DDD85646

2,6-Dichloro-4-(2-piperazin-1-yl-pyridin-4-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(58) Prepared from the sulphonamide of intermediate 2 (250 mg, 0.61 mmol), 2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (211 mg, 0.73 mmol), tribasic potassium phosphate (155 mg, 0.73 mmol), and Pd(dppf)Cl.sub.2.DCM (30 mg, 0.36 mmol) in DMF (2.5 ml) and water (0.50 ml), according to the method of intermediate 11, to give the title compound as an off-white powder (150 mg, 0.30 mmol, 50%). δH (D-6 DMSO, 300K) 9.79 (1H, s), 8.25 (1H, d J 5.9 Hz), 8.20 (2H, s), 7.61 (1H, s), 7.40 (1H, d J 5.9 Hz), 4.08 (4H, s br), 3.63 (3H, s), 3.28 (4H, s br), 2.00 (3H, s), 1.77 (3H, s). m/z (ES.sup.+, 70V) 496.1 (MH.sup.+).

EXAMPLE DDD86206

2-Chloro-4-(2-piperazin-1-yl-pyridin-4-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(59) Prepared from the sulphonamide of intermediate 3 (500 mg, 1.3 mmol), 2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (580 mg, 2.0 mmol), tribasic potassium phosphate (427 mg, 2.0 mmol), and Pd(dppf)Cl.sub.2.DCM (50 mg, 0.06 mmol) in DMF (3.0 ml) and water (0.75 ml), according to the method of intermediate 11, to give the title compound as an off-white powder (412 mg, 0.89 mmol, 68%). δH (D-6 DMSO, 300K) 8.20 (1H, d J 5.2 Hz), 8.14 (1H, d J 1.7 Hz), 7.84 (1H, dd J 1.75 Hz 8.3 Hz), 7.79 (1H, d J 8.3 Hz), 7.13 (1H, s), 6.99 (1H, dd J 1.15 Hz 5.2 Hz), 3.55 (3H, s), 3.51 (4H, s br), 2.79 (4H, s br), 1.90 (3H, s), 1.69 (3H, s). m/z (ES.sup.+, 70V) 461.2 (MH.sup.+).

EXAMPLE DDD86211

2,6-Dichloro-4-[2-(4-methyl-piperazin-1-yl)-pyridin-4-yl]-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(60) Prepared by heating the chloropyridine of intermediate 12 (90 mg, 0.2 mmol) with N-methylpiperazine (100 μl) in EtOH (1.5 ml) at 150° C. for 1 h according to the method of DDD86213 to give the title compound as an off-white powder (45 mg, 0.08 mmol, 40%). δH (CDCl.sub.3, 300K) 8.54 (1H, d J 5.1 Hz), 7.57 (1H, d J 1.8 Hz), 7.53 (1H, d J 0.95 Hz), 7.46 (1H, s), 7.42 (1H, dd J 1.6 Hz 5.1 Hz), 3.69 (3H, s), 3.29 (4H, s br), 2.66 (3H, s), 2.42 (4H, s br), 2.17 (3H, s), 1.80 (3H, s). m/z (ES.sup.+, 70V) 509.1 (MH.sup.+).

EXAMPLE DDD86212

3′-(4-Methyl-piperazin-1-ylmethyl)-biphenyl-4-sulfonic acid (1,3,6-trimethyl-1H-pyrazol-4-yl)-amide

(61) Prototypical Procedure for the Reductive Amination of an Aldehyde with an Alkylamine;

(62) The aldehyde of intermediate 14 (200 mg, 0.54 mmol), N-methylpiperazine (100 mg, 1.0 mmol) and sodium triacetoxyborohydride (400 mg, 1.90 mmol) in CHCl.sub.3 (15 ml) was heated at 50° C. for 24 h. Dilution with DCM (25 ml), washing with water (2×10 ml), drying (MgSO.sub.4) and concentration in vacuo gave a gum which was subjected to chromatography (SiO.sub.2, 50:10:1 EtOAc:MeOH:saturated aqueous ammonia solution) to give the title compound as a white powder (217 mg, 0.48 mmol, 89%). δH (D-6 DMSO, 300K) 9.20 (1H, s), 8.11 (1H, s br), 7.96 (2H, d J 8.4 Hz), 7.83 (1H, d J 6.95 Hz), 7.71 (2H, d J 8.4 Hz), 7.67 (1H, s br), 7.59 (1H, t J 7.6 Hz), 3.63 (2H, s), 3.57 (3H, s), 3.44 (4H, s br), 2.81 (4H, s br), 1.85 (3H, s), 1.58 (3H, s). m/z (ES.sup.+, 70V) 453.1 (MH.sup.+).

EXAMPLE DDD86213

4-(2-Piperazin-1-yl-pyridin-4-yl)-N-(1,3,6-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(63) Prototypical Procedure for Preparation of a 2-Aminopyridine by Displacement Reaction of a 2-Chloropyridine with an Alkylamine;

(64) METHOD 1: The compound of intermediate 11 (250 mg, 0.66 mmol) and piperazine (500 mg, 5.8 mmol) in EtOH (0.75 ml) was heated at 155° C. for 2 h by microwave in a sealed vessel. Dilution with DCM (25 ml), washing with aqueous sodium hydrogencarbonate solution (2×5 ml), drying (MgSO.sub.4) and concentration in vacuo gave a residual oil which was subjected to chromatography (SiO.sub.2, 50:10:1 EtOAc:MeOH:saturated aqueous ammonia solution) to give the title compound as a white powder (189 mg, 0.44 mmol, 67%). δH (D-6 DMSO, 300K) 8.24 (1H, d J 5.2 Hz), 8.00 (2H, dd J 1.8 Hz 6.7 Hz), 7.74 (2H, dd J 1.8 Hz 6.7 Hz), 7.12 (1H, s), 7.00 (1H, dd J 5.2 Hz 1.4 Hz), 3.60 (3H, s), 3.54 (4H, s br), 2.84 (4H, s br), 1.87 (3H, s), 1.68 (3H, s). m/z (ES.sup.+, 70V) 426.1 (MH.sup.+).

(65) METHOD 2: Alternatively this compound could be prepared by Suzuki reaction of the sulphonamide of intermediate 1 (500 mg, 1.68 mmol), 2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (581 mg, 2.0 mmol), tribasic potassium phosphate (427 mg, 2.0 mmol), and Pd(dppf)Cl.sub.2.DCM (50 mg, 0.06 mmol) in DMF (3.0 ml) and water (0.75 ml), according to the method of intermediate 11, to give the title compound as an off-white powder (381 mg, 0.89 mmol, 53%).

EXAMPLE DDD86292

2,6-Dichloro-4-[2-(3-dimethylamino-pyrrolidin-1-yl)-pyridin-4-yl]-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(66) Prepared by heating the chloropyridine of intermediate 12 (250 mg, 0.58 mmol) with 3-dimethylaminopiperidine (200 μl) in EtOH (1.5 ml) at 155° C. for 1 h according to the method of DDD86213 to give the title compound as a white powder (150 mg, 0.29 mmol, 49%). δH (CDCl3, 300K) 8.48 (1H, d J 5.1 Hz), 7.49 (2H, s), 7.39 (1H, d J 4.7 Hz), 7.32 (1H, s), 3.76-3.46 (6H, s br), 3.63 (3H, s), 3.46-3.39 (1H, m), 2.75 (2H, s br), 2.28 (2H, s br), 2.05 (3H, s), 1.85 (3H, s), 1.56 (2H, s br). m/z (ES.sup.+, 70V) 523.2 (MH.sup.+).

EXAMPLE DDD86297

2,6-Dichloro-4-[2-(2-methylamino-ethylamino)-pyridin-4-yl]N-(1,3,6-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(67) Prepared by heating the chloropyridine of intermediate 12 (250 mg, 0.58 mmol) with N-methylethylenediamine (200 μl) in EtOH (1.5 ml) at 155° C. for 1 h according to the method of DDD86213 to give the title compound as a white powder (134 mg, 0.28 mmol, 48%). δH (D-6 DMSO, 300K) 8.53 (1H, d J 5.2 Hz), 7.98 (1H, d J 0.9 Hz), 7.85 (1H, dd J 1.5 Hz 5.2 Hz), 7.28 (1H, s), 7.21 (1H, d J 1.5 Hz), 7.04 (1H, d J 1.5 Hz), 3.60 (3H, s), 3.24-3.20 (2H, m), 2.64-2.58 (2H, m), 2.29 (3H, s), 1.98 (3H, s), 1.82 (3H, s). m/z (ES.sup.+, 70V) 483.1 (MH.sup.+).

EXAMPLE DDD86302

2,6-Dichloro-4-{2-[2-(pyridin-2-ylamino)-ethylamino]-pyridin-4-yl}-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(68) Prepared by heating the chloropyridine of intermediate 12 (250 mg, 0.58 mmol) with N-(2-pyridyl)ethylenediamine (200 μl) in EtOH (1.5 ml) at 155° C. for 1 h according to the method of DDD86213 to give the title compound as a white powder (111 mg, 0.2 mmol, 35%). δH (D-6 DMSO, 300K) 9.41 (1H, s), 8.51 (1H, d J 5.1 Hz), 7.93 (1H, d J 4.9 Hz), 7.91 (1H, s), 7.79 (1H, d J 5.2 Hz), 7.36 (1H, t J 7.1 Hz), 7.27 (1H, s), 7.20-7.18 (1H, m), 7.17 (1H, s), 6.60 (1H, s), 6.54-6.44 (2H, m), 3.55 (3H, s), 3.41-3.23 (4H, m), 1.92 (3H, s), 1.79 (3H, s). m/z (ES.sup.+, 70V) 546.1 (MH.sup.+).

EXAMPLE DDD86303

2,6-Dichloro-4-{2-[2-(pyridin-2-ylamino)-ethylamino]-pyridin-4-yl}-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(69) Prepared by heating the chloropyridine of intermediate 12 (250 mg, 0.58 mmol) with ethylenediamine (200 μl) in EtOH (1.5 ml) at 155° C. for 1 h according to the method of DDD86213 to give the title compound as a white powder (137 mg, 0.29 mmol, 50%). δH (D-6 DMSO, 300K) 8.49 (1H, d J 4.1 Hz), 7.93 (1H, s), 7.80 (1H, d J 4.9 Hz), 7.22 (1H, s br), 7.17 (1H, s), 7.01 (1H, s), 4.03 (2H, s br), 3.55 (3H, s), 3.16 (2H, s br), 2.63 (2H, t J 7.1 Hz), 1.94 (3H, s), 1.78 (3H, s). m/z (ES.sup.+, 70V) 469.2 (MH.sup.+).

EXAMPLE DDD86308

2,6-Dichloro-4-[2-(3-imidazol-1-yl-propylamino)-pyridin-4-yl]-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(70) Prepared by heating the chloropyridine of intermediate 12 (250 mg, 0.58 mmol) with N-(3-aminopropyl)imidazole (200 μl) in EtOH (1.5 ml) at 155° C. for 1 h according to the method of DDD86213 to give the title compound as a white powder (130 mg, 0.24 mmol, 41%). δH (CDCl.sub.3, 300K) 8.46 (1H, dd J 0.5 Hz 5.1 Hz), 7.52 (1H, s), 7.46 (1H, dd J 0.5 Hz 1.5 Hz), 7.35 (1H, dd J 1.5 Hz 5.2 Hz), 7.24 (1H, t J 4.9 Hz), 7.1 Hz (1H, s), 7.00 (1H, d J 1.8 Hz), 6.83 (2H, s), 6.58 (1H, d J 1.8 Hz), 3.92 (2H, t J 6.1 Hz), 3.60 (3H, s), 3.04 (2H, q J 6.1 Hz), 2.13 (3H, s), 2.05 (2H, p J 6.1 Hz), 1.89 (3H, s). m/z (ES.sup.+, 70V) 534.1 (MH.sup.+).

EXAMPLE DDD86309

2,6-Dichloro-4-[2-(2-dimethylamino-ethylamino)-pyridin-4-yl]-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(71) Prepared by heating the chloropyridine of intermediate 12 (250 mg, 0.58 mmol) with N,N-dimethylethylenediamine (200 μl) in EtOH (1.5 ml) at 155° C. for 1 h according to the method of DDD86213 to give the title compound as a white powder (70 mg, 0.14 mmol, 24%). δH (CDCl.sub.3, 300K) 8.50 (1H, d J 5.1 Hz), 7.53 (1H, s), 7.44 (1H, d J 3.8 Hz), 7.39 (1H, t J 4.5 Hz), 7.02 (1H, s), 6.98 (1H, s), 6.76 (1H, s), 3.68 (3H, s), 3.27 (″h, s br), 2.60 (2H, s br), 2.31 (6H, s br), 2.14 (3H, s), 2.89 (3H, s). m/z (ES.sup.+, 70V) 497.1 (MH.sup.+).

EXAMPLE DDD86312

3′-Diethylaminomethyl-biphenyl-4-sulfonic acid (1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

(72) Prepared from the aldehyde of intermediate 14 (80 mg, 0.23 mmol), diethylamine (0.088 ml, 50 mg, 0.069 mmol) and sodium triacetoxyborohydride (146 mg, 0.069 mmol) in CHCl.sub.3 (5.0 ml) at 50° C. for 24 h according to the method of example DDD86212 to give the title compound as a white solid (55 mg, 0.13 mmol, 56%). δH (CDCl.sub.3, 300K) 7.78 (2H, d J 8.6 Hz), 7.71 (2H, d J 8.5 Hz), 7.66 (1H, s br), 7.50 (1H, d J 6.8 Hz), 7.42 (2H, d J 5.8 Hz), 5.84 (1H, s), 3.71 (1H, s br), 3.68 (3H, s), 2.64 (3H, s br), 2.08 (3H, s), 1.62 (3H, s), 1.13 (6H, s br). m/z (ES.sup.+, 70V) 427.2 (MH.sup.+).

EXAMPLE DDD86314

3′-Morpholin-4-ylmethyl-biphenyl-4-sulfonic acid (1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

(73) Prepared from the aldehyde intermediate 14 (150 mg, 0.41 mmol), morpholine (107 μl, 107 mg, 1.23 mmol) and sodium triacetoxyborohydride (261 mg, 1.23 mmol) in CHCl.sub.3 (10.0 ml) at 50° C. for 24 h according to the method of example DDD86212 to give the title compound as a white solid (90 mg, 0.21 mmol, 50%). δH (CDCl.sub.3, 300K) 7.79 (2H, d J 8.3 Hz), 7.69 (2H, d J 8.3 Hz), 7.57 (1H, s br), 7.50 (1H, d J 7.5 Hz), 7.43 (1H, t J 7.5 Hz), 7.39 (1H, d J 7.5 Hz), 5.74 (1H, s br), 3.73 (3H, t J 4.6 Hz), 3.69 (3H, s), 3.57 (2H, s), 2.49 (3H, s br), 2.11 (3H, s), 1.61 (3H, s), 1.55 (1H, s br). m/z (ES.sup.+, 70V) 441.1 (MH.sup.+).

EXAMPLE DDD86315

4-[4′-(1,3,5-Trimethyl-1H-pyrazol-4-ylsulfamoyl)-biphenyl-3-ylmethyl]-piperazine-1-carboxylic acid tert-butyl ester

(74) Prepared from the aldehyde of intermediate 14 (150 mg, 0.41 mmol), N-Boc piperazine (229 mg, 1.23 mmol) and sodium triacetoxyborohydride (261 mg, 1.23 mmol) in CHCl.sub.3 (10.0 ml) at 50° C. for 24 h according to the method of example DDD86212 to give the title compound as a white solid (120 mg, 0.14 mmol, 54%). δH (CDCl.sub.3, 300K) 7.79 (2H, d J 8.4 Hz), 7.69 (2H, d J 8.4 Hz), 7.56 (1H, s br), 7.50 (1H, d, J 7.7 Hz), 7.43 (1H, t J 7.6 Hz), 7.38 (1H, d, J 7.7 Hz), 5.74 (1H, s), 3.69 (3H, s), 3.58 (2H, s), 3.45 (4H, t J 5.0 Hz), 2.43 (4H, t J 4.5 Hz), 2.11 (3H, s), 1.54 (3H, s), 1.46 (9H, s). m/z (ES.sup.+, 70V) 540.1 (MH.sup.+).

EXAMPLE DDD86316

3′-[(2-Dimethylamino-ethylamino)-methyl]biphenyl-4-sulfonic acid (1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

(75) Prepared from the aldehyde of intermediate 14 (150 mg, 0.41 mmol), NN′-dimethylethylenediamine (134 μl, 108 mg, 1.23 mmol) and sodium triacetoxyborohydride (261 mg, 1.23 mmol) in CHCl.sub.3 (10.0 ml) at 50° C. for 18 h according to the method of example DDD86212 to give the title compound as a white solid (60 mg, 0.14 mmol, 33%). δH (CDCl.sub.3, 300K) 7.78 (2H, d J 8.4 Hz), 7.69 (2H, d J 8.5 Hz), 7.59 (1H, s br), 7.48 (1H, d J 7.6 Hz), 7.43 (1H, t J 7.5 Hz), 7.38 (1H, d J 7.5 Hz), 5.75 (1H, s), 3.89 (2H, s), 3.68 (3H, s), 2.74 (2H, t J 5.9 Hz), 2.46 (2H, t J 6.2 Hz), 2.22 (6H, s), 2.08 (3H, s), 1.63 (3H, s). m/z (ES.sup.+, 70V) 442.1 (MH.sup.+).

EXAMPLE DDD86317

3′-Piperazin-1-ylmethyl-biphenyl-4-sulfonic acid (1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

(76) Prepared from the aldehyde of intermediate 14 (150 mg, 0.41 mmol), piperazine (106 mg, 1.23 mmol) and sodium triacetoxyborohydride (261 mg, 1.23 mmol) in CHCl.sub.3 (10.0 ml) at 50° C. for 24 h according to the method of example DDD86212 to give the title compound as a white solid (94 mg, 0.21 mmol, 52.0%). δH (CDCl.sub.3, 300K) 7.79 (2H, d J 8.4 Hz), 7.69 (2H, d J 8.3 Hz), 7.56 (1H, s br), 7.49 (1H, d J 7.6 Hz), 7.42 (1H, t J 7.6 Hz), 7.38 (1H, d J 7.5 Hz), 5.87 (1H, s br), 3.68 (3H, s), 3.58 (2H, s), 2.96 (4H, t J 4.8 Hz), 2.51 (4H, s br), 2.10 (3H, s), 1.62 (3H, s). m/z (ES.sup.+, 70V) 440.1 (MH.sup.+).

EXAMPLE DDD86318

3′-Pyrrolidin-1-ylmethyl-biphenyl-4-sulfonic acid (1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

(77) Prepared from the aldehyde of intermediate 14 (80 mg, 0.23 mmol), pyrrolidine (57.0 μl, 49 mg, 0.069 mmol) and sodium triacetoxyborohydride (146 mg, 0.069 mmol) in CHCl.sub.3 (5.0 ml) at 50° C. for 24 h according to the method of example DDD86212 to give the title compound as a white solid (85 mg, 0.20 mmol, 87%). δH (CDCl.sub.3, 300K) 7.78 (2H, d J 8.4 Hz), 7.71 (2H, d J 8.3 Hz), 7.51 (2H, s br), 7.43 (2H, d J 6.6 Hz), 5.76 (1H, s), 3.77 (2H, s br), 3.68 (3H, s), 2.64 (4 h, s br), 2.08 (3H, s), 1.86 (4H, s br), 1.64 (3H, s). m/z (ES.sup.+, 70V) 425.1 (MH.sup.+).

EXAMPLE DDD86467

2,6-Dichloro-N-(5-isobutyl-1,3-dimethyl-1H-pyrazol-4-yl)-4-(2-piperazin-1-yl-pyridin-4-yl)-benzenesulfonamide

(78) Prepared from the sulphonamide of intermediate 23B (115 mg, 0.25 mmol), 2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (80 mg, 0.28 mmol), tribasic potassium phosphate (60 mg, 0.28 mmol), and Pd(PPh.sub.3).sub.4 (30 mg, 0.026 mmol) in DMF (1.6 ml) and water (0.4 ml), according to the method of intermediate 11, to give the title compound as a yellow solid (50 mg, 0.09 mmol, 37%). δH (D-6 DMSO, 300K) 8.20, (1H, d, J 5.3 Hz), 8.07 (2H, s), 7.16 (1H, s), 7.03 (1H, d, J 5.3 Hz), 3.59 (3H, s), 3.52 (4H, m), 2.80 (4H, m), 2.21 (2H, d J 7.5 Hz), 1.98 (1H, m), 1.77 (3H, s), 0.75 (6H, d J 6.6 Hz). m/z (ES.sup.+, 70V) 537.2 (MH.sup.+).

EXAMPLE DDD86468

2,6-Dichloro-N-(3,5-dimethyl-isoxazol-4-yl)-4-(2-piperazin-1-yl-pyridin-4-yl)-benzenesulfonamide

(79) Prepared from the sulphonamide of intermediate 7 (100 mg, 0.25 mmol), 2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (87 mg, 0.30 mmol), tribasic potassium phosphate (72 mg, 0.34 mmol), and Pd(PPh.sub.3).sub.4 (30 mg, 0.026 mmol) in DMF (1.6 ml) and water (0.4 ml), according to the method of intermediate 11, to give the title compound as a yellow solid (12 mg, 0.025 mmol, 10%). δH (D-6 DMSO, 300K) 8.20, (1H, d J 5.3 Hz), 7.94 (2H, s), 7.21 (1H, s), 7.08 (1H, d J 5.3 Hz), 3.65 (4H, m), 2.97 (4H, m), 1.96 (3H, s), 1.91 (3H, s). m/z (ES.sup.+, 70V) 482.1 (MH.sup.+).

EXAMPLE DDD86469

2,6-Dichloro-4-[3-(4-methyl-piperazin-1-yl)-prop-1-ynyl]N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(80) Prepared from the sulphonamide of intermediate 2 (355 mg, 0.86 mmol), 1-methyl-4-prop-2-ynyl-piperazine (142 mg, 1.03 mmol), CuI (8.2 mg, 0.043 mmol) and Pd(PPh.sub.3).sub.4 (50 mg, 0.043 mmol), in DMF (3.0 ml) and NEt.sub.3 (2.0 ml) according to the method of intermediate 36, to give the title compound as an off-white solid (150 mg, 0.32 mmol, 37%). δH (CDCl.sub.3, 300K) 7.47 (2H, s), 6.58 (1H, s), 3.67 (3H, s), 3.56 (2H, s), 2.67 (4H, s br), 2.51 (4H, s br), 2.32 (3H, s br), 2.13 (3H, s), 1.78 (3H, s). m/z (ES.sup.+, 70V) 470.1 (MH.sup.+).

EXAMPLE DDD86470

2,6-Dichloro-N-(3,5-dimethyl-isoxazol-4-yl)-4-(2-piperazin-1-yl-pyridin-4-yl)-benzenesulfonamide

(81) Prepared from the boronic ester of intermediate 35 (184 mg, 0.4 mmol), 4-(3-bromophenyl)piperidine hydrochloride (133 mg, 0.48 mmol), tribasic potassium phosphate (144 mg, 0.68 mmol), and Pd(PPh.sub.3).sub.4 (48 mg, 0.042 mmol) in DMF (3.2 ml) and water (0.8 ml), according to the method of intermediate 11, to give the title compound as a yellow solid (20 mg, 0.040 mmol, 16%). δH (CDCl.sub.3, 300K) 7.63 (2H, s), 7.41 (3H, m), 7.33 (1H, d J 6.6 Hz), 3.68 (3H, s), 3.23 (2H, d J 12.0 Hz), 2.78 (2H, dt J 12.1 Hz 2.1 Hz), 2.71 (1H, tt J 12.1 Hz 3.6 Hz), 2.18 (3H, s), 1.88 (2H, d J 12.6 Hz), 1.73 (3H, s), 1.70 (2H, qd J 12.5 Hz 3.8 Hz). m/z (ES.sup.+, 70V) 493.1 (MH.sup.+).

EXAMPLE DDD86471

N-(1,3-Dimethyl-1H-pyrazol-4-yl)-4-(2-piperazin-1-yl-pyridin-4-yl)-benzenesulfonamide

(82) Prepared from the sulphonamide of intermediate 28 (83 mg, 0.25 mmol), 2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (80 mg, 0.28 mmol), tribasic potassium phosphate (60 mg, 0.28 mmol), and Pd(PPh.sub.3).sub.4 (30 mg, 0.026 mmol) in DMF (1.6 ml) and water (0.6 ml), according to the method of intermediate 11, to give the title compound as a white solid (48 mg, 0.12 mmol, 47%). δH (D-6 DMSO, 300K) 8.20 (1H, d J 5.2 Hz), 7.95 (2H, d J 8.3 Hz), 7.74 (2H, d J 8.3 Hz), 7.41 (1H, s), 7.08 (1H, s), 6.97 (1H, d J 5.2 Hz), 3.65 (3H, s), 3.50 (4H, m), 2.80 (4H, m), 1.70 (3H, s). m/z (ES.sup.+, 70V) 413.2 (MH.sup.+).

EXAMPLE DDD86474

N-(1-Methyl-1H-pyrazol-4-yl)-4-(2-piperazin-1-yl-pyridin-4-yl)-benzenesulfonamide

(83) Prepared from the sulphonamide of intermediate 30 (79 mg, 0.25 mmol), 2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (80 mg, 0.28 mmol), tribasic potassium phosphate (60 mg, 0.28 mmol), and Pd(PPh.sub.3).sub.4 (30 mg, 0.026 mmol) in DMF (1.6 ml) and water (0.6 ml), according to the method of intermediate 11, to give the title compound as a white solid (46 mg, 0.12 mmol, 47%). δH (D-6 DMSO, 300K) 8.19 (1H, d J 5.2 Hz), 7.93 (2H, d J 8.4 Hz), 7.78 (2H, d J 8.4 Hz), 7.49 (1H, s), 7.06 (2H, s), 6.95 (1H, d J 5.2 Hz), 3.71 (3H, s), 3.49 (4H, m), 2.79 (4H, m). m/z (ES.sup.+, 70V) 399.2 (MH.sup.+).

EXAMPLE DDD86475

2,6-Dichloro-N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-(2-piperazin-1-yl-pyridin-4-yl)-benzenesulfonamide

(84) Prepared from the sulphonamide of intermediate 29 (100 mg, 0.25 mmol), 2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (80 mg, 0.28 mmol), tribasic potassium phosphate (60 mg, 0.28 mmol), and Pd(PPh.sub.3).sub.4 (30 mg, 0.026 mmol) in DMF (1.6 ml) and water (0.6 ml), according to the method of intermediate 11, to give the title compound as a white solid (14 mg, 0.03 mmol, 12%). δH (D-6 DMSO, 300K) 8.16 (1H, d J 5.2 Hz), 7.97 (2H, s), 7.41 (1H, s), 7.12 (1H, s), 7.00 (1H, d J 5.2 Hz), 3.60 (3H, s), 3.50 (4H, m), 2.77 (4H, m), 1.84 (3H, s). m/z (ES.sup.+, 70V) 481.1 (MH.sup.+).

EXAMPLE DDD86478

2,6-Dichloro-N-(1-methyl-1H-pyrazol-4-yl)-4-(2-piperazin-1-yl-pyridin-4-yl)-benzenesulfonamide

(85) Prepared from the sulphonamide of intermediate 31 (96 mg, 0.25 mmol), 2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (80 mg, 0.28 mmol), tribasic potassium phosphate (60 mg, 0.28 mmol), and Pd(PPh.sub.3).sub.4 (30 mg, 0.026 mmol) in DMF (1.6 ml) and water (0.6 ml), according to the method of intermediate 11, to give the title compound as a yellow solid (87 mg, 0.19 mmol, 74%). δH (D-6 DMSO, 300K) 8.19 (1H, d J 5.2 Hz), 7.99 (2H, s), 7.49 (1H, s), 7.14 (1H, s), 7.13 (1H, s), 7.02 (1H, d J 5.2 Hz), 3.70 (3H, s), 3.54 (4H, m), 2.83 (4H, m). m/z (ES.sup.+, 70V) 467.1 (MH.sup.+).

EXAMPLE DDD86479

3,5-Dichloro-3′-piperazin-1-yl-biphenyl-4-sulfonic acid (1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

(86) Prepared from the boronic ester of intermediate 35 (115 mg, 0.25 mmol), 1-(3-bromophenyl)piperazine (72 mg, 0.48 mmol), tribasic potassium phosphate (72 mg, 0.34 mmol), and Pd(PPh.sub.3).sub.4 (30 mg, 0.026 mmol) in DMF (1.6 ml) and water (0.4 ml), according to the method of intermediate 11, to give the title compound as a yellow solid (21 mg, 0.042 mmol, 17%). δH (CDCl.sub.3, 300K) 7.67 (2H, s), 7.39 (1H, t J 7.8 Hz), 7.04 (3H, m), 3.70 (3H, s), 3.25 (4H, m), 3.09 (4H, m), 2.19 (3H, s), 1.81 (3H, s). m/z (ES.sup.+, 70V) 494.1 (MH.sup.+).

EXAMPLE DDD86480

2,6-Dichloro-N-(2-methyl-pyridin-3-yl)-4-(2-piperazin-1-yl-pyridin-4-yl)-benzenesulfonamide

(87) Prepared from the sulphonamide of intermediate 9 (100 mg, 0.25 mmol), 2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (87 mg, 0.30 mmol), tribasic potassium phosphate (180 mg, 0.85 mmol), and Pd(PPh.sub.3).sub.4 (30 mg, 0.026 mmol) in DMF (1.6 ml) and water (0.6 ml), according to the method of intermediate 11, to give the title compound as a tan coloured solid (37 mg, 0.077 mmol, 31%). δH (D-6 DMSO, 300K) 8.18 (1H, d J 5.3 Hz), 7.78 (2H, s), 7.64 (1H, d J 4.5 Hz), 7.31 (1H, d J 7.7 Hz), 7.15 (1H, s), 7.13 (1H, s), 7.02 (1H, d J 4.7 Hz), 6.79 (1H, dd J 8.1 Hz 4.6 Hz), 3.70 (4H, m), 3.05 (4H, m), 2.29 (3H, s). m/z (ES.sup.+, 70V) 478.1 (MH.sup.+).

EXAMPLE DDD86481

2,6-Dichloro-N-(3-isobutyl-1,5-dimethyl-1H-pyrazol-4-yl)-4-(2-piperazin-1-yl-pyridin-4-yl)-benzenesulfonamide

(88) Prepared from the sulphonamide of intermediate 23A (115 mg, 0.25 mmol), 2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (80 mg, 0.28 mmol), tribasic potassium phosphate (60 mg, 0.28 mmol), and Pd(PPh.sub.3).sub.4 (30 mg, 0.026 mmol) in DMF (1.6 ml) and water (0.4 ml), according to the method of intermediate 11, to give the title compound as a yellow solid (73 mg, 0.14 mmol, 54%). δH (D-6 DMSO, 300K) 8.20, (1H, d J 5.2 Hz), 8.06 (2H, s), 7.15 (1H, s), 7.02 (1H, d J 5.2 Hz), 3.60 (3H, s), 3.52 (4H, m), 2.80 (4H, m), 1.98 (3H, s), 1.92 (2H, d J 7.3 Hz), 1.70 (1H, m), 0.70 (6H, d J 6.6 Hz). m/z (ES.sup.+, 70V) 537.2 (MH.sup.+).

EXAMPLE DDD87748

(34-[2-(3-Methyl-piperazin-1-yl)-pyridin-4-yl]-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(89) Prepared from the compound of intermediate 11 (250 mg, 0.66 mmol) and 2-methyl piperazine (500 mg, 5.0 mmol) in EtOH (0.75 ml) according to the method of DDD86213 to give the title compound as a white powder (157 mg, 0.36 mmol, 55%). δH (D-6 DMSO, 300K) 9.21 (1H, s), 8.23 (1H, d J 5.2 Hz), 8.01 (2H, d J 8.4 Hz), 7.74 (2H, d J 8.4 Hz), 7.13 (1H, s), 7.00 (1H, d J 5.2 Hz), 4.28 (2H, t J 13.3 Hz), 3.60 (3H, s), 3.00 (1H, d J 9.6 Hz), 2.80-2.68 (3H, m), 2.39 (1H, t J 11.3 Hz), 1.88 (3H, s), 1.63 (3H, s), 1.08 (3H, d J 6.2 Hz). m/z (ES.sup.+, 70V) 441.2 (MH.sup.+).

EXAMPLE DDD87749

4-(3,4,5,6-Tetrahydro-2H-[1,2′]bipyridinyl-4′-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(90) Prepared from the compound of intermediate 11 (250 mg, 0.66 mmol) and piperidine (500 mg, 5.7 mmol) in EtOH (0.75 ml) according to the method of DDD86213 to give the title compound as a white powder (189 mg, 0.44 mmol, 67%). δH (D-6 DMSO, 300K) 9.20 (1H, s), 8.19 (1H, d J 5.2 Hz), 7.96 (2H, d J 8.4 Hz), 7.74 (2H, d J 8.4 Hz), 7.13 (1H, s), 6.96 (1H, d J 5.2 Hz), 3.68-3.62 (4H, m), 3.61 (3H, s), 1.87 (3H, s), 1-70-1.55 (6H, M), 1.63 (3H, s). m/z (ES.sup.+, 70V) 426.2 (MH.sup.+).

EXAMPLE DDD87751

3′-(2-Hydroxy-ethyl)-biphenyl-4-sulfonic acid (1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

(91) Prepared from the sulphonamide of Intermediate 1 (1.0 g, 2.91 mmol), 3-hydroxyethylphenyl boronic acid (579 mg, 3.49 mmol), tribasic potassium phosphate (740 mg, 3.49 mmol), Pd(dppf)Cl.sub.2.DCM (119 mg, 0.146 mmol) and water (2.0 ml) in oxygen-free DMF (10.0 ml) at 130° C. for 1 h according to the method of intermediate 11, to give the title compound as a colourless solid (500 mg, 1.30 mmol, 45%). δH (CDCl.sub.3, 300K) 7.78 (2H, d J 8.3 Hz), 7.68 (2H, d J 8.4 Hz), 7.49-7.47 (2H, m), 7.43 (1H, t J 8.4 Hz), 7.30 (1H, d J 7.4 Hz), 5.79 (1H, s br), 3.93 (2H, q J 6.3 Hz), 3.68 (3H, s), 2.96 (3H, t J 6.5 Hz), 2.09 (3H, s), 1.61 (3H, s), 1.44 (1H, t J 5.8 Hz). m/z (ES.sup.+, 70V) 386.2 (MH.sup.+).

EXAMPLE DDD87753

3′-[2-(4-Methyl-piperazin-1-yl)-ethyl]-biphenyl-4-sulfonic acid (1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

(92) The compound of example DDD87751 (400 mg, 1.04 mmol) and triethylamine (218 μl, 158 mg, 1.56 mmol) in DCM (3.0 ml) at rt was treated dropwise with methanesulfonylchloride (97 μl, 143 mg, 1.25 mmol) and the reaction stirred for 21 h. The mixture was then diluted with DCM (40.0 ml) and the organic layer washed with H.sub.2O (2×10 ml), dried over MgSO.sub.4 and concentrated in vacuo to yield the crude methanesulfonate intermediate as an off-white solid (460 mg, 0.99 mmol, 95%). δH (CDCl.sub.3, 300K) 7.81 (2H, d J 8.6 Hz), 7.67 (2H, d J 8.6 Hz), 7.52-7.42 (3H, m), 7.33-7.26 (1H, m), 5.76 (1H, s br), 4.48 (2H, t J 6.9 Hz), 3.69 (3H, s), 3.15 (2H, t J 6.5 Hz), 2.92 (3H, s), 2.10 (3H, s), 1.55 (3H, s). m/z (ES.sup.+, 70V) 464.1 (MH.sup.+).

(93) A mixture of the above methanesulfonate (150 mg, 0.32 mmol), sodium carbonate (102 mg, 0.96 mmol) and N-methyl piperazine (106 μl, 96 mg, 0.96 mmol) in CH.sub.3CN (2.0 ml) was heated in a microwave at 120° C. for 30 min. The crude mixture was then filtered through an SCX-2 column which was washed with DCM:MeOH (10:1, 20.0 ml), followed by elution with 7M NH.sub.3 in MeOH (20.0 ml). The eluted fraction was concentrated in vacuo and subjected to chromatography (4-10% MeOH:DCM) to give the title compound as a colourless solid (90 mg, 0.21 mmol, 50%). δH (CDCl.sub.3, 300K) 7.78 (2H, d J 8.5 Hz), 7.67 (2H, d J 8.5 Hz), 7.49-7.47 (2H, m), 7.45-7.43 (2H, m), 7.40 (1H, t J 7.40 Hz), 7.28 (1H, s br), 5.79 (1H, s br), 3.68 (3H, s), 2.89 (2H, t J 7.7 Hz), 2.66 (2H, t J 8.4 Hz), 2.65-2.32 (4H, m), 2.33 (3H, s br), 2.09 (3H, s), 1.60 (7H, s br). m/z (ES.sup.+, 70V) 468.2 (MH.sup.+).

EXAMPLE DDD87754

3′-(3-Phenyl-piperazin-1-ylmethyl)-biphenyl-4-sulfonic acid (1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

(94) Prepared from the aldehyde of intermediate 14 (200 mg, 0.54 mmol), 2-phenylpiperazine (262 mg, 1.62 mmol) and sodium triacetoxyborohydride (343 mg, 1.62 mmol) in CHCl.sub.3 (12.0 ml) at 50° C. for 24 h according to the method of example DDD86212 to give the title compound as a white solid (200 mg, 0.39 mmol, 72%). δH (CDCl.sub.3, 300K) 7.78 (2H, d J 8.5 Hz), 7.69 (2H, d J 8.5 Hz), 7.58 (1H, s br), 7.49 (1H, d J 7.4 Hz), 7.42 (2H, t J 7.5 Hz), 7.38 (2H, dd J 1.5 Hz 7.3 Hz), 7.31 (2H, t J 7.1 Hz) 7.27 (1H, t J 1.3 Hz), 5.80 (1H, s br), 3.93 (1H, dd J 2.3 Hz 10.0 Hz), 3.69 (3H, s), 3.63 (2H, s), 3.14-3.08 (2H, m), 2.94 (1H, d J 10.6 Hz), 2.89 (1H, d J 11.1 Hz), 2.42 (1H, s br), 2.28 (1H, dt 3.5 Hz 7.4 Hz), 2.16 (1H, t J 10.7 Hz), 2.09 (3H, s), 1.61 (3H, s). m/z (ES.sup.+, 70V) 515.2 (MH.sup.+).

EXAMPLE DDD87755

N-(3-Hydroxy-propyl)-4-(2-piperazin-1-yl-pyridin-4-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(95) Prepared from the sulphonamide of intermediate 21 (300 mg, 0.7 mmol), 2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (216 mg, 0.7 mmol), tribasic potassium phosphate (158 mg, 0.7 mmol), Pd(PPh.sub.3).sub.4 (50 mg, 0.04 mmol) and water (1.0 ml) in oxygen-free DMF (5.0 ml) at 130° C. for 1 h, according to the method of intermediate 11 except with the use of Pd(PPh.sub.3).sub.4 as reaction catalyst, to give the title compound as a white solid (100 mg, 0.2 mmol, 26%). δH (D-6 DMSO, 300K) 9.36 (2H, s br), 8.26 (1H, d J 5.6 Hz), 8.08 (2H, d J 8.4 Hz), 7.81 (2H, d J 8.4 Hz), 7.43 (1H, s), 7.23 (1H, d J 5.6 Hz), 3.99-3.92 (4H, m), 3.68-3.63 (1H, m), 3.63 (3H, s), 3.46-3.41 (3H, m), 3.27-3.21 (4H, m), 1.89 (3H, s), 1.57 (3H, s), 1.58-1.52 (2H, m). m/z (ES.sup.+, 70V) 485.2 (MH.sup.+).

EXAMPLE DDD87756

4-[2-(3-Phenyl-piperazin-1-yl)-pyridin-4-yl]-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(96) Prepared from the compound of intermediate 11 (250 mg, 0.66 mmol) and 2-phenyl piperazine (500 mg, 3.1 mmol) in EtOH (0.75 ml) according to the method of DDD86213 to give the title compound as a white powder (182 mg, 0.36 mmol, 55%). δH (D-6 DMSO, 300K) 9.24 (1H, s br), 8.25 (1H, d J 5.2 Hz), 8.01 (2H, d J 8.4 Hz), 7.73 (2H, d J 8.4 Hz), 7.54 (2H, d J 7.4 Hz), 7.41 (2H, t J 7.35 Hz), 7.34 (1H, t J 7.35 Hz), 7.18 (1H, s), 7.03 (1H, d J 5.3 Hz), 4.42-4.39 (31-1, m), 3.81-3.78 1H, m), 3.60 (3H, s), 3.14 (1H, d J 8.8 Hz), 2.93-2.89 (3H, m), 2.70 (1H, t J 11.8 Hz), 1.87 (3H, s), 1.63 (3H, s). m/z (ES.sup.+, 70V) 503.1 (MH.sup.+).

EXAMPLE DDD87758

2′-Diethylaminomethyl-biphenyl-4-sulfonic acid (1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

(97) Prepared from the aldehyde of intermediate 17 (150 mg, 0.41 mmol), diethylamine (127 μl, 90 mg, 1.23 mmol) and sodium triacetoxyborohydride (261 mg, 1.23 mmol) in CHCl.sub.3 (10.0 ml) at 50° C. for 24 h according to the method of example DDD86212 to give the title compound as a white solid (106 mg, 0.25 mmol, 62%). δH (CDCl.sub.3, 300K) 7.76 (2H, d J 8.2 Hz), 7.63 (1H, s br), 7.47 (2H, d J 8.4 Hz), 7.38 (1H, t J 7.0 Hz), 7.31 (1H, t J 7.1 Hz), 7.15 (1H, d J 7.7 Hz), 5.79 (1H, s br), 3.69 (3H, s), 3.41 (2H, m), 2.40 (4H, d J 5.6 Hz), 2.13 (3H, s), 1.63 (3H, s), 0.90 (6H, t J 6.5 Hz). m/z (ES.sup.+, 70V) 427.2 (MH.sup.+).

EXAMPLE DDD87759

2′-Pyrrolidin-1-ylmethyl-biphenyl-4-sulfonic acid (1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

(98) Prepared from the aldehyde of intermediate 17 (150 mg, 0.41 mmol), pyrrolidine (101 μl, 87 mg, 1.23 mmol) and sodium triacetoxyborohydride (261 mg, 1.23 mmol) in CHCl.sub.3 (10.0 ml) at 50° C. for 24 h according to the method of example DDD86212 to give the title compound as a white solid (166 mg, 0.39 mmol, 95%). δH (CDCl.sub.3, 300K) 7.78 (2H, d J 8.2 Hz), 7.54 (3H, d J 7.3 Hz), 7.41 (1H, d J 5.9 Hz), 7.35 (1H, m), 7.21 (1H, d J 7.5 Hz), 5.81 (111, s br), 3.69 (3H, s), 3.55 (2H, s br), 2.45 (4H, s br), 2.13 (3H, s br), 1.76 (4H, s br), 1.62 (3H, s). m/z (ES.sup.+, 70V) 454.1 (MH.sup.+).

EXAMPLE DDD87761

4-[2-(3,5-Dimethyl-piperazin-1-yl)-pyridin-4-yl]-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(99) Prepared from the compound of intermediate 11 (250 mg, 0.66 mmol) and 2,6-dimethylpiperazine (>95% syn isomer, 500 mg, 4.38 mmol) in EtOH (0.75 ml) according to the method of DDD86213 to give the title compound as a white powder (211 mg, 0.46 mmol, 70%). δH (D-6 DMSO, 300K) 9.22 (1H, s), 8.18 (1H, d J 4.0 Hz), 7.97 (2H, d J 7.7 Hz), 7.70 (2H, d J 7.7 Hz), 7.10 (1H, s), 6.95 (1H, s), 4.30 (2H, d J 11.8 Hz), 3.56 (3H, s), 2.76 (2H, s br), 2.26 (2H, t J 11.3 Hz), 1.84 (3H, s), 1.59 (3H, s), 1.04 (6H, d J 4.8 Hz). m/z (ES.sup.+, 70V) 455.2 (MH.sup.+).

EXAMPLE DDD87763

N-Methyl-4-(2-piperazin-1-yl-pyridin-4-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(100) Prepared from the sulphonamide of Intermediate 18 (250 mg, 0.7 mmol), 2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (202 mg, 0.7 mmol), tribasic potassium phosphate (148 mg, 0.7 mmol), Pd(PPh.sub.3).sub.4 (50 mg, 0.04 mmol) and water (1.0 ml) in oxygen-free DMF (5.0 ml) at 130° C. for 1 h, according to the method of intermediate 11 except with the use of Pd(PPh.sub.3).sub.4 as reaction catalyst, to give the title compound as a white solid (148 mg, 0.3 mmol, 48%). δH (CDCl.sub.3, 300K) 8.28 (1H, d, J 3.8 Hz), 7.79 (2H, d, J 7.2 Hz), 7.71 (2H, d, J 7.2 Hz), 6.82 (1H, d, J 3.8 Hz), 6.79 (1H, s), 3.69 (3H, s), 3.57-3.61 (4H, m), 3.21 (3H, s), 2.99-3.04 (4H, m), 2.13 (3H, s), 1.55 (3H, s). m/z (ES.sup.+, 70V) 441.2 (MH.sup.+).

EXAMPLE DDD87764

2′-(4-Methyl-piperazin-1-ylmethyl)-biphenyl-4-sulfonic acid (1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

(101) Prepared from the aldehyde of intermediate 17 (150 mg, 0.41 mmol), N-methylpiperazine (136 μl, 123 mg, 1.23 mmol) and sodium triacetoxyborohydride (261 mg, 1.23 mmol) in CHCl.sub.3 (10.0 ml) at 50° C. for 24 h according to the method of example DDD86212 to give the title compound as a colourless solid (150 mg, 0.33 mmol, 81%). δH (CDCl.sub.3, 300K) 7.75 (2H, d J 8.4 Hz), 7.58 (2H, d J 8.3 Hz), 7.45 (1H, d J 5.9 Hz), 7.39-7.33 (2H, m), 7.22 (1H, dd J 1.6 Hz 7.3 Hz), 5.79 (1H, s br), 3.69 (3H, s), 3.33 (2H, s), 2.42 (4H, s br), 2.31 (3H, s br), 2.11 (3H, s), 1.98 (4H, s br), 1.64 (3H, s). m/z (ES.sup.+, 70V) 454.1 (MH.sup.+).

EXAMPLE DDD87765

3′-(Benzylamino-methyl)-biphenyl-4-sulfonic acid (1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

(102) Prepared from the aldehyde of intermediate 14 (200 mg, 0.54 mmol), benzylamine (176 μl, 173 mg, 1.62 mmol) and sodium triacetoxyborohydride (343 mg, 1.62 mmol) in CHCl.sub.3 (12.0 ml) at 50° C. for 24 h according to the method of example DDD86212 to give the title compound as a white solid (105 mg, 0.23 mmol, 42%). δH (CDCl.sub.3, 300K) 7.78 (2H, d J 8.4 Hz), 7.69 (2H, d J 8.4 Hz), 7.60 (1H, s br), 7.50 (1H, d J 7.5 Hz), 7.44 (1H, t J 7.5 Hz), 7.40 (1H, d J 7.6 Hz), 7.35 (4H, d J 4.8 Hz), 7.29-7.28 (1H, m), 5.85 (1H, s br), 3.90 (2H, s br), 3.86 (2H, s br), 3.68 (3H, s), 2.08 (3H, s), 1.62 (3H, s). m/z (ES.sup.+, 70V) 461.1 (MH.sup.+).

EXAMPLE DDD87767

4-(2-[1,4]Diazepan-1-yl-pyridin-4-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(103) Prepared by heating the compound of intermediate 11 (250 mg, 0.66 mmol) and homopiperazine (500 mg, 5.0 mmol) in EtOH (1.0 ml) at 155° C. for 2 h, according to the method of DDD86213 to give the title compound as a white powder (207 mg, 0.47 mmol, 71%). δH (D-6 DMSO, 300K) 8.20 (1H, d J 5.8 Hz), 7.99 (2H, d J 8.5 Hz), 7.75 (2H, d J 8.5 Hz), 6.90 (1H, s), 6.89 (1H, d J 5.8 Hz), 3.80 (2H, t J 6.1 Hz), 3.75 (2H, t J 5.8 Hz), 2.92 (2H, t J 5.2 Hz), 2.72 (2H, t J 5.6 Hz), 1.88 (3H, s), 1.83 (2H, p J 5.6 Hz), 1.63 (3H, s). m/z (ES.sup.+, 70V) 441.2 (MH.sup.+).

EXAMPLE DDD87768

3′-Piperidin-4-yl-biphenyl-4-sulfonic acid (1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

(104) Prepared from the sulphonamide of intermediate 32 (500 mg, 1.28 mmol), 4-(3-bromophenyl)piperidine hydrochloride (425 mg, 1.54 mmol), tribasic potassium phosphate (652 mg, 3.0 mmol), and Pd(dppf)Cl.sub.2.DCM (100 mg, 0.12 mmol) in DMF (3.0 ml) and water (0.75 ml), according to the method of intermediate 11, to give the title compound as an off-white powder (350 mg, 0.82 mmol, 64%). δH (D-6 DMSO, 300K) 7.90 (2H, d J 8.4 Hz), 7.71 (2H, d 8.4 Hz), 7.61 (1H, s), 7.58 (1H, d J 7.9 Hz), 7.46 (1H, t J 7.7 Hz), 7.33 (1H, d J 7.7 Hz), 3.58 (3H, s), 3.10-3.07 (2H, m br), 2.70 (1H, tt J 12.1 Hz 3.3 Hz), 2.63 (2H, td 10.8 Hz 1.8 Hz), 1.85 (3H, s), 1.79-1.73 (2H, m br), 1.63 (3H, s), 1.62 (qd J 12.2 Hz 3.8 Hz). m/z (ES.sup.+, 70V) 425.2 (MH.sup.+).

EXAMPLE DDD87769

2,6-Dichloro-4-[3-(4-methyl-piperazin-1-yl)-propyl]N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(105) The alkyne of example DDD86469 (65 mg, 0.14 mmol) and 10% w/w palladium on charcoal (13 mg, 20 wt %) in MeOH (7.0 ml) was stirred at rt under for 1.5 h. The mixture was filtered through a celite pad, the filter cake washed with DCM:MeOH (1:1, 2×10 ml), the combined filtrates concentrated in vacuo and subjected to chromatography (4-10% MeOH/DCM) to give the title compound as a white solid (28 mg, 0.059 mmol, 42%). δH (CDCl.sub.3, 300K) 7.29 (2H, s), 6.58 (1H, s), 3.66 (3H, s), 2.63 (2H, s br), 2.47 (6H, s), 2.31 (3H, s), 2.16 (3H, s) 1.79 (2H, s br), 1.72 (3H, s), 1.59 (4H, s br). m/z (ES.sup.+, 70V) 474.1 (MH.sup.+).

EXAMPLE DDD87993

2,6-Dichloro-N-(1,5-dimethyl-1H-pyrazol-4-yl)-4-(2-piperazin-1-yl-pyridin-4-yl)-benzenesulfonamide

(106) Prepared from the sulphonamide of intermediate 27 (100 mg, 0.25 mmol), 2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (80 mg, 0.28 mmol), tribasic potassium phosphate (60 mg, 0.28 mmol), and Pd(PPh.sub.3).sub.4 (30 mg, 0.026 mmol) in DMF (1.6 ml) and water (0.6 ml), according to the method of intermediate 11, to give the title compound as a yellow solid (32 mg, 0.07 mmol, 27%). δH (D-6 DMSO, 300K) 8.20 (1H, d J 5.2 Hz), 8.02 (2H, s), 7.20 (1H, s), 7.04 (1H, d J 5.2 Hz), 7.02 (1H, s), 3.64 (3H, s), 3.54 (4H, m), 2.82 (4H, m), 2.06 (3H, s). m/z (ES.sup.+, 70V) 481.1 (MH.sup.+).

EXAMPLE DDD87994

N-(2-Methyl-pyridin-3-yl)-4-(2-piperazin-1-yl-pyridin-4-yl)-benzenesulfonamide

(107) Prepared from the sulphonamide of intermediate 8 (82 mg, 0.25 mmol), 2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (80 mg, 0.28 mmol), tribasic potassium phosphate (60 mg, 0.28 mmol), and Pd(PPh.sub.3).sub.4 (30 mg, 0.026 mmol) in DMF (1.6 ml) and water (0.6 ml), according to the method of intermediate 11, to give the title compound as a yellow solid (13 mg, 0.03 mmol, 13%). δH (D-6 DMSO, 300K) 8.20 (1H, d J 5.3 Hz), 8.01 (1H, d J 4.2 Hz), 7.90 (2H, d J 8.3 Hz), 7.75 (2H, d J 8.3 Hz), 7.36 (1H, dd J 8.1 Hz 1.1 Hz), 7.11 (1H, s), 7.03 (1H, dd J 8.0 Hz 4.8 Hz), 6.99 (1H, d J 5.2 Hz), 3.62 (4H, m), 2.96 (4H, m), 2.21 (3H, s). m/z (ES.sup.+, 70V) 410.2 (MH.sup.+).

EXAMPLE DDD87995

N-(1,5-Dimethyl-1H-pyrazol-4-yl)-4-(2-piperazin-1-yl-pyridin-4-yl)-benzenesulfonamide

(108) Prepared from the sulphonamide of intermediate 27 (83 mg, 0.25 mmol), 2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (80 mg, 0.28 mmol), tribasic potassium phosphate (60 mg, 0.28 mmol), and Pd(PPh.sub.3).sub.4 (30 mg, 0.026 mmol) in DMF (1.6 ml) and water (0.6 ml), according to the method of intermediate 11, to give the title compound as a yellow solid (22 mg, 0.05 mmol, 21%). δH (D-6 DMSO, 300K) 8.21 (1H, d J 5.2 Hz), 7.96 (2H, d J 8.4 Hz), 7.75 (2H, d 8.4 Hz), 7.09 (1H, s), 6.98 (1H, d J 5.2 Hz), 6.91 (1H, s), 4.13 (1H, s br), 3.63 (3H, s), 3.52 (4H, m), 2.82 (4H, m), 1.92 (3H, s). m/z (ES.sup.+, 70V) 413.2 (MH.sup.+).

EXAMPLE DDD87997

2,5-Difluoro-4-(2-piperazin-1-yl-pyridin-4-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(109) Prepared from Intermediate 4 (200 mg, 0.5 mmol), 2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (152 mg, 0.5 mmol), tribasic potassium phosphate (112 mg, 0.5 mmol), Pd(PPh.sub.3).sub.4 (45 mg, 0.04 mmol) and water (0.8 ml) in oxygen-free DMF (4.0 ml) at 130° C. for 1 h, according to the method of intermediate 11 except with the use of Pd(PPh.sub.3).sub.4 as reaction catalyst, to give the title compound as a white solid (93 mg, 0.2 mmol, 38%). δH (CDCl.sub.3, 300K) 8.28 (1H, d J 5.1 Hz), 7.52 (1H, dd J 5.7 Hz 9.1 Hz), 7.34 (1H, dd J 5.6 Hz 9.8 Hz), 6.74-6.70 (2H, m), 3.68 (3H, s), 3.59-3.54 (4H, m), 3.03-2.99 (4H, m), 2.18 (3H, s), 1.81 (3H, s). m/z (ES.sup.+, 70V) 463.2 (MH.sup.+).

EXAMPLE DDD87999

4-[3-(4-Methyl-piperazin-1-yl)-prop-1-ynyl]-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(110) Prepared from the sulphonamide of intermediate 1 (526 mg, 1.53 mmol), 1-methyl-4-prop-2-ynyl-piperazine (253 mg, 1.83 mmol), CuI (15 mg, 0.077 mmol) and Pd(PPh.sub.3).sub.4 (89 mg, 0.077 mmol), in DMF (3.0 ml) and NEt.sub.3 (2.0 ml) according to the method of intermediate 36, to give the title compound as an off-white solid (390 mg, 0.97 mmol, 64%). δH (CDCl.sub.3, 300K) 7.66 (2H, d J 7.2 Hz), 7.47 (2H, d J 7.6 Hz), 5.85 (1H, s br), 3.67 (3H, s), 3.67 (3H, s), 3.58 (2H, s), 2.84 (4H, s br), 2.48 (4H, s br), 2.03 (3H, s br), 1.64 (3H, s br), 1.52 (3H, s). m/z (ES.sup.+, 70V) 402.1 (MH.sup.+).

EXAMPLE DDD88000

6-[2-(1-Methyl-piperidin-4-yl)-ethylamino]-pyridine-3-sulfonic acid (1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

(111) Prepared from the sulphonamide of intermediate 5 (528 mg, 1.8 mmol) and 2-(1-methylpiperidin-4-yl)ethanamine (500 mg, 3.5 mmol) according to method 1 of EXAMPLE 86213, to give the title compound as a white solid (190 mg, 0.5 mmol, 27%). δH (CDCl.sub.3, 300K) 8.38 (1H, d, J 2.3 Hz), 7.60 (1H, dd J 2.3 Hz 9.0 Hz), 6.31 (1H, d J 9.0 Hz), 5.80 (1H, s), 4.97 (1H, bs), 3.68 (3H, s), 3.38-3.32 (2H, m), 2.87-2.81 (2H, m), 2.26 (3H, s), 2.12 (3H, s), 1.93-1.85 (2H, m), 1.73 (3H, s), 1.74-1.68 (2H, m), 1.63-1.54 (3H, m), 1.31-1.37 (2H, m). m/z (ES.sup.+, 70V) 407.2 (MH.sup.+)

EXAMPLE DDD88002

N-(3,5-Dimethyl-isoxazol-4-yl)-4-(2-piperazin-1-yl-pyridin-4-yl)-benzenesulfonamide

(112) Prepared from the sulphonamide of intermediate 6 (83 mg, 0.25 mmol), 2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (80 mg, 0.28 mmol), tribasic potassium phosphate (60 mg, 0.28 mmol), and Pd(PPh.sub.3).sub.4 (30 mg, 0.026 mmol) in DMF (1.6 ml) and water (0.4 ml), according to the method of intermediate 11, to give the title compound as a tan coloured solid (11 mg, 0.03 mmol, 11%). δH (D-6 DMSO, 300K) 8.20, (1H, d J 5.3 Hz), 7.99 (2H, d J 8.4 Hz), 7.75 (2H, d J 8.4 Hz), 7.10 (1H, s), 6.98 (1H, dd J 5.2 Hz 1.1 Hz), 3.53 (4H, m), 2.83 (4H, m), 1.93 (3H, m), 1.80 (3H, s). m/z (ES.sup.+, 70V) 482.1 (MH.sup.+).

EXAMPLE DDD88003

3′-Piperidin-4-yl-biphenyl-4-sulfonic acid (2-methyl-pyridin-3-yl)-amide

(113) Prepared from the sulphonamide of intermediate 33 (230 mg, 0.62 mmol), 4-(3-bromophenyl)piperidine hydrochloride (204 mg, 0.74 mmol), tribasic potassium phosphate (313 mg, 1.48 mmol), and Pd(dppf)Cl.sub.2.DCM (50 mg, 0.06 mmol) in DMF (3.0 ml) and water (1.0 ml), according to the method of intermediate 11, to give the title compound as an off-white powder (67 mg, 0.16 mmol, 26%). δH (CDCl.sub.3, 300K) 8.35 (1H, dd J 1.3 Hz 4.7 Hz), 7.76 (2H, d J 8.5 Hz), 7.75 (1H, m), 7.43-7.38 (3H, m), 7.28 (1H, m), 7.15 (1H, dd J 4.7 Hz 8.0 Hz), 3.23-3.18 (2H, m), 2.76 (2H, td J 2.1 Hz 12.1 Hz), 2.68 (1H, tt J 3.6 Hz 12.1 Hz), 2.22 (3H, s), 1.89-1.83 (2H, m br), 1.69 (2H, qd J 12.1 Hz 3.9 Hz). m/z (ES.sup.+, 70V) 408.2 (MH.sup.+).

EXAMPLE DDD88005

3′-Dimethylaminomethyl-biphenyl-4-sulfonic acid (1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

(114) Prepared from the aldehyde of intermediate 14 (150 mg, 0.41 mmol), 2M dimethylamine solution in THF (615 ml, 1.23 mmol) and sodium triacetoxyborohydride (261 mg, 1.23 mmol) in CHCl.sub.3 (10.0 ml) at 50° C. for 24 h according to the method of example DDD86212 to give the title compound as a white solid (146 mg, 0.37 mmol, 90%). δH (CDCl.sub.3, 300K) 7.78 (2H, d J 6.9 Hz), 7.70 (2H, d J 7.5 Hz), 7.60 (1H, s br), 7.49 (1H, d J 6.8 Hz), 7.42 (1H, t J 7.8 Hz), 7.36 (1H, d J 6.7 Hz), 5.81 (1H, s br), 3.68 (3H, s), 3.59 (2H, s), 2.33 (6H, s), 2.08 (3H, s), 1.62 (3H, s). m/z (ES.sup.+, 70V) 399.3 (MH.sup.+).

EXAMPLE DDD88006

3′-imidazol-1-ylmethyl-biphenyl-4-sulfonic acid (1,3,6-trimethyl-1H-pyrazol-4-yl)-amide

(115) Prepared from the boronic ester of intermediate 32 (157 mg, 0.38 mmol), 1-(3-bromobenzyl)-1H-imidazole (114 mg, 0.48 mmol), tribasic potassium phosphate (144 mg, 0.68 mmol), and Pd(PPh.sub.3).sub.4 (48 mg, 0.042 mmol) in DMF (1.6 ml) and water (0.4 ml), according to the method of intermediate 11, to give the title compound as a white solid (157 mg, 0.37 mmol, 93%). δH (D-6 DMSO, 300K) 7.84 (3H, m), 7.73-7.60 (4H, m), 7.59 (1H, m), 7.50 (1H, t J 7.7 Hz), 7.30 (1H, d J 7.7 Hz), 7.27 (1H, s), 6.92 (1H, s), 5.28 (2H, s), 3.56 (3H, s), 1.82 (3H, s), 1.59 (3H, s). m/z (ES.sup.+, 70V) 422.2 (MH.sup.+).

EXAMPLE DDD88007

3,5-Dichloro-3′-diethylaminomethyl-biphenyl-4-sulfonic acid (1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

(116) Prepared from the sulphonamide of intermediate 15 (210 mg, 0.52 mmol), diethylamine (0.25 ml), sodium triacetoxyborohydride (220 mg, 1.04 mmol) in chloroform (3.0 ml), according to the method of example DDD85612, to give the title compound as an off-white powder (39 mg, 0.08 mmol, 15%). δH (CDCl.sub.3, 300K) 7.65 (2H, s), 7.53 (1H, s), 7.43-7.37 (3H, m), 6.62 (1H, s), 3.64 (3H, s), 3.60 (2H, s), 2.52 (4H, q J 6.8 Hz), 2.14 (3H, s), 1.77 (3H, s), 1.03 (6H, t J 6.8 Hz). m/z (ES.sup.+, 70V) 495.1 (MH.sup.+).

EXAMPLE DDD88009

3,5-Dichloro-3′-pyrrolidin-1-ylmethyl-biphenyl-4-sulfonic acid (1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

(117) Prepared from the sulphonamide of intermediate 15 (210 mg, 0.52 mmol), pyrolidine (0.25 ml) and sodium triacetoxyborohydride (220 mg, 1.04 mmol) in chloroform (3.0 ml), according to the method of example DDD85612, to give the title compound as an off-white powder (172 mg, 0.35 mmol, 67%). δH (CDCl.sub.3, 300K) 7.65 (2H, s), 7.52 (1H, s), 7.45-7.37 (3H, m), 6.72 (1H, s br), 3.67 (2H, s), 3.64 (3H, s), 2.50 (4H, s br), 2.12 (3H, s), 1.77 (4H, s br), 1.73 (3H, s). m/z (ES.sup.+, 70V) 493.1 (MH.sup.+).

EXAMPLE DDD88186

2-Methyl-4-(2-piperazin-1-yl-pyridin-4-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(118) Prepared from the sulphonamide of intermediate 20 (90 mg, 0.25 mmol), 2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (80 mg, 0.28 mmol), tribasic potassium phosphate (60 mg, 0.28 mmol), and Pd(PPh.sub.3).sub.4 (30 mg, 0.026 mmol) in DMF (1.6 ml) and water (0.6 ml), according to the method of intermediate 11, to give the title compound as a yellow solid (47 mg, 0.11 mmol, 43%). δH (D-6 DMSO, 300K) 8.20 (1H, d J 5.1 Hz), 7.84 (1H, s), 7.70 (1H, dd J 8.3 Hz 1.5 Hz), 7.64 (1H, d J 8.3 Hz), 7.10 (1H, s), 6.99 (1H, dd J 5.2 Hz 1.2 Hz), 3.55 (7H, m), 2.87 (4H, m), 2.65 (3H, s), 1.84 (3H, s), 1.58 (3H, s). m/z (ES.sup.+, 70V) 441.2 (MH.sup.+).

EXAMPLE DDD88187

5′-(4-Methyl-piperazin-1-ylmethyl)-3′-propoxy-biphenyl-4-sulfonic acid (1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

(119) Prepared from the aldehyde of intermediate 24 (150 mg, 0.35 mmol), N-methylpiperazine (0.116 ml, 105 mg, 1.05 mmol) and sodium triacetoxyborohydride (223 mg, 1.05 mmol) in CHCl.sub.3 (10.0 ml) at 50° C. for 24 h according to the method of example DDD86212 to give the title compound as a white solid (143 mg, 0.28 mmol, 80%). δH (CDCl.sub.3, 300K) 7.76 (2H, d J 8.4 Hz), 7.67 (2H, d J 8.4 Hz), 7.13 (1H, s br), 7.00 (1H, s br), 6.95 (1H, s br), 5.74 (1H, s br), 3.98 (2H, t J 6.6 Hz), 3.68 (3H, s), 3.54 (2H, s), 2.49 (4H, s br), 2.30 (3H, s), 2.09 (3H, s), 1.84 (2H, m), 1.60 (7H, s), 1.07 (3H, t J 7.4 Hz). m/z (ES.sup.+, 70V) 512.2 (MH.sup.+).

EXAMPLE DDD88188

2-Fluoro-4-(2-piperazin-1-yl-pyridin-4-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(120) Prepared from the sulphonamide of intermediate 10 (91 mg, 0.25 mmol), 2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (80 mg, 0.28 mmol), tribasic potassium phosphate (60 mg, 0.28 mmol), and Pd(PPh.sub.3).sub.4 (30 mg, 0.026 mmol) in DMF (1.6 ml) and water (0.6 ml), according to the method of intermediate 11, to give the title compound as a pale yellow solid (25 mg, 0.056 mmol, 22%). δH (D-6 DMSO, 300K) 8.03 (1H, m), 7.57 (2H, m), 7.46 (1H, d J 7.7 Hz), 6.90 (1H, s), 6.81 (1H, m), 3.46 (3H, s), 3.43 (4H, m), 2.78 (4H, m), 1.86 (3H, s), 1.65 (3H, s). m/z (ES.sup.+, 70V) 445.2 (MH.sup.+)

EXAMPLE DDD88189

3′-Piperidin-4-yl-biphenyl-4-sulfonic acid (3,5-dimethyl-isoxazol-4-yl)-amide

(121) Prepared from the sulphonamide of intermediate 34 (151 mg, 0.4 mmol), 4-(3-bromophenyl)piperidine hydrochloride (133 mg, 0.48 mmol), tribasic potassium phosphate (144 mg, 0.68 mmol), and Pd(PPh.sub.3).sub.4 (48 mg, 0.042 mmol) in DMF (3.2 ml) and water (0.8 ml), according to the method of intermediate 11, to give the title compound as a white solid (19 mg, 0.046 mmol, 12%). δH (D-6 DMSO, 300K) 7.00, (4H, s), 6.76 (1H, s), 6.74 (1H, d J 7.7 Hz), 6.64 (1H, t J 6.6 Hz), 6.53 (1H, d J 6.9 Hz), 2.46 (2H, d 12.0 Hz), 2.05 (3H, m), 1.25 (1H, s), 1.19 (3H, s), 1.15 (2H, m), 1.10 (3H, s), 0.99 (2H, q, J 12.2 Hz). m/z (ES.sup.+, 70V) 412.2 (MH.sup.+).

EXAMPLE DDD88191

4-[3-(4-Methyl-piperazin-1-yl)-propyl]N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(122) Prepared from the alkyne of example DDD87999 (345 mg, 0.86 mmol) and 10% w/w palladium on charcoal (70 mg, 20 wt %) in MeOH (40 mL) for 2 h according to the method of example DDD00087769 to give the title compound as a pale yellow solid (170 mg, 0.42 mmol, 49%). δH (CDCl.sub.3, 300K) 7.63 (2H, d J 8.3 Hz), 7.27-7.26 (2H, m), 5.72 (1H, s br), 3.67 (3H, s), 2.71 (6H, t J 7.4 Hz), 2.44 (6H, m), 2.08 (3H, s), 1.85 (2H, s br), 1.53 (6H, s), m/z (ES.sup.+, 70V) 406.2 (MH.sup.+).

EXAMPLE DDD00088193

2,6-Dichloro-N-methyl-4-(2-piperazin-1-yl-pyridin-4-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(123) Prepared from the sulphonamide of Intermediate 19 (225 mg, 0.5 mmol), 2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (153 mg, 0.5 mmol), tribasic potassium phosphate (112 mg, 0.5 mmol), Pd(PPh.sub.3).sub.4 (30 mg, 0.03 mmol) and water (0.5 ml) in oxygen-free DMF (3.0 ml) at 120° C. for 20 min, according to the method of intermediate 11, to give the title compound as a white solid (173 mg, 0.3 mmol, 64%). δH (D-6 DMSO, 300K) 9.23 (2H, s br), 8.27 (1H, d J 5.3 Hz), 8.15 (2H, s), 7.42 (1H, s), 7.27 (1H, d J 5.3 Hz), 3.95-3.89 (4H, m br), 3.60 (3H, s), 3.36 (3H, s), 3.25-3.19 (4H, m br), 1.97 (3H, s), 1.76 (3H, s). m/z (ES.sup.+, 70V) 509.1 (MH.sup.+).

EXAMPLE DDD88194

3′-Isopropoxy-5′-(4-methyl-piperazin-1-ylmethyl)-biphenyl-4-sulfonic acid (1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

(124) Prepared from the aldehyde of intermediate 25 (150 mg, 0.35 mmol), N-methylpiperazine (0.116 ml, 105 mg, 1.05 mmol) and sodium triacetoxyborohydride (223 mg, 1.05 mmol) in CHCl.sub.3 (10.0 ml) at 50° C. for 24 h according to the method of example DDD86212 to give the title compound as a colourless solid (120 mg, 0.23 mmol, 67%). δH (CDCl.sub.3, 300K) 7.76 (2H, d J 6.9 Hz), 7.66 (2H, d J 7.5 Hz), 7.11 (1H, s br), 6.99 (1H, s br), 6.94 (1H, s br), 5.75 (1H, s br), 4.64 (1H, s br), 3.68 (3H, s), 3.54 (2H, s), 2.49 (4H, s), 2.31 (3H, s), 2.09 (3H, s), 1.66 (4H, m), 1.61 (3H, s), 1.37 (6H, d J 5.0 Hz). m/z (ES.sup.+, 70V) 512.2 (MH.sup.+).

EXAMPLE DDD88195

3′-Diethylaminomethyl-biphenyl-4-sulfonic acid methyl-(1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

(125) Prepared from the sulphonamide of intermediate 22 (85 mg, 0.2 mmol), diethylamine (49 mg, 0.7 mmol) and sodium triacetoxyborohydride (141 mg, 0.7 mmol) in CHCl.sub.3 (4 ml), according to the method of Example DDD86212 to give the title compound as a white powder (19 mg, 0.043 mmol, 22%). δH (D-6 DMSO, 300K) 9.91 (1H, s br), 8.06 (1H, s), 8.00 (2H, d J 8.5 Hz), 7.89-7.86 (1H, m), 7.81 (2H, d J 8.5 Hz), 7.66-7.61 (2H, m), 4.41 (2H, d J 5.6 Hz), 3.62 (3H, s), 3.16 (3H, s), 3.17-3.08 (3H, m), 1.92 (3H, s), 1.59 (3H, s), 1.28 (6H, t J 7.3 Hz). m/z (ES.sup.+, 70V) 441.2 (MH.sup.+).

EXAMPLE DDD88196

3′-(4-Methyl-piperazin-1-ylmethyl)-biphenyl-4-sulfonic acid methyl-(1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

(126) Prepared from the sulphonamide of intermediate 22 (85 mg, 0.2 mmol), N-methylpiperazine (67 mg, 0.7 mmol) and sodium triacetoxyborohydride (141 mg, 0.7 mmol) in CHCl.sub.3 (4 ml), according to the method of Example DDD86212 to give the title compound as a white powder (65 mg, 0.14 mmol, 69%). δH (D-6 DMSO, 300K) 8.13 (1H, s br), 8.02 (2H, d J 7.4 Hz), 7.89-7.84 (1H, m br), 7.79 (2H, d J 7.4 Hz), 7.69 (1H, s br), 7.62 (1H, s br), 4.57-4.34 (2H, m br), 3.62 (3H, s), 3.74-3.56 (4H, m br), 3.52-3.27 (4H, m br), 3.16 (3H, s), 2.83 (3H, s br), 1.91 (3H, s), 1.60 (3H, s). m/z (ES.sup.+, 70V) 468.2 (MH.sup.+).

EXAMPLE DDD86469

2,6-Dichloro-4-[3-(4-methyl-piperazin-1-yl)-prop-1-ynyl]-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

(127) Prepared from the sulphonamide of intermediate 19 (1.3 g, 3.06 mmol), 4-(propyn-3-yl)-1-methyl piperazine (1.05 g, 7.61 mmol), CuI (50 mg, 0.26 mmol) and Pd(PPh.sub.3).sub.4 (100 mg, 0.08 mmol), in DMF (15 ml) and NEt.sub.3 (8 ml) according to the method of intermediate 36, to give the title compound as a white solid (1.25 g, 2.66 mmol, 87%). δH (CDCl3, 300K) 7.43 (2H, s), 3.67 (3H, s), 3.54 (2H, s), 3.40 (3H, s), 2.73-2.60 (4H, s br), 2.59-2.42 (4H, s br), 2.32 (3H, s), 2.06 (3H, s), 1.83 (3H, s). m/z (ES.sup.+, 70V) 470.2 (MH.sup.+).

EXAMPLE DDD99837

N-(3-isobutyl-1,5-dimethyl-1H-pyrazol-4-yl)-4-(3-(1-methylpiperidin-4-yl)propyl)benzenesulfonamide

(128) Prepared from 4-allyl-1-methylpiperidine (2.18 g, 15.6 mmol) and the compound of intermediate 41 (2.0 g, 5.2 mmol) according to the method of compound DDD100096 to give the title compound as a white powder (1.84 g, 4.12 mmol, 79%). δH (CDCl.sub.3, 300K), 7.55 (2H, d J 7.9 Hz), 7.19 (2H, d J 7.9 Hz), 5.80 (1H, br s), 3.61 (3H, s), 2.76 (2H, m), 2.58 (2H, t J 7.7 Hz), 2.19 (3H, s), 2.01 (3H, s), 1.80 (3H, m), 1.62-1.51 (m, 4H), 1.22-1.11 (4H, m), 0.64 (6H, d J 6.25 Hz). m/z (ES.sup.+, 70V) 446.2 (MH.sup.+).

EXAMPLE DDD100096

2,6-Dichloro-N-(difluoromethyl)-4-(3-(piperidin-4-yl)propyl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzenesulfonamide hydrochloride salt

(129) Prototypical Procedure for Coupling of an Aryl Bromide with a 9BBN-Derived Trialkylborane Under Suzuki-Miyaura Conditions;

(130) A solution of tert-butyl 4-allylpiperidine-1-carboxylate (293 mg, 1.29 mmol, prepared according to the methods cited by Billote, S. Synlett., 1998, 4, 379-380) in 1.0 ml of THF, under argon at rt, was treated dropwise with 9-BBN (0.5M in THF; 2.6 ml, 1.3 mmol). The reaction was then heated in a microwave for 30 min at 90° C. The resulting solution was then transferred via cannula into a stirred mixture of the compound of intermediate 40 (300 mg, 0.645 mmol) and potassium phosphate (272 mg, 1.28 mmol) in DMF (2.5 ml) and water (0.75 ml) under argon. After bubbling argon through the reaction for 5 min at rt Pd(PPh.sub.3).sub.4 (20 mg) was added, the reaction vessel sealed and then heated in a microwave at 60° C. for 30 min. The reaction mixture was then concentrated in vacuo, diluted with DCM (50 ml) and aqueous ammonia solution (50 ml), the organic phase separated, washed with brine (2×25 ml), dried (MgSO.sub.4) and concentrated in vacuo. Chromatography (SiO.sub.2, 4:6 EtOAc:hexanes) gave tert-butyl 4-(3-(3,5-dichloro-4-(N-(difluoromethyl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfamoyl)phenyl)propyl)piperidine-1-carboxylate as a colourless gum. The above named compound in DCM (10 ml) was treated with trifluoroacetic acid (1 ml), stirred at rt for 1 h then concentrated in vacuo. The residual gum was diluted with DCM (25 ml) and aqueous ammonia (25 ml), the organic phase separated, dried (MgSO4) and concentrated. Dilution with DCM (10 ml), treatment with HCl (1M in diethyl ether, 2 ml) followed by filtration under a stream of argon gave the title compound as a white hygroscopic powder (210 mg, 0.385 mmol, 60%). δH (D.sub.2O, 300K) 7.29 (1H, t J 60.0 Hz), 7.22 (2H, s), 3.40 (3H, s), 3.13 (2H, d J 13.2 Hz), 2.68 (2H, t J 11.7 Hz), 2.36 (2H, s br), 1.66 (3H, s), 1.61-0.95 (9H, complex), 1.46 (3H, s). m/z (ES.sup.+, 70V) 509.2 (MH.sup.+).

EXAMPLE DDD100097

2,6-dichloro-N-(difluoromethyl)-4-(3-(1-methylpiperidin-4-yl)propyl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzenesulfonamide

(131) Prepared from 4-allyl-1-methylpiperidine (776 mg, 5.54 mmol) and the compound of intermediate 40 (2.5 g, 5.4 mmol) according to the method of compound DDD100096 to give the title compound as a white powder (2.41 g, 4.6 mmol, 85%), δH (D-6 DMSO 300K) 7.36 (1H, t J 59.6 Hz), 7.58 (2H, s), 3.64 (3H, s), 3.35 (2H, dm), 3.2-3.0 (1H, m br), 2.86 (2H, m), 2.69 (2H, m), 2.66 (2H, t J 7.5 Hz), 1.88 (3H, s), 1.83 (3H, m), 1.66 (3H, s), 1.65-1.57 (2H, m), 1.50-1.39 (2H, m), 1.24-1.17 (2H, m). m/z (ES.sup.+, 70V) 523.2 (MH.sup.+).

EXAMPLE DDD100144

2,6-dichloro-N-(difluoromethyl)-4-(4-(1-methylpiperidin-4-yl)butyl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzenesulfonamide

(132) Prepared from 4-(but-3-enyl)-1-methylpiperidine (320 mg, 2.14 mmol) and the compound of intermediate 40 (500 mg, 1.08 mmol) according to the method of compound DDD100096 to give the title compound as a white powder (197 mg, 34%), δH (D-6 DMSO 500K) 10.06 (1H, bs); 7.69 (1H, t, J 60 Hz); 7.61 (2H, s); 3.64 (3H, s); 3.36 (2H, m); 2.80 (5H, m); 2.65 (2H, m); 1.88 (3H, s); 1.79 (2H, m); 1.59 (3H, s); 1.57 (2H, m); 1.32 (7H, m). m/z (ES.sup.+, 70V) 537.2 (MH.sup.+).

EXAMPLE DDD100153

2,6-dichloro-4-(3-(1-methylpiperidin-4-yl)propyl)-N-(2,2,2-trifluoroethyl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzenesulfonamide

(133) Prepared from 4-allyl-1-methylpiperidine (448 mg, 3.2 mmol) and the compound of intermediate 47 (790 mg, 1.6 mmol) according to the method of DDD100096 to give the title compound as a colourless oil (784 mg, 1.41 mmol, 88%). δH (CDCl.sub.3, 300K) 7.20 (2H, s), 4.87-4.73 (1H, m), 3.94-3.67 (1H, m), 3.67 (3H, s), 3.29 (2H, brd, J=7.3 Hz), 2.63-2.52 (5H, m), 2.40 (2H, brs), 2.18 (3H, s), 1.79 (4H, brd, J=13.5 Hz), 1.61 (3H, s), 1.56 (1H, brs), 1.34-1.29 (4H, m). m/z (ES.sup.+, 70V) 555.1 (MH.sup.+).

EXAMPLE DDD100798

N-(3-isobutyl-1,5-dimethyl-1H-pyrazol-4-yl)-4-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)benzenesulfonamide Hydrochloride

(134) Prepared from the boronic ester of intermediate 42 (321 mg, 0.71 mmol), 8-Bromo-2,3,4,5-tetrahydro-1H-2-benzazepine (160 mg, 0.71 mmol, prepared according to the methods cited by H. Stark et al, Chem Bio Chem, 2004, 5, 508-518 and G. L. Grunewald et al, Bioorg. Med. Chem., 9, 2001, 1957-1965), tribasic potassium phosphate (150 mg, 0.71 mmol), and Pd(PPh.sub.3).sub.4 (30 mg, 0.026 mmol) in DMF (5 ml) and water (1.5 ml), according to the method of intermediate 11, Dilution with DCM (10 ml), treatment with HCl (1M in diethyl ether, 2 ml) followed by evaporation, trituration with ether and filtration under a stream of argon gave the title compound as a white hygroscopic powder (300 mg, 0.61 mmol, 87%). δH (D-6 DMSO, 500K) 9.15 (1H, s), 9.04 (1H, bs), 7.87 (2H, d J 8.6 Hz), 7.85 (1H, d J 1.9 Hz), 7.72 (2H, d J 8.6 Hz), 7.68 (1H, dd J 7.9 Hz 1.9 Hz), 7.41 (1H, d J 7.9 Hz), 4.41 (2H, m), 3.56 (3H, s), 3.37 (2H, m), 3.04 (2H, m), 1.90 (4H, m), 1.77 (3H, s), 1.72 (1H, m), 1.70 (6H, d J 6.6 Hz). m/z (ES.sup.+, 70V) 453.3 (MH.sup.+).

EXAMPLE 100868

N-(3-isobutyl-1,5-dimethyl-1H-pyrazol-4-yl)-4-(2-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)benzenesulfonamide Hydrochloride

(135) The amine of Example DDD100798 (150 mg, 0.31 mmol) was taken up in formic acid (10 ml) and paraformaldehyde (92 mg, 3.10 mmol) added. The reaction mixture was heated at 85° C. for 18 h then allowed to cool and concentrated to dryness. The residue was basified with aqueous ammonia solution (20 ml), extracted with DCM (20 ml) and the organics concentrated in vacuo to give a gum which was subjected to chromatography (SiO.sub.2, 94:5:1 DCM:MeOH:saturated aqueous ammonia solution). Dilution with DCM (10 ml), treatment with HCl (1M in diethyl ether, 2 ml) followed by evaporation, trituration with ether and filtration under a stream of argon gave the title compound as a white hygroscopic powder (60 mg, 0.12 mmol, 39%). δH (D.sub.2O, 500K) 7.81 (2H, m), 7.77 (2H, m), 7.68 (2H, m), 7.42 (1H, m), 4.56 (1H, m), 3.71 (1H, m), 3.69 (3H, s), 3.51 (1H, m), 3.08 (2H, m), 2.88 (3H, bs), 2.15 (1H, m), 1.98 (3H, s), 1.95 (1H, m), 1.89 (2H, m), 1.64 (1H, m), 0.67 (6H, d J 6.7 Hz). m/z (ES.sup.+, 70V) 467.3 (MH.sup.+).

(136) Biological Data

(137) TABLE-US-00001 TABLE 1 Enzyme and Cellular Activity of N-Myristoyltransferase Inhibitors Enzyme activities are for T. brucei NMT. Where present, Human (HuNMT-1), Aspergillus fumigatus (AfNMT) and Leishmania major (LmNMT) enzyme inhibition data are given in parentheses. Cellular activitites are for inhibition of T. brucei brucei (blood stream form, variant 221). ED.sub.50 Reference IC.sub.50 (μM) (μM) Number STRUCTURE NMT Enzyme T. brucei MH+ DDD16771 4.0  >1 324.1 DDD22988 8.3  >1 377.2 DDD48025 11.8   >1 266.1 DDD60006 16.4   >1 349.1 DDD61393 15.0   >1 401.2 DDD61495 6.4  >1 340.1 DDD64558 0 2.1  20.0 (HuNMT-1) 21.1 338.1 DDD64750 30.0   >1 326.1 DDD64780 30.0   >1 338.2 DDD71230 3.5  >1 338.2 DDD71231 4.6  >1 293.1 DDD71232 42.0   >1 308.1 DDD71233 2.6  >1 374.2 DDD71234 2.7  >1 350.1 DDD71235 5.4  >1 359.1 DDD71237 8.8  >1 349.2 DDD71238 0 32.6   >1 291.2 DDD71239 1.0  23.2 335.1 DDD71240 8.0  >1 344.1 DDD71241 1.5  >1 308.2 DDD71242 4.3  >1 322.2 DDD71243 0.50  5.8 350.2 DDD71244 15.9   >1 321.2 DDD71245 5.6  >1 284.1 DDD71246 8.4  >1 316.2 DDD71247 3.4  >1 335.1 DDD71248 0 62.5   >1 336.2 DDD71250 28.1   >1 291.2 DDD71251 >100   .sup.   >1 336.1 DDD71252 17.4   >1 368.2 DDD71253 5.6  >1 306.1 DDD71274 2.0  >1 352.2 DDD71275 62.0   >1 354.2 DDD71276 9.5  >1 338.2 DDD71277 95.0   >1 346.1 DDD71278 12.1   >1 363.2 DDD71279 0 10.0   70.0 (HuNMT-1) >1 321.1 DDD71280 >100   .sup.   >1 307.1 DDD71281 16.1   >1 337.2 DDD71282 4.0  >1 310.2 DDD71283 7.4  >1 317.1 DDD71284 >100   .sup.   >1 325.2 DDD71285 19.3   >1 325.2 DDD71286 9.8  >1 296.1 DDD71287 2.8  >1 323.1 DDD71288 >100   .sup.   >1 307.2 DDD71290 0 41.0   >1 326.1 DDD71291 >100   .sup.   >1 320.2 DDD71292 >100   .sup.   >1 306.1 DDD71293 >100   .sup.   >1 280.1 DDD71294 4.8  >1 332.1 DDD71295 30.0   >1 308.1 DDD71296 >100   .sup.   >1 352.2 DDD71297 10.5   >1 342.1 DDD71590 62.0   >1 352.1 DDD71593 3.2  >1 335.1 DDD00071594 0 9.9  >1 334.1 DDD71600 51.0   >1 347.2 DDD71601 >100   .sup.   >1 324.2 DDD71607 >100   .sup.   >1 399.2 DDD71608 >100   .sup.   >1 338.1 DDD71622 41.0   >1 353.1 DDD71623 42.0   >1 353.1 DDD71630 >100   .sup.   >1 296.1 DDD71637 11.7   >1 335.2 DDD71644 >100   .sup.   >1 296.1 DDD71645 0 >100   .sup.   >1 348.5 DDD73219 69.0   >1 343.2 DDD73220 2.4  >1 353.1 DDD73221 6.6  >1 354.2 DDD73222 1.0  >1 340.1 DDD73223 1.4  >1 371.1 DDD73224 1.5  >1 438.2 DDD73225 >100   .sup.   >1 378.1 DDD73226 >100   .sup.   >1 363.1 DDD73227 0.9  8.1 398.1 DDD73228 00 13.5   >1 324.2 DDD73229 01 >100   .sup.   >1 351.1 DDD73230 02 10.7   >1 445.1 DDD73231 03 0.76  6.7 418.2 DDD73232 04 1.9  18.6 346.2 DDD73233 05 2.7  >1 373.1 DDD73234 06 0.55  14.3 413.9 DDD73235 07 17.0   >1 301.1 DDD73236 08 11.9   >1 365.1 DDD73237 09 10.4   >1 412.2 DDD73238 0 0.63  6.9 405.2 DDD73239 38.7   >50 395.1 DDD73240 1.6  >1 359.1 DDD73241 4.2  >1 344.1 DDD73242 32.0   >1 420.2 DDD73243 5.8  >1 395.2 DDD73262 6.9  >1 450.1 DDD73263 0.92  3.4 441.2 DDD73264 7.0  >1 471.2 DDD73265 22.5   >1 385.2 DDD73266 0 >100   .sup.   >1 339.1 DDD73267 44.5   >1 438.2 DDD73268 3.6  >1 400.1 DDD73269 >100   .sup.   >1 339.1 DDD73271 >100   .sup.   >1 409.1 DDD73272 35.0   >1 482.1 DDD73273 25.5   >1 483.1 DDD73274 32.2   >1 455.2 DDD73277 40.0   >1 478.1 DDD73278 26.9   >1 461.1 DDD73279 0 1.1  2.1 453.2 DDD73280 20.7   >1 450.1 DDD73319 1.1  8.4 385.1 DDD73320 2.6  16.3 415.1 DDD73321 4.3  >1 470.1 DDD73322 0.86  5.4 386.1 DDD73323 89.0   >1 495.1 DDD73324 >100   .sup.   >1 620.1 DDD73325 12.8   >1 440.1 DDD73326 1.4  >1 416.2 DDD73327 0 2.8  >1 400.2 DDD73328 2.4  19.1 402.2 DDD73329 1.6  >1 402.1 DDD73330 2.3  >1 402.1 DDD73331 6.0  >1 428.2 DDD73332 0.34  3.2 411.1 DDD73333 >100   .sup.   >1 402.1 DDD73475 0.88  10.5 457.2 DDD73476 0.32  2.3 (HuNMT-1) 4.8 (AfNMT) 1.8 458.1 DDD73477 0.46  6.0 429.2 DDD73478 0 0.36  4.5 398.1 DDD73479 >100   .sup.   >1 440.1 DDD73480 4.5  22.1 358.2 DDD73481 6.9  >1 426.1 DDD73482 60.0   >1 462.2 DDD73483 >100   .sup.   >1 450.1 DDD73484 0.67  3.1 438.1 DDD73485 34.3   >1 434.1 DDD73486 2.8  >1 436.2 DDD73487 1.2  14.2 376.2 DDD73488 0 0.83  7.9 375.1 DDD73489 12.4   >1 436.2 DDD73490 0.36  4.0 (HuNMT-1) 3.9 (AfNMT) 2.8 427.9 DDD73491 28.4   >1 366.2 DDD73492 13.6   >1 462.1 DDD73493 4.4  >1 453.1 DDD73494 0.71  8.8 452.2 DDD73495 0.96  7.8 400.2 DDD73496 >100   .sup.   >1 428.1 DDD73497 >100   .sup.   >1 366.1 DDD73498 0 0.32  4.3 (HuNMT-1) 14.7 (AfNMT) 2.6 413.2 DDD73499 >100   .sup.   >1 490.2 DDD73500 2.5  >1 425.1 DDD73501 19.0   >1 461.2 DDD73502 4.8  >1 463.2 DDD73503 2.5  10.5 422.1 DDD73504 4.2  >1 373.1 DDD73505 9.7  >1 413.1 DDD73506 10.0   >1 456.1 DDD73507 4.5  >1 411.2 DDD73508 0 5.2  >1 448.1 DDD73509 3.8  >1 371.2 DDD73510 26.9   >1 390.1 DDD73511 >100   .sup.   >1 436.2 DDD73512 6.1  >1 396.1 DDD73513 5.7  >1 401.2 DDD73514 4.7  >1 420.1 DDD73515 1.9  >1 425.2 DDD73516 47.6   >1 438.2 DDD85591 0.59  5.3 452.2 DDD85592 0 44.0   >1 411.2 DDD85593 0.36  3.5 472.1 DDD85594 3.2  21.0 456.1 DDD85595 66.7   >1 286.2 DDD85596 41.7   >1 411.1 DDD85597 8.0  >1 384.1 DDD85598 18.2   >1 384.1 DDD85599 2.4  >1 402.1 DDD85600 1.9  5.9 482.2 DDD85601 23.3   >1 503.1 DDD85602 00 0.14  9.5 (HuNMT-1) 2.9 (AfNMT) 0.63 408.2 DDD85603 01 2.4  >1 477.1 DDD85604 02 3.3  >1 448.2 DDD85605 03 0.57  2.4 427.2 DDD85606 04 4.9  3.6 518.2 DDD85607 05 1.1  7.1 458.2 DDD85608 06 18.5   >1 314.2 DDD85609 07 69.5   >1 444.2 DDD85610 08 61.6   >1 456.1 DDD85611 09 7.2  >1 394.2 DDD85612 0 9.3  >1 454.6 DDD85613 6.6  >1 398.2 DDD85624 0.36  1.5 443.2 DDD85625 0.67  4.6 466.1 DDD85626 0.61  1.9 381.1 DDD85627 0.12  0.62 422.2 DDD85628 11.1   >1 390.1 DDD85629 2.4  38.0 367.2 DDD85630 1.7  >1 451.1 DDD85631 9.3  >1 465.1 DDD85632 0 57.5   >1 544.2 DDD85633 2.0  >50 390.1 DDD85634 27.9   >1 335.1 DDD85635 11.2   48.1 393.1 DDD85636 75.5   >1 508.1 DDD85637 0.50  3.2 441.1 DDD85638 0.90  >1 453.2 DDD85639 11.7   >1 496.1 DDD85640 3.3  >50 366.1 DDD85641 1.7  16.3 499.1 DDD85642 0 5.2  >1 401.2 DDD85643 8.0  >1 406.2 DDD85644 1.3  2.1 521.2 DDD85645 0.36  0.23 495.2 DDD85646 0.001 0.003 (HuNMT-1) 0.009 (NWT) 0.001 496.1 DDD85647 66.1   >1 381.1 DDD85648 47.7   >1 436.2 DDD85649 40.0   >1 422.1 DDD85650 52.6   >1 395.1 DDD85651 1.8  9.8 469.2 DDD86206 0 0.001 0.003 (HuNMT-1) 0.001 461.2 DDD86208 3.5  >1 379.9 DDD86209 1.0  >1 447.0 DDD86210 6.0  >1 370.2 DDD86211 0.69  0.19 509.1 DDD86212 0.011 0.008 (HuNMT-1 ) 0.015 (AfNMT) 0.03 453.1 DDD86213 0.001 0.007 (HuNMT-1) 0.01 (AfNMT) 0.003 426.1 DDD86291 1.0  >1 484.9 DDD86292 1.0  >1 523.2 DDD86293 1.0  >1 326.2 DDD86294 0 1.0  >1 441.9 DDD86295 1.0  >1 498.1 DDD86296 1.2  >1 350.1 DDD86297 1.0  >1 483.1 DDD86298 1.0  >1 436.1 DD86299 1.0  >1 498.2 DDD86300 0.07  1.73 435.1 DDD86301 1.0  >1 469.1 DDD86302 1.0  >1 546.1 DDD86303 1.0  >1 469.2 DDD86304 0 1.0  >1 484.1 DDD86305 0.87  >1 393.1 DDD86306 1.0  >1 378.2 DDD86307 1.0  >1 339.1 DDD86308 1.0  >1 534.1 DDD86309 1.0  >1 497.1 DDD86310 1.0  >1 494.2 DDD86311 1.0  >1 400.2 DDD86312 0.03  0.07 427.2 DDD86314 1.0  >1 441.1 DDD86315 0 1.0  >1 540.1 DDD86316 0.61  5.0 442.1 DDD86317 0.01  0.02 440.1 DDD86318 0.08  0.21 425.1 DDD86467 0.01  0.003 537.2 DDD86468 0.01  0.20 482.1 DDD86469 0.17  0.55 470.2 DDD86470 0.01  0.02 (HuNMT-1) 0.007 (AfNMT) 0.02 493.1 DDD86471 0.01  0.009 413.2 DDD86472 10.0   >1 483.2 DDD86473 0 10.0   >1 523.2 DDD86474 0.07  0.65 399.2 DDD86475 0.001 0.01 (HuNMT-1) 0.003 481.1 DDD86476 5.9  >1 455.2 DDD86477 7.2  >1 418.2 DDD86478 0.04  0.06 (HuNMT-1) 0.24 467.1 DDD86479 0.01  0.016 (HuNMT-1) 0.005 494.1 DDD86480 0.02  0.08 (HuNMT-1) 0.33 478.1 DDD86481 0.001 0.003 (HuNMT-1) 0.002 537.2 DDD87748 0.001 0.008 (HuNMT- 1) 0.001 441.2 DDD87749 0 0.79  9.3 (HuNMT-1) 9.3 (AfNMT) 1.28 426.2 DDD87751 5.0  >1 386.2 DDD87753 0.23  0.18 (HuNMT-1) 0.80 (AfNMT) >1 464.1 DDD87754 0.34  1.6 515.2 DDD87755 0.05  0.98 485.2 DDD87756 0.76  >1 503.1 DDD87757 0.003 0.01 (HuNMT-1) 0.09 (AfNMT) 0.003 434.2 DDD87758 40.1   >1 427.2 DDD87759 0.91  >1 454.1 DDD87760 34.4   >1 510.2 DDD87761 00 0.01  0.04 (HuNMT-1) 0.11 (AfNMT) 0.02 455.2 DDD87762 01 2.6  >1 465.1 DDD87763 02 0.003 0.02 (HuNMT-1) 0.003 441.2 DDD87764 03 0.97  >1 454.1 DDD87765 04 2.8  >1 461.1 DDD87766 05 10.0   >1 404.1 DDD87767 06 0.002 0.008 (HuNMT-1) 0.008 (AfNMT) 0.003 441.2 DDD87768 07 0.01  0.06 425.2 DDD87769 08 0.003 0.27 (AfNMT) 0.008 474.1 DDD87993 09 0.005 0.009 (HuNMT- 1) 0.01 481.1 DDD87994 0 0.01  0.23 (AfNMT) 0.11 410.2 DDD87995 0.06  0.02 413.2 DDD87997 0.03  0.013 (HuNMT-1) 0.02 (AfNMT) 0.003 463.2 DDD87999 0.21  >1 402.1 DDD88000 0.03  1.5 (AfNMT) 0.77 407.2 DDD88002 0.02  0.65 (HuNMT-1) 0.79 (AfNMT) 0.14 482.1 DDD88003 0.16  1.9 408.2 DDD88004 6.2  >1 380.0 DDD88005 0.23  0.1 399.3 DDD88006 0.35  4.2 (AfNMT) 3.9 422.2 DDD88007 0 0.02  0.13 (HuNMT-1) 0.14 (AfNMT) 0.08 495.1 DDD88008 0.11  18.0 420.2 DDD88009 0.02  0.10 493.1 DDD88186 0.003 0.006 (HuNMT-1) 0.003 441.2 DDD88187 0.37  2.15 512.2 DDD88188 0.003 0.009 (HuNMT-1) 0.005 445.2 DDD88189 0.43  >1 412.2 DDD88190 1.1  31.0 393.1 DDD88191 0.12  10.0 (AfNMT) 0.67 406.2 DDD88193 0.003 0.005 (HuNMT-1) 0.007 (AfNMT) 0.005 509.1 DDD88194 0 0.48  2.0 512.2 DDD88195 0.05  0.51 441.2 DDD88196 0.02  0.017 (HuNMT-1) 0.035 (AfNMT) 0.05 468.2 DDD88197 13.8   45.9 456.0 DDD88198 0.71  2.3 456.0 DDD88315 20.0   70.8 (HuNMT-1) >10 399.9 DDD88316 12.7   107 (HuNMT-1) >10 358.0 DDD88317 10.0   >100 (HuNMT-1) >10 379.0 DDD88318 10.0   87.0 (HuNMT-1) >10 362.0 DDD88319 0.045 0.77 (HuNMT-1) 0.69 492.1 DDD88320 0 44.1   >100 (HuNMT-1) >10 330.0 DDD88321 >100   .sup.   >100 (HuNMT-1) >10 316.0 DDD88322 0.182 1.5 (HuNMT-1) 1.93 478.1 DDD88323 0.004 0.29 (HuNMT-1) 0.005 463.2 DDD88324 75.4   3.36 (HuNMT-1) >10 399.9 DDD88325 >100   .sup.   >100 (HuNMT-1) >10 385.9 DDD88326 >100   .sup.   >100 (HuNMT-1) >10 330.0 DDD88523 0.61  6.3 (HuNMT-1) >1 415.2 DDD88533 5.98  17.7 (HuNMT-1) >10 351.1 DDD88549 0.025 0.24 (HuNMT-1) 0.11 468.2 DDD88557 0 0.002 0.301 (HuNMT-1) 0.001 (LmNMT) 0.002 472.2 DDD88558 0.006 0.007 (HuNMT-1) 0.009 522.1 DDD88559 0.008 0.175 (HuNMT-1) 0.038 405.2 DDD88560 0.054 0.272 (HuNMT-1) 2.15 371.1 DDD88580 0.077 1.0 (HuNMT-1) 1.13 391.2 DDD88636 0.92  3.7 (HuNMT-1) 1.89 537.2 DDD88638 0.009 0.047 (HuNMT-1) 0.084 469.3 DDD88640 >1  .sup.   >1 (HuNMT-1) 18.7 406.2 DDD88641 0.029 0.31 (HuNMT-1) 0.31 509.2 DDD88642 0.39 4.48 (HuNMT-1) 0.89 535.2 DDD88643 0 0.063 0.144 (HuNMT-1) 0.49 483.3 DDD88644 0.003 0.188 (HuNMT-1) 0.012 488.2 DDD88645 0.003 0.021 (HuNMT-1) 0.021 509.2 DDD88646 0.002 0.003 (HuNMT-1) 0.002 523.2 DDD90022 0.002 0.004 (HuNMT-1) 0.002 473.2 DDD90023 0.016 0.397 (HuNMT-1) 0.20 419.2 DDD90057 0.085 0.075 (HuNMT-1) 0.73 536.2 DDD90058 0.027 0.740 (HuNMT-1) 0.20 440.2 DDD90059 0.054 0.548 (HuNMT-1) 0.48 442.2 DDD90060 0.006 0.180 (HuNMT-1) 0.02 516.2 DDD90086 0 0.004 0.01 (HuNMT-1) 0.006 501.2 DDD90091 0.009 0.009 (HuNMT-1) 0.063 467.2 DDD90098 0.008 0.047 (HuNMT-1) 0.060 453.2 DDD90106 0.024 0.064 (HuNMT-1) 0.251 413.2 DDD90107 0.004 0.005 (HuNMT-1) 0.040 453.2 DDD90111 0.003 0.019 (HuNMT-1) 0.005 491.2 DDD90112 0.017 0.164 (HuNMT-1) 0.270 405.2 DDD90115 0.260 6.1 (HuNMT-1) 2.21 420.1 DDD90118 0.004 0.005 (HuNMT-1) 0.015 536.2 DDD90142 0.012 0.234 (HuNMT-1) 0.168 461.3 DDD90143 0 0.082 1.37 (HuNMT-1) 0.81 462.3 DDD90144 0.006 0.088 (HuNMT-1) 0.034 433.3 DDD90145 0.09  0.76 (HuNMT-1) 1.00 393.2 DDD90146 0.002 0.018 (HuNMT-1) 0.002 487.2 DDD90147 0.034 0.939 (HuNMT-1) 0.20 448.3 DDD90152 0.50  >1 (HuNMT-1) >1 495.3 DDD90153 0.31  >1 (HuNMT-1) >1 447.3 DDD90154 0.003 0.352 (HuNMT-1) 0.023 502.5 DDD90155 >1  .sup.   >1 (HuNMT-1) 4.0 459.3 DDD99735 0.83  2.9 (HuNMT-1) >1 416.2 DDD99736 0 0.068 0.25 (HuNMT-1) 0.41 496.3 DDD99739 0.005 0.12 (HuNMT-1) 0.058 467.3 DDD99741 0.005 0.021 (HuNMT-1) 0.047 455.3 DDD99742 0.003 0.015 (HuNMT-1) 0.035 (LmNMT) 0.019 441.3 DDD99743 0.003 0.016 (HuNMT-1) 0.005 515.3 DDD99745 2.1  >10 (HuNMT-1) >1 379.3 DDD99746 2.0  >10 (HuNMT-1) >1 402.3 DDD99747 0.008 0.81 (HuNMT-1) 0.067 537.2 DDD99748 0.006 0.019 (HuNMT-1) 0.036 427.2 DDD99749 0.45  >1 (HuNMT-1) >1 365.3 DDD99750 00 >1  .sup.   >1 (HuNMT-1) >1 388.3 DDD99751 01 0.003 0.141 (HuNMT-1) 0.021 502.2 DDD99752 02 0.003 0.051 (HuNMT-1) 0.019 474.2 DDD99753 03 0.029 0.076 (HuNMT-1) 0.406 407.3 DDD99754 04 0.105 2.1 (HuNMT-1) >1 (AfNMT) >1 430.3 DDD99755 05 0.003 0.011 (HuNMT-1) 0.002 488.2 DDD99756 06 0.011 0.98 (HuNMT-1) 0.121 343.3 DDD099757 07 0.006 0.054 (HuNMT-1) 0.061 467.3 DDD99758 08 0.009 0.127 (HuNMT-1) 0.110 391.3 DDD99759 09 0.002 0.008 (HuNMT-1) 0.003 459.0 DDD99760 0 0.005 0.029 (HuNMT-1) 0.010 405.3 DDD99761 0.028 0.250 (HuNMT-1) 0.240 415.3 DDD99763 0.007 0.058 (HuNMT-1) 0.053 503.3 DDD99815 0.025 0.19 (HuNMT-1) 0.123 481.3 DDD99816 0.016 0.153 (HuNMT-1) 0.031 459.2 DDD99817 0.014 0.56 (HuNMT-1) 0.047 455.2 DDD99818 0.011 0.85 (HuNMT-1) 0.047 448.3 DDD99819 0.008 0.041 (HuNMT-1) 0.043 455.2 DDD99820 0.005 0.052 (HuNMT-1) 0.020 421.2 DDD99821 0.16  3.8 (HuNMT-1) 0.59 510.3 DDD99822 0 0.006 0.017 (HuNMT-1) 0.051 509.3 DDD99823 0.006 0.033 (HuNMT-1) 0.041 475.3 DDD99824 0.004 0.013 (HuNMT-1) 0.014 455.2 DDD99825 0.011 0.036 (HuNMT-1) 0.039 (LmNMT) 0.054 421.3 DDD99826 0.016 0.094 (HuNMT-1) 0.104 475.2 DDD99827 0.007 0.029 (HuNMT-1) 0.019 459.2 DDD99830 0.003 0.032 (HuNMT-1) 0.011 (LmNMT) 0.020 419.3 DDD99832 0.003 0.011 (HuNMT-1) 0.044 (AfNMT) 0.010 459.2 DDD99833 0.003 0.168 (HuNMT-1) 0.009 (LmNMT) 0.018 498.2 DDD99834 0.019 0.47 (HuNMT-1) 0.225 484.2 DDD99835 0 0.38  >1 (HuNMT-1) >1 442.0 DDD99836 0.003 0.15 (HuNMT-1) 0.013 516.2 DDD99837 0.007 0.12 (HuNMT-1) 0.20 (AfNMT) 0.036 447.3 DDD99838 0.17  0.37 (HuNMT-1) >1 444.25 DDD100086 0.003 0.145 (HuNMT-1) 0.012 524.2 DDD100088 0.002 0.024 (HuNMT-1) 0.003 501.2 DDD100091 0.002 0.009 (HuNMT-1) 0.004 487.2 DDD100093 0.162 0.021 (HuNMT-1) 0.106 435.3 DDD100094 0.003 0.025 (HuNMT-1) 0.008 481.3 DDD100095 0.005 0.022 (HuNMT-1) 0.055 441.3 DDD100096 0 0.003 0.009 (HuNMT-1) 0.003 509.2 DDD100097 0.002 0.021 (HuNMT-1) 0.001 523.2 DDD100139 1.4  2.3 (HuNMT-1) >1 517.3 DDD100140 0.12  0.74 (HuNMT-1) >1 525.3 DDD100141 0.003 0.033 (HuNMT-1) 0.003 (LmNMT) 0.003 537.2 DDD100142 0.004 0.081 (HuNMT-1) 0.014 538.0 DDD100143 0.003 0.01 (HuNMT-1) 0.017 475.2 DDD100144 0.002 0.006 (HuNMT-1) 0.001 (LmNMT) 0.001 537.0 DDD100145 0.011 0.148 (HuNMT-1) 0.035 (LmNMT) 0.02 523.2 DDD100146 0.36  2.3 (HuNMT-1) >1 481.3 DDD100147 0 3.2  >10 (HuNMT-1) >1 477.9 DDD100148 0.008 0.21 (HuNMT-1) 0.018 558.2 DDD100149 0.014 2.4 (HuNMT-1) 0.132 556.2 DDD100150 1.3  4.0 (HuNMT-1) >1 503.3 DDD100151 0.011 0.134 (HuNMT-1) 0.034 541.1 DDD100153 0.005 0.323 (HuNMT-1) 0.023 555.2 DDD100156 0.016 1.1 (HuNMT-1) 0.048 (LmNMT) 0.148 534.2 DDD100157 0.006 0.21 (HuNMT-1) 0.014 570.2 DDD100158 0.006 0.056 (HuNMT-1) 0.048 447.0 DDD100159 0.004 0.06 (HuNMT-1) 0.009 551.0 DDD100160 0 0.003 0.345 (HuNMT-1) 0.013 537.0 DDD100161 0.002 0.034 (HuNMT-1) 0.006 553.0 DDD100162 0.01  0.173 (HuNMT-1) 0.093 461.4 DDD100163 0.014 1.7 (HuNMT-1) 0.125 538.2 DDD100164 0.002 0.007 (HuNMT-1) 0.005 (LmNMT) 0.001 538.2 DDD100165 0.004 0.11 (HuNMT-1) 0.020 569.2 DDD100166 0.005 0.008 (HuNMT-1) 0.002 524.2 DDD100167 0.004 0.071 (HuNMT-1) 0.014 555.2 DDD100168 0.009 0.168 (HuNMT-1) 0.110 463.2 DDD100169 0.003 0.005 (HuNMT-1) 0.001 (LmNMT) 0.001 539.1 DDD100790 0 0.043 0.52 (HuNMT-1) 0.35 (LmNMT) 0.269 495.3 DDD100791 0.21  2.1 (HuNMT-1) 0.044 (LmNMT) 0.344 576.2 DDD100792 0.01  0.076 (HuNMT-1) 0.23 (LmNMT) 0.143 481.3 DDD100793 0.026 0.33 (HuNMT-1) 1.4 (LmNMT) 0.54 504.3 DDD100794 0.013 0.49 (HuNMT-1) 0.024 (LmNMT) 0.160 562.2 DDD100795 0.003 0.042 (HuNMT-1) 0.002 (LmNMT) 0.005 548.2 DDD100796 0.86  >1 (HuNMT-1) >1 (LmNMT) >1 518.3 DDD100797 0.023 0.077 (HuNMT-1) 0.27 (LmNMT) 0.492 471.3 DDD100798 0.003 0.004 (HuNMT-1) 0.025 (LmNMT) 0.006 453.3 DDD100799 0.02  0.24 (HuNMT-1) 0.47 (LmNMT) 0.293 455.3 DDD100800 0 0.006 0.021 (HuNMT-1) 0.073 (LmNMT) 0.052 455.3 DDD100801 0.004 0.011 (HuNMT-1) 0.011 (LmNMT) 0.014 439.2 DDD100802 0.003 0.101 (HuNMT-1) 0.005 (LmNMT) 0.004 552.0 DDD100803 0.002 0.046 (HuNMT-1) 0.005 (LmNMT) 0.008 571.2 DDD100804 0.006 0.061 (HuNMT-1) 0.077 (LmNMT) 0.035 481.3 DDD100805 0.27  >1 (HuNMT-1) >1 (LmNMT) >1 463.2 DDD100806 0.004 0.057 (HuNMT-1) 0.224 (LmNMT) 0.033 485.3 DDD100807 0.002 0.004 (HuNMT-1) 0.001 (LmNMT) 0.001 523.2 DDD100862 0.358 0.174 (HuNMT-1) >1 μM (LmNMT) >1 μM 441.2 DDD100863 0.006 0.051 (HuNMT-1) 0.091 (LmNMT) 0.015 469.3 DDD100865 0 0.097 0.314 (HuNMT-1) 1.9 (LmNMT) 7.3 441.2 DDD100866 0.010 0.047 (HuNMT-1) 0.054 (LmNMT) 3.2 441.2 DDD100867 0.006 0.039 (HuNMT-1) 0.074 (LmNMT) 0.048 427.2 DDD100868 0.015 0.002 (HuNMT-1) 0.004 (LmNMT) 0.0009 467.3 DDD100869 0.004 0.006 (HuNMT-1) 0.019 (LmNMT) 5.7 518.3 DDD100870 0.005 0.018 (HuNMT-1) 0.045 (LmNMT) 0.013 441.2 DDD100871 7.95  >1 μM (HuNMT-1) >1 μM (LmNMT) 51.0 374.0 DDD100872 0.003 0.017 (HuNMT-1) 0.005 (LmNMT) 0.002 551.2 DDD100873 13.8   >1 μM (HuNMT-1) >1 μM (LmNMT) >1 μM 422.2 DDD100874 0.740 >1 μM (HuNMT-1) >1 μM (LmNMT) >1 μM 422.2 DDD100875 00 2.68  >1 μM (HuNMT-1) >1 μM (LmNMT) 20.5 386.1 DDD100876 01 0.006 0.020 (HuNMT-1) 0.059 (LmNMT) 0.014 453.3 DDD100877 02 123.0   >1 μM (HuNMT-1) >1 μM (LmNMT) 33.9 420.0 DDD100878 03 0.262 2.4 (HuNMT-1) 0.906 (LmNMT) >1 μM 422.2 DDD100879 04 0.803 2.6 (HuNMT-1) 1.59 (LmNMT) >1 μM 408.2 DDD100880 05 >1 μM >1 μM (HuNMT-1) >1 μM (LmNMT) 21.4 436.0 DDD100881 06 0.020 0.233 (HuNMT-1) 0.778 (LmNMT) 0.234 481.3 DDD100882 07 0.305 0.769 (HuNMT-1) >1 μM (LmNMT) 2.45 518.3 DDD100883 08 0.023 >1 μM (HuNMT-1) 0.672 (LmNMT) 0.427 495.3 DDD100884 09 1.08  >1 μM (HuNMT-1) >1 μM (LmNMT) >1 μM 408.2 DDD100885 0 0.032 0.096 (HuNMT-1) 0.211 (LmNMT) 9.72 489.2 DDD100886 0.016 0.019 (HuNMT-1) 0.16 (LmNMT) 0.004 587.2 DDD100887 0.010 0.018 (HuNMT-1) 0.005 (LmNMT) 0.005 545.1 DDD100888 0.004 0.012 (HuNMT-1) 0.005 (LmNMT) 0.003 477.2 DDD100889 5.3  1.3 (HuNMT-1) 1.2 (LmNMT) >1 μM 506.0 DDD100891 0.020 0.100 (HuNMT-1) 0.045 (LmNMT) 0.129 474.2 DDD100965 0.025 0.037 (HuNMT-1) 0.026 (LmNMT) nd 452.2 DDD100966 0.012 0.22 (HuNMT-1) 0.012 (LmNMT) nd 432.2 DDD100968 0.016 0.14 (HuNMT-1) 0.045 (LmNMT) nd 446.2 DDD100969 0.010 0.019 (HuNMT-1) 0.044 (LmNMT) nd 438.2 DDD100971 0 0.04  0.63 (HuNMT-1) 0.55 (LmNMT) nd 494.2 DDD100972 0.005 0.014 (HuNMT-1) 0.005 (LmNMT) nd 446.2 DDD100974 0.026 0.11 (HuNMT-1) 0.028 (LmNMT) nd 474.2 DDD100978 0.019 >1.0 (HuNMT-1) 0.04 (LmNMT) nd 594.2 DDD100979 0.20  0.20 (HuNMT-1) >1.0 (LmNMT) nd 454.2 DDD100980 0.028 0.15 (HuNMT-1) 0.13 (LmNMT) nd 444.2 DDD100985 0.10  0.62 (HuNMT-1) 0.38 (LmNMT) nd 460.2 DDD100986 0.018 0.33 (HuNMT-1) 0.16 (LmNMT) nd 446.2 DDD100990 0.024 0.40 (HuNMT-1) 0.13 (LmNMT) nd 460.2 DDD100991 0.005 0.03 (HuNMT-1) 0.05 (LmNMT) nd 494.2

(138) TABLE-US-00002 TABLE 2 Activity of N-Myristoyltransferase Inhibitors Against Human Cancer Cell Lines IC.sub.50 (μM) Reference HT29 HCT116 SkBr3 RT112 C6 H460 MRC5 HT1080 A549 DDD85646 0.112 0.234 0.108 0.330 1.16 1.32 0.123 0.06 0.157 DDD86206 0.154 0.422 0.141 0.425 1.89 2.53 0.209 0.086 0.213

(139) TABLE-US-00003 TABLE 3 Activity of N-Myristoyltransferase Inhibitors Against Human Cancer Cell Lines IC.sub.50(μM) Reference NCI-H1299 MDA-MB-231 OE19 OE21 DDD85646 0.57 0.23 0.66 0.29 DDD86212 1.08 0.64 4.37 1.39 DDD86470 3.71 0.89 4.57 1.20 DDD86481 0.096 0.047 0.132 0.057

(140) TABLE-US-00004 TABLE 4 Activity of N-Myristoyltransferase Inhibitors Against Human Cancer Cell Lines IC.sub.50(μM) Reference MDA-MB-231 HT-29 HCT116 DDD85646 0.23 0.112 0.234 DDD88558 0.448 0.176 0.629 DDD90086 0.537 0.281 0.921 DDD90149 2.23 >10 1.91 DDD100144 0.218 n.d. 0.282 DDD100169 0.249 n.d. 0.419

(141) Assessment of the CNS penetration of NMT inhibitors was determined in the female NMRI mouse following i.v. dosing (n=3 per dose group, concentration measured after t=5 min).

(142) TABLE-US-00005 TABLE 5 Drug concentration in blood and brain in the female NMRI mouse at t = 5 min following single i.v. dosing (average of three animals) Conc (ng/ml Conc (ng/ml Reference Dose in blood) in brain) Brain:Blood DDD73490 0.33 mg/kg 52 314 6.0 DDD88195  1.0 mg/kg 116 93 0.8 DDD88638  2.0 mg/kg 281 378 1.35 DDD90154  2.0 mg/kg 455 608 1.34 DDD99742  2.0 mg/kg 642 422 0.66 DDD99837  3.0 mg/kg 388 99 0.26 DDD100097  2.0 mg/kg 224 335 1.50 DDD100144  2.0 mg/kg 413 545 1.32 DDD100153  2.0 mg/kg 269 171 0.64

(143) Assessment of the antitrypanosomal efficacy of DDD85646 in an acute model of trypanosomiasis was determined at six dose levels in the female NMRI mouse (n=3 per dose group). Compound was dosed for four days b.i.d. at the stated level, commencing three days after infection with 1×10.sup.4 trypanosomes (T. brucei brucei, blood stream form, variant 221).