THERAPEUTIC AGENTS

Abstract

A compound of formula (I) or a compound of formula (II) or pharmaceutically acceptable salts thereof, wherein R1-R7 and X are as defined in the description, and the use of these compounds in therapy, in particular in treating cancer or as an inhibitor of the interaction of the MDM2 protein with p53.

Claims

1. A compound of Formula I, or Formula II, or a pharmaceutically acceptable salt thereof, ##STR00188## wherein in both formulae I and II: X is selected from O or S; R.sup.1 is selected from substituted or unsubstituted aryl, and substituted or unsubstituted aralkyl; R.sup.2 is selected from: (i) hydroxy-2,2-dimethylpropyl, hydroxy-2,2-cyclopropylpropyl, 2-hydroxymethyl allyl, and a succinic acid derivative, (ii) hydroxycyclooctyl, hydroxymethylcyclohexylmethylene, and hydroxycyclohexyl, and (iii) hydroxymethylbenzyl; R.sup.3 is selected from substituted or unsubstituted aryl, and substituted or unsubstituted aralkyl; and R.sup.4-R.sup.7 represents groups R.sup.4, R.sup.5, R.sup.6 and R.sup.7 which are independently selected from hydrogen, halo, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted alkylamine, substituted or unsubstituted alkoxy, trifluoromethyl, amino, nitro, carboxyl, carbonyl, methylsulfone, trifluoromethylsulfone, cyano and substituted or unsubstituted sulfonamide.

2. A compound according to claim 1, wherein R.sup.1 is substituted or unsubstituted aralkyl.

3. A compound according to claim 2, wherein R.sup.2 is selected from hydroxy-2,2-dimethylpropyl, hydroxy-2,2-cyclopropylpropyl, 2-hydroxymethyl allyl, and a succinic acid derivative.

4. A compound according to claim 2, wherein R.sup.2 is selected from hydroxycyclooctyl, hydroxymethylcyclohexylmethylene, and hydroxycyclohexyl.

5. A compound according to claim 2, wherein R.sup.2 is hydroxymethylbenzyl.

6. A compound according to claim 1, wherein R.sup.1 is substituted benzyl.

7. A compound according to claim 6, wherein R.sup.1 is 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, cyanobenzyl, or 4-iodobenzyl.

8. A compound according to claim 1, wherein R.sup.3 is substituted or unsubstituted phenyl.

9. A compound according to claim 8, wherein R.sup.3 is 4-chlorophenyl or 4-fluorophenyl.

10. A compound according to claim 1, wherein R.sup.4-R.sup.7 are all hydrogen or at least one of R.sup.4-R.sup.7 is a chlorine atom.

11. A compound according to claim 1, wherein R.sup.3 is substituted aryl.

12. A compound according to claim 1, wherein R.sup.1 is substituted 1-ethylphenyl, 4-nitrobenzyl, 4-cyanobenzyl, 4-chlorobenzyl, 4-bromobenzyl or 4-iodobenzyl.

13. A compound according to claim 12, wherein the substituted 1-ethylphenyl is the S-enantiomer.

14. A compound according to claim 1, wherein R.sup.3 is substituted phenyl.

15. A compound according to claim 1, wherein X is O.

16. A pharmaceutical composition comprising an effective amount of at least one compound according to claim 1 and a pharmaceutically acceptable carrier.

17. A compound according to claim 1 wherein the compound is a compound of Formula I, or a pharmaceutically acceptable salt thereof.

18. A compound according to claim 1, or a pharmaceutically acceptable salt thereof wherein the compound is ##STR00189##

19. A compound according to claim 1, or a pharmaceutically acceptable salt thereof wherein the compound is ##STR00190##

Description

[0126] The invention will now be described, by way example only, by reference to the accompanying figures, of which:

[0127] FIG. 1 is a Western Blot assay illustrating the effects of NU8293, NU8295, NU8296 and NU8297 in the SJSA-1 cell line;

[0128] FIG. 2 is a Western Blot assay illustrating the effects of NU8352, NU8353 and NU8354 compared with the effects with Nutlin-3 in the SJSA-1 cell line;

[0129] FIG. 3 is a graph illustrating the effect of the NU8293, NU8296 and NU8297 isoindolinones on p53-dependent transcriptional activity measured by a Luciferase based reporter genes assay;

[0130] FIG. 4 is a western blot illustrating the dose response effects of NU8296 and Nutlin-3 (and NU8291, which is not part of this invention) on PARP and Caspase 3 cleavage in the SJSA-1 cell line;

[0131] FIG. 5 is a graph illustrating the growth inhibitory effects of Nutlin-3 in p53 wild-type and p53 deleted versions of the HCT116 cell line with concentrations for 50% growth inhibition shown;

[0132] FIG. 6 is a graph illustrating the effect of NU8354 as a growth inhibitor in wild-type and p53 mutant versions of the HCT116 cell line with concentrations for 50% growth inhibition shown;

[0133] FIG. 7 is a graph illustrating the induction of Caspase 3 and 7 enzymatic activity by NU8354 in the SJSA-1 cell line;

[0134] FIG. 8 is a graph illustrating the growth inhibition dose response to exposure or Nutlin-3 and NU8354 in the SJSA-1 cell line;

[0135] FIG. 9 is a graph illustrating the growth inhibition dose response to exposure of Nutlin-3 and NU8354 in the LS cell line; and

[0136] FIG. 10 is a graph illustrating the growth inhibition dose response to drug exposure of Nutlin-3 and NU8354 in the JAR cell line.

[0137] FIG. 11 is an analytical chromatogram of NU8354 on a Chiracel AD column (4.6 mm25 cm) with 40% EtOH, pentane as eluant in isocratic mode.

[0138] FIG. 12 shows the cellular activity of Nutlin-3, NU8354 and enantiomers NU8354A and NU8354B in SJSA-1 cells by Western blotting.

[0139] NU8296 corresponds to 3-(4-chlorophenyl)-3-((1S,3R)-3-hydroxy cyclopentyloxy)-2-(4-nitrobenzyl)isoindolin-1-one, a further compound in the isoindolin-1-one series, the structure of which is given below.

##STR00084##

[0140] Nutlin-3 is the proprietary name for ()-4-[4,5-bis-(4-Chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]-piperazin-2-one, the structure of which is given below. Nutlin-3 has been found to have an IC.sub.50 of 454 nM and is included in the tests to provide a comparison of the efficacy of the inventive compounds with a known inhibitor of the MDM2-p53 interaction.

##STR00085##

[0141] FIG. 1 shows the induction of increased levels of p53, p21 and MDM2 protein by treatment of MDM2 amplified SJSA-1 cells with NU8293, NU8295 and NU8291 in the 1-2 M concentration range. This is consistent with the inhibition of MDM2-p53 binding and release of p53 activity from negative regulation by MDM2 in these cells, resulting in the increased expression and accumulation of MDM2 and p21 proteins. NU8297 did not show any evidence of activity in this experiment.

[0142] FIG. 2 shows that NU8534 treatment results in strong induction of MDM2, p53, and p21, when compared with the positive control Nutlin-3; this is clear, for instance, from a comparison of the effects at a concentration of 10 M. These results are consistent with the transcriptional activation of p53 resulting from its release from MDM2 inhibition.

[0143] FIG. 3 shows examples of activation of p53 dependent transcriptional activity by NU8293, NU8296 and NU8297 measured by a luciferase based p53-dependent reporter gene assay. This provides further evidence that this series of compounds specifically induces p53-dependent transcriptional activity, consistent with the release of active p53 by inhibition of MDM2-p53 binding in intact cells. The time course of activation is similar to that seen with nutlin-3 and concentration ranges required are comparable.

[0144] FIG. 4 shows the dose dependence of PARP and caspase-3 cleavage in SJSA-1 cells detected after 48 hours of treatment with NU8296 in comparison to nutlin-3. The levels of PARP and caspase-3 cleavage are comparable to those observed with nutlin-3 in the same dose range.

[0145] FIGS. 5 and 6 show that NU8534 is growth inhibitory in wild-type p53 HCT116 cells, as is Nutlin-3. These effects are consistent with the transcriptional activation of p53 and consequent induction of the p21.sup.WAFI cyan dependent kinase inhibitor and hence growth arrest. Furthermore, NU8354 displays greater growth inhibition in the p53wt HCT116 cell line than the p53-/- HCT116 cells, as does Nutlin-3. These effects demonstrate a predominantly p53-dependent mechanism of growth inhibitory activity. In addition, NU8354 shows greatest growth inhibitory activity in MDM2 amplified and p53wt cell lines.

[0146] FIG. 7 shows that NU8354 induces Caspase 3 and 7 enzymatic activity over a 24 and 48 hr exposure in SJSA cells; this is an indication of the induction of apoptosis and is consistent with the western blot evidence of PARP and caspase-3 cleavage.

[0147] FIGS. 8 to 10 show growth inhibition by NU8354 in the 5-20 M concentration range for a panel of MDM2 amplified cell lines, which are generally found to be more sensitive than cell lines not amplified for MDM2.

[0148] FIG. 11 shows the analytical chromatogram of NU8354 on a Chiracel AD column (4.6 mm25 cm) with 40% EtOH, pentane as eluant in isocratic mode. The (+)-enantiomer NU8354A has a retention time of 9.8 minutes, whereas the ()-enantiomer NU8354B elutes at 12.4 minutes. The absolute configuration of the enantiomers has not been determined.

[0149] FIG. 12 shows the cellular activity of Nutlin-3, NU8354 and enantiomers NU8354A and NU8354B in SJSA-1 cells by Western blotting. Nutlin-3 shows a strong dose dependent increase in MDM2, p53 and p21 levels from 1 to 20 M. A similar but weaker effect is observed for NU8354 with a maximal effect observed at 10 M. The activity of NU8354A is slightly weaker than Nutlin at the 20 M dose and significantly weaker at the lower doses. The NU8354B enantiomer displays little cellular activity with weak induction of p21 and MDM2 at the 20 M dose. These results are consistent with NU8354A being the enantiomer which confers the majority of the biological activity of the racemate and the observed IC.sub.50 in the in vitro ELISA assay.

[0150] In summary, NU8534 shows a range of cellular effects consistent with the disruption of MDM2-p53 binding, the proposed mechanism of action. In comparison with the positive control Nutlin-3, the effects are similar across a panel of cell lines with differing p53 and MDM2 status, in terms of p53 activation, growth inhibition and apoptosis.

Synthetic Data

[0151] The present invention will now be described further by way of example only. The following examples and description of stages in synthetic routes of preparation of various compounds of interest serve further to illustrate the present invention.

3-(4-Fluorophenyl)-3-hydroxy-2-propyl-2,3-dihydroisoindol-1-one

[0152] ##STR00086##

[0153] THF (25 mL) was added to 2-(4-fluorobenzoyl)benzoic add (5 g, 20.4 mmol) followed by thionyl chloride (2.97 mL, 40.9 mmol) and a catalytic amount of DMF (3 drops). The system was stirred under nitrogen for 4 h at room temperature. Removal of the solvent gave 3-chloro-3-(4-fluorophenyl)-3H-isobenzofuran-1-one as a colourless oil (5.35 g, 20.4 mmol. 100%).

[0154] Distilled THF (25 mL) was added to 3-chloro-3-(4-chlorophenyl -3H-isobenzofuran-1-one (5.35 g, 20.4 mmol) followed by n-propylamine (1.85 mL, 22.5 mmol), triethylamine (2.85 mL, 26.5 mmol) resulting in the formation a creamy white/yellow precipitate. The mixture was stirred at room temperature under nitrogen for 4 h then the solvent was removed under vacuum. The residue was taken up in ethyl acetate (30 mL), washed with water (320 mL), brine (10 mL), dried (MgSO.sub.4) and evaporated. Recrystallisation (ethyl acetate) gave the title compound as a white solid (4.35 g, 15.2 mmol, 75%); R.sub.f=0.48 (40:60: EtOAc: petrol). mp 172.3-174.6 C. .sub.max (CH.sub.3OH)/mm 210. IR: 3231, 2965, 1673, 1602, 1504, 1407, 1223 cm.sup.1. .sup.1H NMR: (300 MHz, d.sub.6-DMSO) 0.75 (t, 3H, J=7.4 Hz, CH.sub.2CH.sub.2CH.sub.3), 1.42 (m, 2H, NCH.sub.2CH.sub.2), 2.87 (m, 1H, NCH.sub.2), 3.14 (m, 1H, NCH.sub.2), 7.15 (m, 2H, ArH) 7.25 (m, 1H, ArH), 7.35 (m, 2H, ArH), 7.53 (dquin, 2H, J=7.4, 1.4 Hz, ArH), 7.71 (m, 1H, ArH). .sup.13C NMR: (75 MHz, d.sub.6-DMSO) 11.8. 22, 90.4, 115.4, 115.7, 122.7, 123, 128.3, 128.4, 129.5. 130.8, 132.7, 136.8, 136.9, 149.7, 160.5, 162.2, 163.7, 166.8. LCMS (ESI+) m/z=161.1, 227.1, 268.1, 286.1 [M+H].sup.+. Anal. Calcd. for C.sub.17H.sub.16FNO.sub.2: C, 71.56; H, 5.65; N, 4.91%. Found C, 71.61; H 5.70; N, 4.99%. HRMS (EI) m/z Calcd. for C.sub.17H.sub.16FNO.sub.2: 285.1165. Found 285.1166.

3-(4-Fluorophenyl)-3-(3-hydroxycyclopentyloxy)-2-propyl-2,3-dihydroisoindol-1-one

[0155] ##STR00087##

[0156] Distilled THF (20 mL) was added to 3-(4-fluorophenyl)-3-hydroxy-2-propyl-2,3-dihydroisoindol-1-one (200 mg, 0.7 mmol) followed by thionyl chloride (0.06 mL, 0.84 mmol) and a catalytic amount of DMF (3 drops). The mixture was stirred at room temperature under nitrogen for 4 h and monitored by TLC. Removal of the solvent under vacuum gave 3-chloro-3-(4-fluorophenyl)-2-propyl-2,3-dihydroisoindol-1-one as a colourless oil (212 mg, 0.69 mmol, 100%) which was used immediately without further purification.

[0157] Distilled THF was added to 3-chloro-3-(4-fluorophenyl)-2-propyl-2,3-dihydroisoindol-1-one (212 mg, 0.69 mmol) followed by 1,3-cyclopentanediol (0.65 mL, 6.9 mmol). The mixture was stirred at room temperature under nitrogen for 4 h and monitored by TLC. On completion the solvent was removed under vacuum, the residue was taken up in ethyl acetate (30 mL), washed with water (320 mL), brine (10 mL) and dried (MgSO.sub.4). The solvent was removed to give the crude product. HPLC (H.sub.2O: MeOH, 270 nm) gave NU8279 as a clear glass (126 mg, 0.34 mmol, 49%); R.sub.f=0.21 (40:60: EtOAc:petrol). .sub.max (CH.sub.3OH)/nm 220.5. IR: 3387, 2936, 1683, 1604, 1505, 1366 cm.sup.1. .sup.1H NMR: (300 MHz, d.sub.4-MeOH) 0.77 (t, 3H, J=7.4 Hz, CH.sub.2CH.sub.2CH.sub.3), 1.15 (m, 1H, NCH.sub.2CH.sub.2), 1.32 (m, 1H, NCH.sub.2CH.sub.2), 1.40-2.05 (m, 6H, cyclopentane), 3.12 (m, 1H, NCH.sub.2), 3.29 (m, 1H, NCH.sub.2), 3.90 (m, 1H, cyclopentane), 4.31 (m, 1H, cyclopentane), 7.07 (t, 2H, J=9 Hz, ArH), 7.23 (m, 1H, ArH), 7.39 (m, 2H, ArH), 7.60 (m, 2H, ArH), 7.87 (m, 1H, ArH). .sup.1C NMR: (125 MHz, d.sub.4-MeOH) 12.2, 22.9, 32.7, 33.1, 34.2, 43.1, 44.3, 44.8, 72.8.73, 75.7, 96.5, 116.3, 116.6, 124.3, 125.7, 130, 130.1, 131.6, 133.6, 134.1, 137.1, 148.1, 166.2, 170.7. LCMS (ESI+) m/z=227.1, 268.1, 370.3 [M+H].sup.+, 392.3 [M+Na].sup.+. HRMS (EI) m/z Calcd. for C.sub.22H.sub.24FNO.sub.3: 369.1740. Found 369.1737.

3-(4-Chlorophenyl) -hydroxy-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one

[0158] ##STR00088##

[0159] THF (25 mL) was added to 2(4-chlorobenzoyl)benzoic acid (1 g, 3.8 mmol) followed by thionyl chloride (0.55 mL, 7.6 mmol) and a catalytic amount of DMF (3 drops). The system was stirred under nitrogen for 4 h at room temperature and monitored by TLC. Removal of the solvent gave 3-chloro-3-(4-chlorophenyl)-3H-isobenzofuran-1-one as a colourless oil (1.06 g, 3.8 mmol, 100%).

[0160] Distilled THF (25 mL) was added to 3-chloro-3-(4-chlorophenyl)-3H-isobenzofuran-1-one (3.2 g, 11.5 mmol), 4-nitrobenzylamine hydrochloride (2.3 g, 12.6 mmol), and triethylamine (4.8 mL, 34.5 mmol). The mixture was stirred at room temperature under nitrogen for 4 h and monitored by TLC. On completion the solvent was removed under vacuum, the residue was taken up in ethyl acetate (30 mL), washed with water (320 mL), brine (10 mL) and dried (MgSO.sub.4). The solvent was removed under vacuum. Recrystallisation (ethyl acetate) gave 3-(4-Chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one as a light yellow solid (2.95 g, 7.47 mmol, 65%); R.sub.f=0.4 (40:60: EtOAc:petrol). mp 197.1-199.7 C. .sub.max (CH.sub.3OH)/nm 225. IR: 3215, 1676, 1517, 1395, 1341 cm .sup.1. .sup.1H NMR: (300 MHz, d.sub.6-DMSO) 4.35 (d, 1H, J=16.3 Hz, NCH.sub.2), 4.61 (d, 1H, J=16.3 Hz, NCH.sub.2), 7.28 (m, 4H, ArH), 7.45 (m, 3H, ArH), 7.58 (m, 2H, ArH), 7.79 (m, 1H, ArH), 8.05 (m, 2H, ArH). .sup.13C NMR: (75 MHz, d.sub.6-DMSO) 42.1, 90.5, 123.1, 123.3, 128.4, 128.7, 129.1, 129.9, 130.3, 133.2, 133.3, 138.9, 146.4, 146.5, 149.4, 167.1. LCMS (ESI+) m/z=307.2, 368.2, 377.1. Anal. Calcd for C.sub.21H.sub.15ClN.sub.2O.sub.4: C, 63.89; H, 3.83; N, 7.10%. Found C, 63.78; H, 3.92: N, 7.12%. HRMS (EI) m/z Calcd. for C.sub.21H.sub.15ClN.sub.2O.sub.4: 394.0720. Found 394.0714.

3-(4-Chlorophenyl)-2-[1-(4-chlorophenyl)-ethyl]-3-hydroxy-2,3-dihydroisoindol-1-one

[0161] ##STR00089##

[0162] To a solution of 2-(4-chlorobenzoyl)benzoic acid (5 g, 19.2 mmol, 1 equiv.) in dry THF (20 mL) was added under nitrogen atmosphere thionylchloride (3.0 mL, 38.3 mmol, 2 equiv.) and 3 drops of anhydrous DMF. The reaction mixture was stirred for 4 h at room temperature and concentrated in vacuo. The resulting pale yellow oil was taken up in dry THF (20 mL), and (S)-4-chloro--methylbenzylamine (2.43 g, 15.6 mmol, 1.1 equiv.) and DIPEA (3.49 mL, 21.1 mmol, 1.1 equiv.) were added under nitrogen atmosphere. The reaction mixture was stirred overnight at room temperature and the solvents were removed in vacuo. The residue was taken up in EtOAc (100 mL), filtered, and the filtrate washed with water (350 mL) and brine (150 mL). The organic layer was dried over MgSO.sub.4, filtered and concentrated in vacuo to afford a solid, which was recrystallised (EtOAc/Petrol) as a white crystalline powder (3.10 g, 55%). .sup.1H NMR (300 MHz, CDCl.sub.3): Mixture of two diastereoisomers: 7.74-7.09 (m, 13H, ArH and OH), 4.52 and 4.45 (q, J=6.9 Hz, 1H, CH*), 1.75 and 1.48 (d, J=7.2 Hz, 3H, CH.sub.3). .sup.13C NMR (75 MHz, CDCl.sub.3): Mixture of two diastereoisomers: 166.94, 166.43, 149.17, 149.11, 142.01, 141.51, 139.65, 139.33, 133.24, 133.14, 132.90, 131.76, 131.60, 131.54, 131.47, 129.79, 129.71, 129.52, 128.67, 128.62, 128.26, 127.88, 127.84, 123.13, 122.74, 122.70, 91.19, 90.94, 51.22. 50.46, 20.21, 18.24. FTIR: 3103 (OH), 1665 (CO) cm.sup.1. m/z (ES): 398 [M+H].sup.+. Anal.: calc. for C.sub.22H.sub.17Cl.sub.2NO.sub.2+0.3 H.sub.2O: C: 65.45, H: 4.40, N: 3.47. Found: C: 65.00, H: 4.30, N: 3.60.

General Procedure A

[0163] To a solution of the corresponding isoindolone (1.37 mmol, 1 equiv.) in dry THF (10 mL) was added under nitrogen atmosphere, thionylchloride (214 L, 2.75 mmol, 2 equiv.) and 3 drops of DMF. The reaction mixture was stirred for 4 h at room temperature and concentrated in vacuo. The resulting pale yellow oil was taken up in dry THF (10 mL), and the alcohol (2.75 mmol, 2 equiv) and potassium carbonate (380 mg, 2.75 mmol 2 equiv.) were added. The reaction mixture was stirred overnight at room temperature and the solvents were removed in vacuo. The residue was taken up in EtOAc (50 mL) and washed with water (325 mL), and brine (125 mL). The organic layer was dried over MgSO.sub.4, filtered and concentrated in vacuo to afford an oil which was purified by flash chromatography (silica; EtOAc/petrol).

General Procedure B: Synthesis of 3-Alkoxy-3-(4-chlorophenyl)isoindolin-1-ones

[0164] To a solution of the appropriate 3-chloro-3-(4-chlorophenyl)isoindolin-1-one, THF was added the appropriate alcohol (5.0 mol equiv unless stated otherwise) and K.sub.2CO.sub.3 (5.0 mol equiv unless stated otherwise). The mixture was allowed to stir at room temperature for 4 hours under nitrogen and monitored by TLC. Upon completion the mixture was extracted with EtOAc (15 mL), washed with saturated brine (310 mL), water (310 mL) and dried (MgSO.sub.4). Removal of the solvent under reduced pressure yielded the crude 3-alkoxy-2,3-dihydroisoindolin-1-one.

General Procedure B1: Synthesis of 3-alkoxy-2,3-dihydroisoindolin-1-ones

[0165] To a solution of cis-cyclopentane cis-cyclopentane diol (2.5 equiv) and K.sub.2CO.sub.3 (2.5 equiv) in THF (3 mL) was added the appropriate 3-chloro-3-(4-chlorophenyl)isoindolin-1-one (1 equiv) in THF (3 mL) dropwise over 3 hours with stirring under nitrogen at room temperature. The solution was stirred for a further hour and monitored by TLC. Upon completion the mixture was extracted with EtOAc (15 mL), washed with saturated brine (310 mL), water (310 mL) and dried (MgSO.sub.4). The solvent was removed under reduced pressure to yield the crude 3-alkoxy-2,3-dihydroisoindolin-1-one.

3-(4-Chlorophenyl)-3-hydroxy-2-(4-chlorobenzyl)-isoindolin-1-one

[0166] ##STR00090##

[0167] Distilled THF (25 mL) was added to 3-chloro-3-(4-chlorophenyl)-3H-isobenzofuran-1-one (1.071 g, 3.84 mmol) followed by triethylamine (855.1.1 mg, 8.45 mmol, 1.178 and para-chlorobenzylamine (543.36 mg, 3.84 mmol, 0.467 mL) resulting in the formation of a white precipitate. The mixture was stirred at room temperature under nitrogen for 4 hours and monitored by TLC. Upon completion the mixture was then extracted with EtOAc (15 mL) and washed with saturated sodium bicarbonate (310 mL), water (310 mL) and dried (Na.sub.2SO.sub.4). The solvent was removed under reduced pressure and the resultant precipitate recrystallised (EtOAc, petrol) to give the title product as a fine white crystalline solid (1.191 g. 3.20 mmol, 83%). .sup.1H NMR: (300 MHz, DMSO) ppm 4.23 (d, 1H, J=15.59, H.sub.9) 4.45 (d, 1H, J=15.62 H.sub.9) 7.25 (m, 9H, H.sub.1-H.sub.5, H.sub.10-H.sub.13) 7.56 (m, 2H, H.sub.6-H.sub.7) 7.76 (d, 1H, H.sub.8). .sup.13C NMR: (75 Hz, DMSO), 42.09 (NCH.sub.2), 90.55 (OCN), 122.98, 123.19, 128.02, 128.39, 128.57, 129.76, 130.21, 130.66, 131.60, 133.07, 133.15, 137.44, 139.33, 149.52 (Ar), 167.16 (CO). Mp: 156.2-156.9 C. IR: 1467, 1661, 3184 cm.sup.1.

3(4-Chlorophenyl)-3-hydroxy-2-propylisoindolin-1-one

[0168] ##STR00091##

[0169] Distilled THF (20 mL) was added to 3-chloro-3-(4-chlorophenyl)-3H-isobenzofuran-1-one (535.4 mg. 1.91 mmol) followed by triethylamine (398.9 mg, 0.549 mL, 3.94 mmol) and n-propylamine (159.8 mg, 0.22 mL, 1.792 mmol). The mixture was stirred at room temperature under nitrogen for 4 hours and monitored by TLC. Upon completion the mixture was then extracted with EtOAc (15 mL) and washed with saturated sodium bicarbonate (310 mL), water (310 mL) and dried (Na.sub.2SO.sub.4). Recrysallisation from a minimum amount of boiling ethyl acetate and an excess of petrol yielded the title product as a white crystalline solid (425 mg, 1.409 mmol, 77%). .sup.1H NMR: (300 Hz, CDCl.sub.3) ppm 0.76 (t, 3H, H.sub.11), 1.45 (m, 2H, H.sub.10), 2.86 (m, 1H, H.sub.9), 3.36 (m, 1H, H.sub.9), 7.16 (d, 1H, H.sub.5), 7.38 (dd, 4H, H.sub.1-H.sub.4), 7.45 (m, 2H, H.sub.6 H.sub.7), 7.70 (d, 1H, H.sub.8). .sup.13C NMR: (75 Hz, DMSO); 11.87 (NCH.sub.2CH.sub.2CH.sub.3), 21.96 (NCH.sub.2CH.sub.2), 40.69 (NCH.sub.2), 90.50 (OCN), 122.75, 122.99, 128.24, 128.76, 129.58, 131.04, 131.24, 132.73, 133.13, 139.94. 149.59 (Ar), 166.96 (CO). Mp: 201.5-201.7 C. IR: 1466, 1608, 1664, 2968, 3157 cm.sup.1.

2-Benzyl-3-(4-chlorophenyl)-3-hydroxy-2,3-dihydroisoindolin-1-one

[0170] ##STR00092##

[0171] Distilled THF (25 mL) was added to 3-chloro-3-(4-chlorophenyl)-3H-isobenzofuran-1-one (1.042 g. 3.84 mmol) followed by triethylamine (777.1 mg, 7.68 mmol, 1.06 mL)) and benzylamine (616 mg, 5.76 mmol, 0.79 mL) resulting in the formation of a yellow/cream precipitate. The mixture was stirred at room temperature under nitrogen for 4 hours and monitored by TLC. Upon completion the mixture was then extracted with EtOAc (15 mL) and washed with saturated sodium bicarbonate (310 mL), water (310 mL) and dried (Na.sub.2SO.sub.4). Recrystallisation of the cream precipitate from a minimum amount of boiling ethyl acetate and excess petrol to yielded the title product as a white crystalline solid (1.0378 g, 2.96 mmol, 77% yield). .sup.1H NMR: (300 Hz, CDCl.sub.3) ppm 4.24 (d, 1H, J=15.48 Hz, H.sub.9), 4.42 (d, 1H, J=15.48 Hz, H.sub.9), 7.16 (m, 5H, H.sub.10-H.sub.14), 7.25 (m, 5H, H.sub.1-H.sub.5), 7.56 (m, 2H, H.sub.6-H.sub.7), 7.75 (d, 1H, H.sub.8). .sup.13C NMR: (75 Hz, DMSO); 42.80 (NCH.sub.2), 90.60 (OCN), 122.95, 123.18, 126.78, 128.07, 128.35, 128.41, 128.51, 129.70, 130.81, 132.97, 133.07, 138.42, 139.46, 149.59 (Ar), 167.20 (CO). IR: 1463, 1664, 2936, 3285 cm.sup..

3-(1-Chlorophenyl)-3-hydroxy-2-(4-methylbenzyl)-isoindolin-1-one

[0172] ##STR00093##

[0173] Distilled THF (25 was added to 3-chloro-3-(4-chlorophenyl)-3H-isobenzofuran-1-one (1.071 g, 3.84 mmol) followed by triethylamine (855.1.1 mg, 8.45 mmol, 1.178 mL) and para-methylbenzylamine (465.3 mg, 3.84 mmol, 0.489 mL) resulting in the formation of a bright yellow precipitate. The mixture was stirred at room temperature under nitrogen for 4 hours and monitored by TLC. Upon completion the mixture was then extracted with EtOAc (15 mL) and washed with saturated sodium bicarbonate (310 mL), water (310 mL) dried (Na.sub.2SO.sub.4). Recrystallisation of the cream/yellow residue from a minimum amount of boiling ethyl acetate and excess petrol yielded the title product as a fine pale yellow crystalline solid (1.090 g, 3.10 mmol, 81%). .sup.1H NMR: (300 MHz, DMSO) ppm 2.21 (s, 3H, H.sub.12), 4.20 (d, 1H, J=15.62 Hz, H.sub.9), 4.40 (d, 1H, J=15.36 Hz, H.sub.9), 6.95 (d, 2H J=7.97 Hz, H.sub.11-H.sub.13), 7.04 (d, 2H, J=8.00 Hz, H.sub.10-H.sub.14) 7.27 (m, 5H, H.sub.1-H.sub.5), 7.55 (m, 2H, H.sub.6-H.sub.7) 7.74 (d, 1H, H.sub.8). .sup.13C NMR: (75 Hz, DMSO) 20.90 (CH.sub.3), 42.53 (NCH.sub.2), 90.57 (OCN), 122.89, 123.15, 128.36, 128.38, 128.61, 129.66, 130.85, 132.91, 133.03, 135.37, 135.84, 139.51 (Ar), 167.10 (CO). IR: 1398, 1468, 1660, 2921, 3138 cm.sup.1.

2-(4-(Aminomethyl)benzonitrile)-3-(4-chlorophenyl)-3-hydroxyisoindolin-1-one

[0174] ##STR00094##

[0175] Distilled THF (25 mL) was added to 3-chloro-3-(4-chlorophenyl)-3H-isobenzofuran-1-one (1.071 g, 3.84 mmol) followed by triethylamine (777.14 mg, 7.68 mmol, 1.07 mL) and 4-(aminomethyl)benzonitrile (507.6 mg, 3.84 mmol). The mixture was stirred at room temperature under nitrogen for 4 hours and monitored by TLC. Upon completion the mixture was then extracted with EtOAc (15 mL) and washed with saturated sodium bicarbonate (310 mL), water (310 mL) and dried (Na.sub.2SO.sub.4). Removal of solvent after washing produced a viscous orange oil. Trituration under petrol yielded a yellow/orange solid which was recrystallised from a minimum amount of boiling ethyl acetate and excess petrol to produce the title product as a fine pale yellow crystalline solid (665 mg, 1.83 mmol, 50%). .sup.1H NMR: (300 MHz, DMSO) ppm 4.31 (d, 2H, J=16.12 Hz, 4.55 (d, 2H J=16.15 Hz, H.sub.9), 7.26 (m, 5H, H.sub.1-H.sub.5), 7.37 (d, 2H J=8.29 Hz, H.sub.10, H.sub.13), 7.58 (m, 2H, H.sub.6-H.sub.7), 7.64 (d, 2H J=8.26 Hz, H.sub.11-H.sub.12), 7.77 (d, 1H, H.sub.8). .sup.13C NMR: (75 Hz, DMSO); 42.51 (NCH.sub.2), 60.02 (CN) 90.57 (OCN), 109.82, 119.08, 123.06, 123.25, 128.40, 128.62, 129.16, 129.83, 130.54, 132.03, 133.19, 133.26, 133.52, 139.19, 144.24, 149.48 (Ar), 167.23 (CO). IR: 1397, 1655, 2227 cm.sup.1.

4-((1-4-chlorophenyl)-1-(4-hydroxycyclopent-2-enyloxy)-3-oxoisoindolin-2-yl)methyl)benzonitrile (NU8292)

[0176] ##STR00095##

[0177] Distilled THF (10 mL) was added to 2(4-(aminomethyl)benzonitrile)-3-(4-chlorophenyl)-3-hydroxyisoindolin-1-one (400 mg, 1.10 mmol), thionyl chloride (288.9 mg, 2.42 mmol, 0.18 mL) and catalytic DMF (3 drops) as for general procedure B1. 3-Chloro-3-(4-chlorophenyl)-2-(4-(aminomethyl)benzonitrile) isoindolin-1-one was produced as a viscous clear oil (419 mg, 1.10 mmol) which was used immediately without further purification. Distilled THF (3 mL) was added to 3-chloro-3-(4-chlorophenyl)-2-(4-(aminomethyl)benzonitrile)isoindolin-1-one (419 mg, 1.10 mmol) and the resultant solution added dropwise to cis-cyclopentene diol (275 mg, 2.75 mmol) and dried K.sub.2CO.sub.3 (380.05 mg, 2.75 mmol) in distilled THF (3 mL) as for general procedure B1. Removal of the solvent yielded the crude product as a yellow oil (364 mg). Purification by flash column chromatography yielded the title product as a yellow oily solid (105.4 mg, 0.23 mmol, 21%). .sup.1H NMR: (300 MHz, DMSO) ppm 1.31 (m, 1H, H.sub.15/15), 1.73, 2.11 (m, 1H, H.sub.15/15), 3.89 (br s, 1H, OH), 4.22 (m, 1H, H.sub.16), 4.42 (d, J=7.10 Hz, H.sub.9/9), 4.52 (d, 1H J=7.03 Hz, H.sub.9/9), 4.98, 5.04 (dd, 1H, H.sub.17/18), 5.01, 5.27 (dd, 1H, H.sub.17/18), 5.75 (m, 1H, H.sub.14), 7.24 (m, 7H, H.sub.1-H.sub.5, H.sub.10, H.sub.13) 7.62 (m, 4H, H.sub.6/7, H.sub.11/12), 7.87 (d, 1H, H.sub.8). Mp: 126.4-127.8 C. IR: 1382, 1609, 2229, 3061 cm.sup.1. HR-MS (EI): Calculated mass: [M+Na].sup.+ 479.1133, Found: 479.1134.

3-(4-Chlorophenyl)-3-(4-hydroxycyclopent-2-enyloxy)-2-(4-chlorobenzyl)isoindolin-1-one (NU8293)

[0178] ##STR00096##

[0179] Distilled THF (10 mL) was added to 3-(4-Chlorophenyl)-3-hydroxy-2-(4-chlorobenzyl)-isoindolin-1-one (200 mg, 0.54 mmol), thionyl chloride (141.37 mg, 1.18 mmol, 0.09 mL) and catalytic DMF (3 drops) as for general procedure B1. 3-Chloro-3-(4-chlorophenyl)-2-(4-chlorobenzyl)isoindolin-1-one was produced as a viscous colourless oil (210 mg, 0.54 mmol) which was used immediately without further purification. Distilled THF (3 mL) was added to 3-chloro-3-(4-chlorophenyl)-2-(4-chlorobenzyl)isoindolin-1-one (210.8 mg, 0.54 mmol) and the resultant solution added dropwise to cis-cyclopentene diol (135 mg, 1.35 mmol) and dried potassium carbonate (186.6 mg, 1.35 mmol) in distilled THF (3 mL) as for general procedure B1. Removal of the solvent yielded the crude product as a yellow oil (224 mg). The sample was purified by flash column chromatography (EtOAc:Petrol, 40:60) to yield the title product as a yellow viscous oil. (103.9 mg, 0.23 mmol, 43%). .sup.1H NMR: (300 MHz, DMSO) ppm 1.27 (m, 1H, H.sub.15/15), 1.41, 1.68 (m, 1H, H.sub.15/15) 3.86 (m, 1H, H.sub.16), 4.16 (m, 1H, H.sub.14) 4.31 (d, 1H, J=15.49, H.sub.9/9) 4.50 (d, 1H, J=15.48 H.sub.9/9) 4.93, 5.75 (dd, 1H, H.sub.17/18) 5.25, 5.70 (dd, 1H, H.sub.17/18), 7.21 (m, 9H, H.sub.1-H.sub.5, H.sub.10-H.sub.13) 7.63 (m, 2H, H.sub.6-H.sub.7) 7.85 (d, 1H, H.sub.8), IR: 1467, 1683, 2926, 3397 cm.sup.1.

3-(4-Chlorophenyl)-3-(4-hydroxycyclopent-2-enyloxy)-2-propylisoindolin-1-one (NU8294)

[0180] ##STR00097##

[0181] Distilled THF (5 mL) was added to 3-(4-chlorophenyl)-3-hydroxy-2-propylisoindolin-1-one (104 mg, 0.33 mmol), thionyl chloride (86.83 mg, 0.73 mmol, 0.05 mL) and catalytic DMF (3 drops) as for general procedure B1. 3-Chloro-3-(4-chlorophenyl)-2-propylisoindolin-1-one was produced as an orange oil (105 mg, 0.33 mmol) which was used immediately without further purification. Distilled THF (6 mL) was added to 3-chloro-3-(4-chlorophenyl)-2-propylisoindolin-1-one (211.2, 0.66 mmol), cis-cyclopentene diol (330 mg, 3.3 mmol) and potassium carbonate (456 mg, 3.3 mmol) as for general procedure B. Removal of the solvent yielded the crude product as a colourless oil (160.2 mg). The sample was purified by flash column chromatography (EtOAc:Petrol, 40:60) to yield the title product as an colourless viscous oil. (129 mg, 0.43 mmol, 51% yield). .sup.1H NMR: (300 Hz, DMSO) ppm 0.76 (t, 3H, H.sub.11), 1.36 (m, 1H, H.sub.13/H.sub.13), 1.49, 1.76 (m, 1H, H.sub.13/H.sub.3), 3.12 (m, 2H H.sub.10) 3.96 (m, 1H, H.sub.9/H.sub.9), 4.26 (m, 1H, H.sub.9/H.sub.9), 5.29, 5.87, (dd, 1H, H.sub.15/H.sub.16) 5.74, 5.79 (dd, 1H, H.sub.15/H.sub.16) 7.23 (d, 1H), 7.38 (m, 4H, H.sub.1-H.sub.5), 7.61 (m, 2H, H.sub.6-H.sub.7), 7.76 (d, 1H, H.sub.8). IR: 1365, 1682, 2969, 3363 cm.sup.1.

3-(4-Chlorophenyl)-3-(4-hydroxycyclopent-2-enyloxy)-2-(4-methylbenzyl) isoindolin-1-one (NU8295)

[0182] ##STR00098##

[0183] Distilled THF (10 mL) was added to 3-(4-chlorophenyl)-3-hydroxy-2-(4-methylbenzyl)-isoindolin-1-one (400 mg, 1.13 mmol), thionyl chloride (295.8 mg, 2.48 mmol, 0.18 mL) and catalytic DMF (3 drops) as for general procedure B1. 3-Chloro-3-(4-chlorophenyl)-2-(4-methylbenzyl)isoindolin-1-one was produced as a viscous yellow oil (418 mg, 1.13 mmol) which was used immediately without further purification. Distilled THF (3 mL) was added to 3-chloro-3-(4-chlorophenyl)-2-(4-methylbenzyl)isoindolin-1-one (418.1 mg, 1.13 mmol) and the resultant solution added dropwise to cis-cyclopentene diol (285 mg, 2.85 mmol) and dried K.sub.2CO.sub.3 (390.41 mg, 2.85 mmol) in distilled THF (3 mL) as for general procedure B1. Removal of the solvent yielded the crude product as a green oil (359 g). Purification by flash column chromatography yielded the title product as a colourless viscous oil (242.1 mg, 0.55 mmol, 50%) .sup.1H NMR: (300 MHz, DMSO) ppm 1.19 (m, 1H, H.sub.16/16), 1.67, 2.05 (m, 1H, H.sub.16/16) 2.21 (s, 3H, H.sub.12), 3.85 (m, 1H, H.sub.17), 4.06 (d, 1H, J=15.21 Hz, H.sub.9/9), 4.32 (m, 1H, H.sub.15), 4.53 (d, 1H, J=15.21 Hz, H.sub.9/9), 4.81, 5.74, (dd, 1H, H.sub.18/19) 5.20, 5.66 (dd, 1H, H.sub.18/19), 6.95 (m, 4H, H.sub.10, H.sub.11, H.sub.13, H.sub.14), 7.25 (m, 5H, H.sub.1-H.sub.5), 7.65 (m, 2H, H.sub.6-H.sub.7) 7.74 (d, 1H, H.sub.8). IR: 1380, 1467, 1699, 2922 cm.sup.1. HR-MS (EI): Calculated mass: [M+H].sup.+ 446.1517, Found: 446.1517.

3-(4-Chlorophenyl)-3-(4-hydroxycyclopent-2-enyloxy)-2-(4-nitrobenyzl)isoindolin-1-one (NU8297)

[0184] ##STR00099##

[0185] Distilled THF (10 mL) was added to 3-(4-chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)isoindolin-1-one (200 mg, 0.52 mmol), thionyl chloride (136.8 mg, 1.15 mmol, 0.08 mL) and catalytic DMP (3 drops) as for general procedure B1. 3-Chloro-3-(4-chlorophenyl)-2-(4-nitrobenzyl)isoindolin-1-one was produced as a viscous yellow oil (208.5 mg, 0.52 mmol) which was used immediately without further purification. Distilled THF (3 mL) was added to 3-chloro-3-(4-chlorophenyl)-2-(4-nitrobenzyl)isoindolin-1-one (208.5 mg, 0.52 mmol) and the resultant solution added dropwise to cis-cyclopentene diol (260 mg, 2.6 mmol) and dried potassium carbonate (359 mg, 2.6 mmol) in distilled THF (3 mL) as for general procedure B1. Removal of the solvent yielded the crude product as a yellow oil (262 mg). The sample was purified by flash column chromatography (EtOAc:Petrol, 40:60) to yield the title product as a yellow viscous oil. (211 mg, 44.4 mmol, 85%). .sup.1H NMR: (300 MHz, DMSO) ppm 1.34, (m, 1H, H.sub.15/H.sub.16) 1.74, 2.2 (m, 1H, H.sub.15/H.sub.16) 4.22 (dt, 1H, H.sub.16) 4.40 (d, 1H, J=15.99 Hz, H.sub.9/H.sub.9), 4.63 (d, 1H, J=16.02 Hz, H.sub.9/H.sub.9), 4.93, 4.98, (dd, 1H, H.sub.17/H.sub.18), 5.15, 5.29 (dd, 1H, H.sub.17/H.sub.18), 5.76 (m, 1H, H.sub.14) 7.26 (m, 7H, H.sub.1-H.sub.5, H.sub.10, H.sub.13), 7.66 (m, 2H, H.sub.6-H.sub.7), 7.88 (d, 1H, H.sub.8), 8.00 (m, 2H, H.sub.11, H.sub.12).

2-Benzyl-3-(4-chlorophenyl)-3-(4-hydrocycyclopent-2-enyloxy)isoindolin-1-one (NU8298)

[0186] ##STR00100##

[0187] Distilled THF (25 mL) was added to 2-benzyl-3-(4-chlorophenyl)-3-hydroxy-2,3-dihydroisoindolin-1-one (400 mg, 1.145 mmol), thionyl chloride (299.6 mg, 2.51 mmol, 0.18 mL) and catalytic DMF (3 drops) as for general procedure B1. 3-Chloro-3-(4-chlorophenyl)-2-benzylisoindolin-1-one was produced as a colourless oil (421 mg, 1.145 mmol) which was used immediately without further purification. Distilled THF (25 mL) was added to 3-chloro-3-(4-chlorophenyl)-2-benzylisoindolin-1-one (421 mg, 1.145 mmol), cis-cyclopentene diol (572 mg, 5.725 mmol) and potassium carbonate (702.9 mg, 5.725 mmol) as for general procedure B. Removal of the solvent yielded the crude product as a pink oil (354 mg). The sample was purified by flash column chromatography (EtOAc:Petrol, 40:60) to yield the title product as a cream oily solid (277.5 mg, 0.643 mmol, 56% yield). .sup.1H NMR: (300 Hz, CDCl.sub.3) ppm 0.84. 1.66 (m, 1H, H.sub.16/H.sub.16) 1.26 (m, 1H, H.sub.16/H.sub.16) 3.85 (m, 1H, H.sub.17) 3.36 (m, 1H, H.sub.15) 4.15 (d, 1H, J=15.27 Hz, H.sub.9/H.sub.9), 4.62 (d, 1H, J=15.31 Hz, H.sub.9/H.sub.9), 4.68, 5.73 (dd, 1H, H.sub.18/H.sub.19), 5.21, 5.64 (dd, 1H, H.sub.18/H.sub.19), 7.18 (m, 10H, H.sub.1-H.sub.5, H.sub.10-H.sub.14), 7.62 (m, 2H, H.sub.6-H.sub.7), 7.83 (d, 1H, Mp: 63.4-63.9 C. IR: 1489, 1683, 3061, 3379 cm.sup.1.

3-(4-Chlorophenyl)-3-(4-hydroxybut-2-enyloxy)-2-(4-nitrobenyzl)-2,3-dihydroisoindol-1-one (NU8350)

[0188] ##STR00101##

[0189] The named compound was synthesised from 3-(4-Chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl-2,3-dihydroisoindol-1-one (400 mg, 1.01 mmol, 1 equiv.) and cis-butenediol (445 mg, 5.05 mmol 5 equiv.) using General Procedure A and obtained as a yellow oil (272 mg, 58%). .sup.1H NMR (300 MHz, CDCl.sub.3): 8.04-8.00 (m, 2H, O.sub.2NCCH), 7.93-7.91 (m, 1H, C(O)CCH), 7.57-7.51 (m, 2H, ArH, 7.39-7.36 (m, 2H, ArH), 7.23-7.12 (m, 5H, ArH), 5.62-5.53 (m, 1H, OCH.sub.2CH), 5.35-5.26 (m, 1H, OCH.sub.2CH), 4.64 and 4.26 (dd; AB, J=15.0 Hz, 2H, NCH.sub.2), 3.79 (d, J=6.6 Hz, HOCH.sub.2), 3.48-3.29 (m, 2H, OCH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3): 168.17, 147.45, 145.07, 144.60, 136.86, 134.98, 133.07, 132.00, 131.44, 130.24, 130.02, 128.71, 127.99, 126.79, 123.89, 123.35, 95.00, 59.20, 58.48, 42.57. m/z (ES): 465 [M+H].sup.+. Anal.: calc. for C.sub.25H.sub.21ClN.sub.2O.sub.5: C: 64.59, H: 4.55, N: 6.02. Found: C: 64.39, H: 4.67, N: 5.67.

3-(4-Chlorophenyl)-3-(4-hydroxybut-2-enyloxy)-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (NU8351)

[0190] ##STR00102##

[0191] The named compound was synthesised from 3-(4-Chlorophenyl)-3-hydroxy -2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (400 mg, 1.01 mmol, 1 equiv.) and cis/trans-butenediol (445 mg, 5.05 mmol, 5 equiv.) using General Procedure A and obtained as a yellow oil (291 mg, 62%). .sup.1H NMR (300 MHz, CDCl.sub.3): 8.04-8.01 (m, 2H, O.sub.2NCCH), 7.94-7.91 (m, 1H, C(O)CCH), 7.57-7.51 (m, ArH), 7.40-7.36 (m, 2H, ArH), 7.23-7.13 (m, 5H, ArH), 5.62-5.53 (m, OCH.sub.2CH), 5.35-5.27 (m, 1H, OCH.sub.2CH), 4.64 and 4.26 (dd: AB, J=15.0 Hz, 2H, NCH.sub.2), 3.79 (d, J=6.6 Hz, HOCH.sub.2), 3.48-3.29 (m, 2H, OCH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3): 168.17, 147.50, 145.10, 144.60, 136.91, 135.01, 133.07, 132.01, 131.49, 130.25, 130.04, 128.73, 128.00, 126.83, 123.90, 123.35, 95.03. 59.23, 58.51, 42.60. m/z (ES): 465 [M+H].sup.+. HPLC: R.sub.t=3.51 min. Anal.: calc. for C.sub.25H.sub.21ClN.sub.2O.sub.5: C: 64.59, H: 4.55, N: 6.02, Found: C: 64.23, H: 4.63. N: 5.73.

3-(4-Chlorophenyl)-3-(5-hydroxycyclooctyloxy)-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (NU8352)

[0192] ##STR00103##

[0193] The named compound was synthesised from 3-(4-Chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (400 mg, 1.01 mmol, 1 equiv.) and cis-1,5-cyclooctanediol (728 mg, 5.05 mmol, 5 equiv.) using General Procedure A and obtained as a yellow solid (342 mg, 65%). .sup.1H NMR (300 MHz, CDCl.sub.3): 7.95-7.91 (m, 3H, O.sub.2NCCH and C(O)CCH), 7.60-7.52 (m, 2H, ArH), 7.18-7.03 (m, 7H, ArH), 4.86 and 4.20 (dd: AB, J=15.3 Hz, 2H, NCH.sub.2), 3.59-3.52(m, 1H, HOCH), 3.24-3.18 (m, 1H, OCH), 1.83-1.29 (m, 12H, CH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3): 168.29, 147.21, 145.92, 144.85, 137.61, 134.77, 132.60, 131.79, 130.16, 129.68, 128.34, 128.27, 124.02, 123.62, 123.08, 94.52, 73.62, 71.25, 42.75, 36.51, 35.92, 34.32, 33.94, 20.30, 20.12 Anal.: calc. for C.sub.39H.sub.32ClN.sub.3O.sub.6+0.5 EtOAc: C: 66.34, H: 5.77, N: 5.16, Found: C: 66.25, H: 5.91, N: 5.00. Mp: 69-72 C. (EtOAc).

3-(4-Chlorophenyl)-3-(3-hydroxy-2,2-dimethyl-propoxy)-2-(4-nitro-benzyl)-2,3-dihydro-isoindol-1-one (NU8353)

[0194] ##STR00104##

[0195] The named compound was synthesised from 3-(4-Chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (400 mg, 1.01 mmol, 1 equiv.) and neopentyl glycol (526 mg, 5.05 mmol, 5 equiv.) using General Procedure A and obtained as an off-white solid (267 mg, 55%). .sup.1H NMR (300 MHz, CDCl.sub.3): 8.02-7.98 (m, 2H, O.sub.2NCCH), 7.96-7.93 (m, 1H, C(O)CCH), 7.58-7.55 (m, 2H, ArH), 7.32-7.28 (m, 2H, ArH), 7.15-7.12 (m, 5H, ArH), 4.58 and 4.44 (dd: J=15.3 Hz, 2H, NCH.sub.2), 3.39 (s, 2H, HOCH.sub.2), 2.78 and 2.63 (dd: AB, J=8.7 Hz, 2H, NCH.sub.2), 0.83 (d, J=3.9 Hz, CH.sub.3). .sup.13C NMR (75 MHz, CDCl.sub.3): 168.30, 147.33, 145.19, 144.60, 137.31, 134.90, 133.08, 131.64, 130.17, 129.85, 128.61, 127.95, 123.81, 123.23, 123.16, 94.54, 69.57, 69.02, 42.42, 36.41, 21.75. m/z (ES): 481 [M+H].sup.+. Anal.: calc. for C.sub.26H.sub.25ClN.sub.2O.sub.5+0.25 H.sub.2O: C: 64.32, H: 5.31, N: 5.77, Found: C: 64.32, H: 5.34, N: 5.57.

3-(4-Chlorophenyl)-3-(1-hydroxymethylcyclopropylmethoxy)-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (NU8354)

[0196] ##STR00105##

[0197] The named compound was synthesised from 3-(4-Chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (400 mg, 1.01 mmol, 1 equiv.) and cyclopropane dimethanol (516 mg, 5.05 mmol, 5 equiv.) using General Procedure A and obtained as an off-white solid (305 mg, 63%). .sup.1H NMR (300 MHz, CDCl.sub.3): 8.01-7.98 (m, 2H, O.sub.2NCCH), 7.92-7.89 (m, 1H, C(O)CCH), 7.55-7.52 (m, 2H, ArH), 7.32-7.29 (m, 2H, ArH), 7.19-7.12 (m, 5H, ArH), 4.49 (s, 2H, NCH.sub.2), 3.51-3.43 (m, 2H, HOCH.sub.2), 2.81 (s, 2H, OCH.sub.2). 0.43-0.40 (m, 2H, CH.sub.2), 0.22-0.12 (m, 2H, CH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3): 168.54, 145.52, 144.95, 137.47, 135.29, 133.45, 131.87, 130.50, 130.21, 128.98, 128.30, 124.16, 123.60, 123.48, 94.96, 67.84, 42.75, 22.68, 8.94, 8.90 Anal.: calc. for C.sub.26H.sub.23ClN.sub.2O.sub.5: C: 65.20, H: 4.84, N: 5.85, Found: C: 64.83, H: 4.92, N: 5.63. [0198] Racemic NU8354 was separated into its two enantiomers by chiral HPLC (Chiracel AD column; 1 cm25 cm; 40% EtOH, pentane): [0199] NU8354A, RT=9.8 min; =+22.66, 0.406 g/100 ml; [0200] and NU8354B, RT=12.4 min; =21.10, 0.398 g/100 ml.

3(4-Chlorophenyl)-3-(4-hydroxybut-2-ynyloxy)-2-(4-nitrobenyzl)-2,3 dihydroisoindol-1-one (NU8357)

[0201] ##STR00106##

[0202] The named compound was synthesised from 3-(4-Chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (400 mg, 1.01 mmol, 1 equiv.) and butynediol (435 mg, 5.05 mmol, 5 equiv.) using General Procedure A and obtained as a yellow solid (271 mg, 58%). .sup.1H NMR (300 MHz, CDCl.sub.3): 8.05-7.93 (m, 3H, O.sub.2NCCH and C(O)CCH), 7.61-7.54 (m, 2H, ArH), 7.36-7.33 (m, 2H, ArH), 7.24-7.16 (m, 5H, ArH), 4.60 and 4.52 (d: AB, J=15.0 Hz, 2H, NCH.sub.2), 4.20-4.18 (m, 2H, HOCH.sub.2), 3.83 and 3.52 (dt: AB, J=1.8, 15.3 Hz, 2H, OCH.sub.2), 2.42 (t, J=6.0 Hz, 1H, OH). .sup.13C NMR (75 MHz, CDCl.sub.3): 169.24, 148.20, 145.18, 137.24, 135.88, 133.78, 132.49, 131.29, 130.78, 129.43, 128.79, 124.81, 124.43. 124.14, 95.88, 86.01, 81.28, 54.04, 52.97, 51.55, 43.60. m/z (ES): 463 [M+H].sup.+. Anal: calc. for C.sub.25H.sub.19ClN.sub.2O.sub.5 +0.2 H.sub.2O: C: 64.36, H: 4.20, N: 6.01, Found: C: 64.11, H: 3.72, N: 5.53.

3-(4-Chlorophenyl)-3-(4-hydroxymethylcyclohexylmethoxy)-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (NU8358)

[0203] ##STR00107##

[0204] The named compound was synthesised from 3-(4-Chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (400 mg, 1.01 mmol, 1 equiv.) and trans-cyclohexane-1,4-dimethanol (728 mg, 5.05 mmol, 5 equiv.) using General Procedure A and obtained as a yellow solid (374 mg, 71%). .sup.1H NMR (300 MHz, CDCl.sub.3): 8.05-7.92 (m, 3H, O.sub.2NCCH and C(O)CCH), 7.56-7.53 (m, 2H, ArH), 7.38-7.10 (m, 7H, ArH), 4.59 and 4.35 (d: AB, J=15.0 Hz, 2H, NCH.sub.2), 3.44 (d, J=6.3 Hz, 2H, HOCH.sub.2), 2.65-2.53 (m, 2H, OCH.sub.2), 1.81-1.74 (m, 3H, OH and CH), 1.44-1.32 (m, 2H) 0.93-0.79 (m, 5H). .sup.13C NMR (75 MHz, CDCl.sub.3): 168.26, 145.41, 144.82, 137.42, 134.84, 132.93, 130.01, 128.63, 128.01, 123.80, 123.24, 123.18, 94.67, 68.41, 68.26, 42.41, 40.59, 38,04, 29.68, 29.31, 28.90. m/z (ES): 521 [M+H].sup.+. Anal.: calc. for C.sub.29H.sub.29ClN.sub.2O.sub.5+0.2 H.sub.2O: C: 66.38, H: 5.66, N: 5.34, Found: C: 66.23, H: 5.79. N: 4.99.

3-(4-Chlorophenyl)-3-(2-hydroxymethylcyclohexylmethoxy)-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (NU8359)

[0205] ##STR00108##

[0206] The named compound was synthesised from 3-(4-Chlorophenyl)-3-hydroxy -2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (400 mg, 1.01 mmol, 1 equiv.) and cis-1,2-cyclohexane-dimethanol (728 mg, 5.05 mmol, 5 equiv.) using General Procedure A and obtained as a yellow solid (337 mg, 64%). .sup.1H NMR (300 MHz, CDCl.sub.3): mixture of diastereoisomers: 8.08-7.93 (m, 3H, O.sub.2NCCH and C(O)CCH). 7.58-7.54 (m, 2H, ArH), 7.43-7.36 (m, 2H, ArH), 7.23-7.11 (m, 5H, ArH), 4.61 and 4.25 (d: AB, J=15.0 Hz, 2H, NCH.sub.2); and 4.59 and 4.36 (d: AB, J=15.0 Hz, 2H, NCH.sub.2), 3.53-3.24 (m, 2H, HOCH.sub.2), 2.87-2.61 (m, 2H, OCH.sub.2), 1.87-1.09 (m, 10H, CH). .sup.13C NMR (75 MHz, CDCl.sub.3): mixture of diastereoisomers: 168.25, 147.42, 145.37, 145.20, 144.84, 144.76, 137.28, 137.12, 134.97, 134.88, 133.03, 131.55, 131.41, 130.15, 130.10, 129.98, 129.94, 128.81, 128.69, 127.98, 127.92, 123.91, 123.81, 123.33, 123.30, 123.10, 123.06, 95.07, 94.97, 63.91, 63.57, 63.44, 63.31, 42.50, 42.43, 40.77, 39.99, 37.18, 27.40, 27.09, 26.21, 26.16, 23.77, 23.44, 23.29. Anal.: calc. for C.sub.29H.sub.29ClN.sub.2O.sub.5+0.5 CH.sub.2Cl.sub.2+0.1 H.sub.2O: C: 64.18, H: 5.49, N: 5.11, Found: C: 64.34. H: 5.49, N: 4.95.

3-(4-Chlorophenyl)-3-(4-hydroxycyclohexyloxy)-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (NU8360)

[0207] ##STR00109##

[0208] The named compound was synthesised from 3-(4-Chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (400 mg, 1.01 mmol, 1 equiv.) and cis/trans-1,4-cyclohexanediol (586 mg, 5.05 mmol, 5 equiv.) using General Procedure A and obtained as a white solid (338 mg, 68%). .sup.1H NMR (300 MHz, CDCl.sub.3): mixture of diastereoisomers: 7.93-7.90 (m, 3H, O.sub.2NCCH and C(O)CCH), 7.56-7.51 (m, 2H, ArH), 7.18-7.02 (m, 7H, ArH), 4.78 and 4.24 (d: AB, J=15.0 Hz, 2H, NCH.sub.2); 3.70-3.62 (m, 1H, HOCH), 3.26-3.09 (m, 1H, OCH), 1.86-1.26 (m, 10H, CH .sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3): mixture of diastereoisomers: 168.33, 147.16, 146.01, 144.80, 137.66, 134.74, 132.72, 131.58, 130.21, 130.16, 129.68, 128.31, 128.28, 128.23, 128.19, 123.81, 123.09, 94.30, 94.28, 71.41, 69.22, 68.61, 67.66, 42.65, 32.51, 32.32, 30.95, 30.65, 30.33, 29.19, 29.03. m/z (ES): 493 [M+H].sup.+. HPLC: R.sub.t=3.43 min. Anal.: calc. for C.sub.27H.sub.25ClN.sub.2O.sub.5+0.1 H.sub.2O: C: 65.54. H: 5.14, N: 5.66, Found: C: 65.09, H: 5.20, N: 5.24.

3-(4-Chlorophenyl)-3-(4-hydroxycyclohex-2-enyloxy)-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (NU8361)

[0209] ##STR00110##

[0210] The named compound was synthesised from 3-(4-chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (400 mg, 1.01 mmol, 1 equiv.) and trans-1,4-cyclohex-2-enediol (576 mg, 5.05 mmol, 5 equiv.) using General Procedure A and obtained as a white solid (263 mg, 53%). .sup.1H NMR (300 MHz, CDCl.sub.3): mixture of diastereoisomers: 7.96-7.92 (m, 3H, O.sub.2NCCH and C(O)CCH), 7.61-7.55 (m, 2H, ArH), 7.22-7.03 (m, 7H, ArH), 5.75 and 5.34 (m, 2H, CHCH), 4.83 and 4.28 (m, 2H, NCH.sub.2) 4.27 (m, 1H, HOCH), 3.74-3.71 (m, 1H, OCH) 3.70-3.62 (m, 1H, HOCH), 3.26-3.09 (m, 1H, OCH), 2.12-1.14 (m, 4H, CH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3): mixture of diastereoisomers: 168.57, 147.55, 146.08, 145.06, 144.99, 137.66, 137.57, 135.16, 134.64, 134.10, 133.20, 131.90, 130.68, 130.61, 130.09, 130.04, 129.96, 128.67, 128.65, 128.59, 128.55, 124.28, 124.15, 123.48, 123.46, 94.90, 94.82, 68.43, 68.30, 65.91, 65.76, 43.06, 30.85, 30.52, 28.58. m/z. (ES): 491 [M+H].sup.+. HPLC: R.sub.t=3.39 min. Anal.: calc. for C.sub.27H.sub.23ClN.sub.2O.sub.5+0.2 H.sub.2O: C: 65.57, H: 4.78. N: 5.67, Found: C: 65.32, H: 5.00, N: 5.18.

3-(4-Chlorophenyl)-3-hydroxy-2-[2-(4-nitrophenyl)ethyl]-2,3-dihydroisoindol-1-one

[0211] ##STR00111##

[0212] To a solution of 2-(4-chlorobenzoyl)benzoic acid (5 g, 19.2 mmol, 1 equiv.) in dry THF (20 mL) was added under nitrogen atmosphere thionylchoride (3.0 mL, 38.3 mmol, 2 equiv.) and 3 drops of anhydrous DMF. The reaction mixture was stirred for 4 h at room temperature and concentrated in vacuo. The resulting pale yellow oil was taken up in dry THF (20 mL), and the amine 2-(4-nitrophenyl)ethylamine hydrochloride (4.30 g, 21.1 mmol, 1.1 equiv.) and DIPEA (3.49 mL, 21.1 mmol, 1.1 equiv.) were added under nitrogen atmosphere. The reaction mixture was stirred overnight at room temperature and the solvents were removed in vacuo. The residue was taken up in EtOAc (100 mL), filtered, and the filtrate washed with water (350 mL) and brine (150 mL). The organic layer was dried over MgSO.sub.4, filtered and concentrated in vacuo to afford a buff-coloured solid, which was recrystallised from EtOAc/Petrol ether (4.47 g, 57%). .sup.1H NMR (300 MHz, d.sup.6-DMSO): 8.09 (d, J=8.4 Hz, 2H, O.sub.2NCCH), 7.74 (d, J=6.6 Hz, 1H, C(O)CCH), 7.60-7.51 (m, 2H, ArH), 7.40-7.26 (m, 8H, ArH and OH), 3.69-3.57 (m, 1H, NCH), 3.28-3.19 (m, 1H, NCH), 2.96-2.89 (m, 2H, NCH.sub.2CH.sub.2). .sup.13C NMR (75 MHz, d.sup.6-DMSO): 166.38, 148.77, 147.11, 145.85, 138.81, 132.57, 132.21, 130.08, 129.34, 128.97, 128.05, 127.51, 122.95, 122.36, 122.13. FTIR : 3240, 1166, 1520, 1338 cm .sup.1. m/z (ES): 409 [M+H].sup.+. HPLC: R.sub.t=3.36 min. Anal.: calc. for C.sub.22H.sub.17ClN.sub.2O.sub.4: C 64.63, H 4.19, N 6.85, Found: C 65.02, H 4.27, N 6.74. Mp: 206-208 C. (EtOAc). UV: .sub.max=268 nm (EtOH).

3-(4-Chlorophenyl)-3-(4-hydroxybutoxy)-2-[2-(4-nitrophenyl)ethyl]-2,3-dihydroisoindol-1-one (NU8362)

[0213] ##STR00112##

[0214] The named compound was synthesised from 3-(4-chlorophenyl)-3-hydroxy-2-[2-(4-nitrophenyl)ethyl]-2,3-dihydroisoindol-1-one (562 mg, 1.37 mmol, 1 equiv.) and 1,4-butanediol (616 mg, 6.85 mmol, 5 equiv.) using General Procedure A and obtained as a white solid (306 mg, 63%). .sup.1H NMR (300 MHz, CDCl.sub.3): 8.11-8.08 (m, 2H, O.sub.2NCCH), 7.91-7.88 (m, 1H, C(O)CCH), 7.55-7.53 (m, 2H, ArH), 7.30-7.14 (m, 7H, ArH), 3.66 (m, 2H, NCH.sub.2), 3.45 (t, J=8.1 Hz, 2H, HOCH.sub.2), 3.16-3.11 and 3.03-2.99 (m, 2H, OCH.sub.2), 3.00-2.89 and 2.73-2.66 (m, 2H, NCH.sub.2CH.sub.2), 1.75-1.63 (m, 5H, CH.sub.2 and OH). .sup.13C NMR (75 MHz, CDCl.sub.3): 168.23, 147.02, 146.62, 145.32, 137.69, 134.84, 132.74, 131.98, 129.99, 129.48, 128.74, 127.87, 123.65, 123.51, 123.10, 94.54, 62.79, 62,43, 40.51, 34.21, 29.60, 26.07, HPLC: R.sub.t=3.45 min. Anal.: calc. for C.sub.26H.sub.25ClN.sub.2O.sub.5: C: 64.93, H: 5.24, N: 5.82, Found: C: 64.82, H: 5.18, N: 5.68.

3-(4-Chlorophenyl)-2-[1-(4-chlorophenyl)-ethyl]-3-(4-hydroxybutoxy)-2,3-dihydroisoindol-1-one (NU8365)

[0215] ##STR00113##

[0216] The named compound was synthesised from 3-(4-chlorophenyl)-2-[1-(4-chlorophenyl)-ethyl]-3-hydroxy-2,3-dihydroisoindol-1-one (498 mg, 1.37 mmol, 1 equiv.) and 1,4-butanediol (616 mg, 6.85 mmol, 5 equiv.) using General Procedure A and obtained as a pale yellow oil (242 mg, 51%). .sup.1H NMR (300 MHz, CDCl.sub.3): 7.87-7.83 (m, 1H, C(O)CCH), 7.53-7.46 (m, 2H, ArH), 7.07-7.03 (m, 9H, ArH), 4.41 (q, J=7.2 Hz, 1H, NCH), 3.70 (m, 2H, HOCH.sub.2), 3.29-3.25 and 3.01-2.95 (m, 2H, OCH.sub.2), 1.86 (d, J=7.2 Hz, 3H, CH.sub.3), 1.77-1.68 (m, 4H, CH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3): 168.31, 145.26, 141.47, 137.76, 134.79, 133.15, 133,06, 132.84, 130.20, 129.67, 128.75. 128.41, 128.27, 123.71, 123.27, 95.44, 63.35, 62.89, 52.49, 29.96, 26.48, 20.08. m/z (ES): 470 [M+H].sup.+. R.sub.t=3.76 min. Anal.: calc. for C.sub.26H.sub.25Cl.sub.2NO.sub.3: C: 66.39, H: 5.36, N: 2.98, Found: C: 66.33, H: 5.25, N: 2.46.

3-(4-Chlorophenyl)-3-(4-hydroxymethylbenzyloxy)-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (NU8366)

[0217] ##STR00114##

[0218] The named compound was synthesised from 3-(4-chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (541 mg, 1.37 mmol, 1 equiv.) and 1,4-benzenedimethanol (946 mg, 6.85 mmol, 5 equiv.) using General Procedure A and obtained as a white solid (405 mg, 78%). .sup.1H NMR (300 MHz, CDCl.sub.3): 8.01-7.85 (m, 3H, O.sub.2NCCH and C(O)CCH), 7.61-7.53 (m, 2H, ArH), 7.37-7.18 (m, 9H, ArH), 6.93 (d, J=7.8 Hz, 2H, ArH). 4.85 and 4.67 (d: AB, J=15.0 Hz, 2H, NCH.sub.2), 4.66 (d, J=5.7 Hz, CH.sub.2OH), 3.90 and 3.68 (d: AB, J=11.7 Hz, 2H, OCH.sub.2), 2.12 (t, J=6.0 Hz, 1H, OH). .sup.13C NMR (75 MHz, CDCl.sub.3): 168.52, 147.63, 145.39, 144.90, 141.16, 137.34, 136.39, 135.37, 133.42, 131.73, 130.57, 130.32, 129.19, 128.38, 127.30, 127.11, 124.34, 123.69, 95.52, 65.26, 65.12, 42.89. m/z (ES); 515 [M+H].sup.+. HPLC: R.sub.t=3.56 min. Anal.: calc. for C.sub.29H.sub.23ClN.sub.2O.sub.5: C: 67.64, H: 4.50, N: 5.44, Found: C: 67.38, H: 4.43, N: 5.26.

3-(4-Chlorophenyl)-3-hydroxymethylbenzyloxy)-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (NU8367)

[0219] ##STR00115##

[0220] The named compound was synthesised from 3-(4-chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (541 mg, 1.37 mmol, 1 equiv.) and 1,3-benzenedimethanol (946 mg, 6.85 mmol, 5 equiv.) using General Procedure A and obtained as a white solid (390 mg, 75%). .sup.1H NMR (300 MHz, CDCl.sub.3): 8.01-7.90 (m, 3H, O.sub.2NCCH and C(O)CCH), 7.62-7.53 (m, 2H, ArH), 7.39-7.17 (m, 9H, ArH), 6.95-6.91 (m, 2H, ArH). 4.80 and 4.13 (d: AB, J=15.0 Hz, 2H, NCH.sub.2), 4.64 (d, J=5.1 Hz, CH.sub.2OH), 3.93 and 3.73 (d: AB, J=11.4 Hz, 2H, OCH.sub.2), 1.95 (t, J=5.4 Hz, 1H, OH). .sup.13C NMR (75 MHz, CDCl.sub.3): 168.51, 145.42, 144.88, 141.59, 137.45, 135.37, 133.39, 131.79, 130.56, 130.34, 129.17, 128.81, 128.38, 126.61, 126.51, 125.82, 124.32, 123.69, 95.55, 65.42, 65.35. 42.91. m/z (ES): 515 [M+H].sup.+. R.sub.t=3.58 min. Anal.: calc. for C.sub.29H.sub.23ClN.sub.2O.sub.5+0.15 CH.sub.2Cl.sub.2: C: 66.34, H: 4.46, N: 5.31, Found: C: 66.12, H: 4.44, N: 5.03.

3-(4-Chloro-phenyl)-2-[1-(4-chloro-phenyl)ethyl]-3-hydroxy-2,3-dihydro-isoindol-1-one

[0221] ##STR00116##

[0222] To a solution of (R)-4-chloro--methylbenzylamine hydrochloride (2.95 mL, 21.1 mmol, 1.1 equiv.) in dry THF (20 mL) was added under nitrogen atmosphere thionylchoride (3.0 mL, 38.3 mmol, 2 equiv.) and 3 drops of anhydrous DMF. The reaction mixture was stirred for 4 h at room temperature and concentrated in vacuo. The resulting pale yellow oil was taken up in dry THF (20 mL), and the amine 2-(4-nitrophenyl)ethylamine hydrochloride (4.30 g, 21.1 mmol, 1.1 equiv.) and DIPEA (3.49 mL, 21.1. mmol, 1.1 equiv.) were added under nitrogen atmosphere. The reaction mixture was stirred overnight at room temperature and the solvents were removed in vacuo. The residue was taken up in EtOAc (100 mL), filtered, and the filtrate washed with water (350 mL) and brine (150 mL). The organic layer was dried over MgSO.sub.4, filtered and concentrated in vacuo to afford a white crystalline powder, which was recrystallised from EtOAc/Petrol ether (4.98 g, 65%). .sup.1H NMR (300 MHz, d.sup.6-DMSO): Mixture of two diastereoisomers: 7.64-7.61 (m, 1H, and 1H, ArH), 7.46-7.30 (m, 5H and 5H, ArH), 7.26-7.02 (m, 5H and 5H, ArH), 6.90 (d, J=8.7 Hz, 1H and 1H, ArH), 4.58 and 4.43 (q, J=6.9 Hz, 1H, CH*), 4.18 and 4.11 (br s, 1H, OH), 1.69 and 1.56 (d, J=7.2 Hz, 3H, CH.sub.3). .sup.13C NMR (75 MHz, d.sup.6-DMSO): 167.33, 167.26, 148.29, 148.25, 141.08, 140.53, 137.44, 137.32, 134.74, 134.67, 132.96, 132.91, 132.75, 132.72, 131.30, 131.21, 129.82, 129.45, 129.40, 128.81, 128.70, 128.43, 128.36, 128.25, 128.00, 123.44, 123.41, 122.47, 91.93, 91.50, 52.07, 52.01, 19.84, 18.43. FTIR : 3119, 1667 cm.sup.1. m/z (ES): 398 [M+H].sup.+. HPLC: R.sub.t=3.57 min. Anal.: calc. for C.sub.22H.sub.17Cl.sub.2NO.sub.2: C 66.34, H 4.30, N 3.52, Found: C 66.24, H 4.28, N 3.50.

3-(4-Chloro-phenyl)-2-[1-(4-chloro-phenyl)-ethyl]-3-(4-hydroxy-butoxy)-2,3-dihydro-isoindol-1-one (NU8368)

[0223] ##STR00117##

[0224] The named compound was synthesised from 3-(4-chloro-phenyl)-2-[1-(4-chloro-phenyl)-ethyl]-3-hydroxy-2,3-dihydro-isoindol-1-one (498 mg, 1.37 mmol, 1 equiv.) and 1,4-butanediol (616 mg, 6.85 mmol, 5 equiv.) using General Procedure B and obtained as a clear oil (304 mg, 64%). .sup.1H NMR (300 MHz, CDCl.sub.3): 7.87-7.84 (m, 1H, C(O)CCH), 7.53-7.46 (m, 2H, ArH), 7.07-7.00 (m, 9H, ArH), 4.41 (q, J=7.2 Hz, 1H, NCH), 3.70 (m, 2H, HOCH.sub.2), 3.31-3.24 and 3.02-2.95 (m, 2H, OCH.sub.2), 1.86 (d, J=7.2 Hz, 3H, CH.sub.3), 1.76-1.66 (m, 4H, CH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3): 168.32, 145.27, 141.48, 137.77, 134.80, 133.15, 133.06, 132.84, 130.20, 129.67, 128.74, 128.41, 123.72, 123.27, 95.45, 63.36, 62.88, 52.49, 29.96, 26.48, 20.08. m/z (ES): 470 [M+H].sup.+. Anal.: calc. for C.sub.26H.sub.25Cl.sub.2NO.sub.3+0.3 H.sub.2O: C: 65.62, H: 5.43, N: 2.94, Found: C: 65.58, H: 5.77, N: 2.45.

4-[1-(4-Chloro-phenyl)-1-(4-hydroxy-butoxy)-3-oxo-1,3-dihydro-isoindol-2-ylmethyl]-benzonitrile (NU8370)

[0225] ##STR00118##

[0226] The named compound was synthesised from 2-(4-(aminomethyl)benzonitrile)-3-(4-chlorophenyl)-3-hydroxyisoindolin-1-one (513 mg, 1.37 mmol, 1 equiv.) and 1,4-butanediol (616 mg, 6.85 mmol, 5 equiv.) using General Procedure B and obtained as a white solid (302 mg, 67%). .sup.1H NMR (300 MHz, CDCl.sub.3): 7.94-7.91 (m, 1H, C(O)CCH), 7.55-7.52 (m, 2H, ArH), 7.47 and 7.33 (d: A.sub.2B.sub.2, J=8.4 Hz, 4H, ArH), 7.20 (m, 4H, ArH), 7.13-7.10 (m, 1H, ArH), 4.60 and 4.24 (d: AB, J=15.0 Hz, 2H, NCH.sub.2), 3.56 (t, J=5.4 Hz, 2H, HOCH.sub.2), 2.80-2.74 (m, 2H, OCH.sub.2), 1.53-1.16 (m, 4H, CH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3): 168.18, 145.32, 142.86, 137.20, 134.77, 132.90, 131.86, 131.46, 129.99, 129.85, 128.61, 127.95, 123.77, 123.08, 118.41, 111.33, 94.78, 62.82, 62.34, 42.68, 29.41, 25.67. Anal.: calc. for C.sub.29H.sub.23ClN.sub.2O.sub.3+0.2 H.sub.2O: C: 69.37, H: 5.16, N: 6.22, Found: C: 69.29, H: 5.20, N: 6.04.

[0227] All references to General Procedures A-F made hereinbelow are references to the General Procedures A-F outlined immediately below and do not refer to General Procedures A-C hereinabove.

General Procedure A

[0228] To a suspension of the corresponding phthalic anhydride (1 equiv.) in chlorobenzene (8 equiv.) was added aluminium chloride (2.4 equiv.) The mixture was heated to 90 C. for 2 h and then cooled to room temperature. Ice was added followed by conc. HCl (5 mL) and the mixture was extracted into dichloromethane (DCM) (350 mL) and then washed with 10% Na.sub.2CO.sub.3 solution (250 mL). The Na.sub.2CO.sub.3 washings were combined and acidified to pH3 with conc, HCl. The resulting precipitate was collected by filtration and dried in a vacuum oven.

General Procedure B

[0229] To a solution of the corresponding benzoic acid (1 equiv.) in dry THF (10 mL) was added under a nitrogen atmosphere thionyl chloride (2 equiv.) and 3 drops of anhydrous DMF. The reaction mixture was stirred for 4 h at room temperature and concentrated in vacuo. The resulting pale yellow oil was taken up in dry THF (10 mL) and the amine (1.1 equiv.) and DIPEA (1.1 equiv.) were added under nitrogen atmosphere. The reaction mixture was stirred overnight at room temperature and the solvents were removed in vacuo. The residue was taken up in EtOAc (50 mL), filtered and the filtrate washed with water (325 mL) and brine (125 mL). The organic layer was dried over MgSO.sub.4, filtered and concentrated in vacuo to afford a solid which was recrystallised from EtOAc/petrol ether or purified by flash chromatography (Biotage SP4).

General Procedure C

[0230] To solution of the corresponding isoindolinone (1 equiv.) in dry THF (10 mL) was added under a nitrogen atmosphere thionyl chloride (2 equiv.) and 3 drops of anhydrous DMF. The reaction mixture was stirred for 4 h at room temperature and concentrated in vacuo. The resulting pale yellow oil was taken up in dry THF (10 mL) and the alcohol (2 equiv.) and potassium carbonate (2 equiv.) were added. The reaction mixture was stirred overnight at room temperature and the solvents were removed in vacuo. The residue was taken up in EtOAc (50 mL) and washed with water (325 mL) and brine (125 mL). The organic layer was dried over MgSO.sub.4, filtered and concentrated in vacuo to afford an oil which was purified by flash chromatography (Biotage SP4).

General Procedure D

[0231] To a solution of the corresponding isoindolinone (1 equiv.) in anhydrous DCM (5 mL) was added mCPBA (L1 equiv.). The reaction mixture was stirred at 30 C. for 4 h and then diluted with DCM (30 mL), washed with saturated NaHCO.sub.3 solution (30 mL), water (30 mL) and brine (30 mL). The organic layer was dried over MgSO.sub.4, filtered and concentrated in vacuo to afford an oil which was purified by flash chromatography (Biotage SP4).

General Procedure E

[0232] To a solution of the corresponding ester (1 equiv.) in dry THF was added under a nitrogen atmosphere potassium trimethylsilanolate (1.1 equiv.). The reaction mixture was stirred at room temperature overnight. Further potassium trimethylsilanolate (1.1 equiv.) was added and the mixture was again stirred at room temperature overnight. The solvent was concentrated in vacuo to afford a solid which was purified by flash chromatography (Biotage SP4).

General Procedure F

[0233] To a solution of the corresponding isoindolinone (1 equiv.) in THF (10 mL) was added pyridine (2 equiv.), 4-dimethylamino pyridine (catalytic) and succinic anhydride (2 equiv.). The reaction mixture was heated under reflux for 48 h, cooled to RT and the solvent concentrated in vacuo. The residue was dissolved in EtOAc (50 mL), washed with water (220 mL), brine (20 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The product was purified by flash chromatography.

Intermediates

Synthesis of 2-(4-bromobenzoyl)benzoic acid

[0234] ##STR00119##

[0235] To a suspension of the phthalic anhydride (2 g, 13.50 mmol) in bromobenzene (11.38 mL, 108 mmol) was added aluminium chloride (3.60 g, 27.00 mmol). The mixture was heated to 90 C. for 2 h and then cooled to room temperature. Ice was added followed by cone. HCl (5 mL) and the mixture was extracted into DCM (350 mL) and then washed with 10% Na.sub.2CO.sub.3 solution (250 mL). The Na.sub.2CO.sub.3 washings were combined and acidified to pH3 with conc, HCl. The resulting precipitate was collected by filtration and dried in a vacuum oven. The named compound was obtained as a white solid (3.41 g, 83%).

[0236] .sup.1H NMR (300 MHz, DMSO) 7.39-7.42 (m, 1H, CHCHCHC(CO.sub.2H)), 7.51-7.53 (d AB, J=7.7 Hz, 2H, CHC(Br)), 7.73-7.66 (m, 4H, ArH), 7.97-8.00 (m. 1H, CHCHCHC(CO.sub.2H))

[0237] .sup.13C NMR (DMSO, 75 MHz), 127.61, 128.89, 128.97, 130.09, 130.38, 130.71, 130.92, 132.07, 132.96, 136.46, 167.09, 194.21

[0238] IR: 665, 702, 736, 770, 812, 839, 924, 1009, 1065, 1148, 1252, 1279, 1422, 1485, 1570, 1670, 2546, 2657, 2832, 2988 cm.sup.1

[0239] LCMS (DMSO): Rt=3.01 min (on 5 min column)

[0240] UV (in EtOH): max=259 nm

[0241] Rf: 0.29 (50% EtOAc/petrol)

[0242] MP: 170-172 C.

Synthesis of a Mixture of 2-(4-chlorobenzoyl)-3-methylbenzoic acid and 2-(4-chlorobenzoyl)-6-methylbenzoic acid

[0243] ##STR00120##

[0244] The named compounds were synthesised from 3-methylphthalic anhydride (3 g, 18.50 mmol) using General Procedure A and obtained as a white solid (2.98 g, 59%, ratio of 3- and 6-isomers is 20:1) which was used without further purification.

[0245] .sup.1H NMR (300 MHz, DMSO)

[0246] Major isomer: 2.06 (s, 3H, CH.sub.3), 7.45-7.61 (m, 6H, ArH), 7.86-7.88 (d, J=6.6 Hz, 1H, CHC(CO.sub.2H)), 10.69 (br s, 1H, CH.sub.2H)

[0247] .sup.13C NMR (DMSO, 75 MHz), 18.63, 127.36, 128.94, 129.12, 129.53, 129.65, 130.06, 132.60, 134.94, 135.23, 137.74, 167.31, 193.10

[0248] IR: 675, 738, 754, 831, 919, 1009, 1088, 1144, 1264, 1288, 1400, 11580, 1678, 1749, 2556, 2643, 2817, 2961, 3406 cm.sup.1

[0249] LCMS (DMSO): Rt=3.49 min (on 5 min column)

[0250] UV (in EtOH): max=255 nm

[0251] Rf: 0.37 (50% EtOAc/petrol)

[0252] MP: 179-180 C.

Synthesis of a Mixture of 2-(4-chlorobenzoyl)-4-methylbenzoic acid and 2-(4-chlorobenzoyl)-5-methylbenzoic acid

[0253] ##STR00121##

[0254] The named compounds were synthesised from 4-methylphthalic anhydride (3 g, 18.50 mmol) using General Procedure A and obtained as a white solid (4.60 g, 90%, ratio of 4- and 5-isomers is 2:1) which was used without further purification.

[0255] .sup.1H NMR (300 MHz, DMSO)

[0256] Major isomer: 2.41 (s, 3H, CH.sub.3), 7.23-7.25 (d, J=1.4 Hz, 1H, C(Me)-CHC(COAr)), 7.43-7.48 (m, 1H, C(Me)-CHCHC(CO.sub.2H)), 7.53-7.63 (m, 4H, ArH), 7.89-7.91 (d, J=8.0 Hz, 1H, CHCHC(CO.sub.2H)), 13.10 (br s, 1H, CO.sub.2H)

[0257] Minor isomer: 2.44 (s, 3H, CH.sub.3), 7.32-7.34 (d, J=7.7 Hz, 1H, C(Me)-CHCHC(COAr), 7.36-7.40 (m, 1H, C(Me)-CHCHC(COAr), 7.53-7.63 (m, 4H, ArH), 7.80-7.82 (d, J=1.1 Hz, 1H, C(Me)-CHC(CO.sub.2H)), 13.10 (br s, 1H, CO.sub.2H)

[0258] .sup.13C NMR (DMSO, 75 MHz), 21.28, 127.79, 127.95, 129.07, 130.12, 130.78, 133.17, 136.45, 137.22, 138.11, 140.24, 167.00, 190.90

[0259] IR: 683, 751, 780, 838, 934, 962, 1009, 1088, 1153, 1211, 1288, 1398, 1422, 1486, 1570, 1677, 2164, 2828, 3062 cm.sup.1

[0260] LCMS (DMSO): Rt 3.24 min (on 5 min column)

[0261] UV (in EtOH): max=253 nm

[0262] Rf: 0.42 (50% EtOAc/petrol)

[0263] MP: 163-164 C.

Synthesis of a Mixture of 4-tert-butyl-2-(4-chlorobenzoyl)benzoic acid and 5-tert-butyl-2-(4-chlorobenzoyl)benzoic acid

[0264] ##STR00122##

[0265] The named compounds were synthesised from 4-tertbutylphthalic anhydride (2.5 g, 12.24 mmol) using General Procedure A and obtained as a cream solid (3.56 g, 92%, ratio of 4- and 5-isomers is 1.3:1) which was used without further purification.

[0266] .sup.1H NMR (300 MHz, DMSO)

[0267] Major isomer: 1.29 (s, 9H, (CH.sub.3).sub.3), 7.35-7.38 (d, J=1.8 Hz, 1H, C(.sup.tBu)-CHCHC(CO.sub.2H)), 7.54-7.69 (m, 4H, ArH), 7.69-7.75 (m, 1H, C(.sup.tBu)CHC(COAr)), 7.94-7.97 (d, J=8.3 Hz, 1H, CHCHC(CO.sub.2H))

[0268] Minor isomer: 1.34 (s, 9H, (CH.sub.3).sub.3), 7.40-7.41 (d, J=8.0 Hz, 1H, C(.sup.tBu)-CHCHC(COAr), 7.54-7.69 (m, 4H, ArH), 7.74-7.77 (m, 1H, C(.sup.tBu)-CHCHC(COAr), 7.99-8.00 (d, J=1.9 Hz, 1H, C(.sup.tBu)-CHC(CO.sub.2H))

[0269] Both isomers:

[0270] .sup.13C NMR (DMSO, 75 MHz), 31.07, 31.18, 34.96, 35.24, 124.45, 126.68, 126.99, 127.59, 127.85, 128.69, 129.06, 129.56, 130.22, 130.52, 130.87, 130.92, 136.41, 138.27, 138.61, 141.35, 153.12, 156.11, 166.93, 167.41, 195.70, 195.88

[0271] IR: 683, 712, 762, 808, 843, 907, 932, 1007, 1083, 1119, 1159, 1252, 1280, 1364, 1398, 1417, 1476, 1585, 2869, 2964 cm.sup.1

[0272] LCMS (DMSO): Rt=3.56 min (on 5 min column)

[0273] UV (in EtOH): max=255 nm

[0274] Rf=0.52 (50% EtOAc/petrol).

[0275] MP: 173-174 C.

Synthesis of 3-chloro-2-(4-chlorobenzoyl)benzoic acid and 6-chloro-2-(4-chlorobenzoyl)benzoic acid

[0276] ##STR00123##

[0277] The named compounds were synthesised from 3-chlorophthalic anhydride (5 g, 27.39 mmol) using General Procedure A and obtained as a yellow solid (6.71 g, 83%, ratio of 3- and 6-isomers is 99:1) which was used without further purification.

[0278] .sup.1H NMR (300 MHz, DMSO)

[0279] Major isomer (20): 7.56-7.59 (d, AB, J=8.6 Hz, CHC(Cl)CH), 7.65-7.71 (m, 3H, ArH), 7.84-7.87 (dd, J=0.9, 8.0 Hz, 1H, CHC(Cl)C(COAr)), 8.03-8.06 (dd, J=0.9, 8.0 Hz, 1H, CHC(CO.sub.2H)), 13.65 (br s, 1H, CO.sub.2H)

[0280] Minor isomer (21): too weak to analyse

[0281] .sup.13C NMR (DMSO, 75 MHz), 129.38, 130.51, 130.59, 130.64, 131.36, 131.82, 134.20, 135.73, 138.55, 139.88, 165.93, 195.17

[0282] IR: 672, 714, 743, 756, 824, 864, 920, 1009, 1090, 1154, 1206, 1255, 1298, 1400, 1461, 1582, 1676, 2656, 2825, 3067 cm.sup.1

[0283] LCMS (DMSO): Rt=3.34 min (on 5 min column)

[0284] UV (in EtOH): max=256 nm

[0285] Rf=0.29 (50% EtOAc/petrol)

[0286] MP: 184-185 C.

Synthesis of 4-bromo-2-(4-chlorobenzoyl)benzoic acid and 5-bromo-2-(4-chlorobenzoyl)benzoic acid

[0287] ##STR00124##

[0288] The named compounds were synthesised from 4-tertbutylphthalic anhydride 2.5 g, 12.24 mmol) using General Procedure A and obtained as a cream solid (3.47 g, 66%, ratio of 4- and 5-isomers is 1:1) which was used without further purification.

[0289] .sup.1H NMR (300 MHz, DMSO)

[0290] Compound 36: 7.54-7.66 (m, 4H, C.sub.6H.sub.4Cl), 7.84-7.93 (m, 2H, ArH), 8.08-8.09 (d, J=1.7 Hz, 1H, C(Br)CHC(CO.sub.2H)), 13.60 (br s, CO.sub.2H))

[0291] Compound 35: 7.54-7.66 (m, 4H, C.sub.6H.sub.4Cl), 7.70-7.72 (d, J=1.5 Hz, 1H, C(Br)CHC(COAr)), 7.84-7.93 (m, 2H, ArH), 13.60 (br s, 1H, CO.sub.2H)

[0292] .sup.13C NMR (DMSO, 75 MHz), 128.16, 129.15, 130.21, 130.90, 131.37, 132.12, 133.18, 135.21, 135.52, 138. 35, 170.54, 193.35

[0293] IR: 756, 841, 883, 927, 1013, 1092, 1152, 1177, 1285, 1400, 1423, 1483, 1580, 1672, 2546 cm.sup.1

[0294] LCMS (DMSO): Rt=3.43 min (on 5 min column)

[0295] UV (in EtOH): max=255 nm

[0296] Rf=0.24 (50% EtOAc/petrol)

[0297] MP: 210-211 C.

Synthesis of 4,5-dichloro-2-(4-chlorobenzoyl)benzoic acid

[0298] ##STR00125##

[0299] The named compound was synthesised from 4,5-dichlorophthalic anhydride (2.5 g, 11.52 mmol) using General Procedure A and obtained as a yellow solid (1.98 g, 52%).

[0300] .sup.1H NMR (300 MHz, DMSO) 7.56-7.59 (d AB, J=8.3 Hz, CC.sub.2H.sub.2C.sub.2H.sub.2CCl), 7.67-7.70 (d AB, J=8.3 Hz, CC.sub.2H.sub.2C.sub.2H.sub.2CCl), 7.87 (s, 1H, CHC(COAr)), 8.14 (s, 1H, CHC(CO.sub.2H)), 13.85 (br s, 1H, CO.sub.2H)

[0301] .sup.13C NMR (DMSO, 75 MHz), 129.21, 130.76, 131.07, 131.11, 131.97, 134.15, 137.45, 138.23, 138.70, 139.76, 170.36, 198.58

[0302] IR: 768, 843, 868, 893, 964, 1009, 1090, 1126, 1167, 1257, 1343, 1422, 1478, 1545, 1582, 1678, 2228, 2563, 2834 cm.sup.1

[0303] UV (in EtOH): max=254 nm

[0304] Rf=0.18 (50% EtOAc/petrol)

[0305] MP: 195-197 C.

Synthesis of a Mixture of 2-(4-chlorobenzoyl)-4-fluorobenzoic acid and 2-(4-chlorobenzoyl)-5-fluorobenzoic acid

[0306] ##STR00126##

[0307] The named compounds were synthesised from 4-fluorophthalic anhydride (2.5 g, 15.05 mmol) using General Procedure A and obtained as a cream solid (3.51 g, 84%, ratio of 4- and 5-isomers is 3:2). The mixture was used without further purification.

[0308] .sup.1H NMR (300 MHz, DMSO)

[0309] Major isomer: 7.24-7.27 (dd, J=2.0, 8.5 Hz 1H, C(F)CHC(COAr), 7.40-7.46 (m, 1H, C(F)CHCHC(CO.sub.2H)), 7.49-7.52 (m, 2H, ArH), 7.57-7.61 (m, 2H, ArH), 8.02-8.07 (dd, J=5.4, 8.5 Hz, 1H, CHCH(CO.sub.2H))

[0310] Minor isomer: 7.40-7.46 (m, 1H, C(F)CHCHC(COAr)), 7.49-7.52 (m, 3H, ArH), 7.57-7.61 (m, 2H, ArH), 7.66-7.70 (dd, J=1.9, 9.2 Hz, 1H, C(F)CH(CO.sub.2H))

[0311] .sup.13C NMR (DMSO, 75 MHz), 116.98, 119.25, 128.62, 129.15, 130.85, 130.92, 136.01, 138,40, 139.09, 166.10, 166.26, 196.59

[0312] IR: 681, 753, 784, 841, 860, 945, 974, 1011, 1086, 1140, 1174, 1211, 1278, 1401, 1427, 1486, 1580, 1672, 2822, 3070 cm.sup.1

[0313] LCMS (DMSO): Rt=3.76 min (on 5 min column)

[0314] UV (in EtOH): max=256 nm

[0315] Rf=0.33 (50% EtOAc/petrol)

[0316] MP: 153-155 C.

Synthesis of 2(4-chlorobenzoyl)cyclohex-1-enecarboxylic acid

[0317] ##STR00127##

[0318] The named compound was synthesised from 3,4,5,6-tetrahydrophthalic anhydride (208 g, 13.69 mmol) using General Procedure A, purified by chromatography (Biotage SP4; 20%-40% EtOAc/petrol) and obtained as a yellow tail (2.69 g, 74%).

[0319] .sup.1H NMR (300 MHz, DMSO) 1.50-1.70 (m, 4H, CH.sub.2C(COAr)C(CO.sub.2H)CH.sub.2), 2.15-2.17 (m, 4H, CH.sub.2CH.sub.2CH.sub.2C(CO.sub.2H)), 7.93-7.48 (m, 4H, ArH), 8.16 (br s. 1H, CO.sub.2H)

[0320] .sup.13C NMR (DMSO, 75 MHz), 19.79, 21.01, 21.37, 21.45, 127.79, 128.84, 133.95, 137.48, 146.33, 149.31, 171.24, 192.87

[0321] IR: 687, 729, 757, 819, 907, 938, 966, 1038, 1072, 1169, 1206, 1246, 1375, 1422, 1489, 1597, 1736, 2865, 2937, 3318 cm.sup.1

[0322] LCMS (DMSO): Rt=3.72 min (on 5 min column)

[0323] UV (in EtOH): max 254 nm

[0324] Rf=0.48 (50% EtOAc/petrol)

Final Compounds

Synthesis of 3-(4-bromophenyl)-3-(4-hydroxybutoxy)-2-(4-nitrobenzyl)isoindolin-1-one (NU8390)

[0325] ##STR00128##

[0326] The named compound was synthesised from NU8389 (0.50 g, 1.14 mmol) and 1,4-butanediol (0.20 mL, 2.28 mmol) using General Procedure C, purification by chromatography (Biotage SP4; 10%-50% EtOAc/petrol) and obtained as a pale yellow oil (0.50 g, 85%).

[0327] .sup.1H NMR (300 MHz, CDCl.sub.3) 1.36-1.45 (m, 4H, OCH.sub.2CH.sub.2CH.sub.2), 2.76 (t, J=6.1 Hz, OCH.sub.2), 3.49 (t, J=6.2 Hz, HOCH.sub.2), 4.25 and 4.60 (dd: AB, J=15.0 Hz, 2H, NCH.sub.2), 7.08-7.13 (m, 3H, ArH), 7.29-7.36 (m, 4H, ArH), 7.48-7.51 (m, 2ArH), 7.87-7.89 (m, 1H, C(O)CCH), 7.97-8.00 (m, 2H, O.sub.2NCCH)

[0328] .sup.13C NMR (CDCl.sub.3, 75 MHz), 26.01, 29.69, 42.69, 62.51, 63.19, 95.14, 123.21, 123.45, 123.55, 124.09, 128.61, 130.25, 130.34, 131.76, 131.92, 133.27, 138.13, 145.10, 145.58, 147.72, 168.49

[0329] IR: 696, 760, 804, 853, 928, 1005, 1063, 1099, 1177, 1276, 1341, 1381, 1425, 1467, 1519, 1605, 1687, 2872, 2925, 3397 cm.sup.1

[0330] LCMS (DMSO): Rt=3.72 min (on 5 min column)

[0331] UV (in EtOH): max=267 nm

[0332] Rf: 0.26 (50% EtOAc/petrol)

[0333] CHN: C.sub.25H.sub.23BrN.sub.2O.sub.5 requires C: 58.72, H: 4.53, N: 5.48, found C: 58.70, H: 4.24, N: 5.25

Synthesis of 3-(4-bromophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-2-(4-nitrobenzyl)isoindolin-1-one (NU8391)

[0334] ##STR00129##

[0335] The named compound was synthesised from NU8389 (0.50 g, 1.14 mmol) and 1,1-bis(hydroxymethyl)cyclopropane (0.22 mL, 2.28 mmol) using General Procedure C, purification by chromatography (Biotage SP4: 10%-50% EtOAc/petrol) and obtained as white crystals (0.47 g, 78%).

[0336] .sup.1H NMR (300 MHz, CDCl.sub.3) 0.13-0.22 (m, 2H, CH.sub.2), 0.42-0.43 (m, 2H, CH.sub.2), 2.78-2.85 (m, 2H, OCH.sub.2), 3.44-3.52 (m, 2H, HOCH.sub.2), 4.50 (s, 2H, NCH.sub.2), 7.09-7.18 (m, 3H, ArH), 7.28-7.33 (m, 4H, ArH), 7.52-7.55 (m, 2H, ArH), 7.89-7.93 (m, 1H, C(O)CCH), 7.96-8.01 (m, 2H, O.sub.2NCCH)

[0337] .sup.13C NMR (CDCl.sub.3, 75 MHz), 8.90, 22.64, 42.70, 67.72, 94.95, 123.33, 123.48, 123.59, 124.14, 128.59, 130.01, 130.20, 130.51, 131.94, 133.47, 138.00, 144.95, 145.42, 147.61, 168.54

[0338] IR: 697, 759, 805, 855, 928, 1007, 1065, 1097, 1177, 1275, 1341, 1426, 1466, 1519, 1605, 1685, 2873, 2917, 3078 cm.sup.1

[0339] LCMS (DMSO): Rt=3.88 min (on 5 min column)

[0340] UV (in EtOH): max=267 nm

[0341] Rf: 0.32 (50% EtOAc/petrol)

[0342] MP: 76-77 C.

[0343] CHN: C.sub.26H.sub.23BrN.sub.2O.sub.5 requires C: 59.67, H: 4.43 N: 5.35, found C: 59.71, H: 4.39, N: 5.17

Synthesis of 3-(4-bromophenyl)-3-(3-hydroxypropoxy)-2-(4-nitrobenzyl)isoindolin-1-one (NU8392)

[0344] ##STR00130##

[0345] The named compound was synthesised from NU8389 (0.50 g, 11.14 mmol) and 1,3-propanediol (0.16 mL, 2.28 mmol) using General Procedure C, purification by chromatography (Biotage SP4; 10%-50% EtOAc/petrol) and obtained as a pale yellow oil (0.40 g, 70%).

[0346] .sup.1H NMR (300 MHz, CDCl.sub.3) 1.46-1.61 (m, 2H, OCH.sub.2CH.sub.2), 2.92 (td, J=6.0, 1.9 Hz, OCH.sub.2), 3.60 (t, J=6.1 Hz, HOCH.sub.2), 4.34 and 4.60 (dd: AB, J=15.1 Hz, 2H, NCH.sub.2), 6.95-6.99 (m, 1H, ArH), 7.10-7.17 (m, 2H, ArH), 7.27-7.39 (m, 4H, ArH), 7.50-7.55 (m, 2H, ArH), 7.89-7.92 (m, 1H, C(O)CCH), 7.97-8.04 (m, 2H, O.sub.2NCCH)

[0347] .sup.13C NMR (CDCl.sub.3, 75 MHz), 32.45, 42.71, 60.23, 60.80, 95.21, 123.31, 123.48, 123.61, 124.17, 128.57, 130.24, 130.47, 131.75, 131.99, 133.40, 137.99, 145.07, 145.43, 147.64, 168.58

[0348] IR: 697, 760, 805, 853, 927, 1010, 1063, 1098, 1177, 1278, 1339, 1381, 1423, 1467, 1518, 1603, 1688, 2879, 2925, 3409 cm.sup.1

[0349] LCMS (DMSO): Rt=3.73 min (on 5 min column)

[0350] UV (in EtOH): max=266 nm

[0351] Rf: 0.24 (50% EtOAc/petrol),

[0352] CHN: C.sub.24H.sub.21BrN.sub.2O.sub.5 requires C: 57.96, H: 4.26, N: 5.63, found C: 58.16, H: 4.28, N: 5.43

Synthesis of 3-(4-chlorophenyl)-3-hydroxy-4-methyl-2-(4-nitrobenzyl)isoindolin-1-one (NU8393) and 3-(4-chlorophenyl)-3-hydroxy-7-methyl-2-(4-nitrobenzyl)isoindolin-1-one (NU8394)

[0353] ##STR00131##

[0354] The named compounds were synthesised from a mixture of 2-(4-chlorobenzoyl)-3-methylbenzoic acid and 2-(4-chlorobenzoyl)-6-methylbenzoic acid (2 g, 7.28 mmol) and 4-nitrobenzylamine hydrochloride (1.51 g, 8.01 mmol) using General Procedure B, purified by chromatography (Biotage SP4; 10%-20% EtOAc/petrol) and obtained as a yellow solid (NU8393) and cream solid (NU8394) (1.45 g, 49%, ratio of 4- and 7-isomers is 20:1).

[0355] Analysis of Major Isomer (NU8393):

[0356] .sup.1H NMR (300 MHz, CDCl.sub.3) 2.07 (s, 3H, CH.sub.3), 4.02 (br s, 1H, OH), 4.16 and 4.46 (dd, J=15.3 Hz, 2H, NCH.sub.2), 7.19-7.23 (m, 6H, ArH), 7.29-7.31 (dd, J=7.5, 1.5 Hz, 1H, CHCHC(Me), 7.39-7.44 (t, J=7.6 Hz, 1H, CHCHC(Me)-), 7.60-7.62 (dd, J=7.3, 1.1 Hz, 1H, C(O)CCH), 7.93-7.97 (m, 2H, CHNO.sub.2)

[0357] .sup.13C NMR (CDCl.sub.3, 75 MHz), 19.86, 42.76, 90.65, 121.58, 123.67, 125.66, 126.70, 128.39, 129.02, 129.69, 131.33, 132.01, 134.21, 136.85, 139.43, 1 45.52, 148.29, 166.89

[0358] IR: 695, 729, 760, 800, 851, 932, 982, 1014, 1075, 1193, 1271, 1341, 1397, 1487, 1517, 1609, 1680, 3238 cm.sup.1

[0359] LCMS (DMSO): Rt=3.75 min (on 5 min column)

[0360] HPLC purity (as area %): >95

[0361] UV (in EtOH): max=269 nm

[0362] EI-MS: calculated mass of ion 409.0950 [M+H].sup.+, measured mass of ion 409.0951 [M+H].sup.+

[0363] Rf=0.47 (50% EtOAc/petrol)

[0364] MP: 175-176 C.

[0365] CHN: C.sub.22H.sub.17ClN.sub.2O.sub.4 requires C: 64.63, H: 4.19, N: 6.85, found C: 64.78, H: 4.40, N: 6.58

[0366] Analysis of Minor Isomer (NU8394):

[0367] .sup.1H NMR (300 MHz, CDCl.sub.3) 2.62 (s, 3H, CH.sub.3), 3.79 (br s, 1H, OH), 4.30 and 4.61 (dd, J=15.3 Hz, 2H, NCH.sub.2), 7.07-7.19 (m, 1H, ArH), 7.21-7.26 (m, 5H, ArH), 7.31-7.41 (m, 3H, ArH), 7.97-8.00 (m, 2H, CHNO.sub.2)

[0368] .sup.13C NMR (CDCl.sub.3, 75 MHz), 17.43, 42.78, 90.68, 120.41, 123.74, 126.76, 127.30, 128.18, 129.13, 129.79, 132.57, 133.06, 135.31, 137.40, 138.59, 145.87, 149.32, 168.65

[0369] IR: 696, 725, 779, 802 854, 932, 966, 1011, 1088, 1171, 1199, 1279, 1337, 1378, 1423, 1481, 1516, 1602, 1678, 2852, 2923, 3338 cm.sup.1

[0370] LCMS (DMSO): Rt=3.70 min (on 5 min column)

[0371] HPLC purity (as area %): 90

[0372] UV (in EtOH): max=270 nm

[0373] EI-MS: calculated mass of ion 409.0950 [M+H].sup.+, measured mass of ion 409.0945 [M+H].sup.+

[0374] Rf: 0.58 (50% EtOAc/petro)

[0375] MP: 158-159 C.

Synthesis of 3-(4-chloro-phenyl)-3(1-hydroxymethyl-cyclopropylmethoxy)-2-(4-nitro-benzyl)-2,3-dihydro-isoindol-1-one (NU8354)

[0376] ##STR00132##

[0377] The named compound was synthesised from NU8260 (400 mg, 1.01 mmol) and 1,1-bis(hydroxymethyl)cyclopropane (0.19 mL, 2.03 mmol) using General Procedure C, purified by chromatography (Biotage SP4; 10%-50% EtOAc/petrol) and obtained as a cream solid (442 mg, 92%).

[0378] .sup.1H NMR (300 MHz, CDCl.sub.3) 0.12-0.22 (m, 2H, CH.sub.2), 0.40-0.43 (m, 2H, CH.sub.2), 2.81 (s, 2H, OCH.sub.2), 3.43-3.51 (m, 2H, HOCH.sub.2), 4.49 (s, 2H, NCH.sub.2), 7.12-7.19 (m, 5H, ArH), 7.29-7.32 (m, 2H, ArH), 7.52-7.55 (m, 2H, ArH), 7.89-7.92 (m, 1H, C(O)CCH), 7.98-8.01 (m, 2H, O.sub.2NCCH)

[0379] .sup.13C NMR (CDCl.sub.3, 75 MHz), 8.90, 8.94, 22.68, 42.75, 67.84, 94.96, 123.48, 123.60, 124.16, 128.30, 128.98, 130.21, 130.50, 131.87, 133.45, 135.29, 137.47, 144.95, 145.52, 168.54

[0380] IR: 702, 769, 820, 858, 928, 955, 1009, 1036, 1065, 1090, 1176, 1231, 1277, 1341, 1383, 1427, 1470, 1514, 1599, 1705, 2878, 3076, 3471 cm.sup.1

[0381] LCMS (DMSO): Rt=3.78 min (on 5 min column)

[0382] UV (in EtOH): max=267 nm

[0383] EI-MS: calculated mass of ion 478.1290 [M+H].sup.+, measured mass of ion 478.1291 [M+H].sup.+

[0384] Rf: 0.32 (50% EtOAc/petrol)

[0385] MP: 148-149 C.

[0386] CHN: C.sub.26H.sub.23ClN.sub.2O.sub.5 requires C: 65.21, H: 4.84, N: 5.85, found C: 65.21, H: 4.99, N: 5.58

[0387] Separation of enantiomers achieved by chiral preparative DPLC (Daicel Chiralpak AD-H 25010 mm; Hexane/Ethanol (4:1))

[0388] NU8354A (yellow solid)

[0389] Optical rotation: Specific rotation []=+22.66 (at 24.8 C., wavelength=589 nm, tube length=0.25 dm, concentration=0.406 g/100 ml)

[0390] NU8354B (off-white solid)

[0391] Optical Rotation: Specific rotation []=20.10 (at 24.8 C. wavelength=589 nm, tube length=0.25 dm, concentration=0.398 g/100 ml)

Synthesis of 3-(4-chlorophenyl)-3-hydroxy-5-methyl-2-(4-nitrobenzyl)isoindolin-1-one (NU8395) and 3-(4-chlorophenyl)-3-hydroxy-6-methyl-2-(4-nitrobenzyl)isoindolin-1-one (NU8412)

[0392] ##STR00133##

[0393] The named compounds were synthesised from a mixture of 2-(4-chlorobenzoyl)-4-methylbenzoic acid and 2-(4-chlorobenzoyl)-5-methylbenzoic acid (2 g, 7.28 mmol) and 4-nitrobenzylamine hydrochloride (1.51 g, 8.01 mmol) using General Procedure B, purified by chromatography (Biotage SP4; 10%-20% EtOAc/petrol) and obtained as a white solid (NU8395) and white solid (NU8412) (1.25 g, 42%, ratio of 5- and 6-isomers is 2:1).

[0394] Analysis of Major Isomer (NU8395):

[0395] .sup.1H NMR (300 MHz, CDCl.sub.3) 1.36 (s, 9H, C(CH.sub.3)), 3.64 (br s, 1H, OH), 4.21 and 4.64 (dd, J=15.3 Hz, 2H, NCH.sub.2)7.19-7.24 (dd, J=1.3 Hz, 1H, CCHC(Me)), 7.21-7.22 (m, 4H, ArH), 7.25-7.34 (m, 3H, ArH) 7.65-7.68 (dd, J=7.7 Hz, 1H, C(O)CCH), 7.97-8.01 (m, 2H, CHNO.sub.2)

[0396] .sup.13C NMR (CDCl.sub.3, 75 MHz), 22.12, 40.91, 94.13, 123.73, 124.04, 128.17, 129.16, 129.76, 130.42, 132.88, 134.89, 136.93, 139.91, 140.77, 141.02, 145.33, 148.58, 166.11

[0397] IR: 696, 729, 745, 770, 788, 800, 833, 853, 929. 961, 988, 1015, 1044, 1089, 1103, 1128, 1155, 1184, 1203, 1271, 1309, 1341, 1390, 1427, 1491, 1516, 1603, 1623, 1660, 1937, 2202, 2851, 2918, 3053, 3088, 3231 cm.sup.1

[0398] LCMS (DMSO): Rt=3.74 min (on 5 min column)

[0399] HPLC purity (as area %): >98

[0400] UV (in EtOH): max=268 nm

[0401] EI-MS: calculated mass of ion 426.1215 [M+NH.sub.4].sup.+, measured mass of ion 426.1212 [M+NH.sub.4].sup.+

[0402] Rf: 0.50 (50% EtOAc/petrol)

[0403] MP: 221-222 C.

[0404] CHN: C.sub.22H.sub.17ClN.sub.2O.sub.4 requires C: 64.63, H: 4.19, N: 6.85, found C: 64.76, H: 4.13, N: 6.58

[0405] Analysis of Minor Isomer (NU8412):

[0406] .sup.1H NMR (300 MHz, CDCl.sub.3) 2.40 (s, 3H, CH.sub.3), 4.27 (br s, 1H, OH), 4.26 and 4.56 (dd, J=15.3 Hz, 2H, NCH.sub.2), 7.13-7.21 (m, 5H, ArH), 7.25-7.28 (m, 2H, ArH). 7.30-7.34 (m, 1H, CHCHC(Me)-), 7.43-7.45 (dd, J=1.2 Hz, 1H, C(O)CCH), 7.93-7.96 (m, 2H, CHNO.sub.2)

[0407] .sup.13C NMR (CDCl.sub.3, 75 MHz), 21.64, 42.74, 91.34, 122,82, 123.65, 124.24, 128.18, 129.04, 129.77, 130.52. 134.42, 135.21, 137.27, 140.05, 140.80, 145.67, 146.24, 168.25

[0408] IR: 704, 731, 770, 787, 806, 831, 854, 932, 1013, 1061, 1090, 1132, 1174, 1199, 1256, 1310, 1343, 1383, 1433, 1491, 1518, 1607, 16610, 1678, 1983, 2018, 2224, 2255, 2853, 2922, 3320, 3342 cm.sup.1

[0409] LCMS (DMSO): Rt=4.09 min (on 5 min column)

[0410] UV (in EtOH): max=268 nm

[0411] EI-MS: calculated mass of ion 407.0804 [MH].sup., measured mass of ion 407.0800 [MH].sup.

[0412] Rf: 0.53 (50% EtOAc/petrol)

[0413] MP: 208-209 C.

[0414] CHN: C.sub.22H.sub.17ClN.sub.2O.sub.4 requires C: 64.63, H: 4.19, N: 6.85, found C: 64.95, H: 4.19, N: 6.83

Synthesis of 5-tert-butyl-3-(4-chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)isoindolin-1-one (NU8396) and 6-tert-butyl-3-(4-chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)isoindolin-1-one (NU8397)

[0415] ##STR00134##

[0416] The named compounds were synthesised from a mixture of 4-tert-butyl-2-(4-chlorobenzoyl)benzoic acid and 5-tert-butyl-2-(4-chlorobenzoyl)benzoic acid (2.31 g, 7.28 mmol) and 4-nitrobenzylamine hydrochloride (1.51 g, 8.01 mmol) using General Procedure B, purified by chromatography (Biotage SP4: 10%-20% EtOAc/petrol) and obtained as a white solid (NU8396) and cream solid (NU8397) (2.43 g. 74%, ratio of 5- and 6-isomers is 1.3:1).

[0417] Analysis of Major Isomer (NU8396):

[0418] .sup.1H NMR (300 MHz, CDCl.sub.3) 4.25 and 4.68 (dd, J=15.4 Hz, 2H, NCH.sub.2), 7.22-7.27 (m, 5H, ArH), 7.32-7.35 (m, 2H, ArH), 7.54-7.57 (dd, J=8.06, 1.62 Hz, 1H, CHCHC(.sup.tBu)-), 7.72-7.75 (dd, J=8.0 Hz, 1H, C(O)CCHCHC(.sup.tBu)-), 8.00-8.03 (m, 2H, CHNO.sub.2)

[0419] .sup.13C NMR (CDCl.sub.3, 75 MHz), 31.58, 41.48, 41.54, 91.51, 119.64, 123.70, 125.51, 126.81, 127.26, 128.20, 129.13, 129.71, 133.51, 134.89, 138.81, 141.91, 145.87, 149.50, 167.81

[0420] IR: 704, 802, 850, 932, 958, 1011, 1052, 1090, 1194, 1277, 1339, 1395, 1423, 1487, 1515, 1603, 1666, 2160, 2955, 3260, 3461 cm.sup.1

[0421] LCMS (DMSO): Rt=3.74 min on 5 min column)

[0422] HPLC purity (as area %): >93

[0423] UV (in EtOH): max=268 nm

[0424] EI-MS: calculated mass of ion 451.1419 [M+H].sup.+, measured mass of ion 451.1413 [M+H].sup.+

[0425] Rf: 0.58 (50% EtOAc/petrol)

[0426] MP: 247-248 C.

[0427] CHN: C.sub.25H.sub.23ClN.sub.2O.sub.4 requires C: 66.59, H: 5.14, N: 6.21, found C: 66.64, H: 5.19, N: 5.89

[0428] Analysis of Minor Isomer (NU8397):

[0429] .sup.1H NMR (300 MHz, CDCl.sub.3) 1.36 (s, 9H, C(CH.sub.3)), 3.64 (br s, 1H, OH), 4.15 and 4.59 (dd, J=15.3 Hz, 2H, NCH.sub.2),7.19-7.24 (m, 5H, ArH), 7.27-7.30 (m, 2H, ArH), 7.57-7.61 (dd, J=8.04, 1.81 Hz, 1H, CHCHC(.sup.tBu)-), 7.90-7.91 (dd, J=1.5 Hz, 1H, C(O)CCHC(.sup.tBu)-), 7.97-8.00 (m, 2H, CHNO.sub.2)

[0430] .sup.13C NMR (CDCl.sub.3, 75 MHz), 31.63, 35.54, 42.75, 91.31 120.95, 122.56, 123.67, 128.18, 129.08, 129.75, 130.93, 145.75

[0431] IR: 706, 727, 808, 833, 849, 901, 924, 939, 1013, 1049, 1088, 1134, 1198, 1258, 1271, 1309, 1345, 1393, 1439, 1487, 1517, 1603, 1682, 1792, 1898, 1923, 1948, 1969, 2065, 2104, 2217, 2365, 2866, 2963, 3381 cm.sup.1

[0432] LCMS (DMSO): Rt=3.96 min (on 5 min column)

[0433] HPLC purity (as area %): >97

[0434] UV (in EtOH): max=268 nm

[0435] EI-MS: calculated mass of ion 451.1419 [M+H].sup.+, measured mass of ion 451.1420 [M+H].sup.+

[0436] Rf: 0.64 (50% EtOAc/petrol)

[0437] MP: 226-227 C.

[0438] CHN: C.sub.25H.sub.23ClN.sub.2O.sub.4+0.5 EtOAc requires C: 65.52, H: 5.50, N: 5.66, found C: 65.44, H: 5.27, N: 5.47

Synthesis of 4-chloro- (4-chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)isoindolin-1-one (NU8398)

[0439] ##STR00135##

[0440] The named compound was synthesised from a mixture of 3-chloro-2-(4-chlorobenzoyl)benzoic acid and 6-chloro-2-(4-chlorobenzoyl)benzoic acid (2.15 g, 7.28 mmol) and 4-nitrobenzylamine hydrochloride (1.51 g, 8.01 mmol) using General Procedure B, purified by chromatography (Biotage SP4; 10%-20% EtOAc/petrol) and obtained as a while solid (1.96 g, 63%).

[0441] .sup.1H NMR (300 MHz, CDCl.sub.3) 4.28 (br s, 1H, OH), 4.28 and 4.63 (dd, AB, J=15.4 Hz, NCH.sub.2), 7.19-7.22 (m, 4H, ArH), 7.31-7.33 (m, 2H, ArH), 7.44-7.49 (m, 2H, ArH), 7.72-7.75 (dd, J=3.2, 8.5 Hz, 1H, (C(O)CCH), 7.98-8.00 (m, 2H, CHNO.sub.2)

[0442] .sup.13C NMR (CDCl.sub.3, 75 MHz), 42.37, 90.90, 122.20, 123.22, 123.35, 128.2, 128.68, 129.44, 129.75, 131.69, 131.89, 134.14, 135.15, 147.37, 163.60, 163.86

[0443] IR: 696, 729, 759, 808, 856, 932, 996, 1070, 1092, 1144, 1174, 1271, 1342, 1397, 1462, 1518, 1592, 1682, 2026, 2171, 3220 cm.sup.1

[0444] LCMS (DMSO): 8.47 min (on 12 min column)

[0445] UV (in EtOH): max=268 nm

[0446] EI-MS: calculated mass of ion 429.0403 [M+H].sup.+, measured mass of ion 429.0401 [M+H].sup.+

[0447] Rf: 0.47 (50% EtOAc/petrol)

[0448] MP: 202-203 C.

[0449] CHN: C.sub.21H.sub.14Cl.sub.2N.sub.2O.sub.4+0.2 EtOAc requires C: 58.59, H: 3.52, N: 6.27, found C: 58.27, H: 3.21, N: 6.48

Synthesis of 6-tert-butyl-3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl) methoxy)-2-(4-nitrobenzyl)isoindolin-1-one (NU8399)

[0450] ##STR00136##

[0451] The named compound was synthesised from NU8397 (200 mg, 0.44 mmol) and 1,1-bis(hydroxymethyl)cyclopropane (0.09 mL, 0.89 mmol) using General Procedure C, purified by chromatography (Biotage SP4; 10%-50% EtOAc/petrol) and obtained as white crystals (182 mg, 75%).

[0452] .sup.1H NMR (300 MHz, CDCl.sub.3) 0.20-0.30 (m, 2H, cyclopropane CH.sub.2), 0.47-0.50 (m, 2H, Cyclopropane CH.sub.2), 1.42 (s, 9H, C(CH.sub.3)), 2.12 (br s, 1H, OH), 2.86-2.90 (dd, AB, J=9.5 Hz, COCH.sub.2), 3.51-3.60 (m, 2H, CH.sub.20I1), 4.57 (s, 2H, NCH.sub.2), 7.13-7.16 (dd, J=7.9 Hz, 1H, CHCHC(.sup.tBu)), 7.21-7.26 (m, 4H, ArH), 7.37-7.40 (m, 2H, ArH), 7.62-7.65 (dd, J=8.0, 1.8 Hz, 1H, CHCHC(.sup.tBu)), 7.99-8.00 (dd, J=1.3 Hz, 1H, C(O)CCH), 8.04-8.06 (m, 2H, CHNO.sub.2)

[0453] .sup.13C NMR (CDCl.sub.3, 75 MHz), 6.48, 20.00, 31.73, 41.69, 42.50, 68.00, 68.14, 94.86, 120.99, 122.07, 123.01, 123.62, 126.57, 126.82, 128.29, 128.95, 130.17, 135.15, 137.97, 139.28, 145.28, 147.59, 167.20

[0454] IR: 649, 704, 729, 754, 801, 813, 835, 853, 927, 949, 1012, 1031, 1059, 1091, 1135, 1177, 1200, 1259, 1280, 1313, 1342, 1377, 1398, 1434, 1463, 1489, 1520, 1600, 1686, 2013, 2093, 2139, 2165, 2189, 2208, 2870, 2922, 2960, 3001, 3075, 3428 cm .sup.1

[0455] LCMS (DMSO): Rt=3.72 min (on 5 min column)

[0456] HPLC purity (as area %): >98

[0457] UV (in EtOH): max=267 nm

[0458] EI-MS: calculated mass of ion 552.2260 [M+NH.sub.4].sup.+, measured mass of ion 552.2253 [M+NH.sub.4].sup.+

[0459] Rf: 0.53 (50% EtOAc/petrol)

[0460] MP: 104-105 C.

[0461] CHN: C.sub.30H.sub.31ClN.sub.2O.sub.3 requires C: 67.35, H: 5.84, N: 5.24, found C: 67.26, H: 5.89, N: 5.21

Synthesis of 5-tert-butyl-3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl) methoxy)-2-(4-nitrobenzyl)isoindolin-1-one (NU8400)

[0462] ##STR00137##

[0463] The named compound was synthesised from NU8396 (200 mg, 0.44 mmol) and 1,1-bis(hydroxymethyl)cyclopropane (0.09 mL, 0.89 mmol) using General Procedure C, purified by chromatography (Biotage SP4; 10%-50% EtOAc/petrol) and obtained as white crystals (43 mg, 18%).

[0464] .sup.1H NMR (300 MHz, CDCl.sub.3) 0.10-0.13 (m, 2H, cyclopropane CH.sub.2), 0.41-0.44 (m, 2H, Cyclopropane CH.sub.2), 1.26 (s, 9H, C(CH.sub.3)), 1.69 (br s, 1H, OH), 2.71-2,78 (m, 2H, COCH.sub.2), 3.41-3.52 (dd, AB, J=11.0 Hz, CH.sub.2OH), 4.38-4.53 (dd, J=15.2 Hz, 2H, NCH.sub.2), 7.13-7.15 (dd, J=1.1 Hz, 1H, CCHC(.sup.tBu)), 7.16-7.21 (m, 4H, ArH), 7.29-7.32 (m, 2H, ArH), 7.55-7.58 (dd, J=8.1, 1.6 Hz, 1H, CHCHC(.sup.tBu)), 7.81-7.83 (dd, J=7.9 Hz, 1H, C(O)CCH), 7.98-8.01 (m, 2H, CHNO.sub.2)

[0465] .sup.13C NMR (CDCl.sub.3, 75 MHz), 8.95, 9.02, 22.69, 31.56, 42.72, 42.80, 67.94, 67.99, 93.23, 123.55, 123.70, 126.59, 127.79, 128.27, 128.91, 130.03, 130.11, 131.28, 133.01, 135.15, 138.50, 145.17, 147.27, 168.57

[0466] IR: 663, 691, 704, 730, 801, 843, 872, 893, 934, 951, 1013, 1059, 1091, 1132, 1189, 1240, 1260, 1281, 1342, 1382, 1398, 1425, 1465, 1490, 1520, 1605, 1686, 2010, 2872, 2926, 3073, 3413 cm.sup.1

[0467] LCMS: Rt=3.80 min (on 5 min column)

[0468] HPLC purity (as area %)=>97

[0469] UV (in EtOH): max=268 nm

[0470] EI-MS: calculated mass of ion 552.2260 [M+NH.sub.4].sup.+, measured mass of ion 552.2260 [M+NH.sub.4].sup.+

[0471] Rf: 0.50 (50% EtOAc/petrol)

[0472] MP: 89-90 C.

[0473] CHN: C.sub.30H.sub.31ClN.sub.2O.sub.5 requires C: 67.35, H: 5.84, N: 5.24, found C: 67.45, H: 6.01, N: 5.05

Synthesis of 3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-5-methyl-2-(4-nitrobenzyl)isoindolin-1-one (NU8401)

[0474] ##STR00138##

[0475] The named compound was synthesised from a mixture of NU8395 and NU8412 (200 mg, 0.49 mmol) and 1,1-bis(hydroxymethyl)cycloproparte (0.10 mL, 0.98 mmol) using General Procedure C, purified by chromatography (Biotage SP4; 10%-30% EtOAc/petrol) and obtained as a white solid (116 mg, 48%).

[0476] .sup.1H NMR (300 MHz, CDCl.sub.3) 0.07-0.28 (m, 2H, cyclopropane CH.sub.2), 0.34-0.57 (m, 2H, cyclopropane CH.sub.2), 2.33-2.40 (s, 3H, CH.sub.3), 2.74-2.88 (m, 2H, COCH.sub.2), 3.39-3.56 (m, 2H, CH.sub.2OH)), 4.35-4.62 (s, 2H, NCH.sub.2), 6.90-6.96 (m, 1H, ArH), 7.11-7.20 (m, 4H, ArH), 7.27-7.41 (m, 3H, ArH), 7.74-7.84 (dd, J=7.8 Hz, 1H, C(O)CCH), 7.92-8.08 (m, 2H, CHNO.sub.2)

[0477] .sup.13C NMR (CDCl.sub.3, 75 MHz), 8.89, 8.98, 22.16, 22.70, 42.71, 67.87, 67.98, 94.77, 123.59, 123.87, 124.02, 128.22, 128.29, 128.96, 130.20, 131.51, 135.10, 135.26, 137.63, 140.40, 145.85, 147.74, 166.79

[0478] IR: 662, 683, 704, 734, 766, 781, 801, 829, 845, 860, 893, 916, 937, 961, 1011, 1032, 1077, 1094, 1134, 1156, 1175, 1211, 1273, 1342, 1391, 1420, 1463, 1487, 1518, 1609, 1682, 1925, 2162, 2853, 2882, 2925, 3009, 3086, 3406 cm.sup.1

[0479] LCMS (DMSO): Rt=3.73 min (on 5 min column)

[0480] HPLC purity (as area %): >96

[0481] UV (in EtOH): max=266 nm

[0482] EI-MS: calculated mass of ion 493.1525 [M+H].sup.+, measured mass of ion 493.1521 [M+H].sup.+

[0483] Rf=0.53 (50% EtOAc/petrol)

[0484] MP: 177-178 C.

[0485] CHN: C.sub.27H.sub.25ClN.sub.2O.sub.5 requires C: 65.79, H: 5.11, N: 5.68, found C: 65.57, H: 5.15, N: 5.45

Synthesis of 3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-4-methyl-2-(4-nitrobenzyl)isoindolin-1-one (NU8405)

[0486] ##STR00139##

[0487] The named compound was synthesised from NU8393 (413 mg, 1.01 mmol) and 1,1-bis(hydroxymethyl)cyclopropane (0.19 mL, 2.03 mmol) using General Procedure C, purified by chromatography (Biotage SP4; 20%-40% EtOAc/petrol) and obtained as a yellow solid (252 mg, 50%).)

[0488] .sup.1H NMR (300 MHz, CDCl.sub.3) 0.07-0.17 (m, 2H, cyclopropane CH.sub.2), 0.25-0.34 (m, 2H, Cyclopropane CH.sub.2), 1.8.1 (s, 3H, CH.sub.3), 1.92 (br s, 1H, OH), 2.60-2.83 (dd, AB, J=9.4 Hz, COCH.sub.2), 3.33-3.41 (m, 2H, CH.sub.2OH), 4.19 and 4.42 (dd, AB, J=15.3 Hz, 2H, NCH.sub.2), 6.88-6.97 (m, 2H, ArH)), 7.04-7.06 (m, 2H, ArH), 7.11-7.13 (dd, J=7.5 Hz, 1H, CHC(Me)), 7.26-7.30 (t, J=7.5 Hz, 1H, CHCHC(Me)), 7.57-7.60 (dd, J=7.4 Hz, 1H, C(O)CH), 7.75-7.79 (m, 2H, CHNO.sub.2)

[0489] .sup.13C NMR (CDCl.sub.3, 75 MHz), 8.82, 8.95, 17.30, 17.40, 22.68, 42.28, 67.60. 94.73, 121.62, 123.47, 128,45, 128.82, 129.94, 130.81, 132.18, 134.69, 135.24. 136.92, 142.26, 145.11, 147.50, 168.60

[0490] IR: 696, 762, 797, 930, 1013, 1067, 1186, 1229, 1286, 1340, 1393, 1427, 1487, 1520, 1605, 1677, 2864, 3455 cm.sup.1

[0491] LCMS (DMSO): Rt=3.68 min (on 5 min column)

[0492] HPLC purity (as area %): >96

[0493] UV (in EtOH): max=268 nm

[0494] EI-MS: calculated mass of ion 493.1525 [M+H].sup.+, measured mass of ion 493.1523 [M+H].sup.+

[0495] Rf: 0.36 (50% EtOAc/petrol): MP: 146-147 C.

[0496] CHN: C.sub.27H.sub.25ClN.sub.2O.sub.5 requires C: 65.79, H: 5.11, N: 5.68, found C: 65.78, H: 4.81, N: 5.65

Synthesis of 4-chloro-3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl) methoxy)-2-(4-nitrobenzyl)isoindolin-1-one (NU8406)

[0497] ##STR00140##

[0498] The named compound was synthesised from NU8398 (433 mg, 1.01 mmol) and 1,1-bis(hydroxymethyl)cyclopropane (0.19 mL, 2.03 mmol) using General Procedure C, purified by chromatography (Biotage SP4; 20%-50% EtOAc/petrol) and obtained as yellow crystals (321 mg, 62%).

[0499] .sup.1H NMR (300 MHz, CDCl.sub.3) 0.21-0.42 (m, 2H, cyclopropane CH.sub.2), 0.47-0.54 (m, 2H, cyclopropane CH.sub.2), 2.12 (br s, 1H, OH), 2.89-3.05 (m, 2H, COCH.sub.2), 3.52-3.61 (m, 2H, CH.sub.2OH), 4.30-4.59 (dd, AB, J=15.2 Hz, NCH.sub.2),7.15-7.18 (m, 4H, ArH), 7.28-7.33 (m, 2H, ArH), 7.48-7.58 (m, 2H, ArH), 7.87-7.89 (dd, J=7.1, 1.1 Hz, 1H, C(O)CCH), 7.98-8.01 (m, 2H, CHNO.sub.2)

[0500] .sup.13C NMR (CDCl.sub.3, 75 MHz), 8.84, 8.90, 22.59, 42.54, 67.58, 68.10, 94.71, 122.63, 123.56, 128.65, 128.77, 130.09, 130.40, 132.28, 134.37, 135.27, 135.55, 135.57, 141.10, 144.62, 147.64, 167.04

[0501] IR: 696, 759, 816, 853, 930, 1011, 1074, 1144, 1171, 1234, 1341, 1384, 1428, 1462, 1489, 1519, 1699, 2872, 2923, 3422 cm.sup.1

[0502] HPLC purity (as area %): >92

[0503] UV (in EtOH): max=267 nm

[0504] EI-MS: calculated mass of ion 530.1244 [M+NH.sub.4].sup.+, measured mass of ion 530.1242 [M+NH.sub.4].sup.+

[0505] Rf: 0.30 (50% EtOAc/petrol): MP: 76-77 C.

[0506] CHN: C.sub.26H.sub.22Cl.sub.2N.sub.2O.sub.5 requires C: 60.83, H: 4.32, N: 5.46, found C: 60.68, H: 4.30, N: 5.40

Synthesis of 5-bromo-3(4-chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)isoindolin-1-one (NU8414) and 6-bromo-3-(4-chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)isoindolin-1-one (NU8413)

[0507] ##STR00141##

[0508] The named compounds were synthesised from a mixture of 4-bromo-2-(4-chlorobenzoyl)benzoic acid and 5-bromo-2-(4-chlorobenzoyl)benzoic acid (2.48 g, 7.28 mmol) and 4-nitrobenzylamine hydrochloride (1.51 g, 8.01 mmol) using General Procedure B, purified by chromatography (Biotage SP4; 20% EtOAc/petrol) and obtained as a cream solid (NU8414) and cream solid (NU8413) (1.83 g, 53%, ratio of 5- and 6-isomers is 1:1).

[0509] Analysis of NU8414:

[0510] .sup.1H NMR (300 MHz, MeOD) 4.50 and 4.68 (dd, J=15.7 Hz, 2H, NCH.sub.2), 4.88 (br s, 1H, OH), 7.24-7.32 (m, 4H, ArH), 7.37-7.47 (m, 3H, ArH), 7.73-7.77 (dd, J=9.6 Hz, 1H, CHCHC(Br)-), 7.99-8.01 (m, 1H, C(OH)CCHCBr-), 8.04-8.09 (m, 2H, CHNO.sub.2)

[0511] .sup.13C NMR (MeOD, 75 MHz), 41.27, 93.73, 123.41, 124.51, 125.12, 127.77, 129.08, 129.64, 130.09, 130.90, 133.50, 134.67, 134.72, 140.45, 140.72, 142.17, 168.08

[0512] IR: 698, 781, 801, 827, 851, 895, 934, 1013, 1043, 1071, 1094, 1128, 1253, 1342, 1392, 1415, 1516, 1603, 1676, 2405, 2932, 3227 cm.sup.1

[0513] LCMS (DMSO): Rt=4.13 min (on 5 min column)

[0514] HPLC purity (as area %)=99

[0515] UV (in EtOH): max=267 nm

[0516] EI-MS: calculated mass of ion 471.9820 [MH], measured mass of ion 471.9818 [MH]

[0517] Rf: 0.59 (50% EtOAc/petrol); MP: 221-222 C.

[0518] CHN: C.sub.21H.sub.14BrClN.sub.2O.sub.4 requires C: 53.25, H: 2.98, N: 5.91 found C: 53.48, H: 2.99, N: 5.79

[0519] Analysis of NU8413:

[0520] .sup.1H NMR (300 MHz, CDCl.sub.3) 3.94 (br s, 1H, OH), 4.22 and 4.53 (dd, J=15.3 Hz, 2H, NCH.sub.2), 7.06-7.09 (d, J=8.0 Hz, 1H, CHCHC(Br)-), 7.11-7.14 (m, 4H, ArH), 7.17-7.22 (m, 2H, ArH), 7.56-7.60 (dd, J=8.0, 1.8 Hz, 1H, CHCHC(Br)-), 1.71-7.72 (dd, J=1.6 Hz, 1H, C(O)CCH), 7.88-7.91 (m, 2H, CHNO.sub.2)

[0521] .sup.13C NMR (CDCl.sub.3, 75 MHz), 41.63, 94.94, 122.73, 123.76, 124.66, 127.26, 128.07, 129.28, 129.82, 132.04, 133.88, 135.53, 136.67, 143.14, 145.09, 145.38, 165.32

[0522] IR: 718, 754, 801, 827, 851, 930, 1011, 1063, 1090, 1183, 1273, 1311 1342, 1389, 1437, 1487, 1516, 1599, 1672, 2853, 2923, 3163 cm.sup.1

[0523] LCMS (DMSO): Rt=4.21 min (on 5 min column)

[0524] HPLC purity (as area %)=98

[0525] UV (in EtOH): max=267 nm

[0526] EI-MS: calculated mass of ion 471.9820 [MH], measured mass of 471.9814 [MH]

[0527] Rf: 0.66 (50% EtOAc/petrol); MP: 218-219 C.

Synthesis of 4-((1-(4-chlorophenyl)-1-((1-(hydroxymethyl) cyclopropyl)methoxy)-3-oxoisoindolin-2-yl)methyl)benzonitrile (NU8415)

[0528] ##STR00142##

[0529] The named compound was synthesised from NU8306 (379 mg, 1.01 mmol) and 1,1-bis(hydroxymethyl)cyclopropane (0.19 mL, 2.03 mmol) using General Procedure C, purified by chromatography (Biotage SP4; 20%-50% EtOAc/petrol) and obtained as white crystals (221 mg, 51%).

[0530] .sup.1H NMR (300 MHz, CDCl.sub.3) 0.01-0.19 (m, 2H, cyclopropane CH.sub.2), 0.34-0.42 (m, 2H, cyclopropane CH.sub.2), 1.96 (s, 1H, OH), 2.72-2.79 (m, 2H, COCH.sub.2), 3.39-3.49 (dd, J=11.3, 18.2 Hz, 2H, CH.sub.2OH)), 4.40 (s, 2H, NCH.sub.2), 7.05-7.12 (m, 5H, ArH), 7.18-7.21 (d, AB quartet, J=8.2 Hz, 2H, CHCHCCN), 7.35-7.37 (d, AB quartet, J=8.2 Hz, 2H, CHCCN), 7.45-7.50 (m, 2H, ArH), 7.82-7.85 (m, 1H, C(O)CCH)

[0531] .sup.13C NMR (CDCl.sub.3, 75 MHz), 8.86, 22.61, 42.97, 67.43, 67.60, 94.88, 111.53, 118.74, 123.50, 124.06, 128.32, 128.88, 130.09, 130.45, 131.81, 132.17, 133.44, 135.07, 137.52, 143.10, 145.51, 168.57

[0532] IR: 700, 762, 810, 849, 926, 955, 1009, 1041, 1063, 1276, 1302, 1350, 1395, 1425, 1468, 1491, 1605, 1680, 2228, 2854, 2926, 3408 cm.sup.1

[0533] LCMS (DMSO): Rt=3.90 min (on 5 min column)

[0534] HPLC purity (as area %): >98

[0535] UV (in EtOH): max=225 nm

[0536] EI-MS: calculated mass of ion 459.1470 [M+H].sup.+, measured mass of ion 459.1471 [M+H].sup.+

[0537] Rf: 0.32 (50% EtOAc/petrol); MP: 136-137 C.

[0538] CHN: C.sub.27H.sub.23ClN.sub.2O.sub.3 requires C: 70.66, H: 5.05, N: 6.10, found C: 70.39, H: 5.05, N: 6.09

Synthesis of 2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-((1-hydroxymethyl) cyclopropyl)methoxy)isoindolin-1-one (NU8416)

[0539] ##STR00143##

[0540] The named compound was synthesised from NU8314 (200 mg, 0.52, mmol) and 1,1-bis(hydroxymethyl)cyclopropane (0.10 mL, 1.04 mmol) using General Procedure C, purified by chromatography (Biotage SP4; 20%-40% EtOAc/petrol) and obtained as white crystals (192 mg, 79%).

[0541] .sup.1H NMR (300 MHz, CDCl.sub.3) 0.05-0.12 (m, 2H, cyclopropane CH.sub.2), 0.34-0.39 (m, 2H, cyclopropane CH.sub.2), 1.97 (s, 1H, OH), 2.63-2.79 (dd, AB, J=9.4 Hz, 2H, COCH.sub.2), 3.34-3.50 (dd, AB, J=11.3 Hz, 2H, CH.sub.2OH)) 4.16-4.49 (dd, AB, J=14.9 Hz, 2H, NCH.sub.2), 7.07-7.09 (m, 4H, ArH), 7.10-7.14 (m, 5H, ArH), 7.44-7.47 (m, 2H, ArH), 7.83-7.86 (m, 1H, C(O)CCH)

[0542] .sup.13C NMR (CDCl.sub.3, 75 MHz), 8.82, 22.55, 42.76, 60.56, 67.70, 95.09, 123.33, 124.00, 128.30, 128.57, 128.90, 130.28, 130.94, 132.00, 133.22, 133.58, 134.94, 136.32, 137.66, 145.68, 168.48

[0543] IR: 700, 728, 761, 803, 812, 847, 924, 953, 1009, 1037, 1067, 1092, 1176, 1232, 1285, 1318, 1355, 1383, 1425, 1470, 1487, 1609, 1098, 2882 2927, 3489 cm.sup.1

[0544] LCMS (DMSO): Rt=3.91 min (on 5 min column)

[0545] HPLC purity (as area %): >99

[0546] UV (in EtOH): max=222 nm

[0547] EI-MS: calculated mass of ion 468.1128 [M+H].sup.+, measured mass of ion 468.1128 [M+H].sup.+

[0548] Rf=0.41 (50% EtOAc/petrol); MP: 118-119 C.

Synthesis of 2-(4-bromobenzyl)-3-(4-chlorophenyl)-3-(1-(hydroxymethyl) cyclopropyl)methoxy)isoindolin-1-one (NU8417)

[0549] ##STR00144##

[0550] The named compound was synthesised from NU8315 (433 mg, 1.01 mmol) and 1,1-bis(hydroxymethyl)cyclopropane (0.19 mL, 2.03 mmol) using General Procedure C, purified by chromatography (Biotage SP4; 20%-40% EtOAc/petrol) and obtained as white crystals (333 mg, 64%).

[0551] .sup.1H NMR (300 MHz, DMSO) 0.02-0.08 (m, 2H, cyclopropane CH.sub.2), 0.26-0.33 (m, 2H, cyclopropane CH.sub.2), 2.59-2.80 (dd, AB, J=9.0 Hz, 2H, COCH.sub.2), 3.16-3.45 (m, 2H, CH.sub.2OH)), 4.21-4.42 (dd, AB, J=15.4 Hz, 2H, NCH.sub.2), 4.45 (s. 1H, OH), 7.03-7.06 (d, J=8.4 Hz, 2H, ArH), 7.19-7.22 (m, 3H, ArH), 7.29-7.40 (m, 4H, ArH), 7.56-7.65 (m, 2H, ArH), 7.83-7.85 (m, 1H, C(O)CCH)

[0552] .sup.13C NMR (DMSO, 75 MHz), 7.94. 22.19, 40.98, 65.96, 73.03, 94.24, 120.42, 123.40, 123.59, 123.83, 128.45, 128.66, 130.99, 131.16, 131.40, 131.76, 133.49, 137.13, 138.13, 143.48, 167.64

[0553] IR: 679, 721, 760, 795, 814, 849, 922, 953, 1008, 1036, 1066, 1092, 1177, 1232, 1285, 1317,1356, 1385, 1420, 1471, 1612, 1692, 2586, 2884, 2944, 3499 cm.sup.1

[0554] LCMS (DMSO): Rt=4.06 min (on 5 min column)

[0555] HPLC purity (as area %): >99

[0556] UV (in EtOH): max=223 nm

[0557] EI-MS: calculated mass of ion 512.0623 [M+H].sup.+, measured mass of ion 512.0627 [M+H].sup.+

[0558] Rf=0.41 (50% EtOAc/petrol); MP: 161-162 C.

[0559] CHN: C.sub.26H.sub.23BrClNO.sub.3 requires C: 60.89, H: 4.52, N: 2.73, found C: 60.95, H: 4.61, N: 2.74

Synthesis of 3-(4-chlorophenyl)-2-((R)-1-(4-chlorophenyl)ethyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)isoindolin-1-one (NU8418)

[0560] ##STR00145##

[0561] The named compound was synthesised from NU8301 (401 mg, 1.01 mmol) and 1 bis(hydroxymethyl)cyclopropane (0.19 mL, 2.03 mmol) using General Procedure C, purified by chromatography (Biotage SP4; 20%-40% EtOAc/petrol) and obtained as a pale yellow oil (146 mg, 30%).

[0562] .sup.1H NMR (300 MHz, CDCl.sub.3) 0.36-0.44 (m, 2H, cyclopropane CH.sub.2), 0.48-0.59 (m, 2H, cyclopropane CH.sub.2), 1.88 (d, J=7.3 Hz, 3H, CH.sub.3), 2.30 (br s, 1H, OH), 2.88-3.30 (dd, AB, J=9.5 Hz, 2H, COCH.sub.2), 3.58-3.67 (m, 2H, CH.sub.2OH)), 4.30-4.38 (q, J=7.2, 14.4 Hz, 1H, NCH), 6.96-7.01 (m, 7H, ArH), 7.04-7.07 (m, 1H, ArH), 7.43-7.47 (m, 2H, ArH), 7.80-7.83 (m, 1H, C(O)CCH)

[0563] .sup.13C NMR (CDCl.sub.3, 75 MHz), 8.96, 9.03, 20.41, 22.93, 52.80, 60.59, 67.83, 95.25, 123.28, 123.75, 128.27, 128.43, 128.68, 129.57, 130.31, 133.09, 133.08, 134.82, 137.55, 141.72, 144.99, 168.30

[0564] IR: 699, 727, 762, 815, 868, 938, 1011, 1032, 1070, 1018, 1176, 1321, 1398, 1467, 1489, 1597, 1682, 2876, 2930, 3389 cm.sup.1

[0565] LCMS (DMSO): Rt=4.15 min (on 5 min column)

[0566] HPLC purity (as area %); >97

[0567] UV (in EtOH): max=221 nm

[0568] EI-MS: calculated mass of ion 482.1284 [M+H].sup.+, measured mass of ion 482.1279 [M+H].sup.+

[0569] Rf=0.42 (50% EtOAc/petrol)

Synthesis of 3-(4-chlorophenyl)-2-((S)-1-(4-chlorophenyl)ethyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)isoindolin-1-one (NU8419)

[0570] ##STR00146##

[0571] The named compound was synthesised from NU8347 (401 mg, 1.01 mmol) and 1,1-bis(hydroxymethyl)cyclopropane (0.19 mL, 2.03 mmol) using General Procedure C, purified by chromatography (Biotage SP4; 10%-30% EtOAc/petrol) and obtained as a pale yellow oil (60 mg, 12%).

[0572] .sup.1H NMR (300 MHz, CDCl.sub.3) 0.36-0.44 (m, 2H, cyclopropane CH.sub.2), 0.48-0.59 (m, 2H, cyclopropane CH.sub.2), 1.88 (d, J=7.3 Hz, 3H, CH.sub.3), 2.30 (br s, 1H, OH), 2.88-3.30 (dd, AB, J=9.5 Hz, 2H, COCH.sub.2), 3.58-3.67 (m, 2H, CH.sub.2OH)), 4.30-4.38 (q, J=7.2, 14.4 Hz, 1H, NCH), 6.96-7.01 (m, 7H, ArH), 7.04-7.07 (m, 1H, ArH), 7.43-7.47 (m, 2H, ArH), 7.80-7.83 (m, 1H, C(O)CCH)

[0573] .sup.13C NMR (CDCl.sub.3, 75 MHz), 8.96, 9.03, 20.41, 22,93, 52.80, 60.59, 67.83, 95.25, 123.28, 123.75, 128.27, 128.43, 128.68, 129.57, 130.31, 133.09, 133.08, 134.82, 137.55, 141.72, 144.99, 168.30

[0574] IR: 698, 727, 761, 815, 866, 1011, 1031, 1068, 1090, 1176, 1331, 1396, 1487, 1583, 1695, 2876, 2923, 3415 cm.sup.1

[0575] LCMS (DMSO): Rt=4.19 min (on 5 min column)

[0576] HPLC purity (as area %): >98

[0577] UV (in EtOH): max=221 nm

[0578] EI-MS: calculated mass of ion 482.1284 [M+H].sup.+, measured mass of ion 482.1285 [M+H].sup.+

[0579] Rf=0.42 (50% EtOAc/petrol)

Synthesis of 5-bromo-3-(4-chlorophenyl)-3-((1-(hydroxymethyl) cyclopropyl) methoxy)-2-(4-nitrobenzyl)isoindolin-1-one (NU8424)

[0580] ##STR00147##

[0581] The named compound was synthesised from NU8414 (200 mg, 0.42 mmol) and 1,1-bis(hydroxymethyl)cyclopropane (0.08 mL, 0.84 mmol) using General Procedure C, purified by chromatography (Biotage SP4; 20%-40% EtOAc/petrol) and obtained as a yellow oil (204 mg, 87%).

[0582] .sup.1H NMR (300 MHz, CDCl.sub.3) 0.17-0.27 (m, 2H, cyclopropane CH.sub.2), 0.44-0.51 (m, 2H, cyclopropane CH.sub.2), 2.05 (s, 1H, OH), 2.83-2.90 (dd, AB, J=9.5 Hz, 2H, COCH.sub.2), 3.49-3.58 (dd, AB, J=11.5 Hz, 2H, CH.sub.2OH), 4.45-4.56 (dd, AB, J=15.4 Hz, 2H, NCH.sub.2), 7.16-7.19 (m, 4H, ArH), 7.29-7.33 (m, 3H, ArH), 7.66-7.70 (dd, J=1.6, 8.9 Hz, 1H, CHCHBr), 7.78-7.80 (dd, J=8.0 Hz, 1H, C(O)CCH), 7.99-8.02 (d, AB, J=8.7 Hz, 2H, CHCNO.sub.2)

[0583] .sup.13C NMR (CDCl.sub.3, 75 MHz), 8.90, 22.62, 42.79, 67.47, 67.72, 94.47, 123.62, 125.52, 126.92, 128.25, 128.41, 129.12, 130.24, 130.60, 134.00, 135.54, 136.72, 144.61, 147.35, 147.71, 167.66

[0584] IR: 702, 726, 799, 818, 855, 883, 934, 1011, 1032, 1078, 1128, 1176, 1277, 1343, 1387, 1420, 1488, 1521, 1601, 1684, 2854, 2922, 3420 cm.sup.1

[0585] HPLC purity (as are %): >86

[0586] UV (in EtOH): max=267 nm

[0587] EI-MS: calculated mass of ion 574.0739 [M+NH.sub.4].sup.+, measured mass of ion 574.0735 [M+NH.sub.4].sup.+

[0588] Rf=0.37 (50% EtOAc/petrol); MP: 56-158 C.

Synthesis of 6-bromo-3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl) methoxy)-2-(4-nitrobenzyl)isoindolin-1-one (NU8425)

[0589] ##STR00148##

[0590] The named compound was synthesised from NU8413 (200 mg, 0.42 mmol) and 1,1-bis(hydroxymethyl)cyclopropane (0.08 mL, 0.84 mmol) using General Procedure C, purified by chromatography (Biotage SP4; 20%-40% EtOAc/petrol) and obtained as an orange solid (154 mg, 66%).

[0591] .sup.1H NMR (300 MHz, CDCl.sub.3) 0.21-0.31 (m, 2H, cyclopropane CH.sub.2), 0.49-0.56 (m, 2H, cyclopropane CH.sub.2), 2.13 (br s, 1H, OH), 2.88-2.92 (m, 2H, COCH.sub.2), 3.53-3.62 (dd, AB, J=11.4 Hz, 2H, CH.sub.2OH), 4.52-4.62 (dd, AB, J=15.9 Hz, 2H, NCH.sub.2), 7.12-7.14 (d, J=8.0 Hz, 1H, CHCHCBr), 7.20-7.26 (m, 4H, ArH), 7.34-7.38 (m, 2H, ArH), 7.72-7.75 (dd, J=1.8, 8.0 Hz, 1H, CHCHCBr-), 8.04-8.07 (m, 2H, CHCNO.sub.2), 8.09-8.10 (d, J=1.6 Hz, 1H, C(O)CCHC-Br)

[0592] .sup.13C NMR (CDCl.sub.3, 75 MHz), 8.88, 8.93, 22.65, 42.84, 67.50, 67.72, 94.75, 123.62, 124.81, 125.13, 127.39, 128.24, 129.07, 130.21, 133.68, 133.71, 135.46, 136.52, 136.83, 144.17, 144.60, 147.70, 167.09,

[0593] IR: 696, 725, 820, 854, 926, 1011, 1176, 1277, 1341, 1376, 1425, 1489, 1519, 1602, 1699, 2924, 3077, 3422 cm.sup.1

[0594] HPLC purity (as area %); >98

[0595] UV (in EtOH): max=267 nm

[0596] EI-MS: calculated mass of ion 556.0395 [M].sup.+, measured mass of ion 556.0389 [M].sup.+

[0597] Rf=0.41 (50% EtOAc/petrol); MP: 66-68 C.

Synthesis of 3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-2-(pyridin-2-yl)methyl)isoindolin-1-one (NU8429)

[0598] ##STR00149##

[0599] The named compound was synthesised from NU8423 (354 mg, 1.01 mmol) and 1,1-bis(hydroxymethyl)cyclopropane (0.19 mL, 2.03 mmol) using General Procedure C, purified by chromatography (Biotage SP4; 50% EtOAc/petrolEtOAc) and obtained as yellow crystals (383 mg, 87%).

[0600] .sup.1H NMR (300 MHz, CDCl.sub.3) 0.04-0.17 (m, 2H, cyclopropane CH.sub.2), 0.30-0.37 (m, 2H, cyclopropane CH.sub.2), 2.57-3.18 (dd, J=9.3 Hz, 2H, COCH.sub.2), 3.25-3.63 (dd, J=11.3 Hz, 2H, CH.sub.2OH), 4.10 (br s, 1H, OH), 4.36-4.48 (dd, AB, J=15.2 Hz, 2H, NCH.sub.2), 6.94-7.02 (m, 3H, ArH), 7.04-7.07 (m, 1H, ArH), 7.10-7.15 (m, 2H, ArH), 7.19-7.22 (m, H, ArH), 7.35-7.42 (m, 3H, ArH), 7.76-7.79 (m, 1H, C(O)CCH), 8.22-8.23 (m, 1H, CNCH)

[0601] .sup.13C NMR (CDCl.sub.3, 75 MHz), 8.79, 8.86, 22.64 , 45.64, 67.13, 67.55, 94.79, 122.33, 123.40, 123.93, 124.07, 128.30, 128.69, 130.18, 132.12, 133.09, 134.57, 136.53, 137.86, 145.68, 148.96, 157.14, 168.40

[0602] IR: 700, 760, 813, 846, 928, 969, 1009, 1038, 1069, 1088, 1113, 1179, 1229, 1279, 1315, 1352, 1377, 1421, 1469, 1595, 1695, 2854, 2909, 3277 cm.sup.1

[0603] HPLC purity (as area %); >97

[0604] UV (in EtOH): max=261 nm

[0605] EI-MS: calculated mass of ion 435.1470 [M+H].sup.+, measured mass of ion 435.1471 [M+H].sup.+

[0606] Rf=0.01 (50% EtOAc/petrol); MP 123-125 C.

Synthesis of 3-(4-chlorophenyl)-5-fluoro-3-hydroxy-2-(4-nitrobenzyl)isoindolin-1-one (NCL-00010485) and 3-(4-chlorophenyl)-6-fluoro-3-hydroxy-2-(4-nitrobenzyl)isoindolin-1-one (NCL-00010486)

[0607] ##STR00150##

[0608] The named compounds were synthesised from a mixture of 2-(4-chlorobenzoyl)-4-fluorobenzoic acid and 2-(4-chlorobenzoyl)-5-fluorobenzoic acid (2.39 g, 8.58 mmol) and 4-nitrobenzylamine hydrochloride (1.78 g, 9.44 mmol) using General Procedure B, purified by chromatography (Biotage SP4; 25% EtOAc/petrol) and obtained as a cream main solid (NCL-00010485) and a yellow solid (NCL-00010486) (2.56 g, 72%, ratio of 5- and 6-isomers is 3:2).

[0609] Analysis of Major Isomer (NCL-00010485):

[0610] .sup.1H NMR (300 MHz, CDCl.sub.3) 4.22-4.66 (dd, AB, J=15.4 Hz, 2H, NCH.sub.2), 5.28 (s, 1H, OH), 6.85-6.89 (dd, J=7.7, 2.2 Hz, 1H, C(OH)CCHC(F)), 7.06-7.13 (m, 1H, C(O)CCHCH), 7.15-7.22 (m, 4H, C.sub.6H.sub.4Cl), 7.30-7.36 (d AB, J=8.7 Hz, 2H, C.sub.2H.sub.2C.sub.2H.sub.2C(NO.sub.2)), 7.72-7.76 (dd, J=8.3, 4.8 Hz, 1H, C(O)CCH), 7.93-7.96 (d AB, J=8.7 Hz, 2H, C.sub.2H.sub.2C(NO.sub.2))

[0611] .sup.13C NMR (DMSO, 75 MHz), 42.35, 86.69, 113.40, 117.58, 123.23, 125.67, 126.79, 128.46, 128.74, 129.39, 133.52, 138.52, 140.85, 146.22, 147.54, 158.81, 166.24

[0612] IR: 710, 775, 804, 832, 933, 970, 1015, 1054, 1092, 1155, 1201, 1263, 1342, 1394, 1484, 1519, 1607, 1676, 3235 cm.sup.1

[0613] LCMS (DMSO): Rt=4.03 min (on 5 min column)

[0614] HPLC purity (as area %): >98

[0615] UV (in EtOH): max=272 nm

[0616] EI-MS: calculated mass of ion 430.0964 [M+NH.sub.4].sup.+, measured mass of ion 430.0958 [M+NH.sub.4].sup.+

[0617] Rf=0.50 (50% EtOAc/petrol); MP: 222-224 C.

[0618] Analysis of Minor Isomer (NCL-00010486):

[0619] .sup.1H NMR (300 MHz, CDCl.sub.3) 4.25-4.65 (dd AB, J=15.4 Hz, 2H, NCH.sub.2), 4.73 (s, 1H, OH), 7.13-7.24 (m, 6H, ArH), 7.30-7.33 (d AB, J=8.7 Hz, 2H, C.sub.2H.sub.2C.sub.2H.sub.2C(NO.sub.2)), 7.35-7.39 (dd, J=7.2, 2.1 Hz, 1H, C(O)CCH), 7.94-7.98 (d AB, J=8.7 Hz, 2H, C.sub.2H.sub.2C(NO.sub.2))

[0620] .sup.13C NMR (DMSO, 75 MHz), 42.43, 90.42, 113.29, 116.37, 123.23, 125.58, 128.45, 128.70, 129.42, 133.48, 134.84, 138.76, 139.16, 142.38, 146.18, 160.19,166.08

[0621] IR: 776, 806, 831, 851, 891, 932, 1013, 1059, 1092, 1173, 1197, 1267, 1310, 1342, 1390, 1449, 1484, 1518, 1607, 1680, 2160, 2852, 2925, 3267 cm.sup.1

[0622] LCMS (DMSO): Rt=4.03 min (on 5 min column)

[0623] HPLC purity (as area %): >97

[0624] UV (in EtOH): max=267 nm

[0625] EI-MS: calculated mass of ion 412.0621 [M+H].sup.+, measured mass of ion 412.0619 [M+H].sup.+

[0626] Rf=0.58 (50% EtOAc/petrol); MP: 188-190 C.

Synthesis of 5,6-dichloro-3-(4-chlorophenyl)-3-((1-hydroxymethyl)cyclopropyl) methoxy)-2-(4-nitrobenzyl)isoindolin-1-one (NCL-00010487)

[0627] ##STR00151##

[0628] The named compound was synthesised from NU8432 (350 mg, 075 mmol) and 1,1-bis(hydroxymethyl)cyclopropane (0.16 mL, 1.67 mmol) using General Procedure C, purified by chromatography (Biotage SP4; 20%-40% EtOAc/petrol) and obtained as a yellow oil (302 mg, 73%).

[0629] .sup.1H NMR (300 MHz, CDCl.sub.3) 0.20-0.30 (m, 2H, CH.sub.2), 0.46-0.50 (m, 2H, CH.sub.2), 2.25 (s, 1H, OH), 2.90 (s, 2H, OCH.sub.2), 3.50-3.60 (dd AB, J=11.2, 8.8 Hz, 2H, HOCH.sub.2), 4.46-4.58 (dd AB, J=15.2, 5.6 Hz, 2H, NCH.sub.2), 7.19-7.20 (m, 4H, C.sub.6H.sub.4Cl), 7.29-7.32 (m, 3H, N.sub.2OCCHCH and C(O)CCH), 7.98-8.01 (m, 3H, O.sub.2NCCH and C(O)CCH)

[0630] .sup.13C NMR (CDCl.sub.3, 75 MHz), 8.87, 8.90, 22.60, 42.93, 67.27, 67.68, 94.36, 123.63, 125.76, 126.01, 128.22, 129.17, 130.23, 131.44, 135.56, 135.66, 136.41, 138.31, 144.38, 144.77, 147.72, 166.46

[0631] IR: 754, 804, 837, 889, 934, 1011, 1070, 1095, 1166, 1201, 1235, 1339, 1402, 1489, 1514, 1601, 1688, 2857, 2923, 3482 cm.sup.1

[0632] LCMS (DMSO): Rt=4.65 min (on 5 min column)

[0633] HPLC purity (as area %): >99

[0634] UV (in EtOH): max=266 nm

[0635] EI-MS: calculated mass of ion 569.0408 [M+Na].sup.+, measured mass of ion 569.0408 [M+Na].sup.+

[0636] Rf=0.45 (50% EtOAc/petrol)

Synthesis of 4-((7-chloro-1-(4-chlorophenyl)-hydroxy-3-oxoisoindolin-2-yl)methyl) benzonitrile (NCL-00010488) and 4-((4-chloro-1-(4-chlorophenyl)-1-hydroxy-3-oxoisoindolin-2-yl)methyl)benzonitrile (73/NCL-00010489)

[0637] ##STR00152##

[0638] The named compounds were synthesised from a mixture of 3-chloro-2-(4-chlorobenzoyl)benzoic acid and 6-chloro-2-(4-chlorobenzoyl)benzoic acid (2.15 g, 7.28 mmol) and 4-cyanobenzylamine hydrochloride (1.35 g, 8.01 mmol) using General Procedure B, purified by chromatography (Biotage SP4; 20% EtOAc/petrol) and obtained as a while solid (NCL-00010488) and brown crystals (NCL-00010489) (1.98 g, 66%, ratio of 7- and 4-isomers is 99:1)

[0639] Analysis of Major Isomer (NCL-00010488):

[0640] .sup.1H NMR (300 MHz, CDCl.sub.3) 3.50 (br s, 1H, OH), 4.22-4.61 (dd AB, J=15.3 Hz, 2H, NCH.sub.2), 7.22-7.30 (m, 6H, ArH), 7.40-7.51 (m, 4H, ArH), 7.75-7.78 (dd, J=5.8, 2.6 Hz, 1H, C(O)CCH)

[0641] .sup.13C NMR (CDCl.sub.3, 75 MHz), 42.97, 91.15, 107.13, 109.45, 122.61, 128.49, 129.02, 129.65, 130.01, 130.54, 132.09, 132.13, 132.34, 132.40, 135.02, 143.99, 145.12, 165.73

[0642] IR: 669, 710, 766, 812, 853, 930, 1002, 1069, 1088, 1146, 1175, 1277, 1352, 1404, 1462, 1490, 1582, 1661, 2228, 2919, 3205 cm.sup.1

[0643] LCMS (DMSO): Rt=3.99 min (on 5 min column)

[0644] HPLC purity (as area %): >97

[0645] UV (in EtOH): max=227 nm

[0646] EI-MS: calculated mass of ion 407.0360 [MH].sup., measured mass of ion 407.0363 [MH].sup.

[0647] Rf=0.42 (50% EtOAc/petrol); MP: 210-211 C.

[0648] Analysis of Minor Isomer (NCL-00010489):

[0649] .sup.1H NMR (300 MHz, CDCl.sub.3) 4.02 (br s, 1H, OH), 4.29-4.60 (dd AB, J=15.1 Hz, 2H, NCH.sub.2), 7.16-7.19 (dd, J=7.2, 1.2 Hz, 1H, C(OH)CH), 7.20-7.22 (m, 4H, C.sub.6H.sub.4Cl), 7.26-7.29 (m, 2H, ArH), 7.37-7.47 (m, 4H, ArH)

[0650] .sup.13C NMR (CDCl.sub.3, 75 MHz), 43.17, 94.29, 100.01, 115.88, 128.17, 128.53, 129.18, 129.92, 131.95, 132.32, 132.77, 134.26, 134.36, 135.53, 136.47, 143.28, 144.23, 167.99

[0651] IR: 672, 698, 736, 789, 801, 845, 928, 956, 1013, 1088, 1169, 1205, 1269, 1350, 1382, 1460, 1489, 1597, 1686, 1790, 2226, 1851, 2922, 3076, 3358 cm.sup.1

[0652] LCMS (DMSO): Rt=3.95 min (on 5 min column)

[0653] HPLC purity (as area %): >88

[0654] UV (in EtOH): max=227 nm

[0655] EI-MS: calculated mass of ion 426.0771 [M+NH.sub.4].sup.+, measured mass of on 426.0777 [M+NH.sub.4].sup.+

[0656] Rf=0.57 (50% EtOAc/petrol); MP: 191-193 C.

Synthesis of 2-(4-bromobenzyl)-4-chloro-3-(4-chlorophenyl)-3-hydroxyisoindolin-1-one (NCL-00010490)

[0657] ##STR00153##

[0658] The named compound was synthesised from a mixture of 3-chloro-2-(4-chlorobenzoyl)benzoic acid and 6-chloro-2-(4-chlorobenzoyl)benzoic acid (2.15 g, 7.28 mmol) and 4-bromobenzylamine (1.49 g, 8.01 mmol) using General Procedure B, purified by chromatography (Biotage SP4; 20% EtOAc/petrol) and obtained as a white solid (1.57 g, 47%).

[0659] .sup.1H NMR (300 MHz, DMSO) 3.40 (br s, 1H, OH), 4.06-4.55 (dd AB, J=15.0 Hz, 2H, NCH.sub.2), 7.01-7.07 (m, 2H, CC.sub.2H.sub.2C.sub.2H.sub.2CBr), 7.23-7.32 (m, 6H, ArH), 7.44-7.50 (m, 2H, ArH), 7.72-7.75 (dd, J=5.7, 2.8 Hz, 1H, C(O)CCH)

[0660] .sup.13H NMR (DMSO, 75 MHz), 44.30, 91.18, 121.62, 122.51, 126.33, 127.34, 128.29, 128.58, 128.94, 130.81, 131.73, 134.30, 137.00, 139.90, 141.07, 145.12, 167.02

[0661] IR: 671, 711, 766, 814, 847, 928, 1009, 1072, 1150, 1198, 1285, 1356, 1399, 1464, 1489, 1585, 1656, 3193 cm.sup.1

[0662] LCMS (DMSO): Rt=4.72 min (on 5 min column)

[0663] HPLC purity (as area %): >97

[0664] UV (in EtOH): max=222 nm

[0665] EI-MS: calculated mass of ion 459.9512 [MH].sup., measured lass of ion 459.9515 [MNH].sup.

[0666] Rf=0.57 (50% EtOAc petrol); MP: 211-212 C.

Synthesis of 4-((7-chloro-1-(4-chlorophenyl)-1-(hydroxymethyl)cyclopropyl) methoxy)-3-oxoisoindolin-2-yl)methyl)benzonitrile (NCL-00010492)

[0667] ##STR00154##

[0668] The named compound was synthesised from NCL-00010488 (413 mg, 1.01 mmol) and 1,1-bis(hydroxymethyl)cyclopropane (0.19 mL, 2.03 mmol) using General Procedure C, purified by chromatography (Biotage SP4; 20%-60% EtOAc/petrol) and obtained as white crystals (305 mg, 61%).)

[0669] .sup.1H NMR (300 MHz, CDCl.sub.3) 0.23-0.34 (m, 2H, cyclopropane CH.sub.2), 0.38-0.46 (m, 2H, cyclopropane CH.sub.2), 2.28 (s, 3H, OH), 2.78-2.92 (dd AB, J=9.1 Hz, 2H, OCH.sub.2), 3.43-3.53 (dd AB, J=11.4 Hz, 2H, CH.sub.2OH), 4.30-4.45 (dd AB, J=15.2 Hz, 2H, NCH.sub.2), 7.02-7.10 (m, 2H, ArH), 7.12-7.16 (m, 4H, ArH), 7.33-7.37 (m, 2H, C.sub.2H.sub.2C(CN)), 7.38-7.42 (m, 1H, CHCHC(Cl)CC(OCH.sub.2), 7.43-7.49 (m, 1H, CHC(Cl)CC(OCH.sub.2)), 7.78-7.80 (dd, J=7.2, 1.2 Hz, 1H, C(O)CCH)

[0670] .sup.13C NMR (CDCl.sub.3, 75 MHz), 8.80, 8.86, 22.54, 42.80, 67.46, 68.04, 94.69, 111.59, 118.67, 122.60, 128.66, 128.72, 129.98, 130.36, 132.17, 132.25, 134.33, 134.41, 135.17, 135.56, 141.10, 142.72, 167.04

[0671] IR: 761, 814, 854, 928, 1012, 1144, 1172, 1233, 1275, 1651, 1384, 1423, 1462, 1588, 1697, 2229, 2874, 2920, 3423 cm.sup.1

[0672] LCMS (DMSO): Rt=4.02 min (on 5 min column)

[0673] HPLC purity (as area %): >96

[0674] UV (in EtOH): max=226 nm

[0675] EI-MS: calculated mass of ion 426.0255 [M+H].sup.+, measured mass of ion 426.0257 [M+H].sup.+

[0676] Rf=0.26 (50% EtOAc/petrol); MP: 70-72 C.

Synthesis of 2-(4-bromobenzyl)-4-chloro-3-(4-chlorophenyl -3-((1-hydroxymethyl) cyclopropyl)methoxy)isoindolin-1-one (NCL-00010493)

[0677] ##STR00155##

[0678] The named compound was synthesised from NCL-00010490 (468 mg, 1.01 mmol) and 1,1-bis(hydroxymethyl)cyclopropane (0.19 mL, 2.03 mmol) using General Procedure C, purified by chromatography (Biotage SP4; 20%-40% EtOAc/petrol) and obtained as white crystals (304 mg, 55%).

[0679] .sup.1H NMR (300 MHz, DMSO) 0.06-0.27 (m, 2H, cyclopropane CH.sub.2), 0.35-0.40 (m, 2H, cyclopropane CH.sub.2), 2.23 (s, 3H, OH), 2.82 (s, 2H, OCH.sub.2), 3.41-3.50 (dd AB, J=11.8 Hz, 2H, CH.sub.2OH), 4.15-4.38 (dd AB, J=14.9 Hz, 2H, NCH.sub.2), 6.93-6.96 (d, AB, J=8.4 Hz, 2H, C.sub.2H.sub.2C.sub.2H.sub.2CBr), 7.10-7.15 (m, 4H, ArH), 7.19-7.23 (d AB, J=8.4 Hz, 2H, C.sub.2H.sub.2C(Br)), 7.37-7.47 (m, 2H, ArH), 7.77-7.81 (dd, J=7.1, 1.2 Hz, 1H, C(O)CCH),

[0680] .sup.13C NMR (DMSO, 75 MHz), 8.83, 8.97, 22.50, 42.70, 67.65, 68.08, 94.91, 121.69, 122.54, 128.72, 130.23, 131.15, 131.59, 132,10, 134.17, 134.63, 135.06, 135.63, 136.46, 141.22, 166.96

[0681] IR: 713, 759, 818, 924, 951, 1009, 1071, 1144, 1172, 1233, 1349, 1383, 1461, 1487, 1587, 1690, 2873, 2923, 3404 cm.sup.1

[0682] LCMS (DMSO)): Rt=4.27 min (on 5 min column)

[0683] HPLC purity (as area %): >94

[0684] UV (in EtOH): max=222 nm

[0685] EI-MS: calculated mass of ion 563.0498 [M+NH.sub.4].sup.+, measured mass of ion 563.0491 [M+NH.sub.4].sup.+

[0686] Rf=0.39 (50% EtOAc/petrol); MP: 59-61 C.

Synthesis of 3-(4-chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)-2,3,4,5,6,7-hexahydroisoindol-1-one (NCL-00010494)

[0687] ##STR00156##

[0688] The named compound was synthesised from 2-(4-chlorobenzoyl)cyclohex-1-enecarboxylic acid (1.00 g, 3.78 mmol) and 4-nitrobenzylamine hydrochloride (0.78 g, 4.16 mmol) using General Procedure B, purified by chromatography (Biotage SP4; 30% EtOAc/petrol) and obtained as a yellow solid (0.67g, 44%).

[0689] .sup.1H NMR (300 MHz, CDCl.sub.3) 1.60-1.80 (m, 4H, C()CCH.sub.2CH.sub.2CH.sub.2CH.sub.2CC(OH), 2.20-2.33 (m, 4H, C(O)CCH.sub.2CH.sub.2CH.sub.2CH.sub.2CC(OH)), 4.19-4.61 (dd AB, J=15.6 Hz, 2H, NCH.sub.2), 4.73 (s, 1H, OH), 7.24-7.30 (m, 4H, C.sub.6H.sub.4CCl), 7.33-7.36 (d AB, J=8.6 Hz, 2H, C.sub.2H.sub.2C.sub.2H.sub.2CH.sub.2C(NO.sub.2)), 7.97-8.00 (d AB, J=8.6 Hz, 2H, C.sub.2H.sub.2C(NO.sub.2))

[0690] .sup.13C NMR (CDCl.sub.3, 75 MHz), 20.31, 21.02, 22.11, 22.26, 42.59, 92.16, 123.50, 127.94, 129.09, 129.66, 131.47, 134.97, 136.12, 146.31, 147.42, 157.64, 171.18

[0691] IR: 697, 727, 797, 824, 853, 914, 968, 1013, 1045, 1092, 1136, 1202, 1283, 1339, 1435, 1489, 1520, 1603, 1661, 2853, 2932, 3159 cm.sup.1

[0692] LCMS (DMSO): Rt=4.02 min (on 5 min column)

[0693] HPLC purity (as area %): >98

[0694] UV (in EtOH): max=272 nm

[0695] EI-MS: calculated mass of ion 399.1106 [M+H].sup.+, measured mass of ion 399.1112 [M+H].sup.+

[0696] Rf=0.39 (50% EtOAc/petrol); MP: 144-146 C.

Synthesis of 3-(4-chlorophenyl)-5-fluoro-3-((1-hydroxymethyl)cyclopropyl) methoxy)-2-(4-nitrobenzyl)isoindolin-1-one (NCL-00010495)

[0697] ##STR00157##

[0698] The named compound was synthesised from NCL-00010485 (150 mg, 0.36 mmol) and 1,1-bis(hydroxymethyl)cyclopropane (0.07 mL, 0.72 mmol) using General Procedure C, purified by chromatography (Biotage SP4; 20%-40% EtOAc/petrol) and obtained as white crystals (85 mg, 47%).

[0699] .sup.1H NMR (300 MHz, CDCl.sub.3) 0.10-0.25 (m, 2H, cyclopropane CH.sub.2), 0.40-0.49 (m, 2H, cyclopropane CH.sub.2), 1.69 (s, 3H, OH), 2.84 (s, 2H, OCH.sub.2), 3.43-3.54 (dd AB, J=11.3 Hz, 2H, CH.sub.2OH), 4.48 (s, 2H, NCH.sub.2), 6.82-6.85 (dd, J=7.5, 2.0 Hz, 1H, ArH), 7.15-7.17 (m, 4H, C.sub.6H.sub.4CCl), 7.18-7.25 (dt, J=8.7, 2.2 Hz, 1H, ArH)), 7.28-7.31 (d AB, J=8.6 Hz, 2H, C.sub.2H.sub.2C.sub.2H.sub.2C(NO.sub.2)), 7.87-7.92 (dd, J=8.3, 4.8 Hz, 1H, C()CCH), 7.98-8.01 (d AB, J=8.7 Hz, 2H, C.sub.2H.sub.2C(NO.sub.2))

[0700] .sup.13C NMR (CDCl.sub.3, 75 MHz), 8.91, 22.64, 42.86, 67.62, 67.77, 94.30, 110.87, 111.19, 118.11, 118.39, 123.63, 126.40, 128.22, 129.12, 130.22, 135.56, 136.88, 144.75, 148.23, 167.48, 168.20

[0701] IR: 683, 772, 802, 836, 936, 1013, 1059, 1093, 1150, 1178, 1220, 1264, 1383, 1427, 1487, 1520, 1605, 1697, 2876, 2927, 3082, 3407 cm .sup.1

[0702] LCMS (DMSO) Rt=4.12 min (on 5 min column)

[0703] HPLC purity (as area %): >98

[0704] UV (in EtOH): max=267 nm

[0705] EI-MS; calculated mass of ion 514.1540 [M+NH.sub.4].sup.+, measured mass of ion 514.1540 [M+NH.sub.4].sup.+

[0706] Rf=0.35 (50% EtOAc/petrol); MP: 61-63 C.

Synthesis of 3-(4-chlorophenyl)-6-fluoro-3-((1-(1-hydroxymethyl)cyclopropyl) methoxy)-2-(4-nitrobenzyl)isoindolin-1-one (NCL-00010496)

[0707] ##STR00158##

[0708] The named compound was synthesised from NCL-00010486 (150 mL, 0.36 mmol) and 1,1-bis(hydroxymethyl)cyclopropane (0.07 mL, 0.72 mmol) using General Procedure C, purified by chromatography (Biotage SP4; 20%-40% EtOAc/petrol) and obtained as white crystals (115 mg, 64%).

[0709] .sup.1H NMR (300 MHz, CDCl.sub.3) 0.22-0.31 (m, 2H, cyclopropane 0.48-0.55 (m, 2H, cyclopropane CH.sub.2), 2.10 (s, 3H, OH), 2.90 (s, 2H, OCH.sub.2), 3.52-3.62 (dd AB, J=11.4 Hz, 2H, CH.sub.2OH), 4.51-4.62 (dd AB, J=15.5 Hz, 2H, NCH.sub.2), 7.19-7.25 (m, 5H, C.sub.6H.sub.4CCl and C(F)CHCH), 7.27-7.30 (dd, J=8.6, 2.2 Hz, 1H, C(F)CHCH)), 7.34-7.37 (d AB, J=8.6 Hz, 2H, C.sub.2H.sub.2C.sub.2H.sub.2C(NO.sub.2)), 7.62-7.65 (dd, J=7.2, 2.1 Hz, 1H, C(O)CCH), 8.04-8.06 (d AB, J=8.6 Hz, 2H, C.sub.2H.sub.2C(NO.sub.2))

[0710] .sup.13C NMR (CDCl.sub.3, 75 MHz), 8.87, 8.92, 22.64, 42.90, 67.55, 67.64, 94.64, 110.93, 111.25, 121.03, 123.61, 125.35, 125.46, 128.25, 129.03, 130.20, 135.38, 137.11, 141.00, 144.64, 162.64, 167.32

[0711] IR: 701, 777, 802, 830, 928, 1011, 1065, 1092, 1177, 1227, 1264, 1342, 1379, 1447, 1484, 1520, 1605, 1694, 2874, 2928, 3408 cm.sup.1

[0712] LCMS (DMSO): Rt=4.05 min (on 5 min column)

[0713] HPLC purity (as area %): >98

[0714] UV (in EtOH): max=267 nm

[0715] EI-MS: calculated mass of ion 514,1540 [M+NH.sub.4].sup.+, measured mass of ion 514.1537 [M+NH.sub.4].sup.+

[0716] Rf=0.45 (50% EtOAc/petrol); MP: 64-66 C.

Synthesis of 4-chloro-3-(4-chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)isoindolin-1-one (NU8398) and 7-chloro-3-(4-chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (AW379B, NCL-00016654)

[0717] ##STR00159##

[0718] The named compounds were synthesised from a mixture of 3-chloro-2-(4-chlorobenzoyl)benzoic acid and 6-chloro-2-(4-chlorobenzoyl)benzoic acid (2.15 g, 7.28 mmol) and 4-nitrobenzylamine hydrochloride (1.51 g, 8.01 mmol) using General Procedure B, purified by chromatography (Silica; 10%-20% EtOAc/petrol) and obtained as a white solid (NU8398) and a white solid (NCL-00016654) (1.96 g, 63%, ratio of isomers NU8398:NCL-00016654 is 99:1).

[0719] Analysis of Major Isomer (NU8398):

[0720] .sup.1H NMR (300 MHz, CDCl.sub.3) 4.28 (br s, 1H, OH), 4.28 and 4.63 (dd, AB, J=15.4 Hz, 2H, NCH.sub.2), 7.19-7.22 (m, 4H, ArH), 7.31-7.33 (m, 2H, ArH), 7.44-7.49 (m, 2H, ArH), 7.72-7.75 (dd, J=3.2, 8.5 Hz, 1H, (C(O)CCH), 7.98-8.00 (m, 2H, CHNO.sub.2), .sup.13C NMR (CDCl.sub.3, 75 MHz), 42.37, 90.90, 122.20, 123.22, 123.35, 128.21, 128.68, 129.44, 129.75, 131.69, 131.89, 134.14, 135.15, 147.37, 163.60, 163.86. IR: 696, 729, 759, 808, 856, 932, 996, 1070, 1092, 1144, 1174, 1271, 1342, 1397, 1462, 1518, 1592, 1682, 2026, 2171, 3220 cm.sup.1. LCMS (DMSO): 8.47 min (on 12 min column). UV (in EtOH): max=268 nm. EI-MS: calculated mass of ion 429.0403 measured mass of ion 429.0401 [M+H].sup.+. Rf: 0.47 (50% EtOAc/petrol). MP: 202-203 C. CHN: C.sub.21H.sub.14Cl.sub.2N.sub.2O.sub.4+0.2 EtOAc requires C: 58.59, H: 3.52, N: 6.27, found C: 58.27, H: 3.21, N: 6.48.

[0721] Analysis of Minor Isomer (NCL-00016654)

[0722] .sup.1H NMR (300 MHz, CDCl.sub.3) 3.90 (s, 1H, OH), 4.30-4.66 (dd, AB, J=15.2 Hz, 2H, NCH.sub.2), 7.17-7.20 (dd, J=1.2, 7.2 Hz, 1H, CHC(COH)), 7.21-7.24 (m, 4H, C.sub.6H.sub.4Cl), 7.29-7.35 (dd AB, J=8.8 Hz, 2H, CC.sub.2H.sub.2C.sub.2H.sub.2CNO.sub.2), 7.37-7.48 (m, 2H, ArH), 7.94-8.00 (dd AB, J=8.8 Hz, 2H, CC.sub.2H.sub.2C.sub.2H.sub.2CNO.sub.2). .sup.13C NMR (CDCl.sub.3, 75 MHz), 42.88, 90.25, 121.72, 123.70, 126.42, 128.16, 129.23, 130.01, 132.04, 132.10, 135.64, 136.58, 145.18, 147.78, 151.26, 165.68. IR: 612, 852, 934, 1093, 1343, 1387, 1515, 1604, 1686, 2850, 2932, 3078, 3332 cm.sup.1. LCMS (DMSO): RT=3.47 min (on 5 min column), m/z=427 ES.sup.. HPLC purity (as area %): >98. UV (in EtOH): max=270 nm. EI-MS: calculated mass of ion 429.0403 [M+H].sup.+, measured mass of ion 429.0403 [M+H].sup.+. Rf=0.55 (50% EtOAc/petrol). MP: 172-174 C.

Synthesis of 2-(4-acetylbenzyl)-3-(4-chlorophenyl)-3-hydroxy-2,3-dihydroisoindol-1-one (NCL-00016045/AW344)

[0723] ##STR00160##

[0724] The named compound was synthesised from 2-(4-chlorobenzoyl)-benzoic acid (687 mg, 2.63 mmol) and 4-acetylbenzylammonium trifluoroacetate (630 mg, 2.40 mmol) using General Procedure B, purified by chromatography (Silica; 10%-50% EtOAc/petrol) and obtained as white crystals (552 mg, 54%).

[0725] .sup.1H NMR (300 MHz, CDCl.sub.3) 2.44 (s, 3H, CH.sub.3), 4.10-4.60 (dd AB, J=15.1 Hz, 2H, NCH.sub.2), 5.03 (s, 1H, OH), 7.15-7.21 (m, 4H, ArH), 7.24-7.28 (m, 3H, ArH), 7.40-7.52 (m, 2H, ArH), 7.57-7.60 (d AB, J=8.2 Hz, 2H, ArH), 7.65-7.69 (m, 1H, CHC(CO)). .sup.13C NMR (CDCl.sub.3, 75 MHz), 26.39, 42.98, 91.38, 123.01, 123.59, 128.23, 128.32, 128.76, 129.14, 129.75, 130.64, 133.01, 134.69, 136.17, 137.96, 143.66, 149.26, 168.06, 198.01. IR: 696, 725, 770, 804, 849, 905, 956, 1013, 1061, 1089, 1200, 1263, 1352, 1398, 1427, 1468, 1603, 1666, 2055, 2846, 2934, 3007, 3140 cm.sup.1, LCMS (DMSO): RT=3.78 min (on 5 min column), m/z=392 ES.sup.+. HPLC purity (as area %): >98. UV (in EtOH): max=254 nm. EI-MS: calculated mass of ion 392.1048 [M+H].sup., measured mass of ion 392.1051 [M+H].sup.+. Rf=0.19 (25% EtOAc/petrol). MP: 147-150 C.

Synthesis of 2-(4-benzoylbenzyl)-3-(4-chlorophenyl)-3-hydroxy-2,3-dihydroisoindol-1-one (AW357, NCL-00014532)

[0726] ##STR00161##

[0727] The named compound was synthesised from 2-(4-chlorobenzoyl)-benzoic acid (791 mg, 3.03 mmol) and 4-acetylbenzylammonium trifluoroacetate (640 mg, 1.97 mmol) using General Procedure B, purified by chromatography (Silica; 10%-30% EtOAc/petrol) and obtained as white crystals (414 mg, 46%).

[0728] .sup.1H NMR (300 MHz, CDCl.sub.3) 4.20-4.56 (dd AB, J=15.1 Hz, 2H, NCH.sub.2), 6.01 (s, 1H, OH), 7.14-7.20 (m, 4H, ArH), 7.21-7.28 (m, 3H, ArH), 7.31-7.43 (m, 6H, ArH), 7.50-7.53 (m, 1H, CHC(CO)), 7.56-7.62 (m, 3H, ArH). .sup.13C NMR (CDCl.sub.3, 75 MHz), 43.02, 91.46, 123.09, 123.74, 128.37, 128.55, 128.83, 128.99, 129.87, 130.15, 130.26, 130.57, 132.65, 133.16, 134.78, 136.45, 137.86, 137.97, 143.06, 149.28, 168.18, 196.74. IR: 698, 735, 763, 810, 864, 927, 1015, 1063, 1090, 1198, 1275, 1313, 1350, 1400, 1468, 1597, 1655, 2023, 2157, 2931, 3065, 3179 cm.sup.1. LCMS (DMSO): 3.88 min (on 5 min column), m/z=454 ES.sup.+

[0729] HPLC purity (as area %): >97. UV (in EtOH): max=259 nm. EI-MS: calculated mass of ion 454.1204 [M+H].sup.+, measured mass of ion 454.1206 [M+H].sup.+. Rf=0.45 (25% EtOAc/petrol). MP: 163-164 C.

Synthesis of 3-(4-chlorophenyl)-3-hydroxy-2-(4-iodobenzyl)-2,3-dihydroisoindol-1-one (AW345, NCL-00014527)

[0730] ##STR00162##

[0731] The named compound was synthesised from 2-(4-chlorobenzoyl)-benzoic acid (1.76 g, 6.75 mmol) and 4-iodobenzylamine hydrochloride (2 g, 7.42 mmol) using General Procedure B, recrystallised from EtOAc/petrol, purified by chromatography (Silica; 6%-50% EtOAc/petrol) and obtained as a white solid (1.72 g, 52%).

[0732] .sup.1H NMR (300 MHz, CDCl.sub.3) 3.37 (s, 1H, OH), 4.17-4.46 (dd AB, J=15.6 Hz, 2H, NCH.sub.2), 6.98-7.01 (d AB, J=7.8 Hz, 2H, CC.sub.2H.sub.2C.sub.2H.sub.2C(I)), 7.23-7.32 (m, 5H, ArH), 7.50-7.62 (m, 4H, ArH), 7.75-7.78 (m, 1H, CHC(CO)). .sup.13C NMR (CDCl.sub.3, 75 MHz), 167.15, 149.54, 139.34, 138.32, 136.90, 133.21, 133.03, 130.80, 130.70, 129.73, 128.57, 128.38, 123.18, 122.98, 92.38, 90.59, 42.32. IR: 694, 719, 762, 790, 845, 926, 1007, 1063, 1093, 1119, 1198, 1288, 1352, 1391, 1412, 1467, 1659, 2912, 3175, 3178 cm.sup.1. LCMS (DMSO): RT=4.89 min (on 5 min column), m/z=476 ES.sup.+. HPLC purity (as area %): >99. UV (in ETOH): max=231 nm. EI-MS: calculated mass of ion 475.9909 [M+H].sup.+, measured mass of ion 475.9905 [M+H].sup.+. Rf=0.29 (25% EtOAc/petrol). MP: 184-185 C.

Synthesis of 3-(4-chlorophenyl)-3-(1-hydroxymethylcyclopropylmethoxy)-2-(4-iodobenzyl)-2,3-dihydroisoindol-1-one (AW350, NCL-00014529)

[0733] ##STR00163##

[0734] The named compound was synthesised from NCL-00014527 (499 mg, 1.01 mmol) and 1,1-bis(hydroxymethyl)cyclopropane (0.19 mL, 2.03 mmol) using General Procedure C, purified by chromatography (Silica; 10%-40% EtOAc/petrol) and obtained as white crystals (487 mg, 83%).

[0735] .sup.1H NMR (300 MHz, CDCl.sub.3) 0.10-0.15 (m, 2H, cyclopropane CH.sub.2), 0.35-0.42 (m, 2H, cyclopropane CH.sub.2), 1.85 (s, 1H, OH), 2.62-2.80 (dd AB, J=9.4 Hz, 2H, iso-OCH.sub.2), 3.32-3.48 (m, 2H, CH.sub.2OH) 4.12-4.50 (dd AB, J=14.8 Hz, 2H, NCH.sub.2), 6.85-6.93 (d AB, J=8.3 Hz, 2H, CC.sub.2H.sub.2C.sub.2H.sub.2C(I)), 7.09-7.13 (m, 1H, CHCHC(CO)), 7.13-7.18 (m, 4H, ArH), 7.44-7.51 (m, 4H, ArH), 7.85-7.89 (m, 1H, CHC(CO)). .sup.13C NMR (CDCl.sub.3, 75 MHz), 8.85, 22.56, 42.94, 67.81, 67.93, 94.68, 95.11, 123.30, 124.00, 128.27, 128.93, 130.28, 131.54, 133.20, 135.03, 137.45, 137.48, 137.63, 144.90, 145.62, 168.40. IR: 679, 758, 792, 812, 847, 877, 922, 953, 1035, 1065, 1091, 1177, 1229, 1277, 1318, 1356, 1386, 1418, 1471, 1611, 1684, 1769, 2817, 2880, 2943, 3005, 3063, 3508 cm.sup.1. LCMS (DMSO): RT=4.03 min (on 5 min column), m/z=560 ES.sup.+. HPLC purity (as area %): >98. UV (in EtOH): max=229 nm. EI-MS: calculated mass of ion 560.0484 [M+H].sup.+, measured mass of ion 560.0472 [M+H].sup.+. Rf=0.36 (50% EtOAc/petrol). MP: 164-165 C.

Synthesis of 3-(4-chlorophenyl)-2-(4-fluorobenzyl)-3-(1-hydroxymethylcyclopropylmethoxy)-2,3-dihydro-isoindol-1-one (AW351, NCL-00014530)

[0736] ##STR00164##

[0737] The named compound was synthesised from 3-(4-chloro-phenyl)-2-(4-fluoro-benzyl)-3-hydroxy-2,3-dihydroisoindol-1-one (372 mg, 1.01 mmol) and 1,1-bis(hydroxymethyl)cyclopropane (0.19 mL, 2.03 mmol) using General Procedure C, purified by chromatography (Silica; 10%-40% EtOAc/petrol) and obtained as yellow crystals (238 mg, 52%).

[0738] .sup.1H NMR (300 MHz, CDCl.sub.3) 0.01-0.04 (m, 2H, cyclopropane CH.sub.2), 0.29-0.34 (m, 2H, cyclopropane CH.sub.2), 2.05 (s, 1H, OH), 2.57-2.75 (dd AB, J=9.4 Hz, 2H, iso-OCH.sub.2), 3.28-3.46 (dd AB, J=11.3 Hz, 2H, CH.sub.2OH) 4.11-4.45 (dd AB, J=14.8 Hz, 2H, NCH.sub.2), 6.71-6.77 (m, 2H, ArH), 7.03-7.08 (m, 3H, ArH), 7.08-7.13 (m, 4H, ArH), 7.39-7.42 (m, 2H, ArH), 7.78-7.82 (m, 1H, CHC(CO)). .sup.13C NMR (CDCl.sub.3, 75 MHz), 8.80, 21.08, 42.70, 67.75, 95.11, 115.06, 123.31, 123.96, 128.30, 128.87, 130.25, 131.20, 131.30, 133.16, 133.70, 134.89, 137.76, 145.75, 164.12, 168.47, IR: 760, 808, 844, 918, 951, 1008, 1042, 1063, 1086, 1110, 1158, 1222, 1309, 1346, 1393, 1429, 1468, 1508, 1602, 1674, 2848, 2929, 3005, 3080, 3396 cm.sup.1. LCMS (DMSO): RT=3.78 min (on 5 min column), m/z=452 ES.sup.+. HPLC purity (as area %): >96. UV (in EtOH): max=254 nm. EI-MS: calculated mass of ion 452.1423 [M+H].sup.+, measured mass of ion 452.1419 [M+H].sup.+. Rf=0.49 (50% EtOAc/petrol). MP: 130-132 C.

Synthesis of 2-(4-acetylbenzyl)-3-(4-chlorophenyl)-3-(1-hydroxymethylcyclopropylmethoxy)-2,3-dihydroisoindol-1-one (AW354, NCL-00014531)

[0739] ##STR00165##

[0740] The named compound was synthesised from NCL-00016045 (270 mg, 0.69 mmol) and 1,1-bis(hydroxymethyl)cyclopropane (0.13 mL, 1.38 mmol) using General Procedure C, purified by chromatography (Silica; 20%-70% EtOAc/petrol) and obtained as a yellow oil (108 mg, 33%).

[0741] .sup.1H NMR (300 MHz, CDCl.sub.3) 0.05-0.03 (m, 2H, cyclopropane CH.sub.2), 0.20-0.31 (m, cyclopropane CH.sub.2), 1.76 (br s, 1H, OH), 2.42 (s, 3H, CH.sub.3) 2.58-2.70 (dd AB, J=9.4 Hz, 2H, iso-OCH.sub.2), 3.23-3.37 (dd AB, J=11.3 Hz, 2H, CH.sub.2OH) 4.20-4.44 (dd AB, J=15.0 Hz, 2H, NCH.sub.2), 6.95-7.10 (m, 5H, ArH), 7.11-7.16 (m, 2H, ArH), 7.38-7.41 (m, 2H, ArH), 7.59-7.64 (m, 2H, ArH), 7.76-7.80 (m, 1H, CHC(CO)) .sup.13C NMR (CDCl.sub.3, 75 MHz), 8.84, 21.10, 26.63, 43.12, 67.85, 69.40, 95.09, 123.37, 124.07, 128.31, 128.48, 128.89, 129.61, 130.35, 132.04, 133.26, 135.03, 136.75, 137.61, 142.97, 145.65, 168.47, 197.58

[0742] IR: 698, 763, 811, 849, 926, 957, 1012, 1061, 1092, 1177, 1267, 1353, 1383, 1417, 1466, 1607, 1680, 2875, 2922, 3001, 3368, 3402 cm.sup.1. LCMS (DMSO): 4.14 min (on 5 min column). HPLC purity (as area %): >97. UV (in EtOH): max=251 nm. EI-MS: calculated mass of ion 476.1623 [M+H].sup.+, measured mass of ion 476.618 [M+H].sup.+. Rf=0.21 (50% EtOAc/petrol).

Synthesis of 2-(4-benzoylbenzyl)-3-(4-chlorophenyl)-3-(1-hydroxymethylcyclopropylmethoxy)-2,3-dihydroisoindol-1-one (AW360, NCL-00014533)

[0743] ##STR00166##

[0744] The named compound was synthesised from NCL-00014532 (142 mg, 0.31 mmol) and 1,1-bis(hydroxymethyl)cyclopropane (0.06 mL, 0.63 mmol) using General Procedure C, purified by chromatography (Silica; 10%-50% EtOAc/petrol) and obtained as yellow crystals (124 mg, 74%).

[0745] .sup.1H NMR (300 MHz, CDCl.sub.3) 0.08-0.03 (m, 2H, cyclopropane CH.sub.2), 0.25-0.30 (m, 2H, cyclopropane CH.sub.2), 1.94 (br s, 1H, OH), 2.60-2.69 (dd AB, J=9.4 Hz, 2H, iso-OCH.sub.2), 3.23-3.37 (dd AB, J=11.3 Hz, 2H, CH.sub.2OH) 4.22-4.42 (dd AB, J=15.0 Hz, 2H, NCH.sub.2), 6.96-7.05 (m, 5H, C.sub.6H.sub.4CCl & CHCHC(CON), 7.09-7.12 (d AB, J=8.1 Hz, 2H, NCH2-CC.sub.2H.sub.2C.sub.2H.sub.2C(C(O)Ph), 7.25-7.42 (m, 7H, ArH), 7.53-7.56 (d AB, J=8.1 Hz, 2H, NCH2-CC.sub.2H.sub.2C.sub.2H.sub.2C(C(O)Ph), 7.73-7.76 (m, 1H, CHC(CO)). .sup.13C NMR (CDCl.sub.3, 75 MHz), 8.86, 22.65, 43.11, 67.74, 69.30, 95.07, 123.41, 124.08, 128.40, 128.56, 128.87, 129.07, 129.26, 130.18, 130.36, 132.04, 132.55, 133.28, 134.97, 137.09, 137.72, 138.15, 142.32, 145.69, 168.52, 196.28. IR: 699, 727, 764, 813, 858, 922, 1013, 1063, 1092, 1177, 1276, 1314, 1383, 1466, 1605, 1656, 1690, 2877, 2921, 3063, 3411 cm.sup.1. LCMS (DMSO): 4.88 min (on 5 min column). HPLC purity (as area %): >94. UV (in EtOH): max=261 nm. EI-MS: calculated mass of ion 560.1599 [M+Na].sup.+, measured mass of ion 560.1601 [M+Na].sup.+. Rf=0.40 (50% EtOAc/petrol). MP: 69-71 C.

Synthesis of 3-(4-chlorophenyl)-3-hydroxy-naphthalen-1-ylmethyl-2,3-dihydroisoindol-1-one (AW364, NCL-00016046)

[0746] ##STR00167##

[0747] The named compound was synthesised from 2-(4-chlorobenzoyl)-benzoic acid (2.24 g, 8.59 mmol) and 1-naphthylmethylamine (1.36 mL, 9.44 mmol) using General Procedure B, purified by chromatography (Silica; 6%-50% EtOAc/petrol) and obtained as yellow crystals (0.35 g, 10%).

[0748] .sup.1H NMR (300 MHz, MeOD) 4.90 (s, 1H, OH), 4.90-5.27 (dd AB, J=15.2 Hz, 2H, NCH.sub.2), 6.75-6.79 (m, 2H, ArH), 6.95-6.98 (d AB, J=8.5 Hz, 2H, ArH), 7.13-7.27 (m, 3H, ArH), 7.35-7.61 (m, 5H, ArH), 7.72-7.75 (m, 1H, CHC(CO)), 7.86-7.89 (m, 1H, ArH), 8.17-8.19 (m, 1H, NCH.sub.2CC(C)CH)). .sup.13C NMR (MeOD, 75 MHz), 41.89, 92.80, 124.27, 124.59, 125.20, 126.37, 126.89, 127.38, 129.00, 129.05, 129.32, 129.40, 129.96, 131.05, 132.00, 133.36, 134.02, 134.55, 135.03, 135.47, 139.68, 151.56. 170.26. IR: 694, 762, 833, 929, 973, 1011, 1060, 1091, 1112, 1195, 1268, 1360, 1396, 1468, 1599, 1674, 2070, 2873, 2967, 3053, 3270, 3331 cm.sup.1. LCMS (DMSO): RT=4.19 min (on 5 min column), m/z=398 ES.sup.+. HPLC purity (as area %): >92. UV (in EtOH): max=223 nm. EI-MS: calculated mass of ion 400.1099 [M+H].sup., measured mass of ion 400.1099 [M+H].sup.+. Rf=0.15 (25% EtOAc/petrol). MP: 75-76 C.

Synthesis of 2-(3-bromobenzyl)-3-(4-chlorophenyl)-3-hydroxy-2,3-dihydroisoindol-1-one (AW365, NCL-00016047)

[0749] ##STR00168##

[0750] The named compound was synthesised from 2-(4-chlorobenzoyl)-benzoic acid (2.24 g, 8.59 mmol) and 3-bromobenzylamine hydrochloride (2.10 g, 9.44 mmol) using General Procedure B, recrystallised from EtOAc/petrol and obtained as orange crystals (2.12 g, 58%).

[0751] .sup.1H NMR (300 MHz, CDCl.sub.3) 4.12-4.33 (dd AB, J=15.0 Hz, 2H, NCH.sub.2), 4.54 (br s, 1H, OH), 6.93-7.04 (m, 2H, CHCHCHCBr), 7.08-7.10 (m, 1H, ArH), 7.12-7.19 (m, 4H, C.sub.6H.sub.4Cl), 7.20-7.29 (m, 2H, ArH), 7.41-7.53 (m, 2H, ArH), 7.64-7.69 (m, 1H, CHCC(O)). .sup.13C NMR (CDCl.sub.3, 75 MHz), 42.70, 91.40, 122.52, 122.56, 123.06, 123.95, 127.78, 128.27, 128.89, 130.01, 130.15, 130.54, 132.20, 133.36, 135.09, 137.20, 140.35, 149.08, 168.05. IR: 664, 696, 721, 764, 802, 837, 879, 926, 976, 1011, 1059, 1088, 1191, 1306, 1348, 1399, 1427, 1468, 1572, 1600, 1668, 2875, 2932, 3016, 3246 cm.sup.1. LCMS (DMSO): RT=4.32 min (on 5 min column), m/z=428 ES.sup.. HPLC purity (as area %): >98. UV (in EtOH): max=254 nm. EI-MS: calculated mass of ion 428.0047 [M+H].sup.+, measured mass of ion 428.0041 [M+H].sup.+. Rf=0.42 (50% EtOAc/petrol). MP: 167-170 C.

Synthesis of 3-(4-chlorophenyl)-3-(1-hydroxymethylcyclopropylmethoxy) -2-naphthalen-1-ylmethyl-2,3-dihydroisoindol-1-one (AW366, NCL-00016106)

[0752] ##STR00169##

[0753] The named compound was synthesised from NCL-00016046 (270 mg, 0.69 mmol) and 1,1-bis(hydroxymethyl)cyclopropane (0.13 mL, 1.38 mmol) using General Procedure C, purified by chromatography (Biotage SP4; 6%-25% EtOAc/petrol) and obtained as cream crystals (153 mg, 47%).

[0754] .sup.1H NMR (300 MHz, CDCl.sub.3) 0.35-0.15 (m, 2H, cyclopropane CH), 0.12-0.25 (m, 2H, cyclopropane CH), 1.80 (br s, 1H, OH), 2.38-2.70 (dd AB, J=9.4 Hz, 2H, CH.sub.2OC), 3.18-3.31 (dd AB, J=11.1 Hz, 2H, CH.sub.2OH), 4.63-5.27 (dd AB, J=14.9 Hz, 2H, NCH.sub.2), 7.02-7.07 (m, 5H, C.sub.6H.sub.4Cl & ArH), 7.15-7.30 (m, 2H, ArH), 7.43-7.48 (m, 4H, ArH), 7.68-7.71 (m, 1H, NCH.sub.2CCHCHCHC), 7.76-7.79 (m, 1H, CHC(CO)), 7.93-7.97 (m, 1H, NCH.sub.2CC(C)CHCHCHCHCC), 8.29-8.32 (m, 1H, NCH.sub.2CC(C)CH)).

[0755] .sup.13C NMR (CDCl.sub.3, 75 MHz), 8.58, 8.61, 22.36, 41.25, 67.68, 67.78, 95.41, 123.17, 124.09, 124.54, 125.35, 126.02, 126.70, 128.05, 128.50, 128.68, 128.85, 129.09, 130.15, 131.92, 132.40, 132.91, 133.19, 134.03, 134.49, 137.55, 146.16, 168.32. IR: 696, 767, 810, 839, 923, 945, 1012, 1065, 1110, 1271, 1356, 1389, 1467, 1487, 1598, 1685, 2874, 2923, 3004, 3051, 3395 cm.sup.1. LCMS (DMSO): RT=3.99 min (on 5 min column), m/z=484 ES.sup.+. HPLC purity (as area %): >95. UV (in EtOH): max=223 nm. EI-MS: calculated mass of ion 484.1674 [M+H].sup.+, measured mass of ion 484.1673 [M+H].sup.+. Rf=0.10 (25% EtOAc/petrol). MP: 82-84 C.

Synthesis of 2-(3-bromobenzyl)-3-(4-chlorophenyl)-3-(1-hydroxymethylcyclopropylmethoxy)-2,3-dihydro-isoindol-1-one (AW367, NCL-00016107)

[0756] ##STR00170##

[0757] The named compound was synthesised from NCL-00016047 (292 mg, 0.68 mmol) and 1,1-bis(hydroxymethyl)cyclopropane (0.13 mL, 1.35 mmol) using General Procedure C, purified by Chromatography (Biotage SP4; 6%-50% EtOAc/petrol) and obtained as a pale yellow oil (253 mg, 73%).

[0758] .sup.1H NMR (300 MHz, CDCl.sub.3) 0.05-0.05 (m, 2H, cyclopropane CH), 0.22-0.31 (m, 2H, cyclopropane CH), 2.33 (br s, 1H, OH), 2.54-2.73 (dd AB, J=9.3 Hz, 2H, CH.sub.2OC), 3.26-3.32 (dd AB, J=11.0 Hz, 2H, CH.sub.2OH), 4.10-4.31 (dd AB, J=14.9 Hz, 2H, NCH.sub.2), 6.81-6.87 (m, 1H, CHCHCHCBr), 6.95-7.05 (m, 7H, ArH), 7.09-7.11 (m, 1H, CHCHCC(O)), 7.33-7.35 (m, 2H, CHCHCC(OCH.sub.2)), 7.71-7.74 (m, 1H, CHCC(O)). .sup.13C NMR (CDCl.sub.3, 75 MHz), 8.76. 8.82, 22.58, 42.81, 67.52, 67.60, 94.99, 122.50, 123.40, 124.03, 128.19, 128.32, 128.86, 130.02, 130.30, 130.60, 132.00, 132.55, 133.25, 134.98, 137.61, 140.02, 145.69, 168.40. IR: 666, 695, 711, 761, 812, 838, 927, 1009, 1063, 1090, 1307, 1346, 1380, 1427, 1467, 1571, 1595, 1686, 2874, 2920, 3001, 3065, 3429 cm.sup.1. LCMS (DMSO): RT=3.93 min (on 5 min column), m/z=511 ES.sup.+. HPLC purity (as area %): >98. UV (in EtOH): max=203 nm. EI-MS: calculated mass of ion 512.0623 [M+H].sup.+, measured mass of ion 512.0620 [M+H].sup.+. Rf=0.36 (50% EtOAc/petrol).

Synthesis of 3-hydroxy-2-(4-nitrobenzyl)-3-phenyl-2,3-dihydroisoindol-1-one (AW403/NCL-00016655)

[0759] ##STR00171##

[0760] The named compound was synthesised from 2-benzoyl-benzoic acid (0.5 g, 2.21 mmol) and 4-nitrobenzylamine hydrochloride (0.46 g, 2.43 mmol) using General Procedure B, recrystallised from EtOAc/petrol and obtained as a yellow solid (0.56 g, 70%).

[0761] .sup.1H NMR (300 MHz, CDCl.sub.3) 3.36 (s, 1H, OH), 4.26-4.71 (dd AB, J=15.3 Hz, 2H, NCH.sub.2), 7.22-7.34 (m, 8H, ArH), 7.48-7.57 (m, 2H, ArH), 7.81-7.84 (m, 1H, CHCC(O)), 7.96-8.01 (dd AB, J=8.8 Hz, 2H, C.sub.2H.sub.2CNO.sub.2). .sup.13C NMR (CDCl.sub.3, 75 MHz), 41.02, 91.09, 123.65, 124.05, 125.56, 126.65, 127.64, 128.93, 129.05, 129.82, 133.48, 138.08, 138.25, 142.31, 145.80, 148.57, 168.29, IR: 688, 756, 851, 934, 1055, 1105, 1192, 1283, 1337, 1398, 1468, 1514, 1605, 3083, 3181 cm.sup.1. LCMS (DMSO): RT 3.13 min (on 5 min column), m/z=359 ES.sup.. HPLC purity (as area %): >99. UV (in EtOH): max=269 nm. EI-MS: calculated mass of ion 361.1183 [M+H].sup.+, measured mass of ion 361.1186 [M+H].sup.+. Rf=0.35 (50% EtOAc/petrol). MP: 190-191 C.

Synthesis of 3-(1-hydroxymethylcyclopropylmethoxy)-2-(4-nitrobenzyl)-3-phenyl-2,3-dihydroisoindol-1-one (AW405/NCL-0016656)

[0762] ##STR00172##

[0763] The named compound was synthesised from NCL-00016655 (300 mg, 0.83 mmol) and 1,1-bis(hydroxymethyl)cyclopropane (0.16 mL, 1.67 mmol) using General Procedure C, purified by chromatography (Biotage SP4; 10%-50% EtOAc/petrol) and obtained as pale yellow crystals (298 mg, 81%).

[0764] .sup.1H NMR (300 MHz, CDCl.sub.3) 0.02-0.01 (m, 2H, cyclopropane CH.sub.2), 0.15-0.25 (m, 2H, cyclopropane CH.sub.2), 2.05 (s, 1H, OH), 2.49-2.65 (m, 2H, COCH.sub.2), 3.20-3.40 (m, 2H, CH.sub.2OH), 4.20-4.40 (m, 2H, NCH.sub.2), 6.80-7.10 (m, 8H, ArH), 7.25-7.35 (m, 2H, ArH), 7.70-7.90 (m, 3H, CHCC(O) & C.sub.2H.sub.2CNO.sub.2)

[0765] .sup.13C NMR (CDCl.sub.3, 75 MHz), 8.59, 21.07, 42.08, 66.02, 66.13, 94.53, 123.34, 123.83, 126.54, 128.29, 128.81, 129.67, 130.13, 131.52, 133.04, 137.95, 138.03, 144.61, 145.46, 146.88, 168.36. IR: 696, 753, 796, 854, 910, 938, 1022, 1057, 1103, 1179, 1243, 1278, 1341, 1384, 1466, 1518, 1605, 1686, 2853, 2921, 3077, 3414 cm.sup.1. LCMS (DMSO): RT=3.22 min (on 5 min column). HPLC purity (as area %): >97. UV (in EtOH): max=267 nm. EI-MS: calculated mass of ion 445.1758 [M+H].sup.+, measured mass of ion 445.1757 [M+H].sup.+. Rf=0.27 (50% EtOAc petrol). MP: 58-60 C.

Synthesis of succinic acid mono-{1-[7-chloro-1-(4-chloro-phenyl)-2-(4-nitrobenzyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yloxymethyl]cyclopropylmethyl} ester (AW393/NCL-00016149)

[0766] ##STR00173##

[0767] The named compound was synthesised from NU8406 (100 mg, 0.19 mmol), pyridine (0.03 mL, 0.39 mmol), 4-dimethylamino pyridine (5 mg, 0.04 mmol) and succinic anhydride (39 mg, 0.39 mmol) in anhydrous THF (10 mL) using General Procedure F, purified by chromatography (Biotage SP4; 50% EtOAc/petrol20% MeOH/EtOAc) and obtained as white crystals (60 mg, 50%).

[0768] .sup.1H NMR (300 MHz, CDCl.sub.3) 0.20-0.42 (m, 2H, cyclopropane CH.sub.2), 0.45-0.52 (m, 2H, cyclopropane CH.sub.2), 2.45-2.52 (br m, 4H, CH.sub.2CH.sub.2CO.sub.2H), 2.62-2.93 (dd, AB, J=9.3 Hz, 2H, iso-COCH.sub.2), 4.00-4.15 (m, 2H, CH.sub.2OCOCH.sub.2CH.sub.2CO.sub.2H), 4.30-4.60 (dd, AB, J=15.2 Hz, 2H, NCH.sub.2), 7.01-7.31 (m, 6H, ArH), 7.42-7.57 (m, 2H, ArH), 7.80-8.10 (br m, 4H, ArH and CO.sub.2H). .sup.13C NMR (CDCl.sub.3, 75 MHz), 9.38, 20.00, 29.20, 29.45, 42.50, 67.27, 68.58, 94.68, 122.67, 123.53, 128.51, 128.70, 128.86, 130.06, 130.56, 132.31, 134.37, 135.36, 141.10, 142.22, 144.50, 147.67, 167.32, 172.27, 176.16. IR: 594, 730, 819, 1076, 1165, 1344, 1521, 1707, 1708, 2882, 2929, 3079 cm.sup.1. LCMS (DMSO): RT=3.67 min (on 5 min column). m/z=612 ES.sup..

[0769] HPLC purity (as area %): >95. EI-MS: calculated mass of ion 613.11139 [M+H].sup.+, measured mass of ion 613.1139 [M+H].sup.+. Rf=0.06 (50% EtOAc/petrol). MP: 42-44 C.

Synthesis of succinic acid mono-{1-[7-chloro-1-(4-chlorophenyl)-2-(4-cyanobenzyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yloxymethyl]cyclopropylmethyl} ester (AW417/NCL-00016659)

[0770] ##STR00174##

[0771] The named compound was synthesised from NCL-00010492 (110 mg, 0.22 mmol), pyridine (36 L, 0.45 mmol), 4-dimethylamino pyridine (5 mg, 0.04 mmol) and succinic anhydride (45 mg, 0.45 mmol) in anhydrous THF (10 mL) using General Procedure F, purified by chromatography (Biotage SP4; 50% EtOAc/petrol20% MeOH/EtOAc) and obtained as white crystals (20 mg, 15%).

[0772] .sup.1H NMR (300 MHz, CDCl.sub.3) 0.27-0.20 (m, 2H, cyclopropane CH.sub.2), 0.29-0.36 (m, 2H, cyclopropane CH.sub.2), 2.30-2.42 (br m, 4H, CH.sub.2CH.sub.2CO.sub.2H), 2.55-2.66 (dd, AB, J=9.3 Hz, 2H, iso-COCH.sub.2), 3.85-3.90 (m, 2H, CH.sub.2OCOCH.sub.2CH.sub.2CO.sub.2H), 4.05-4.32 (dd, AB, J=15.2 Hz, 2H, NCH.sub.2), 6.80-6.92 (br m, 5H, C.sub.6H.sub.4Cl and CO.sub.2H), 6.93 (d AB, J=8.3 Hz, 2H, CC.sub.2H.sub.2C.sub.2H.sub.2CCN), 7.18 (d AB, J=8.3 Hz, 2H, CC.sub.2H.sub.2C.sub.2H.sub.2CCN), 7.23-7.25 (dd, J=8.0, 0.9 Hz, 1H, CHCHC(Cl)CC(OCH.sub.2), 7.28-7.32 (m, 1H, CHC(Cl)CC(OCH.sub.2)), 7.62-7.65 (dd, J=7.4, 0.9 Hz, 1H, C(O)CCH). .sup.13C NMR (CDCl.sub.3, 75 MHz), 9.01, 9.07, 19.49, 28.90, 28.99, 29.70, 42.28, 66.69, 68.23, 94.20, 111.07, 118.54, 122.37, 128.34, 129.58, 130.03, 131.88, 132,03, 133.86, 134.03, 134.71, 134.84, 140.60, 142.29, 167.08, 172.22, 176.80. IR: 728, 761, 814, 853, 928, 1009, 1074, 1161, 1207, 1373, 1458, 1719, 1730, 2227, 2857, 2926, 3005, 3071 cm.sup.1.

[0773] LCMS (DMSO): RT=3.41 min (on 5 min column), m/z=592 ES.sup.. HPLC purity (as area %): >96. UV (in EtOH): max=226.5 nm. EI-MS: calculated mass of ion 593.1241 [M+NH.sub.4].sup.+, measured mass of ion 593.1240 [M+NH.sub.4].sup.+. Rf=0.05 (50% EtOAc/petrol). MP: 72-74 C.

Synthesis of succinic acid mono-{1-[2-(4-bromobenzyl)-7-chloro-1-(4-chlorophenyl)-3-oxo-2,3-dihydro1H-isoindol-1-yloxymethyl]cyclopropylmethyl} (AW436, NCL-00016653)

[0774] ##STR00175##

[0775] The named compound was synthesised from NCL-00010493 (150 mg, 0.27 mmol), pyridine (44 L, 0.55 mmol), 4-dimethylamino pyridine (7 mg, 0.05 mmol) and succinic anhydride (55 mg, 0.55 mmol) in anhydrous THF (10 mL) using General Procedure I, purified by chromatography (Biotage SP4; 50% EtOAc/petrolEtOAc) and obtained as a brown oil (93 mg, 53%).

[0776] .sup.1H NMR (300 MHz, CDCl.sub.3) 0.04-0.18 (m, 2H, cyclopropane CH.sub.2), 0.27-0.35 (m, 2H, cyclopropane CH.sub.2), 2.37-2.46 (br m, 4H, CH.sub.2CH.sub.2CO.sub.2H), 2.52-2.69 (dd, AB, J=9.3 Hz, 2H, iso-COCH.sub.2), 3.74-4.03 (dd AB, J=11.4 Hz, 2H, CH.sub.2OCOCH.sub.2CH.sub.2CO.sub.2H), 4.05-4.17 (dd, AB, J=14.9 Hz, 2H, NCH.sub.2), 6.78 (d AB, J=8.4 Hz, 2H, C.sub.2H.sub.2C.sub.2H.sub.2CBr), 6.90-7.01, (m, 4H, CC.sub.2H.sub.4CCl), 7.06 (d AB, J=8.4 Hz, 2H, C.sub.2H.sub.2C(Br)), 7.25-7.27 (dd, J=7.9, 0.8 Hz, CHCHC(Cl)CC(OCH.sub.2), 7.30-7.33 (m, 1H, CHC(Cl)CC(OCH.sub.2) 7.65-7.67 (dd, J=7.4, 0.8 Hz, 1H, C(O)CCH) 9.00 (br s, 1H, COOH). .sup.13C NMR (CDCl.sub.3, 75 MHz), 8.92, 8.98, 19.34, 28.87, 28.90, 42.21, 66.60, 68.37, 94.45, 121.33, 122.28, 128.33, 128.43, 129.91, 130.78, 131.21, 131.88, 133.86, 134.02, 134.67, 134.84, 135.97, 140.75, 166.97, 172.14, 177.17. IR: 760, 817, 926, 1009, 1070, 1159, 1350, 1387, 1462, 1487, 1588, 1704, 1730, 2854, 2921 cm.sup.1. LCMS (DMSO): RT=3.64 min (on 5 min column), m/z=648 ES.sup.+. HPLC purity (as area %): >96. UV (in EtOH): max=222.5 nm. EI-MS: calculated mass of ion 663.0659 [M+NH.sub.4].sup.+, measured mass of ion 663.0653 [M+NH.sub.4].sup.+

[0777] Rf=0.08 (50% EtOAc/petrol).

3-(4-chlorophenyl)-3-hydroxy-2-(4-methylbenzyl)isoindolin-1-one (tjb 14/02)

[0778] ##STR00176##

[0779] The named compound was synthesised from 2-(4-chlorobenzoyl)-benzoic acid (2.0 g, 7.6 mmol) and 4-methyl benzylamine (1.07 mL, 8.4 mmol) using General Procedure B, purified by chromatography (Biotage SP4; 10-80% EtOAc/hexane) and obtained as a white solid (2.045 g, 72%).)

[0780] .sup.1H NMR (500 MHz, CDCl.sub.3) 7.74-7.77 (1H, m, 7-H), 7.53-7.59 (2H, m, 5 & 6-H), 7.28-7.31, (3H, m, ArH), 7.24,-7.26 (2H, m, ArH). 7.05 (2H, d, J=8.0, ArH), 6.96 (2H, d, J=8.0, ArH), 4.41 (1H, d, J=15.4, 2-CH), 4.20, (1H, d, J=15.4, 2-CH), 2.22 (3H, s, CH.sub.3). .sup.13C NMR (125 MHz, CDCl.sub.3) 166.7, 149.1, 139.0, 135.5, 135.0, 132.7, 132.6, 130.3, 129.4, 128.3, 128.2, 128.0, 127.9, 122.8, 122.6, 90.2, 42.1, 20.6. Found; 364.1101 [M+H]: C.sub.22H.sub.19NO.sub.2Cl, requires 364.1099.

3-(4-chlorophenyl)-3-hydroxy-2-(4-methoxybenzyl)isoindolin-1-one (tjb 16/02)

[0781] ##STR00177##

[0782] The named compound was synthesised from 2-(4-chlorobenzoyl)-benzoic acid (2.0 g, 7.6 mmol) and 4-methoxy benzylamine (0.542 mL, 4.18 mmol) using General Procedure B, purified by chromatography (Biotage SP4; 10-80% EtOAc/hexane) and obtained as a white solid (0.830 g, 57%).

[0783] .sup.1H NMR (500 MHz, CDCl.sub.3) 7.78-7.80 (1H, m, 7-H), 7.57-7.61 (2H, m, 5 & 6-H), 7.29-7.33 (3H, m, ArH), 7.25-7.27 (2H, m, ArH), 7.10-7.13 (2H, m, ArH), 6.73-6.76 (2H, m, ArH), 4.40 (1H, d, J=15.2, 2-CH). 4.26 (1H, d, J=15.2, 2-CH), 3.72 (3H, s, CH.sub.3). .sup.13C NMR (125 MHz, CDCl.sub.3) 166.7, 157.9, 149.1, 139.0, 132.6, 132.5, 130.3, 130.0, 129.4. 129.3, 128.2, 128.0, 122.8, 122.5, 113, 190.1, 55.0, 41.72. Found; 380.1055 [M+H]; C.sub.22H.sub.19NO.sub.3Cl, requires 380.1048.

3-(4-chlorophenyl)-3-(1-hydroxy-2-cyclopropyl-3-methoxy)-2-(4-methylbenzyl)isoindolin-1-one (NCL-00016865)

[0784] ##STR00178##

[0785] The named compound was synthesised from 3-(4-chlorophenyl)-3-hydroxy-2-(4-methylbenzyl)isoindolin-1-one (300 mg, 0.83 mmol) and 1,1-bis(hydroxymethyl)cyclopropane (0.16 mL, 1.67 mmol) using General Procedure C, purified by chromatography (Biotage SP4; 10%-80% EtOAc/n-hexane) and obtained as a glassy solid (187 mg, 54%).

[0786] .sup.1H NMR (500 MHz, CDCl.sub.3) 7.82-7.84 (1H, m, 7-H), 7.41-7.45 (2H, m, 5 & 6-H), 7.15 (4H, s, ArH), 7.04-7.07 (3H, m, 4 & ArH), 6.93 (2H, d, J=7.8, ArH), 4.60 (1H, d, J=14.8, 2-CH), 3.95 (1H, d, J=14.8. 2-CH), 3.31 (1H, d, J=11.3, 1-H), 3.25 (1H, d, J=11.3, 1-H), 2.64 (1H, d, J=9.5, 3-H), 2.55 (1H, d, J=9.5, 3-H), 2.21 (3H, s, CH.sub.3), 1.54 (1H, br s, 1-OH), 0.27-0.30 (2H, m, H.sub.2), 0.02-0.03 (2, m, H.sub.2). .sup.13C NMR (125 MHz, CDCl.sub.3) 168.2, 145.3, 137.3, 137.1, 134.5, 134.4, 132.8, 131.7, 129.9, 129.2, 128.9, 128.7, 127.9, 123.7, 122.8, 95.0, 68.0, 67.7, 42.9, 29.7, 22.1, 21.0, 8.6. Found; 448.1673 [M+H]; C.sub.27H.sub.27NO.sub.3Cl, requires 448.1674.

3-(4-chlorophenyl)-3-(1-hydroxy-2-cyclopropyl-3-methoxy)-2-(4-methoxybenzyl)isoindolin-1-one (NCL-00016866)

[0787] ##STR00179##

[0788] The named compound was synthesised from 3-(4-chlorophenyl)-3-hydroxy-2-(4-methoxybenzyl)isoindolin-1-one (300 mg, 0.79 mmol) and 1,1-bis(hydroxymethyl)cyclopropane (0.12 mL, 1.58 mmol) using General Procedure C, purified by chromatography (Biotage SP4; 10%-80% EtOAc/n-hexane) and obtained as a glassy solid (181 mg, 53%).

[0789] .sup.1H NMR (500 MHz, CDCl.sub.3) 7.75-7.86 (1H, m, 7-H), 7.35-7.39 (2H, m, 5 & 6-H), 7.08 (4H, m, ArH), 6.99-7.02 (3H, m, 4 & ArH), 6.57-6.60 (2H, m, ArH), 4.45 (1H, d, J=14.8, 2-CH), 3.97 (1H, d, J=14.8, 2-CH), 3.62 (3H, s, CH.sub.3), 3.32 (1H, d, J=11.3, 1-H), 3.22 (1H, d, J=11.3, 1-H), 2.62 (1H, d, J=9.4, 3-H), 2.53 (1H, d, J=9.4, 3-H), 1.53 (1H, br s, 1-OH), 0.23-0.28 (2H, m, H.sub.2), 0.02-0.02 (2H, m, H.sub.2). .sup.13C NMR (125 MHz, CDCl.sub.3) 168.1, 158.9, 145.3, 137.2, 134.4, 132.8, 131.7, 130.5, 129.9, 129.8, 128.6, 127.9, 123.6, 122.7, 113.6, 94.9, 68.0, 67.7, 55.3, 42.5, 22.1, 8.7, 8.6. Found; 464.1619 [M +H]; C.sub.27H.sub.27NO.sub.3Cl, requires 464.1623.

3-(4-chlorophenyl)-3-(1-hydroxy-2-cyclopropyl-3-methoxy)-2-(4-carboxamidebenzyl)isoindolin-1-one (NCL-00016867)

[0790] ##STR00180##

[0791] To a solution of NCL-00010492 (200 mg, 0.436 mmol) in t-BuOH (8.48 mL) at 50 C. was added finely powdered KOH (647 mg). The resulting suspension was stirred at this temperature until TLC (10% MeOH/DCM) indicated the complete consumption of the starting material (3 h). The hot reaction mixture was filtered through Celite and the pad rinsed with several portions of THF. The filtrate was partitioned between EtOAc (10 mL) and H.sub.2O (10 mL) and the organic layer separated; the aqueous layer was extracted with EtOAc (210 mL). The combined organic layers were washed with brine (15 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue was dissolved in THF before the addition of a minimum amount of silica and the resulting suspension was concentrated in vacuo. Purification by flash column chromatography on silica gel, eluting with 2-10% MeOH in DCM afforded the title compound as a glassy solid (62 mg, 30%).

[0792] .sup.1H NMR (500 MHz, CDCl.sub.3) 7.77-7.80 (1H, m, 7-H), 7.51 (2H, d, J=8.2, ArH), 7.38-7.42 (2H, m, 5 & 6-H), 7.13-7.15 (2H, m ArH), 7.06 (4H, m, ArH), 7.00-7.02 (1H, m, 4-H), 6.11, (1H, br s, NH), 5.71 (1H, br s, NH), 4.48 (1H, d, J=15.0, 2-CH), 4.16 (1H, d, J=15.0, 2-CH), 3.31 (1H, d, J=10, 1-H), 3.25 (1H, d, J=10, 1-H), 2.62 (2H, s, 3-H.sub.2), 1.66 (1H, br s, 1-OH) 0.24-0.34 (2H, m, H.sub.2), 0.01-0.04 (2H, m, H.sub.2). .sup.13C NMR (125 MHz, CDCl.sub.3) 169.2, 168.3, 145.1, 141.5, 137.0, 134.6, 133.1, 132.3, 131.4, 130.1, 129.3, 128.7, 127.9, 127.3, 123.8, 123,0. 94.8, 67.6, 67.4, 50.8, 42.7, 22.2, 8.6.

[0793] Found; 499.1395 [M+Na]; C.sub.27H.sub.25N.sub.2O.sub.4ClNa, requires 499.1395.

Synthesis of 3-(4-chlorophenyl)-2(4-fluorobenzyl)-3-hydroxy-2,3-dihydroisoindol-1-one (AW349, NCL-0014528)

[0794] ##STR00181##

[0795] The named compound was synthesised from -(4-chlorobenzoyl)benzoic acid (2.24 g, 8.59 mmol) and 4-fluorobenzylamine (1.08 mL, 9.44 mmol) using General Procedure B, recrystillised from EtOAc/petrol, purified by chromatography (Biotage SP4; Silica; 10%-30% EtOAc/petrol) and obtained as white crystals (157 g, 50%).

[0796] .sup.1H NMR (300 MHz, CDCl.sub.3) 4.40-4.53 (dd AB, J=15.2 Hz, 2H, NCH.sub.2), 4.58 (s, 1H, OH), 6.80-6.89 (m, 2H, CC.sub.2H.sub.2C.sub.2H.sub.2C(F)), 7.14-7.29 (m, 7H, ArH), 7.50-7.60 (m, 2H, ArH), 7.80-7.86 (m, 1H, CHC(CO)). .sup.13C NMR (CDCl.sub.3, 75 MHz), 43.58, 92.63, 115.85, 116.13, 124.37, 124.52, 129.65, 129.82, 131.12, 131.91, 132.02, 134.55, 135.57, 135.70, 139.95, 151.19, 165.35, 170.25. IR: 696, 723, 766, 810, 835, 922, 1011, 1059, 1088, 1191, 1223, 12658, 1323, 1356, 1397, 1466, 1506, 1602, 1664, 2021, 2851, 2925, 3301 cm.sup.1. LCMS (DMSO): RT=3.71 min (on 5 min column), m/z=368 ES.sup.+. HPLC purity (as area %): >98. UV (in EtOH): max=254 nm. EI-MS: calculated mass of ion 368.0848 [M+H].sup.+, measured mass of ion 368.0846 [M+H].sup.+. Rf=0.49 (50% EtOAc/petrol). MP: 149-150 C.

Synthesis of 3-(4-fluorophenyl)-3-hydroxy-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (AW408/NCL-00016657)

[0797] ##STR00182##

[0798] The named compound was synthesised from 2-(4-fluorobenzoyl)-benzoic acid (2.10 g, 8.60 mmol) and 4-nitrobenzylamine hydrochloride (1.78 g, 9.46 mmol) using General Procedure B, recrystallised from EtOAc/petrol, purified by chromatography (Biotage: silica, 10%-40% EtOAc/petrol) and obtained as a yellow solid (1.01 g, 31%).

[0799] .sup.1H NMR (300 MHz, CDCl.sub.3) 4.21 (s, 1H, OH), 4.17-4.15 (dd AB, J=15.4 Hz, 2H, NCH.sub.2), 6.84-6.88 (m, 2H, ArH), 7.19-7.25 (m, 5H, ArH), 7.39-7.48 (m, 2H, ArH), 7.66-7.88 (m, 1H, CHCC(O)), 7.88-7.91 (dd AB, J=8.8 Hz, 2H, C.sub.2H.sub.2CNO.sub.2). .sup.13C NMR (CDCl.sub.3, 75 MHz), 42.20, 91.07, 115.33, 115.51, 122.85, 123.28, 123.52, 128.28, 128.35, 129.42, 129.87, 133.27, 133.78, 145.30, 146.90, 148.72, 167.92. IR: 660, 692, 697, 760, 795, 814, 849, 892, 932, 1011, 1059, 1095, 1153, 1194, 1219, 1271, 1337, 1395, 1421, 1468, 1509, 1601, 1668, 3078, 3282 cm.sup.1. LCMS (DMSO)): RT=3.18 min (on 5 min column), m/z=377 ES.sup.. HPLC purity (as area %): >95. UV (in EtOH): max=266 nm. EI-MS: calculated mass of ion 379.1089 [M+H].sup.+, measured mass of ion 379.1084 [M+H].sup.+. Rf=0.46 (50% EtOAc/petrol). MP: 183-185 C.

Synthesis of 3-(4-fluorophenyl)-3-(1-hydroxymethylcyclopropylmethoxy)-2-(4-nitrobenzyl)-2,3-dihydro-isoindol-1-one (AW413/NCL-00016896)

[0800] ##STR00183##

[0801] The named compound was synthesised from NCL-00016657 (380 mg, 1.01 mmol) and 1,1-bis(hydroxymethyl)cyclopropane (0.19 mL, 2.03 mmol) using General Procedure C, purified by chromatography (Biotage SP4; silica; 25%-50% EtOAc/petrol) and obtained as a pale yellow oil (327 mg, 70%). R.sub.f=0.29 (50:50 EtOAc:petrol). mp 57-58 C. .sub.max (CH.sub.3OH)/nm=266. IR: 711, 727, 762, 802, 818, 853, 918, 1014, 1061, 1098, 1157, 1183, 1229, 1278, 1341, 1383, 1411, 1468, 1514, 1602, 1690, 2876, 2924, 3079, 3393 cm.sup.1. .sup.1H NMR: (300 MHz, CDCl.sub.3) 0.14-0.31 (m, 2H, cyclopropane CH.sub.2), 0.43-0.51 (m, 2H, cyclopropane CH.sub.2), 2.17 (br s, 1H, OH), 2.82-2.91 (dd AB, J=9.4 Hz, 2H, CH.sub.2OC), 3.49-3.57 (dd AB, J=11.4 Hz, 2H, CH.sub.2OH), 4.48-4.62 (dd AB, J=15.2 Hz, 2H, NCH.sub.2), 6.81-6.92 (m, 2H, ArH), 7.17-7.28 (m, 3H, ArH), 7.31-7.35 (dd AB, J=8.7 Hz, 2H, CC.sub.2H2CC.sub.2H.sub.2C(NO.sub.2)), 7.52-7.60 (m, 2H, ArH), 7.90-7.96 (m, 1H, CHCC(O)), 7.98-8.02 (dd AB, J=8.7 Hz, 2H, CC.sub.2H.sub.2C.sub.2H.sub.2C(NO.sub.2)). .sup.13C NMR: (CDCl.sub.3, 75 MHz) 8.85, 8.90, 22.66, 42.63, 67.65, 67.66, 94.92, 115.50, 123.54, 124.06, 128.74, 128.85, 130.16, 130.43, 131.81, 133.45, 134.67, 145.10, 145.71, 147.61, 161.51, 168.59. LCMS (DMSO): RT=3.46 min (on 5 min column), m/z=462 ES.sup.+. HPLC purity (as area %): >99. HRMS (EI): m/z Calcd. for ion: 463.1664 [M+H].sup.+. Found: 463.1662 [M+H].sup.+.

Synthesis of 3-chloro-2-(4-chlorobenzoyl)-4-fluorobenzoic acid (AW442)

[0802] ##STR00184##

[0803] n-Butyl lithium (2.5M solution, 5.27 mL, 13.18 mmol) was added to a stirred solution of diisopropylamine (1.93 mL, 13.75 mmol) in anhydrous THF (2.5 mL) at 75 C. under a nitrogen atmosphere, and maintained at 30 C. for a further 1 h to produce lithium diisopropylamide (LDA). After re-cooling to 75 C., a solution of 3-chloro-4-fluorobenzoic acid (1 g, 5.73 mmol) in THF (20 mL) was added over 1 h, and stirring continued overnight at 75 C. under nitrogen. A solution of methyl 4-chlorobenzoate (1.95 g, 11.46 mmol) in THF (20 mL) was added over 10 min, stirring was continued at 70 C. for 2 h and then at RT for 4 h. Water (30 mL) was added and the aqueous layer was washed with ether (350 mL), acidified with 1M HCl, extracted with DCM (350 mL), dried over MgSO.sub.4 and concentrated in vacuo to afford a yellow solid. Partial purification was attempted with chromatography (Biotage, silica, 50% EtOAc/petrol to 20% MeOH/EtOAc). The crude product (0.60 g, 34%) was used in the next step without further purification. R.sub.f=0.05 (50:50 EtOAc:petrol). mp=188-190 C. .sub.max ((CH.sub.3OH)/nm=260. IR: 706, 749, 785, 843, 901, 958, 987, 1003, 1090, 1166, 1254, 1395, 1487, 1562, 1586, 1671, 1770, 2855, 2924, 3398 cm.sup.1.

[0804] .sup.1H NMR: (300 MHz, MeOD) 7.27-7.32 (dd AB, J=8.5 Hz, 2H, CC.sub.2H.sub.2C.sub.2H.sub.2C(Cl)), 7.39-7.42 (m, 1H, CHC(F)C(Cl)), 7.60-7.66 (dd AB, J=8.5 Hz, 2H, CC.sub.2H.sub.2C.sub.2H.sub.2C(Cl)), 8.17 (d, J=8.30 Hz, 1H, CHCHC(F)C(Cl), 13.60 (br s, 1H, CO.sub.2H). .sup.13C NMR (MeOD, 75 MHz), 119.90, 124.16, 132.022, 132.46, 133.89, 134.91, 135.87, 139.02, 163.04, 165,05, 197.46. LCMS (DMSO): RT=3.43 min (on 5 min column), m/z=311 ES.sup..

Synthesis of 4-chloro-3(4-chlorophenyl)-5-fluoro-3-hydroxy-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (AW448/NCL-00016897)

[0805] ##STR00185##

[0806] The named compound was synthesised from crude 3-chloro-2-(4-chlorobenzoyl)-4-fluorobenzoic acid (150 mg, 0.479 mmol) and 4-nitrobenzylamine hydrochloride (181 mg, 0.958 mmol) using General Procedure B, purified by chromatography (Biotage SP4; silica; 10-40% EtOAc/petrol), recrystallised from EtOAc/petrol and obtained as a white solid (0.04 mg, 2%). R.sub.f=0.43 (50:50 EtOAc:petrol). mp=289-291 C. .sub.max (CH.sub.3OH)/nm=265. IR: 672, 705, 738, 816, 853, 897, 959, 1012, 1090, 1148, 1204, 1256, 1345, 1401, 1423, 1516, 1585, 1676, 2859, 2974, 3210 cm.sup.1.

[0807] .sup.1H NMR: (300 MHz, CDCl.sub.3) 4.30 (br s, 1H, OH), 4.31-4.70 (dd, J=15.5 Hz, 2H, NCH.sub.2), 6.90 (dd AB, J=8.1 Hz, 2H, CC.sub.2H.sub.2C.sub.2H.sub.2C(Cl)), 7.22-7.26 (m, 2H, CC.sub.2H.sub.2C.sub.2H.sub.2C(Cl)), 7.38 (dd AB, J=8.4 Hz, 2H, CC.sub.2H.sub.2C.sub.2H.sub.2C(NO.sub.2)), 7.64 (d, J=8.0 Hz, 1H, CHC(F)C(Cl)), 7.99 (d, J=8.4 Hz, 1H, CHCHC(F)C(Cl)), 8.05 (dd AB, J=8.4 Hz, 2H, CC.sub.2H.sub.2C.sub.2H.sub.2C(NO.sub.2)). .sup.13C NMR: (CDCl.sub.3, 75 MHz) 42.73, 90.17, 123.42, 123.54, 126.35, 128.08, 128.46, 128.93, 129.38, 130.55, 131.80, 131.80, 134.71, 141.26, 144.16, 144.57, 167.99, 168.46. LCMS (DMSO): RT=4.06 (on 5 min column), m/z=445 ES.sup.. HPLC purity (as area %): >95. HRMS (EI): m/z Calcd. for ion: 445.0164 [MH]. Found: 445.0159 [MH].

Synthesis of 4-chloro-3-(4-chlorophenyl)-3-((1-hydroxymethyl)cyclopropyl)methoxy)-2-(4-nitrobenzyl)isoindolin-1-one (NU8406A/NCL-00013774 and NU8406B/NCL-00013775)

[0808] ##STR00186##

[0809] The named compound was synthesised from NU8398 (433 mg, 1.01 mmol) and 1,1-bis(hydroxymethyl)cyclopropane (0.19 mL, 2.03 mmol) using General Procedure C, purified by chromatography (Biotage SP4; silica; 20%-50% EtOAc/petrol) and obtained as yellow crystals (321 mg, 62%). R.sub.t=0.30 (50:50 EtOAc:petrol). mp 76-77 C. .sub.max (CH.sub.3OH)/nm=267. IR: 696, 759, 816, 853, 930, 1011, 1074, 1144, 1171, 1234, 1341, 1384, 1428, 1462, 1489, 1519, 1699, 2872, 2923, 3422 cm.sup.1.

[0810] .sup.1H NMR: (300 MHz, CDCl.sub.3) 0.21-0.42 (m, 2H, cyclopropane CH.sub.2), 0.47-0.54 (m, 2H, cyclopropane CH.sub.2), 2.12 (br s, 1H, OH), 2.89-3.05 (m, 2H, COCH.sub.2), 3.52-3.61 (m, 2H, CH.sub.2OH), 4.30-4.59 (dd, AB, J=15.2 Hz, NCH.sub.2),7.15-7.18 (m, 4H, ArH), 7.28-7.33 (m, 2H, ArH), 7.48-7.58 (m, 2H, ArH), 7.87-7.89 (dd, J=7.1, 1.1 Hz, 1H, C(O)CCH), 7.98-8.01 (m, 2H, CHNO.sub.2). .sup.13C NMR: (CDCl.sub.3, 75 MHz) 8.84, 8.90, 22.59, 42.54, 67.58, 68.10, 94.71, 122.63, 123.56, 128.65, 128.77, 130.09, 130.40, 132.28, 134.37, 135.27, 135.55, 135.57, 141.10, 144.62, 147.64, 167.04. HPLC purity (as area %): >92. HRMS (EI): m/z Calcd. for ion: 530.1244 [M+NH.sub.4].sup.+. Found: 530.1242 [M+NH.sub.4].sup.+. Anal. Calcd. for C.sub.26H.sub.22Cl.sub.2N.sub.2O.sub.5: C, 60.83; H, 4.32; N, 5.46%. Found: C, 60.68; H, 4.30; N, 5.40%.

[0811] Separation of enantiomers was achieved by chiral preparative HPLC (Diacel Chiralpak AD-H 25010 mm; Hexane/Ethanol (4:1))

[0812] NU8406A/NCL00013774 (White Crystals)

[0813] Optical rotation: Specific rotation []=4.98 (at 22.4 C., wavelength=589 nm, tube length=0.25 dm, concentration=0.402 g/100 mL).

[0814] NU8406B/NCL-00013775 (White Crystals)

[0815] Optical Rotation: Specific rotation []+4.85 C. (at 22.6 C., wavelength=589 nm, tube length=0.25 dm, concentration=0.412 g/100 mL).

Synthesis of 3-(4-chlorophenyl)-3-(2-hydroxymethylallyloxy)-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (AW468/NCL-00016895)

[0816] ##STR00187##

[0817] The named compound was synthesised from NU8260 (400 mg, 1.01 mmol) and 2-methylene-1,3-propanediol (0.17 mL, 2.03 mmol) using General Procedure C, purified by chromatography (Biotage SP4; 10%-40% EtOAc/petrol) and obtained as a yellow oil (342 mg, 73%). R.sub.f=0.24 (50:50 EtOAc:petrol). .sub.max (CH.sub.3OH)/nm 268. IR: 702, 764, 808, 853, 922, 969, 1011, 1058, 1092, 1177, 1278, 1341, 1381, 1425, 1466, 1489, 1519, 1603, 1689, 2859, 2922, 3080, 3407 cm .sup.1.

[0818] .sup.1H NMR (300 MHz, CDCl.sub.3) 2.46 (br s, 1H, OH), 3.20-3.40 (dd, J=11.9 Hz, 2H, iso-OCH.sub.2), 4.00 (s, 2H, CH.sub.2OH), 4.31-4.61 (dd, J=15.1 Hz, 2H, NCH.sub.2), 4.88 (s, 1H, CCH), 5.04 (s, 1H, CCH), 7.12-7.15 (m, 1H, ArH), 7.15-7.21 (dd AB, J=8.7 Hz, 4H, C.sub.6H.sub.4Cl), 7.33-7.36 (dd AB, J=8.7 Hz, 2H)), 7.49-7.53 (m, 2H, ArH), 7.87-7.91 (m, 1H, ArH), 7.95-7.98 (dd AB, 2H, CC.sub.2H.sub.2C.sub.2H.sub.2C(NO.sub.2)). .sup.13C NMR (CDCl.sub.3, 75 MHz), 42.37, 63.63, 63.73, 94.80, 112.29, 123.27, 123.34, 123.86, 127.92, 128.69, 130.00, 130.29, 131.10, 133.23, 134.78, 136.74, 144.17, 144.57, 144.73, 147.03, 168.32. LCMS (DMSO): Rt=3.74 min (on 5 min column), m/z=465 (ES.sup.+). HPLC purity (as area %): >98. HRMS (EI): m/z Calcd. for ion: 464.113900 [M].sup.+. Found: 464.115410 [M].sup.+.

[0819] It is, of course, to be understood that the invention is not intended to be restricted to the details of the above embodiments which are described by way of example only.

REFERENCES

[0820] 1. Lane, D. P. Nature 1992, 358, 15-16. [0821] 2. Vousden, K. H.; Lu. X. Nat. Rev. Cancer 2002, 2, 594-604. [0822] 3. Momand, J.; Zambetti G. P.; Olson, D. C.; George, D.; Levine, A. Cell 1992, 69, 1237-1245.