FSH receptor antagonists

Abstract

The invention relates to FSH receptor antagonist according to general formula I ##STR00001##
or a pharmaceutically acceptable salt thereof and to a pharmaceutical composition containing the same. The compounds can be used for the treatment and prevention of endometriosis, for the treatment and prevention of pre-menopausal and peri-menopausal hormone-dependent breast cancer, for contraception, and for the treatment of uterine fibroids and other menstrual-related disorders.

Claims

1. A compound according to Formula I ##STR00055## or a pharmaceutically acceptable salt thereof, wherein X is C(R10) or N; Y is N; R3 is phenyl, (2-8C)heteroaryl, benzoyl, (2-8C)heteroarylcarbonyl, the phenyl or heteroaryl moieties of which may optionally be substituted with one or more substituents selected from R11, or R3 is (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-6C)cycloalkyl, (1-6C)alkylcarbonyl, (2-6C)alkenylcarbonyl, (2-6C)alkynylcarbonyl or (3-6C)cycloalkylcarbonyl; R7 and R8 are independently H or (1-4C)alkoxy; R9 is hydroxy or H, or R9 is (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-4C)alkoxy, (2-4C)alkenoxy, (3-6C)cycloalkyl, (3-6)cycloalkoxy, (3-6C)cycloalkyl(1-4C)alkoxy, (2-6C)heterocycloalkylcarbonyl, (di)[1-4C]alkylaminocarbonyl, (2-6C)heterocycloalkyl, the alkyl or (hetero)cycloalkyl moieties of which may optionally be substituted with one or more substituents selected from R12 or, R9 is (2-8C)heteroaryl, phenyl, phenyl(1-4C)alkoxy, (2-8C)heteroaryl(1-4C)alkoxy, the phenyl or heteroaryl moieties of which may optionally be substituted with one or more substituents selected from R16; R10 is H or (1-4C)alkoxy; R11 is hydroxy, amino, halogen, nitro, trifluoromethyl, cyano, (1-4C)alkyl, (1-4C)alkoxy or (di)[1-4C)alkyl]amino; R12 is hydroxy, amino, halogen, cyano, (1-4C)alkoxy or (di)[1-4C)alkyl]amino; R13 and R14 are independently H or (1-3C)alkyl; R15 is H, (1-3C)alkyl, or R14 and R15 may be joined in a (3-6C)cycloalkyl ring; and R16 is hydroxy, amino, halogen, nitro, trifluoromethyl, cyano, (1-4C)alkyl, (1-4C)alkoxy or (di)[1-4C)alkyl]amino.

2. The compound according to claim 1 wherein R8 is (1-4C)alkoxy; and R9 is hydroxy or R9 is (1-6C)alkyl, (2-6C)alkenyl, (1-4C)alkoxy, (2-4C)alkenoxy, (3-6)cycloalkoxy, (3-6C)cycloalkyl(1-4C)alkoxy, (2-6C)heterocycloalkylcarbonyl, (di)[1-4C]alkylaminocarbonyl, the alkyl or (hetero)cycloalkyl moieties of which may optionally be substituted with one or more substituents selected from R12 or, R9 is (2-8C)heteroaryl, phenyl(1-4C)alkoxy, the phenyl or heteroaryl moieties of which may optionally be substituted with one or more substituents selected from R16; or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2 wherein R13, R14 and R15 are H; or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 3 wherein R9 is (1-6C)alkyl, (1-4C)alkoxy or (3-6C)cycloalkyl(1-4C)alkoxy, the alkyl moieties of which may optionally be substituted with one or more substituents selected from R12; or R9 is (2-8C)heteroaryl or phenyl(1-4C)alkoxy, the phenyl or heteroaryl moieties of which may optionally be substituted with one or more substituents selected from R16; or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 4 wherein R3 is phenyl, (2-8C)-heteroaryl, benzoyl, (2-8C)heteroarylcarbonyl, the phenyl or heteroaryl moieties of which may optionally be substituted with one or more substituents selected from R11, or R3 is (1-6C)alkyl, (2-6C)alkenyl, (1-6C)alkylcarbonyl or (3-6C)cycloalkylcarbonyl; or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 5 wherein R3 is phenyl or (2-8C)heteroaryl, both optionally substituted with one or more substituents selected from R11 or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 6 wherein X is C(R10); or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1 selected from the group of: (R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-5,6-dihydroimidazo[2,1-a]isoquinoline-2-carboxamide; 3-(2-fluorophenyl)-N((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-5,6-dihydroimidazo[2,1-a]isoquinoline-2-carboxamide; N((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-3-(2-methoxyphenyl)-5,6-dihydroimidazo[2,1-a]isoquinoline-2-carboxamide; N((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-3-(2-methoxypyridin-3-yl)-5,6-dihydroimidazo[2,1-a]isoquinoline-2-carboxamide; N((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-3-(2-methoxyphenyl)-5,6-dihydroimidazo[1,2-h][1,7]naphthyridine-2-carboxamide; or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition which comprises a compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

10. A pharmaceutical composition according to claim 9, which further comprises at least one additional therapeutically active agent.

11. A method of treating endometriosis, pre-menopausal and peri-menopausal hormone-dependent breast cancer, uterine fibroids, or dysfunctional uterine bleeding, comprising administering a compound according to claim 1.

12. A method of contraception comprising administering a compound according to claim 1.

Description

LEGENDS TO THE FIGURES

(1) FIG. 1

(2) Estradiol (E2) concentration (in ng/mL) in culture supernatant of human granulosa cells, after 48 h incubation with recFSH or with test compound of example 5 in combination with 250 mU/ml recFSH in culture medium with IBMX, followed by 2 h incubation with 10 M testosterone in culture medium without IBMX (n=3; means.e.m.).

(3) The invention is illustrated by the following examples.

EXAMPLES

(4) General Comments

(5) The following abbreviations are used in the examples: DCM=dichloromethane, DMF=N,N-dimethylformamide, HCl=hydrogen chloride, NaHCO.sub.3=sodium bicarbonate, MgSO.sub.4=magnesium sulphate, THF=tetrahydrofuran, Na.sub.2SO.sub.4=sodium sulphate, DME=dimethoxyethane, LC-MS=liquid chromatography-mass spectrometry, HPLC=high-performance liquid chromatography, MeCN=acetonitrile, Pd/C=palladium on carbon, HATU=2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate, DIPEA=N,N-Diisopropylethylamine, DMSO=dimethylsulfoxide, H.sub.2=hydrogen, HBr=hydrogen bromide, NH.sub.4Cl=ammonium chloride, N.sub.2=nitrogen, TBTU=N,N,N,N-tetramethyl-O-(benzotriazol-1-YL)uronium tetrafluoroborate, KCN=potassium cyanide, (NH.sub.4).sub.2CO.sub.2, =ammonium bicarbonate, DCE=1,1-dichloroethane, Na.sub.2CO.sub.3=sodium carbonate, (BOC).sub.2O=Di-tert-butyl dicarbonate.

(6) The names of the final products described in the examples were generated using the convert name to structure tool in ChemDraw version 9.01.

(7) ##STR00020##

Example 1

(R)N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-1-methyl-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(a). N-(3,4-dimethoxyphenethyl)propionamide

(8) To a solution of 3,4 methoxyphenethylamine (10 g) in DCM (100 ml) were added under a nitrogen atmosphere at 00 C. DIPEA (13.5 ml) and propionylcloride (5.7 ml) dropwise over a period of 10 minutes. The reaction mixture was stirred for 1 hour. The reaction mixture was diluted with DCM and sequentially washed with a aqueous 0.2M HCl solution, a aqueous saturated NaHCO.sub.3 solution, water and brine. The organic layer was dried over MgSO.sub.4, filtered and the solvents were removed under vacuum.

(9) Yield: 13.03 g

(10) MS (ESI) m/z: 238 (M+H).sup.+.

(b). 1-ethyl-6,7-dimethoxy-3,4-dihydroisoquinoline

(11) To a solution of compound 1a (12 g) in toluene (65 ml) was added dropwise phosphorus oxychloride (12 ml) under nitrogen atmosphere at 95 C., over a period of 1 hour. The mixture was heated at 120 C. for 2 hours and allowed to cool to room temperature overnight. The resulting HCl salt was collected by filtration and washed with diethylether to give the product as a brown solid

(12) Yield: 15.48 g

(c). ethyl 8,9-dimethoxy-1-methyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

(13) To a solution of compound 1b (15.5 g) and potassium carbonate (16.5 g) in acetonitrile (100 ml) was added dropwise ethyl bromopyruvate (7.6 ml). The reaction mixture was heated at 100 C. for 1 hour. The reaction mixture was filtered and concentrated. The residue was dissolved in ethyl acetate, washed with water, dried over MgSO.sub.4, filtered and concentrated to a brown solid. The residue was purified by chromatography on silica gel eluting with hexane and increasing amounts of ethyl acetate. The pure fractions were collected and concentrated to a yellow solid.

(14) Yield: 7.51 g

(d). ethyl 8,9-dimethoxy-1-methyl-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

(15) Compound 1c (205 mg), phenylbromide (78 ul), triphenylphospine (34 mg) and cesium carbonate (459 mg) were suspended in degassed dioxane (4 ml). The mixture was further degassed for 10 minutes. Palladium (II) acetate (15 mg) was added and the reaction mixture was degassed for 5 minutes and heated at 100 C. for 18 hours. The reaction was not complete. The reaction was degassed and recharged with triphenylphospine (34 mg, 0.13 mmol) and palladium (II) acetate (15 mg). The reaction mixture was heated for another 18 hours. The reaction mixture was diluted with ethyl acetate and water and filtered through celite. The organic phase was dried (MgSO.sub.4), filtered and concentrated to a brown oil. The residue was purified by chromatography on silica gel eluting with hexane and increasing amounts of ethyl acetate. The pure fractions were collected and concentrated to a yellow solid.

(16) Yield: 136 mg

(17) MS (ESI) m/z: 392 (M+H).sup.+.

(18) .sup.1H NMR (ppm) (CHCl.sub.3-d): 7.43-7.38 (3H, m), 7.36-7.32 (2H, m), 7.26 (1H, s, under CHC.sub.3 shift), 6.75 (1H, s), 4.06 (2H, 1, J=7.13 Hz), 3.95 (3H, s), 3.90 (3H, s), 3.78 (2H, t, J=6.27 Hz), 2.85 (2H, t, J=628 Hz), 2.67 (3H, s), 1.01 (3H, t, J=7.12 Hz)

(e). 8,9-dimethoxy-1-methyl-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylic Acid

(19) To a suspension of compound 1d (135 mg) in ethanol (3.5 ml) was added a aqueous solution of 2M sodium hydroxide (1.7 ml). The reaction mixture was heated at 65 C. for 2 nights. The reaction mixture was concentrated and extracted with ethyl acetate and a aqueous 1M HCl solution. The organic phase was dried (MgSO.sub.4) and concentrated in vacuo.

(20) Yield: 120 mg (mixture of starting material and product).

(f). (R)N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-1-methyl-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(21) 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (98 mg), 1-hydroxybenzotriazole (69 mg), DIPEA (0.178 ml) and D-tryptophanol (78 mg) were added to a solution of intermediate 1e (124 mg) in DMF (4 ml). The reaction mixture was stirred for 18 hours at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed sequentially with a aqueous 1M HCl solution, a saturated aqueous NaHCO.sub.3 solution and brine. The reaction mixture was dried (MgSO.sub.4), filtered and concentrated to a pale brown oil. The residue was purified by chromatography on silica gel eluting with DCM and increasing amounts of diethylether and methanol. The pure fractions were collected and concentrated in vacuo. The residue was purified by preparative HPLC eluting with acetonitrile and water.

(22) Yield: 16.5 mg.

(23) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.06 (1H, s), 7.55-7.74 (2H, m), 7.42-7.24 (9H, m), 7.17 (1H, t, J=7.59 Hz), 7.08 (1H, t, J=7.5 Hz), 6.78 (1H, d, J=2.32 Hz), 6.74 (1H, s), 5.44 (1H, d, J=7.18 Hz), 4.32-4.23 (1H, m), 3.94 (3H, s), 3.90 (3H, s), 3.844-3.73 (2H, m), 3.55 (1H, d, J=10.60 Hz), 3.45 (1H, s), 2.86 (3H, t, J=6.56 Hz), 2.78-2.55 (5H, m).

(24) ##STR00021##

Example 2

N-(1-hydroxy-3-(1H-indol-3-yl)-2-methylpropan-2-yl)-8,9-dimethoxy-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(a). ethyl 9-hydroxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

(25) To a solution of 1-methyl-7-hydroxy-6-methoxy-3,4-dihydroisoquinoline (100 mg) in EtOH (5 ml) was added dropwise under a nitrogen atmosphere ethylbromopyruvate (0.065 ml) and the reaction mixture was heated under reflux for 2 hours. The reaction mixture was allowed to cool to ambient temperature, quenched with a saturated aqueous NaHCO.sub.3 solution and extracted with ethyl acetate. The organic layer was dried (MgSO.sub.4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with heptane and increasing amounts of ethyl acetate.

(26) Yield: 82 mg

(b). ethyl 9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

(27) To a solution of compound 2a (561 mg) in DMF (10 ml) were added potassium carbonate (810 mg) followed by 2-bromopropane (0.36 ml). The reaction mixture was stirred at 65 C. overnight. The reaction mixture was allowed to cool to ambient temperature, quenched with a saturated aqueous NaHCO.sub.3 solution and extracted with ethyl acetate. The organic layer was dried (MgSO.sub.4) and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with heptane and increasing amounts of ethyl acetate.

(28) Yield: 445 mg

(29) MS (ESI) m/z: 330 (M+H).sup.+.

(c). ethyl 3-(3-fluorophenyl)-9-isopropoxy-8-methoxy-5,6-dihydropyrolo[2,1-a]isoquinoline-2-carboxylate

(30) Four identical solutions of intermediate 2b (1.0 g), 3-fluoroiodobenzene (423 l), triphenylphosphine (157 mg) and cesium carbonate (1.95 g) in dioxane (20 ml) were degassed by bubbling through a gentle stream of nitrogen for 30 minutes. Palladium acetate (67 mg) was added to each reaction tube and the mixtures were degassed for a further 15 minutes before being sealed under nitrogen and heated to 110 C. for 6 hours. LC-MS indicated the reaction was approximately 50% complete, hence the mixtures were degassed with nitrogen for 20 minutes and a further aliquot of the 3-fluoroiodobenzene (211 l), palladium acetate (34 mg) and triphenylphospine (79 mg) were added to each. The mixtures were degassed for a further 15 minutes before being sealed under nitrogen and heated for 16 hours at 110 C. LC-MS indicated the reactions were all approximately 65% complete hence they were combined and filtered through a pad of celite and washed with dioxane and ethyl acetate. Ethyl acetate was added to the solution and washed with water (3). The organic layer was passed through a hydrophobic frit and the solvent removed under vacuum. The residue was purified by chromatography on silica gel eluting with petrol and increasing amounts of ethyl acetate. The target fractions were combined and dried under vacuum to give a solid that was triturated with diethyl ether to give the product, as an off-white solid

(31) Yield: 3.34 g

(32) MS (ESI) m/z: 424 (M+H).sup.+.

(33) .sup.1H NMR (ppm) (CHCl.sub.3-d): 7.44-7.37 (1H, m), 7.18 (1H, dd, J=7.7, 1.0 Hz), 7.14-7.08 (3H, m), 6.90 (1H, s), 6.71 (1H, s), 4.62-4.54 (1H, m), 4.16 (2H, q, J=7.1 Hz), 3.89-3.83 (5H, m), 2.93 (2H, t, J=6.5 Hz), 1.41 (6H, d, J=6.1 Hz), 1.18 (3H, t, J=7.1 Hz).

(d). 3-(3-fluorophenyl)-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylic Acid

(34) To a solution of compound 2c (0.5 g) in ethanol (12 ml) was added a 2M aqueous sodium hydroxide solution (6 ml). The reaction mixture was heated to 70 C. and stirred for 18 hours. The solvents were removed under vacuum. The solid was suspended in ethyl acetate and acidified with a aqueous 2M HCl solution to pH 1. The phases were separated and the aqueous phase was re-extracted with ethyl acetate twice. The combined organic layers were washed with water and brine, before drying over MgSO.sub.4. The solvents were removed under vacuum to yield a pale brown solid.

(35) Yield: 0.45 g

(e). 2-amino-3-(1H-indol-3-yl)-2-methylpropan-1-ol

(36) To a solution of alpha-methyl-DL-tryptophan (100 mg) in dry THF (10 ml) was added a borane-tetrahydrofuran complex (1.14 ml) dropwise. The reaction mixture was heated at 65 C. for 4.5 hours. The reaction mixture was quenched with ethanol (3 ml). The reaction mixture was concentrated and extracted with ethyl acetate and water. The organic layer was dried (MgSO.sub.4), filtered and concentrated in vacuo. The residue was purified by preparative HPLC eluting with acetonitrile and water. The pure fractions were collected and freeze dried.

(37) Yield: 33.7 mg

(f). tert-butyl 3-(cyanomethyl)-1H-indole-1-carboxylate

(38) 3-indoleacetonitrile (50 g), di-tert-butyl dicarbonate (76.8 g) and 4-dimethylaminopyridine (1.96 g) were added to DCM (200 ml). The mixture was stirred at room temperature overnight. The solution was washed with brine and water and then dried (Na.sub.2SO.sub.4). The organic layer was concentrated and the residue was purified by chromatography on silica gel eluting with heptane and increasing amounts of ethyl acetate.

(39) Yield: 68 g

(g). 1-(1H-indol-3-yl)cyclopropanecarbonitrile

(40) Sodium hydride (4 equiv) was suspended in DMSO (6 ml/g). The mixture was heated to 70-75 C. for 30 minutes. The mixture was allowed to cool to room temperature before adding it in portions to a cooled suspension of compound 1f (1 equiv) and dibromo alkane (1 equiv) in diethylether (2.5 volume of DMSO) at 0 C. If the temperature rises above 5 C. a by-product is formed. The mixture was allowed to warm to room temperature and was stirred overnight to complete cyclisation. The suspension was diluted with water and acidified with a aqueous 2N HCl solution. The mixture was extracted with ethyl acetate twice and the organic layers were dried (Na.sub.2SO.sub.4). The organic layer was concentrated before dissolving in dioxane. To the solution 4N HCl in dioxane was added (5 equiv) and was stirred overnight at room temperature. The crude mixture was diluted with water and basified with a aqueous 2N sodium hydroxide solution. The aqueous layer was extracted with ethyl acetate (2), dried (Na.sub.2SO.sub.4) and filtered. The organic layers were concentrated and the crude residue was used as such in the next step.

(h). 1-(1H-indol-3-yl)cyclopropanecarbaldehyde

(41) Compound 2g crude was dissolved in toluene. The solution was cooled to 45 C. and DIBAL-H (1.5-2.0 equiv) was added dropwise. The mixture was allowed to warm to 0 C. and this was stirred for 1 hour at 0 C. The mixture was quenched with a mixture of diethylether and a saturated aqueous NH.sub.4Cl solution (1:1) and subsequently with a aqueous 1.6 N HCl solution (in 1:1 or 1:1.5 ratio to the Ether mixture). A thick suspension was formed and the suspension was vigorously stirred at room temperature overnight. The mixture was diluted with water and basified with a aqueous 2N sodium hydroxide solution. The aqueous layer was extracted with ethyl acetate and the organic layer was dried (Na.sub.2SO.sub.4) and filtered. The organic layer was concentrated and used as such in the next step.

(i). 5-(1-(1H-indol-3-yl)cyclopropyl)imidazolidine-2,4-dione

(42) Compound 2h (1 equiv) was suspended in ethanol/water (1:1). To the solution KCN (1.5 equiv) and (NH.sub.4).sub.2CO.sub.2 (3.0 equiv) were added and the mixture was poured into a pressure tube. The mixture was heated to 80 C. in an oil bath for 6 hours. The mixture was allowed to cool to room temperature overnight. The mixture was diluted with water and acidified with a aqueous 2N HCl solution. The aqueous layer was extracted with ethyl acetate and diethylether. The organic layers were dried (Na.sub.2SO.sub.4), filtered and concentrated. The residue was purified by chromatography on silica gel eluting with heptane and increasing amounts of ethyl acetate. The product sticks on the column so rinsing with ethyl acetate or methanol was needed.

(43) Yield: 3 g

(j). 2-(1-(1H-indol-3-yl)cyclopropyl)-2-aminoacetic Acid

(44) Compound 2j (1 equiv) and barium hydroxide (4 equiv) were suspended in water/dioxane (1:1) and poured into a microwave tube. The mixture was heated to 170 C. (external temperature of heating mantel) for minimum of 2 days. The mixture was filtrated and washed with water. The layers were separated and the aqueous layer was concentrated. The solid was washed with DCM and dried under vacuum (50 C.).

(45) crude 1.55 g

(k). 2-(1-(1H-indol-3-yl)cyclopropyl)-2-aminoethanol

(46) Compound 2j (1 eq.) was dissolved in THF and cooled to 0 C. To the solution a suspension of lithium aluminium hydride (6 equiv) in THF was added in portions. The mixture was allowed to warm to room temperature and stirred for 30 minutes before heating it to reflux for 6 hours. The mixture was stirred overnight at room temperature. This was cooled to 0 C. and subsequently water and a aqueous 2N sodium hydroxide solution were added (1:2:1 ratio). The mixture was stirred for 30 min. allowing it to rise to room temperature. The mixture was filtered over celite and rinsed with diethylether. The mixture was dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo.

(47) Yield: 365 mg

(l). N-(1-hydroxy-3-(1H-indol-3-yl)-2-methylpropan-2-yl)-8,9-dimethoxy-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(48) 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (58.2 mg), 1-hydroxybenzotriazole (28.7 mg), triethylamine (0.084 ml) and 2e (762 mg) were added to a solution of intermediate 2d (124 mg) in DMF (4 ml). The reaction mixture was stirred for 18 hours at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed sequentially with a aqueous 1M HCl solution, a saturated aqueous NaHCO.sub.3 solution and brine. The reaction mixture was dried (MgSO.sub.4), filtered and concentrated to a pale brown oil. The residue was purified by preparative HPLC eluting with acetonitrile and water.

(49) Yield: 74 mg.

(50) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.10 (1H, s), 7.77 (1H, d, J=8.19 Hz), 7.39 (1H, d, J=8.13 Hz), 7.29-7.16 (6H, m), 7.13-6.92 (5H, m), 6.80 (1H, d, J=2.48 Hz), 6.72 (2H, d, J=12.30 Hz), 5.63 (1H, d, J=9.32 Hz), 4.61-4.54 (1H, m), 4.40 (1H, td, J=8.65, 3.51 Hz), 3.87-3.72 (5H, m), 3.25 (1H, t, J=9.55 Hz), 2.92 (2H, t, J=6.54 Hz), 2.43-2.25 (2H, m), 1.64 (1H, t, J=12.86), 1.55 (7H, s), 1.46-1.35 (7H, m), 1.37-1.22 (3H, m)

Example 3

N-(1-(1-(1H-indol-3-yl)cyclopropyl)-2-hydroxyethyl)-8,9-dimethoxy-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(51) Compound 3 was prepared in an analogous fashion as described for example 2, with compound 2k as reagent.

(52) Yield: 27.6 mg.

(53) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.00 (1H, s), 7.71 (1H, d, J=7.91 Hz), 7.37 (1H, d, J=8.09 Hz), 7.29-7.16 (5H, m), 7.16-6.98 (5H, m), 6.77 (1H, d, J=2.44 Hz), 6.71 (2H, d, J=3.87 Hz), 5.91 (1H, d, J=8.00 Hz), 4.61-4.54 (1H, m), 3.92-3.77 (5H, m), 3.72 (1H, td, J=7.87, 3.96), 3.54-3.47 (1H, m), 2.92 (2H, t, J=6.51 Hz), 2.67-2.61 (1H, m), 1.42 (6H, dd, J=8.67, 6.07), 0.95-0.89 (2H, m), 0.85 (1H, dd, J=9.10, 2.61 Hz), 0.73 (1H, dd, J=8.99, 2.77 Hz)

(54) ##STR00022##

Example 4

(R)-3-(3,5-dimethylphenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(a). methyl 3-(3,5-dimethylphenyl)-8,9-dimethoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

(55) A mixture of 6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline-1-carboxylic acid (3.52) and 3,5-dimethylbenzoylchloride (3.25 g) in THF (3 ml) with molecular sieves was heated in the microwave for 5 minutes at 150 C. The molecular sieves were filtered and acetic anhydride (4.55 g) and methylpropiolate (1.38 g) were added. The mixture was stirred in the microwave for 5 minutes at 150 C. The reaction mixture was diluted with ethyl acetate and extracted sequentially with a aqueous 1M HCl solution, water and brine. The organic layer was dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with heptane and increasing amounts of ethyl acetate.

(56) Yield: 1.7 g mixture of regioisomers 2:8

(57) MS (ESI) m/z: 392 (M+H).sup.+.

(b). 3-(3,5-dimethylphenyl)-8,9-dimethoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylic Acid

(58) A suspension of compound 4a (1.2 g) in a aqueous 3M lithium hydroxide solution (3 ml) and dioxane (1 ml) was heated for 5 minutes in the microwave at 180 C. The reaction mixture was acidified with a aqueous 2N HCl solution to pH=2 and the precipitate was filtered.

(59) Yield: 1.0 g mixture of regioisomers 2:8

(60) MS (ESI) m/z: 378 (M+H).sup.+.

(c). (R)-3-(3,5-dimethylphenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(61) 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (360 mg), 1-hydroxybenzotriazole (127 mg), DIPEA (0.46 ml) and D-tryptophanol (357 mg) were added to a solution of intermediate 4b (254 mg) in DMF (15 ml). The reaction mixture was stirred for 18 hours at ambient temperature. The reaction mixture was quenched with a saturated aqueous NaHCO.sub.3 solution and extracted with ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with water (twice) and brine, dried (MgSO.sub.4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with heptane and increasing amounts of ethyl acetate. The pure fractions were collected and concentrated in vacuo. The residue was purified by preparative HPLC eluting with acetonitrile and water. The pure fractions were freeze dried.

(62) Yield: 99.2 mg

(63) MS (ESI) m/z: 550 (M+H).sup.+.

(64) ##STR00023##

Example 5

(R)N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(a). ethyl 8,9-dimethoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

(65) To a mixture of 1-methyl-6,7-dimethoxy-3,4-dihydroisoquinoline (2 g) and potassium carbonate (2.4 g) in ethanol (50 ml) was added dropwise ethylbromopyruvate (1.22 ml). The reaction mixture was refluxed for 3 hrs. The reaction was allowed to cool to ambient temperature before a saturated aqueous NaHCO.sub.3 solution was added. The aqueous phase was extracted with ethyl acetate twice. The combined organic layers were washed with brine. The organic layer was dried (MgSO.sub.4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with heptane and increasing amounts of ethyl acetate.

(66) Yield: 2.1 g

(67) MS (ESI) m/z: 302 (M+H).sup.+.

(b). ethyl 3-bromo-8,9-dimethoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

(68) A solution of N-bromosuccinimide (0.91 g) in DCM (50 ml) was added dropwise over a period of 45 minutes to a solution of intermediate 5a (1.88 g) in DCM (50 ml). The reaction mixture was stirred for 2 hours before quenching with a saturated aqueous NaHCO.sub.3 solution. The aqueous phase was extracted with DCM twice and the combined organics layers were washed with water and brine, dried (MgSO.sub.4) and filtered. The solvents were removed under vacuum to yield a crude solid that was purified by chromatography on silica gel eluting with petrol and increasing amounts of ethyl acetate to give the product, as an off white solid

(69) Yield: 1.36 g

(70) .sup.1H NMR (ppm) (CHCl.sub.3-d): 7.06 (1H, s), 6.86 (1H, s), 6.71 (1H, s), 4.60-4.50 (1H, m), 4.33 (2H, q, J=7.12 Hz), 4.16-4.07 (2H, m), 3.87 (3H, s), 3.01 (2H, t, J=6.64 Hz), 1.41-1.36 (9H, m)

(c). ethyl 8,9-dimethoxy-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

(71) Tetrakis(triphenylphosphine)palladium(0) (975 mg) was added to a degassed solution of intermediate 5b (60 mg), phenylboronic acid (625 mg) and potassium carbonate (1.063 g) in a 10:1 mixture of DME:water (30 ml). The mixture was degassed by gently bubbling through nitrogen for a further 5 minutes before sealing under nitrogen and then heating to 90 C. for 3 hours. The reaction was allowed to cool to ambient temperature before a saturated aqueous NaHCO.sub.3 solution was added. The aqueous phase was extracted with ethyl acetate twice. The combined organic layers were washed with brine. The organic layer was dried (MgSO.sub.4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with heptane and increasing amounts of ethyl acetate.

(72) Yield: 990 mg

(73) MS (ESI) m/z: 378 (M+H).sup.+.

(d). 8,9-dimethoxy-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylic Acid

(74) A aqueous 2M sodium hydroxide solution (2 ml) was added to a solution of intermediate 5c (129 mg) in ethanol (5 ml). The mixture was heated to 60 C. for 6 hours. The reaction was allowed to cool to ambient temperature before a aqueous 2M HCl solution (3.1 ml) was added. The mixture was extracted with ethyl acetate and water. The organic layer was washed with brine. The organic layer was dried (MgSO.sub.4), filtered and concentrated in vacuo.

(75) Yield: 116 mg

(76) MS (ESI) m/z: 350 (M+H).sup.+.

(e). (R)N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(77) 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (226 mg), 1-hydroxybenzotriazole (160 mg), DIPEA (0.39 ml) and D-tryptophanol (299 mg) were added to a solution of intermediate 5d (275 mg) in DMF (15 ml). The reaction mixture was stirred for 18 hours at ambient temperature. The reaction mixture was quenched with a saturated aqueous NaHCO.sub.3 solution and extracted with ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with water twice and brine. The organic layer was dried (MgSO.sub.4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with heptane and increasing amounts of ethyl acetate.

(78) Yield: 293.6 mg

(79) MS (ESI) m/z: 522 (M+H).sup.+.

(80) ##STR00024##

Example 6

(R)N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-3-(4-fluorophenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(a). 8,9-dimethoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylic Acid

(81) A aqueous 2M sodium hydroxide (50 ml) was added to a solution of intermediate 5a (3.01 g) in ethanol (100 ml). The mixture was heated to 65 C. for 18 hours. The solvents were removed under vacuum and the crude residue was suspended in ethyl acetate before acidifying to pH 2 with a aqueous 2M HCl solution. A white precipitate was removed by filtration and dried under vacuum (908 mg). The aqueous phase was re-extracted with ethyl acetate. The combined organic layers were washed with water (25 ml), dried (MgSO.sub.4) and filtered. The solvents were removed under vacuum to give a grey solid. The two solids were combined to give the product, as an off white solid that was used without further purification.

(82) Yield: 2.3 g

(b). (R)-1-(tert-butyldimethylsilyloxy)-3-(1H-indol-3-yl)propan-2-amine

(83) To a solution of D-Tryptophanol (1.024 g) and imidazole (403 mg) in DCM (40 ml) and THF (8 ml) was added a solution of tert-butyldimethylsilyl chloride (0.852 g) in DCM (5 ml) dropwise. The reaction was allowed to warm to room temperature overnight. The reaction mixture was quenched with a saturated aqueous NaHCO.sub.3 solution and the reaction mixture was extracted with dichloromethane. The aqueous phase was washed with dichloromethane and the combined organic layers were washed with brine, dried (MgSO.sub.4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with heptane and increasing amounts of ethyl acetate.

(84) Yield: 1.11 g.

(85) MS (ESI) m/z: 305 (M+H).sup.+.

(c). (R)N-(1-(tert-butyldimethylsilyloxy)-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(86) Compound 6b (2.34 g) was added to a solution of intermediate 6a (1.91 g) in DMF (75 ml). 1-Hydroxybenzotriazole (1.42 g), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (2.01 g) and diisopropylethylamine (3.66 ml) were added to the reaction mixture and the reaction mixture was stirred at ambient temperature for 72 hours. The reaction mixture was dissolved in ethyl acetate and washed with water (3). A precipitate was removed by filtration and determined to be pure product by HPLC (1.90 g). The aqueous phase was re-extracted with ethyl acetate (3) and the combined organic layers were washed with water and a saturated aqueous NaHCO.sub.3 solution, dried (MgSO.sub.4) and filtered. The solvents were removed under vacuum to give a pale brown solid. The two collected solids were combined to give the product as a pale brown solid which was used without further purification.

(87) Yield: 3.56 g

(88) Reaction Conditions d and e were Carried Out in Sequence without Isolation of Intermediate D.

(d/e). (R)N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-3-(4-fluorophenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(89) Palladium (II) acetate (4.5 mg) was added to a degassed solution of intermediate 6c (112 mg), 4-fluorobenzene (53 mg), cesium carbonate (141 mg) and triphenylphosphine (11 mg) in dioxane (3 ml) and the mixture was degassed with nitrogen for a further 15 minutes. The reaction tube was sealed and then heated to 100 C. for 18 hours. The reaction was determined to be incomplete, hence a further aliquot of palladium (II) acetate (4.5 mg), triphenylphosphine (11 mg) and 4-fluorobenzene (53 mg) was added. The mixture was degassed with nitrogen for 15 minutes, sealed under nitrogen and then heated to 100 C. for 18 hours. The reaction was determined to be approximately 50% complete by HPLC hence the solvents were removed under vacuum and the residue obtained was partitioned between ethyl acetate (5 ml) and water. The aqueous phase was re-extracted with ethyl acetate and the combined organic layers were washed with water and then concentrated to dryness giving a dark brown oil. The oil was redissolved in THF (1 ml) before the addition of tetrabutylammonium fluoride in THF (0.3 ml, 1 N), stirring for 2 hours. The solvents were removed under vacuum to give a dark oil that was purified by preparative HPLC eluting with acetonitrile and water to give the product, as an off white solid

(90) Yield: 22 mg

(91) MS (ESI) m/z: 540 (M+H).sup.+.

(92) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.10 (1H, s), 7.57 (1H, d, J=7.87 Hz), 7.37 (1H, d, J=8.09 Hz), 7.03 (1H, s), 6.97-6.88 (3H, m), 6.76 (1H, s), 6.68 (1H, s), 5.66 (1H, d, J=7.08 Hz), 4.37-4.30 (1H, m), 3.93 (2H, s), 3.88 (2H, s), 3.75-3.62 (3H, m), 3.58 (1H, dd, J=10.91, 5.91 Hz), 3.07 (1H, s), 2.96-2.81 (4H, m).

Example 7

(R)N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(93) Compound 7 was prepared in an analogous fashion as described for example 6.

(94) MS (ESI) m/z: 528 (M+H).sup.+.

(95) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.00 (1H, s), 7.57 (1H, d, J=7.9 Hz), 7.39-7.35 (2H, m), 7.19 (1H, t, J=3.9 Hz), 7.12 (1H, t, J=7.5 Hz), 7.07 (1H, s), 6.96-6.90 (4H, m), 6.68 (1H, s), 5.86 (1H, d, J=6.9 Hz), 4.37-4.31 (1H, m), 3.93 (3H, s), 3.89 (3H, s), 3.81 (2H, t, J=6.6 Hz), 3.68 (1H, d, J=11.4 Hz), 3.57 (1H, dd, J=11.0, 5.9 Hz), 3.05 (1H, s), 2.92 (2H, t, J=6.7 Hz), 2.89-2.77 (2H, m).

Example 8

(R)N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-3-(4-methoxyphenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(96) Compound 8 was prepared in an analogous fashion as described for example 6.

(97) MS (ESI) m/z: 552 (M+H).sup.+.

(98) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.09 (1H, s), 7.54 (1H, d, J=7.89 Hz), 7.33 (1H, d, J=8.08 Hz), 6.93-6.82 (4H, m), 6.78 (1H, d, J=2.24 Hz), 6.68 (1H, s), 5.73 (1H, d, J=6.81 Hz), 4.34-4.26 (1H, m), 3.90 (6H, d, J=16.25 Hz), 3.86-3.68 (4H, m), 3.72-3.61 (1H, m), 3.54 (1H, t, J=7.52 Hz), 3.24 (1H, s), 2.93-2.69 (4H, m),

Example 9

(R)N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-3-(4-nitrophenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(99) Compound 9 was prepared in an analogous fashion as described for example 6.

(100) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.13 (1H, s), 8.11 (1H, s), 7.60 (1H, d, J=7.86 Hz), 7.43 (2H, d, J=8.56 Hz), 7.39 (1H, d, J=8.17), 7.26-7.19 (1H, m), 7.15 (1H, d, J=7.56 Hz), 7.02-6.98 (2H, m), 6.70 (1H, s), 6.56 (1H, s), 5.84 (1H, d, J=7.24 Hz), 4.45-4.35 (1H, m), 3.97-3.93 (3H, m), 3.90-3.87 (3H, m), 3.84-3.79 (2H, m), 3.73-3.66 (2H, m), 3.02 (2H, dd, J=6.47, 3.36 Hz), 2.93 (2H, t, J=6.57 Hz), 2.78 (1H, s).

Example 10

(R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(101) Compound 10 was prepared in an analogous fashion as described for example 6.

(102) MS (ESI) m/z: 540 (M+H).sup.+.

(103) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.15 (1H, s), 7.57 (1H, d, J=7.89 Hz), 7.35 (1H, d, J=8.09 Hz), 6.87 (1H, s), 6.75 (1H, s), 6.68 (1H, s), 5.72 (1H, d, J=6.98 Hz), 4.36-4.29 (1H, m), 3.90 (6H, d, J=17.08 Hz), 3.77 (2H, t, J=6.54 Hz), 3.69-3.54 (2H, m), 3.14 (1H, s), 2.96-2.80 (4H, m).

Example 11

(R)N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(methylamino)-3-(pyridin-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(104) Compound 11 was prepared in an analogous fashion as described for example 6.

(105) MS (ESI) m/z: 523 (M+H).sup.+.

(106) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.42-8.31 (2H, m), 8.12 (1H, s), 7.67-7.58 (2H, m), 7.18-7.02 (4H, m), 6.92-6.85 (2H, m), 6.69 (1H, s), 4.39-4.33 (1H, m), 4.02 (2H, t, J=6.49 Hz), 3.91 (6H, d, J=14.15 Hz), 3.77 (1H, dd, J=11.01, 3.36 Hz), 3.71-3.62 (1H, m), 3.01-2.88 (4H, m), 1.68 (3H, s).

Example 12

(R)N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-3-(3-methoxyphenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(107) Compound 12 was prepared in an analogous fashion as described for example 6.

(108) MS (ESI) m/z: 552 (M+H).sup.+.

(109) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.09 (1H, s), 7.54 (1H, d, J=7.89 Hz), 7.33 (1H, d, J=8.08 Hz), 6.93-6.82 (4H, m), 6.78 (1H, d, J=2.24 Hz), 6.68 (1H, s), 5.73 (1H, d, J=6.81 Hz), 4.34-4.26 (1H, m), 3.90 (6H, d, J=16.25 Hz), 3.86-3.68 (4H, m), 3.72-3.61 (1H, m), 3.54 (1H, t, J=7.52 Hz), 3.24 (1H, s), 2.93-2.69 (4H, m),

(110) ##STR00025## ##STR00026##

Example 13

(R)-3-(4-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(a). ethyl 3-bromo-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

(111) A solution of N-bromosuccinimide (0.91 g) in DCM (50 ml) was added dropwise over 45 minutes to a solution of intermediate 2b (1.88 g) in DCM (50 ml). The reaction mixture was stirred for 2 hours before quenching with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with DCM twice and the combined organic layers were washed with water and brine, dried (MgSO.sub.4) and filtered. The solvents were removed under vacuum to yield a crude solid. The residue was purified by chromatography on silica gel eluting with petrol and increasing amounts of ethyl acetate.

(112) Yield: 1.36 g

(113) .sup.1H NMR (ppm) (CHCl.sub.3-d): 7.06 (1H, s), 6.86 (1H, s), 6.71 (1H, s), 4.60-4.50 (1H, m), 4.33 (2H, q, J=7.12 Hz), 4.16-4.07 (2H, m), 3.87 (3H, s), 3.01 (2H, t, J=6.64 Hz), 1.41-1.36 (9H, m)

(b). 3-bromo-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylic Acid

(114) Sodium hydroxide (1.33 g) in water (15 ml) was added to a solution of intermediate 13a (1.33 g) in ethanol (15 ml). The mixture was heated to 80 C. for 18 hours. The solvents were removed under vacuum and the crude residue was suspended in ethyl acetate (30 ml) before acidifying to pH 2 with a aqueous 2M HCl solution. The phases were separated and the aqueous phase was re-extracted with ethyl acetate twice. The combined organic layers were washed with water and brine, dried (MgSO.sub.4) and filtered. The solvents were removed under vacuum to give the product, as an off white solid.

(115) Yield: 1.2 g

(116) .sup.1H NMR (ppm) (DMSO-d.sub.6): 12.12 (1H, s), 7.24 (1H, s), 7.01 (1H, s), 6.91 (1H, s), 4.67-4.60 (1H, m), 4.08-4.01 (2H, m), 3.77 (3H, s), 2.99 (2H, t, J=6.60 Hz), 1.25 (6H, d, J=6.01 Hz)

(c). (R)-3-bromo-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(117) 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.91 g), 1-hydroxybenzotriazole (0.47 g), triethylamine (1.32 ml) and D-tryptophanol (0.72 g) were added to a solution of intermediate 13b (1.2 g) in DMF (20 ml). The reaction mixture was stirred for 18 hours and then the solvents were removed under vacuum to give an oily solid. The crude residue was partitioned between ethyl acetate and water and the aqueous phase was re-extracted with ethyl acetate twice. The combined organic layers were washed with a aqueous 0.2M HCl solution, saturated aqueous sodium bicarbonate solution, water and brine before drying over magnesium sulfate. The solvents were removed under vacuum to give the product, as an off white solid

(118) Yield: 1.73 g

(119) .sup.1H NMR (ppm) (DMSO-d): 10.76 (1H, s), 7.68 (1H, d, J=7.85 Hz), 7.34 (2H, dd, J=16.04, 8.06 Hz), 7.15 (1H, s), 7.09-7.03 (2H, m), 7.02-6.96 (2H, m), 6.93 (1H, s), 4.78 (1H, t, J=5.58 Hz), 4.56 (1H, t, J=6.08 Hz), 4.20 (1H, d, J=7.52 Hz), 4.06-3.99 (3H, m), 3.77 (3H, s), 3.51 (1H, d, J=5.71 Hz), 3.46-3.42 (1H, m), 3.02-2.88 (4H, m), 1.30-1.24 (6H, m),

(d). (R)-3-(4-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(120) Tetrakis(triphenylphosphine)palladium(0) (12.6 mg) was added to a degassed solution of intermediate 12c (60 mg), 4-fluorophenylboronic acid (23 mg) and potassium carbonate (45 mg) in a 10:1 mixture of DME:water (4 ml). The mixture was degassed by gently bubbling through nitrogen for a further 5 minutes before sealing under nitrogen and then heating to 85 C. for 18 hours. The reaction was allowed to cool to ambient temperature before water was added, extracting with ethyl acetate (3). The combined organic layers were passed through a hydrophobic frit and concentrated under vacuum. The crude brown residue was purified by preparative HPLC eluting with acetonitrile and water to give the product, as an off white solid

(121) Yield: 28 mg

(122) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.10 (1H, s), 7.57 (1H, d, J=7.91 Hz), 7.37 (1H, d, J=8.11 Hz), 6.97-6.88 (3H, m), 6.73 (1H, s), 6.68 (1H, s), 5.65 (1H, d, J=7.08 Hz), 4.60-4.52 (1H, m), 4.36-4.29 (1H, m), 3.85 (3H, s), 3.76-3.54 (4H, m), 3.09 (1H, t, J=5.28 Hz), 2.94-2.81 (4H, m), 1.40 (6H, d, J=6.12 Hz).

Example 14

(R)N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-3-m-tolyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(123) Compound 14 was prepared in an analogous fashion as described for example 13.

(124) MS (ESI) m/z: 564 (M+H).sup.+.

(125) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.00 (1H, s), 7.54 (1H, d, J=7.91 Hz), 7.34 (1H, d, J=8.10 Hz), 6.86 (1H, s), 6.81 (1H, d, J=2.22 Hz), 6.68 (1H, s), 5.66 (1H, d, J=6.86 Hz), 4.60-4.52 (1H, m), 4.32-4.24 (1H, m), 3.85 (3H, s), 3.77 (2H, t, J=6.62 Hz), 3.67-3.60 (1H, m), 3.51 (1H, dd, J=10.99, 6.04 Hz), 3.14 (1H, s), 2.90 (2H, t, J=6.54 Hz), 2.84-2.67 (2H, m), 2.31 (3H, s), 1.41 (6H, d, J=6.08 Hz).

Example 15

(R)-3-(6-aminopyridin-3-yl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(126) Compound 15 was prepared in an analogous fashion as described for example 13.

(127) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.12 (1H, s), 7.58 (1H, d, J=7.91 Hz), 7.39-7.03 (8H, m), 6.85 (1H, s), 6.70 (2H, d, J=10.30 Hz), 5.70 (1H, d, J=6.90 Hz), 4.59-4.50 (1H, m), 4.36-4.28 (1H, m), 3.86 (3H, s), 3.81-3.74 (2H, m), 3.68 (1H, d, J=10.89), 3.60 (1H, dd, J=10.93, 5.87 Hz), 3.15 (1H, s), 2.96-2.80 (4H, m), 1.43-1.39 (6H, m).

Example 16

(R)-3-(3-chlorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(128) Compound 16 was prepared in an analogous fashion as described for example 13

(129) MS (ESI) m/z: 584, 586 (M+H).sup.+.

(130) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.12 (1H, s), 7.58 (1H, d, J=7.91 Hz), 7.39-7.03 (8H, m), 6.85 (1H, d, J=2.20 Hz), 6.70 (2H, d, J=10.30 Hz), 5.70 (1H, d, J=6.90 Hz), 4.59-4.50 (1H, m), 4.36-4.28 (1H, m), 3.86 (3H, s), 3.81-3.74 (2H, m), 3.68 (1H, d, J=10.89 Hz), 3.60 (1H, dd, J=10.93, 5.87 Hz), 3.15 (1H, s), 2.96-2.80 (4H, m), 1.43-1.39 (6H, m).

Example 17

(R)N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-3-(4-hydroxyphenyl)-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(131) Compound 17 was prepared in an analogous fashion as described for example 13.

(132) MS (ESI) m/z: 565 (M+H).sup.+.

(133) .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.79 (1H, s), 7.97 (1H, d, J=8.19 Hz), 7.81 (1H, s), 7.61 (1H, d, J=7.85 Hz), 7.41 (1H, s), 7.31 (1H, d, J=8.06 Hz), 7.19-7.13 (2H, m), 7.04 (1H, t, J=7.55 Hz), 6.94 (2H, t, J=10.04 Hz), 6.45 (2H, t, J=9.29 Hz), 4.73 (1H, s), 4.07-3.99 (1H, m), 3.84 (6H, d, J=17.14 Hz), 3.46 (1H, dd, J=10.80, 4.96 Hz), 2.98 (1H, dd, J=14.51, 5.98 Hz), 2.86-2.75 (5H, m).

Example 18

3-(2-fluorophenyl)-N((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(134) Compound 18 was prepared in an analogous fashion as described for example 13.

(135) MS (ESI) m/z: 568 (M+H).sup.+.

(136) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.06 (1H, s), 7.58 (1H, s), 7.39-7.28 (2H, m), 6.93 (1H, d, J=15.19 Hz), 6.69 (2H, s), 5.74 (1H, t, J=8.35 Hz), 4.61-4.52 (1H, m), 4.32 (1H, s), 3.89-3.64 (5H, m), 3.64-3.56 (1H, m), 3.10 (1H, d, J=47.31 Hz), 2.95-2.82 (4H, m), 1.41 (8H, s).

Example 19

(R)-3-(furan-2-yl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(137) Compound 19 was prepared in an analogous fashion as described for example 13.

(138) MS (ESI) m/z: 540 (M+H).sup.+.

(139) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.18 (1H, s), 7.63 (1H, d, J=7.85 Hz), 7.40-7.32 (2H, m), 7.26-7.04 (3H, m), 6.98 (1H, s), 6.78 (1H, s), 6.69 (1H, s), 6.45 (1H, d, J=3.29 Hz), 6.35 (1H, s), 6.28 (1H, d, J=6.93 Hz), 4.59-4.49 (1H, m), 3.93 (2H, t, J=6.57 Hz), 3.86 (3H, s), 3.73 (1H, s), 3.65 (1H, d, J=9.86 Hz), 3.19 (1H, s), 3.00-2.89 (4H, m), 1.40 (6H, d, J=6.08 Hz).

Example 20

(R)-3-(3-cyanophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(140) Compound 20 was prepared in an analogous fashion as described for example 13.

(141) MS (ESI) m/z: 575 (M+H).sup.+.

Example 21

(R)N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-3-(3-(trifluoromethyl)phenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(142) Compound 21 was prepared in an analogous fashion as described for example 13.

(143) MS (ESI) m/z: 618 (M+H).sup.+.

(144) ##STR00027##

Example 22

(R)N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-3-isobutyl-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(a). ethyl 3-formyl-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

(145) N-butyl lithium (2.5 M in hexanes, 10.95 ml) was added dropwise to a 0 C. solution of diisopropylamine (3.3 g) in THF (60 ml), stirring for 10 minutes before cooling to 78 C. A solution of intermediate 2b (7.5 g) in THF (90 ml) was carefully added keeping the reaction temperature below 70 C., over 10 minutes. The solution was stirred at this temperature for a further 20 minutes before the addition of DMF (2.0 ml). The reaction mixture was stirred for a further 30 minutes. The reaction mixture was allowed to warm to room temperature over 1 hour and was then quenched by addition of a solution of saturated aqueous sodium bicarbonate solution and water. The crude product was extracted into ethyl acetate (2) and the combined organic layers were washed with water and brine, dried (MgSO.sub.4) and filtered. The solvents were removed under vacuum to give a dark oil that was triturated with diethyl ether (60 ml) giving a solid that was removed by filtration and dried in air. The filtrate liquors were purified on silica gel (120 g) eluting with 4:1 iso-hexane:ethyl acetate. Evaporation of the product fractions gave additional product as a crystalline off white solid. The two solids were combined to give the product as an off white solid

(146) Yield: 2.80 g

(147) .sup.1H NMR (ppm) (CHCl.sub.3-d): 10.38 (1H, s), 7.13 (1H, s), 6.90 (1H, s), 6.78-6.74 (1H, m), 4.74-4.67 (2H, m), 4.60-4.51 (1H, m), 4.38 (2H, dd, J=14.26, 7.13 Hz), 3.90-3.83 (3H, m), 3.05-2.97 (2H, m), 1.45-1.33 (9H, m).

(b). ethyl 9-isopropoxy-8-methoxy-3-(2-methylprop-1-enyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

(148) Sodium hydride (60% dispersion in oil, 27 mg) was added to a solution of intermediate 22a (200 mg) and iso-propyltriphenylphosphonium iodide (290 mg) in THF (3 ml) before heating to 70 C. for 2 hours. The reaction mixture was cooled to room temperature and then partitioned between ethyl acetate and water. The organic phase was concentrated to dryness under vacuum to give a dark oil that was purified by chromatography on silica gel eluting with heptane and increasing amounts of ethyl acetate.

(149) Yield: 160 mg

(150) .sup.1H NMR (ppm) (CHCl.sub.3-d): 7.10-7.05 (1H, m), 6.79-6.74 (1H, m), 6.70 (1H, s), 6.18 (1H, s), 4.62-4.50 (1H, m), 4.33-4.21 (2H, m), 3.91-3.82 (5H, m), 2.93 (2H, t, J=6.47 Hz), 1.96 (3H, s), 1.62 (3H, s), 1.39 (6H, d, J=6.09 Hz), 1.34 (3H, t, J=7.12 Hz).

(c). ethyl 9-isopropoxy-8-methoxy-3-(2-methylprop-1-enyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

(151) A aqueous 2N sodium hydroxide solution (1 ml) was added to a solution of intermediate 22b (185 mg) in ethanol (2 ml) before heating to 70 C. four 18 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was re-extracted with ethyl acetate and the combined organic layers were washed with water, dried over sodium sulphate, filtered and concentrated under vacuum to give the product as a yellow solid.

(152) Yield: 155 mg

(153) MS (ESI) m/z: 356 (M+H).sup.+.

(154) .sup.1H NMR (ppm) (CHCl.sub.3-d): 7.09 (1H, s), 6.86 (1H, s), 6.71 (1H, s), 6.18 (1H, d, J=1.90 Hz), 4.58-4.51 (1H, m), 3.92-3.85 (5H, m), 2.98-2.92 (2H, m), 1.98 (3H, d, J=1.45 Hz), 1.65 (3H, d, J=1.24 Hz), 1.45-1.36 (6H, m), 1.29-1.20 (1H, m).

(d). 3-isobutyl-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylic Acid

(155) A solution of intermediate 22c (75 mg) in 1:2 DCM:methanol (5 ml) was passed through the H-Cube hydrogenator at 1 ml/min/30 C./60 bar H.sub.2 over a 10% Pd/C cartridge until the reaction was determined to be complete by HPLC. The solvents were removed under vacuum to give the product as a colourless oil

(156) Yield: 51 mg

(157) .sup.1H NMR (ppm) (CHCl.sub.3-d): 7.08 (1H, s), 6.83 (1H, s), 6.71 (1H, s), 4.59-4.51 (1H, m), 4.02-3.95 (2H, m), 3.90-3.83 (3H, m), 3.49 (1H, s), 3.01-2.88 (4H, m), 2.02-1.94 (1H, m), 1.39 (6H, d, J=6.07 Hz), 0.97 (6H, d, J=6.62 Hz).

(e). (R)N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-3-isobutyl-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(158) 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (41 mg) was added to a solution of intermediate 22d (50 mg) and 1-hydroxybenzotriazole (20 mg) in DMF (1 ml). The mixture was stirred for 5 minutes before the addition of D-tryptophanol (28 g), stirring for a further 18 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was separated and washed with water, dried by passing through a hydrophobic frit and then concentrated to dryness to give an orange oil. The crude oil was purified by reverse phase preparative HPLC to give the product as a white solid

(159) Yield: 28 mg

(160) MS (ESI) m/z: 530 (M+H).sup.+.

(161) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.12 (1H, s), 7.73 (1H, d, J=7.73 Hz), 7.40 (1H, d, J=7.95 Hz), 7.25-7.16 (2H, m), 7.12 (1H, d, J=2.33 Hz), 6.88 (1H, s), 6.71-6.67 (1H, m), 6.08-6.02 (2H, m), 4.60-4.52 (1H, m), 4.45-4.39 (1H, m), 3.96-3.88 (2H, m), 3.85 (3H, s), 3.82 (1H, dd, J=6.72, 3.72 Hz), 3.79-3.71 (1H, m), 3.58-3.53 (1H, m), 3.20-3.06 (2H, m), 2.97-2.80 (4H, m), 1.97-1.87 (1H, m), 1.43-1.34 (6H, m), 0.94-0.87 (6H, m).

Example 23

(R)N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-3-(2-methylprop-1-enyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(162) Compound 23 was prepared in an analogous fashion as described for example 13, starting with 22c en performing step e.

(163) MS (ESI) m/z: 528 (M+H).sup.+.

(164) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.07 (1H, s), 7.69 (1H, d, J=7.85 Hz), 7.37 (1H, d, J=8.06 Hz), 7.23-7.18 (1H, m), 7.16-7.11 (1H, m), 7.07 (1H, d, J=2.40 Hz), 6.75 (1H, s), 6.68 (1H, s), 6.45 (1H, d, J=6.73 Hz), 5.88 (1H, s), 4.57-4.50 (1H, m), 4.48-4.42 (1H, m), 3.85 (3H, s), 3.82-3.71 (4H, m), 3.40 (1H, s), 3.06 (2H, d, J=6.97 Hz), 2.94-2.87 (2H, m), 1.72 (2H, s), 1.56 (6H, s), 1.43-1.37 (6H, m).

(165) ##STR00028## ##STR00029##

Example 24

(R)N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-3-isobutyryl-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(a). ethyl 3-isobutyryl-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

(166) Lithium diisopropylamide (0.2 M stock solution, 2.28 ml) was added dropwise to a 78 C. solution of intermediate 2b (100 mg) in dry THF (2 ml) under a nitrogen atmosphere. The mixture was stirred for 30 minutes at 78 C. before the addition of isobutyryl chloride (64 l) in one portion, stirring for a further 15 minutes at 78 C. then allowing to warm to room temperature over 10 minutes. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution and then partitioned between water and ethyl acetate (3). The combined organic layers were passed through a hydrophobic frit and concentrated under vacuum. The residue was purified by chromatography on silica gel eluting with petrol and increasing amounts of ethyl acetate to give the product, as a clear gum

(167) Yield: 100 mg

(168) .sup.1H NMR (ppm) (CHC.sub.3-d): 7.09 (1H, s), 6.77 (1H, s), 6.72 (1H, s), 4.60-4.49 (1H, m), 4.33 (2H, q, J=7.1 Hz), 4.17 (2H, t, J=6.7 Hz), 3.87 (3H, s), 3.61-3.48 (1H, m), 2.97 (2H, t, J=6.6 Hz), 1.42-1.31 (9H, m), 1.17 (6H, d, J=6.8 Hz).

(b). 3-isobutyryl-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylic Acid

(169) Sodium hydroxide (29 mg) in water (0.3 ml) was added to a solution of intermediate 24a (97 mg) in ethanol (3 ml). The mixture was heated for 6 hours at 70 C. The solvents were removed under vacuum and the crude residue was dissolved in water and washed with diethyl ether (3). The aqueous phase was acidified to pH 3 with a aqueous 2N HCl solution and then extracted with DCM (3). The combined organic layers were passed through a hydrophobic frit and concentrated under vacuum to give the product, as grey solid

(170) Yield: 75 mg

(171) .sup.1H NMR (ppm) (CHCl.sub.3-d): 7.11 (1H, s), 6.90 (1H, s), 6.73 (1H, s), 4.60-4.51 (1H, m), 4.17 (2H, t, J=6.6 Hz), 3.88 (3H, s), 3.63-3.52 (1H, m), 3.00 (2H, t, J=6.5 Hz), 1.40 (6H, d, J=6.1 Hz), 1.19 (6H, d, J=6.8 Hz).

(c). (R)N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-3-isobutyryl-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(172) 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (58 mg) was added to a solution of intermediate 24b (74 mg), diisopropylethylamine (105 l), 1-hydroxybenzotriazole (41 mg) and D-tryptophanol (46 mg) in dry DMF (2 ml). The mixture was stirred at room temperature for 60 hours. Water was added and the product was extracted into ethyl acetate (5). The combined organic layers were passed through a hydrophobic frit and concentrated under vacuum to give a pale brown oil. The residue was redissolved in DMSO and purified by preparative HPLC eluting with acetonitrile and water to give the product, as an off white solid

(173) Yield: 47 mg

(174) MS (ESI) m/z: 544 (M+H).sup.+.

(175) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.22 (1H, s), 7.72 (1H, d, J=7.8 Hz), 7.38 (1H, d, J=8.0 Hz), 7.27-7.12 (2H, m), 7.11 (1H, d, J=2.4 Hz), 6.95 (1H, s), 6.70 (1H, s), 6.43 (1H, d, J=7.3 Hz), 6.22 (1H, s), 4.58-4.43 (2H, m), 4.38-4.24 (2H, m), 3.86 (3H, s), 3.84-3.71 (2H, m), 3.46-3.36 (1H, m), 3.14 (2H, d, J=6.9 Hz), 2.96-2.89 (3H, m), 1.39 (6H, d, J=6.1 Hz), 1.10 (6H, t, J=6.5 Hz).

Example 25

(R)N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-3-pivaloyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(176) Compound 25 was prepared in an analogous fashion as described for example 24.

(177) MS (ESI) m/z: 558 (M+H).sup.+.

(178) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.11 (1H, s), 7.72 (1H, d, J=7.8 Hz), 7.41 (1H, d, J=8.0 Hz), 7.28-7.15 (2H, m), 7.11 (1H, s), 6.91 (1H, s), 6.68 (1H, s), 6.12 (1H, d, J=6.7 Hz), 6.07 (1H, s), 4.59-4.51 (1H, m), 4.40-4.30 (1H, m), 3.90-3.71 (7H, m), 3.32 (1H, t, J=5.4 Hz), 3.17-3.05 (2H, m), 2.98-2.87 (2H, m), 1.41 (6H, t, J=5.6 Hz), 1.25 (9H, s).

Example 26

(R)-3-butyryl-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(179) Compound 26 was prepared in an analogous fashion as described for example 24.

(180) MS (ESI) m/z: 544 (M+H).sup.+.

(181) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.16 (1H, s), 7.72 (1H, d, J=7.85 Hz), 7.39 (1H, d, J=8.07 Hz), 6.95 (1H, s), 6.71 (1H, s), 6.48 (1H, d, J=7.35 Hz), 6.24 (1H, s), 4.58-4.36 (4H, m), 3.92-3.69 (4H, m), 3.22-3.08 (2H, m), 2.93 (2H, t, J=6.79 Hz), 2.89-2.70 (3H, m), 1.39 (6H, d, J=6.08 Hz), 0.89 (3H, t, J=7.39 Hz).

Example 27

(R)-3-(cyclopropanecarbonyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(182) Compound 27 was prepared in an analogous fashion as described for example 24.

(183) MS (ESI) m/z: 542 (M+H).sup.+.

(184) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.31 (1H, s), 7.70 (1H, d, J=7.8 Hz), 7.36-7.29 (2H, m), 7.17 (1H, t, J=3.9 Hz), 7.15-7.07 (2H, m), 7.02 (1H, s), 6.70 (1H, s), 6.57 (1H, s), 4.57-4.41 (2H, m), 4.38 (2H, t, J=6.7 Hz), 3.86 (3H, s), 3.90-3.64 (2H, m), 3.26 (1H, t, J=5.4 Hz), 3.11 (2H, d, J=7.0 Hz), 2.94 (2H, t, J=6.7 Hz), 2.43-2.34 (1H, m), 1.38 (6H, d, J=6.1 Hz), 1.21-1.16 (2H, m), 0.96-0.90 (2H, m).

Example 28

(R)N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-3-(thiophene-2-carbonyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(185) Compound 28 was prepared in an analogous fashion as described for example 24.

(186) MS (ESI) m/z: 584 (M+H).sup.+.

(187) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.02 (1H, s), 7.68-7.62 (2H, m), 7.59 (1H, dd, J=3.8, 1.1 Hz), 7.34 (1H, d, J=8.1 Hz), 7.19 (1H, t, J=7.7 Hz), 7.14-7.07 (3H, m), 7.04 (1H, d, J=2.3 Hz), 6.73 (2H, d, J=11.8 Hz), 6.66 (1H, d, J=6.9 Hz), 4.58-4.51 (1H, m), 4.22-4.14 (3H, m), 3.87 (3H, s), 3.51-3.47 (2H, m), 3.01-2.94 (2H, m), 2.91-2.81 (3H, m), 1.40 (6H, d, J=6.1 Hz).

Example 29

(R)-3-benzoyl-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(188) Compound 29 was prepared in an analogous fashion as described for example 24.

(189) MS (ESI) m/z: 578 (M+H).sup.+.

(190) .sup.1H NMR (ppm) (CHCl.sub.3-d): 7.97 (1H, s), 7.75 (2H, d, J=7.7 Hz), 7.63 (1H, d, J=7.9 Hz), 7.57 (1H, t, J=7.4 Hz), 7.43 (2H, t, J=7.6 Hz), 7.33 (1H, d, J=8.1 Hz), 7.19 (2H, t, J=8.2 Hz), 7.11 (2H, t, J=7.6 Hz), 7.03 (1H, d, J=2.3 Hz), 6.84 (1H, s), 6.70 (1H, s), 4.58-4.51 (1H, m), 4.19-4.13 (1H, m), 4.03 (2H, t, J=6.7 Hz), 3.87 (3H, s), 3.52-3.43 (2H, m), 2.96-2.82 (5H, m), 1.41 (6H, d, J=6.1 Hz).

(191) ##STR00030##

Example 30

(R)N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-diisopropoxy-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(a). 6,7-diisopropoxy-1-methyl-3,4-dihydroisoquinoline

(192) A solution of 1-methyl-6,7-dimethoxy-3,4-dihydroisoquinoline (35.8 g) in aqueous HBr (48%, 175 ml) was heated at 90 C. for 4.5 hours. 11% starting material, 71% mono-demethyl and 18% di-demethyl product according to LC-MS. Toluene was added to the reaction mixture and the solvent was evaporated in vacuo. The residue was dissolved in DMF (300 ml), before addition of potassium carbonate (82 g). 2-Bromopropane (41.7 ml) was added to the stirred suspension before heating at 70 C. for 18 hrs. 40% conversion according to LC-MS, hence a further aliquot of 2-bromopropane and potassium carbonate were added to the reaction mixture and heated at 70 C. for 3 hrs. The reaction mixture was extracted with ethyl acetate and water. The aqueous layer was washed with ethyl acetate and the combined organic layers were washed sequentially with water and brine, dried (MgSO.sub.4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel with petrol and increasing amounts of ethyl acetate, yielding in a pale brown solid 0.7 g, consisting of 82% mono-demethyl product, 8% di-demethyl product and 12% starting material. This material was used without further purification

(b). ethyl 8,9-diisopropoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

(193) To a mixture of 30a (26.8 g) and potassium carbonate (35 g) in acetonitrile (270 ml) was added dropwise ethylbromopyruvate (17.3 ml). The reaction mixture was refluxed for 3 hrs. The reaction was allowed to cool to ambient temperature before a saturated aqueous NaHCO.sub.3 solution was added. The aqueous phase was extracted with ethyl acetate twice. The combined organic layers were washed with brine. The organic layer was dried (MgSO.sub.4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with petrol and increasing amounts of ethyl acetate. The pure fractions of the desired product were concentrated in vacuo.

(c). ethyl 8,9-diisopropoxy-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

(194) Compound 30b (232 mg), phenylbromide (117 mg), triphenylphosphine (34 mg) and cesium carbonate (459 mg) were suspended in degassed dioxane (4 ml). Palladium(II) acetate (15 mg) was added and the mixture was further degassed for 5 minutes and heated at 100 C. for 18 hours. The reaction mixture was degassed and recharged with triphenylphosphine and palladium(II) acetate and heated for a further 18 hours. The reaction mixture was diluted with ethyl acetate and water and filtered through celite. The organic phase was dried (MgSO.sub.4), filtered and concentrated to a yellow oil. The residue was purified by chromatography on silica gel with hexane and increasing amounts of ethyl acetate. The pure fractions were concentrated to a colorless oil.

(195) Yield: 162 mg

(196) MS (ESI) m/z: 434 (M+H).sup.+.

(d). 8,9-diisopropoxy-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylic Acid

(197) A aqueous 2N sodium hydroxide solution (21.9 ml) was added to a solution of intermediate 30c (161 mg) in ethanol (4 ml). The mixture was heated for 18 hours at 60 C. The solvents were removed under vacuum and the crude residue was partitioned between a aqueous 1N HCl solution and ethyl acetate. The organic phase was dried (MgSO.sub.4), filtered and concentrated to a pale brown solid.

(198) Yield: 145 mg

(199) MS (ESI) m/z: 406 (M+H).sup.+.

(e). (R)N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-diisopropoxy-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(200) 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (104 mg) was added to a solution of intermediate 30d (145 mg), diisopropylethylamine (188 l), 1-hydroxybenzotriazole (73 mg) and D-tryptophanol (82 mg) in dry DMF (4 ml). The mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and washed sequentially with a aqueous 1N HCl solution, a saturated aqueous NaHCO.sub.3 solution and brine. The organic layer was dried (MgSO.sub.4) and concentrated in vacuo to a pale brown oil. The residue was purified by chromatography on silica gel with DCM and increasing amounts of methanol (max. 7% in DCM). The pure fraction were collected and concentrated in vacuo, yielding in a pale yellow solid.

(201) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.32 (1H, s), 7.52 (1H, d, J=7.89 Hz), 7.35-7.19 (6H, m), 7.20-7.06 (3H, m), 6.83 (1H, s), 6.78 (1H, d, J=2.3 Hz), 6.71 (1H, s), 5.64 (1H, d, J=6.95), 4.54-4.40 (2H, m), 4.33-4.23 (1H, m), 3.73 (2H, t, J=6.50 Hz), 3.61 (1H, d, J=10.88 Hz), 3.51 (1H, dd, J=10.94, 5.95 Hz), 3.31 (1H, s), 2.88-2.68 (4H, m), 1.34 (12H, dd, J=11.62, 6.09 Hz).

(202) ##STR00031##

Example 31

(R)-3-(3-fluorophenyl)-9-hydroxy-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(a). ethyl 3-(3-fluorophenyl)-8,9-dimethoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

(203) Compound 31a was prepared in an analogous fashion as described for example 5c.

(b). ethyl 3-(3-fluorophenyl)-8,9-dimethoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

(204) To a solution of compound 31a (124 mg) in DCE (2 ml) was added aluminium chloride (120 mg). The mixture was heated at 50 C. for 75 minutes. The reaction mixture was diluted with DCM and quenched with solid NaHCO.sub.3 and acidified with a aqueous 2M HCl solution. The organic layer was washed with water and brine, dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo to give a pale yellow oil.

(205) Yield: 114 mg (the product is a mixture of regioisomers (20:80). The crude product used without further purification.

(c) 3-(3-fluorophenyl)-9-hydroxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylic Acid

(206) To a solution of the mixture of isomers 31b (114 mg) in ethanol (2 ml) was added a aqueous 2M sodium hydroxide solution (0.75 ml). The mixture was heated at 50 C. for 18 hrs. The reaction mixture was diluted with ethyl acetate and extracted with a aqueous 2M HCl solution. The organic layer was washed with water, brine, dried (MgSO.sub.4), filtered and concentrated in vacuo to yield a pale yellow oil.

(207) Yield: 110 mg

(d). (R)-3-(3-fluorophenyl)-9-hydroxy-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(208) 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (87 mg) was added to a solution of a mixture of regioisomers 31c (110 mg), triethylamine (126 l), 1-hydroxybenzotriazole (43 mg) and D-tryptophanol (71 mg) in dry DMF (2 ml). The reaction mixture was stirred at room temperature for 60 hours. The solvent was removed under vacuum to give a yellow oil. The oil was redissolved in ethyl acetate and washed with water (3). The combined organic layers were passed through a hydrophobic frit and concentrated under vacuum. The crude residue was redissolved in MeCN and purified by preparative HPLC, eluting with acetonitrile and water to give the product as an off-white solid

(209) Yield: 16 mg

(210) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.4 (1H, s), 7.65-7.55 (2H, m), 7.19-7.25 (3H, m), 7.19-7.00 (7H, m), 6.68 (1H, s), 6.00 (1H, d, J=7.25), 5.82 (1 h, bs), 4.40-4.30 (1H, m), 3.90 (3H, s), 3.67-3.53 (2H, m), 2.98-2.70 (6H, m).

(211) ##STR00032##

Example 32

(R)-9-(allyloxy)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(a). ethyl 3-(3-fluorophenyl)-9-hydroxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

(212) Boron tribromide (1.05 ml) was added dropwise to a 40 C. solution of intermediate 2c (890 mg) in DCM (25 ml) under a nitrogen atmosphere. The reaction mixture was stirred for 30 minutes, then a further aliquot of boron tribromide (1.05 ml) was added dropwise and the mixture stirred for a further 2 hours at 40 C. The reaction was quenched with water and the aqueous phase was extracted with DCM (3). The combined organic layers were passed through a hydrophobic frit and the solvent was removed under vacuum. The residue was purified by chromatography on silica gel eluting with heptane and increasing amounts of ethyl acetate to give the product as a pale pink solid.

(213) Yield: 550 mg

(214) .sup.1H NMR (ppm) (CHCl.sub.3-d): 7.45-7.37 (1H, m), 7.22-7.08 (4H, m), 6.90 (1H, s), 6.69 (1H, s), 5.58 (1H, s), 4.16 (2H, q, J=7.1 Hz), 3.90 (3H, s), 3.86 (2H, t, J=6.5 Hz), 2.92 (2H, t, J=6.5 Hz), 1.18 (3H, t, J=7.1 Hz).

(b). ethyl 9-(allyloxy)-3-(3-fluorophenyl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

(215) Allyl chloride (24 l) was added to a solution of intermediate 32a (76 mg) and potassium carbonate (42 mg) in DMF (2 ml), heating to 60 C. for 18 hours. The mixture was concentrated to dryness under vacuum and the residue was suspended in water. The crude product was extracted into ethyl acetate (3) and the combined organic layers were passed through a hydrophobic frit and concentrated under vacuum to give the product as an off white solid

(216) Yield: 82 mg

(217) .sup.1H NMR (ppm) (CHCl.sub.3-d): 7.45-7.37 (1H, m), 7.20-7.09 (4H, m), 6.89 (1H, s), 6.71 (1H, s), 6.18-6.07 (1H, m), 5.46 (1H, dq, J=17.3, 1.6 Hz), 5.34 (1H, d, J=1.5 Hz), 4.67 (2H, d, J=5.4 Hz), 4.16 (2H, q, J=7.12 Hz), 3.90-3.82 (5H, m), 2.97-2.89 (2H, m), 1.18 (3H, t, J=7.1 Hz).

(c). 9-(allyloxy)-3-(3-fluorophenyl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylic Acid

(218) Sodium hydroxide (23 mg) in water (0.3 ml) was added to a solution of intermediate 32b (80 mg) in ethanol (3 ml). The mixture was heated to 80 C. for 3 hours. The solvents were removed under vacuum and the residue redissolved in water and washed with diethyl ether (3). The aqueous layer was acidified to pH 4 with a aqueous 4M HCl solution and extracted into DCM (3) and ethyl acetate (3). The combined organic layers were passed through a hydrophobic frit and concentrated under vacuum to give the product, as an off white solid

(219) Yield: 73 mg

(220) MS (ESI) m/z: 394 (M+H).sup.+.

(d). (R)-9-(allyloxy)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(221) 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (52 mg) was added to a solution of intermediate 32c (71 mg), diisopropylethylamine (94 l), 1-hydroxybenzotriazole (37 mg) and D-tryptophanol (41 mg) in dry DMF (2 ml). The reaction mixture was stirred at room temperature for 60 hours. The solvent was removed under vacuum to give a yellow oil. The oil was redissolved in ethyl acetate and washed with water (3). The combined organic layers were passed through a hydrophobic frit and concentrated under vacuum. The crude residue was redissolved in MeCN and purified by preparative HPLC eluting with acetonitrile and water to give the product as an off-white solid

(222) Yield: 14 mg, 9%.

(223) MS (ESI) m/z: 566 (M+H).sup.+.

(224) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.08 (1H, s), 7.57 (1H, d, J=7.9 Hz), 7.36 (1H, d, J=8.1 Hz), 7.26-7.15 (2H, m), 7.11 (1H, t, J=7.5 Hz), 7.05-6.96 (4H, m), 6.88 (1H, d, J=2.3 Hz), 6.70 (2H, d, J=11.1 Hz), 6.17-6.06 (1H, m), 5.69 (1H, d, J=7.0 Hz), 5.45 (1H, dd, J=17.3, 1.7 Hz), 5.32 (1H, dd, J=10.5, 1.5 Hz), 4.65 (2H, d, J=5.4 Hz), 4.37-4.29 (1H, m), 3.88 (3H, s), 3.77 (2H, t, J=6.6 Hz), 3.70-3.55 (2H, m), 3.06 (1H, s), 2.94-2.80 (4H, m).

Example 33

(R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(2-methoxyethoxy)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(225) Compound 33 was prepared in an analogous fashion as described for example 32.

(226) MS (ESI) m/z: 584 (M+H).sup.+.

(227) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.35 (1H, s), 7.56 (1H, d, J=7.9 Hz), 7.34 (1H, d, J=8.1 Hz), 7.26-7.14 (2H, m), 7.13-6.95 (5H, m), 6.87 (1H, d, J=2.3 Hz), 6.68 (2H, d, J=6.6 Hz), 5.76 (1H, d, J=7.0 Hz), 4.37-4.27 (1H, m), 4.20 (2H, t, J=4.8 Hz), 3.85 (3H, s), 3.81 (2H, t, J=4.8 Hz), 3.75 (2H, t, J=6.5 Hz), 3.68-3.53 (2H, m), 3.47 (3H, s), 2.95-2.78 (4H, m).

Example 34

(R)-9-(benzyloxy)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(228) Compound 34 was prepared in an analogous fashion as described for example 32.

(229) MS (ESI) m/z: 616 (M+H).sup.+.

(230) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.41 (1H, s), 7.53 (1H, d, J=7.9 Hz), 7.45 (2H, d, J=7.5 Hz), 7.35 (2H, t, J=7.5 Hz), 7.30-7.23 (2H, m), 7.22-7.09 (2H, m), 7.10-7.02 (2H, m), 6.98-6.91 (3H, m), 6.79 (1H, d, J=2.4 Hz), 6.67 (2H, d, J=4.2 Hz), 5.76 (1H, d, J=7.1 Hz), 5.13 (2H, s), 4.36-4.26 (1H, m), 3.85 (3H, s), 3.69 (2H, t, J=6.4 Hz), 3.62-3.48 (2H, m), 3.39 (1H, s), 2.91-2.72 (4H, m).

Example 35

(R)-9-(cyclopentylmethoxy)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(231) Compound 35 was prepared in an analogous fashion as described for example 32.

(232) MS (ESI) m/z: 594 (M+H).sup.+.

(233) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.01 (1H, s), 7.57 (1H, d, J=7.9 Hz), 7.36 (1H, d, J=8.10 Hz), 7.24-7.17 (2H, m), 7.12 (1H, t, J=7.5 Hz), 7.08-6.96 (4H, m), 6.88 (1H, d, J=2.3 Hz), 6.75 (1H, s), 6.68 (1H, s), 5.68 (1H, d, J=6.9 Hz), 4.83-4.78 (1H, m), 4.36-4.30 (1H, m), 3.85 (3H, s), 3.77 (2H, t, J=6.6 Hz), 3.71-3.55 (2H, m), 3.06 (1H, s), 2.94-2.80 (4H, m), 2.04-1.90 (6H, m), 1.91-1.82 (2H, m).

Example 36

(R)-9-(cyclopropylmethoxy)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(234) Compound 36 was prepared in an analogous fashion as described for example 32.

(235) MS (ESI) m/z: 580 (M+H).sup.+.

(236) .sup.1H NMR (ppm) (CHCl.sub.3-d): 7.99 (1H, s), 7.58 (1H, d, J=7.9 Hz), 7.37 (1H, d, J=8.1 Hz), 7.28-7.18 (2H, m), 7.12 (1H, t, J=7.5 Hz), 7.09-6.99 (4H, m), 6.89 (1H, d, J=2.3 Hz), 6.70 (2H, d, J=9.9 Hz), 5.69 (1H, d, J=6.9 Hz), 4.35-4.30 (1H, m), 3.93-3.86 (5H, m), 3.78 (2H, t, J=6.5 Hz), 3.71-3.65 (1H, m), 3.62-3.55 (1H, m), 3.03 (1H, t, J=5.4 Hz), 2.94-2.83 (4H, m), 1.40-1.35 (1H, m), 0.71-0.65 (2H, m), 0.43-0.38 (2H, m).

Example 37

3-(3-fluorophenyl)-N((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(pentan-2-yloxy)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(237) Compound 37 was prepared in an analogous fashion as described for example 32.

(238) MS (ESI) m/z: 596 (M+H).sup.+.

(239) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.01 (1H, s), 7.57 (1H, d, J=7.9 Hz), 7.37 (1H, d, J=8.1 Hz), 7.21 (2H, t, J=7.6 Hz), 7.12 (1H, t, J=7.5 Hz), 7.08-6.98 (4H, m), 6.88 (1H, d, J=2.3 Hz), 6.74 (1H, s), 6.69 (1H, s), 5.68 (1H, d, J=6.9 Hz), 4.41-4.29 (2H, m), 3.85 (3H, s), 3.78 (2H, t, J=6.6 Hz), 3.71-3.65 (1H, m), 3.62-3.55 (1H, m), 3.10 (1H, t, J=5.4 Hz), 2.93-2.83 (4H, m), 1.86-1.50 (4H, m), 1.35 (3H, dd, J=6.1, 2.0 Hz), 1.03-0.94 (3H, m).

Example 38

(R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-(2-hydroxyethoxy)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(240) Compound 38 was prepared in an analogous fashion as described for example 32.

(241) MS (ESI) m/z: 570 (M+H).sup.+.

(242) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.06 (1H, s), 7.58 (1H, d, J=7.9 Hz), 7.37 (1H, d, J=8.1 Hz), 7.25-7.18 (2H, m), 7.14-6.97 (5H, m), 6.91 (1H, d, J=2.3 Hz), 6.69 (2H, d, J=9.4 Hz), 5.71 (1H, d, J=6.9 Hz), 4.36-4.30 (1H, m), 4.19 (2H, t, J=4.5 Hz), 3.98 (2H, t, J=4.3 Hz), 3.87 (3H, s), 3.78 (2H, t, J=6.5 Hz), 3.71-3.55 (2H, m), 3.07 (1H, s), 2.97-2.82 (4H, m), 2.58 (1H, s).

Example 39

(R)-9-(2-(dimethylamino)ethoxy)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(243) Compound 39 was prepared in an analogous fashion as described for example 32.

(244) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.47 (1H, s), 7.59 (1H, d, J=7.9 Hz), 7.38 (1H, d, J=8.0 Hz), 7.31-7.15 (2H, m), 7.15-6.98 (5H, m), 6.95 (1H, s), 6.68 (1H, s), 6.60 (1H, s), 5.77 (1H, s), 4.46-4.18 (1H, m), 4.22 (2H, t, J=6.1 Hz), 3.86 (3H, s), 3.78 (2H, t, J=6.6 Hz), 3.74-3.57 (6H, m), 2.43 (6H, s).

(245) ##STR00033##

Example 40

9-(2,3-dihydroxypropoxy)-N((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(a). ethyl 9-(allyloxy)-8-methoxy-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

(246) Compound 40a was prepared in an analogous fashion as described for compound 32b

(247) .sup.1H NMR (ppm) (CHCl.sub.3-d): 7.48 (1H, dd, J=4.1, 2.3 Hz), 7.15-7.10 (3H, m), 6.89 (1H, s), 6.71 (1H, s), 6.18-6.07 (1H, m), 5.48 (1H, dd, J=17.2, 1.7 Hz), 5.32 (1H, dd, J=10.5, 1.5 Hz), 4.67 (2H, dt, J=5.4, 1.5 Hz), 4.19 (2H, q, J=7.1 Hz), 3.94 (2H, t, J=6.60 Hz), 3.89 (3H, s), 2.94 (2H, t, J=6.6 Hz), 1.21 (3H, t, J=7.1 Hz).

(b). ethyl 9-(2,3-dihydroxypropoxy)-8-methoxy-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

(248) Osmium tetraoxide (1.5 mg) was added to a solution of intermediate 40a (100 mg) and N-methylmorpholine N-oxide (42 mg) in a 1:1 mixture of water and THF (2 ml). The reaction tube was sealed and stirred at room temperature for 16 hours. The crude product was extracted into DCM (3) and the combined organics were passed through a hydrophobic frit and purified by chromatography on silica gel eluting with DCM and increasing amounts of methanol.

(249) Yield: 45 mg

(250) MS (ESI) m/z: 444 (M+H).sup.+.

(251) .sup.1H NMR (ppm) (CHCl.sub.3-d): 7.48 (1H, t, J=3.3 Hz), 7.16-7.11 (3H, m), 6.91 (1H, s), 6.72 (1H, s), 4.26-4.09 (5H, m), 3.94 (2H, t, J=6.5 Hz), 3.96-3.75 (5H, m), 3.15 (1H, s), 2.95 (2H, t, J=6.6 Hz), 2.45 (1H, s), 1.22 (3H, t, J=7.1 Hz).

(c). 9-(2,3-di hydroxypropoxy)-8-methoxy-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylic Acid

(252) Sodium hydroxide (12 mg) in water (0.2 ml) was added to a solution of intermediate 40b (44 mg) in ethanol (2 ml). The reaction mixture was heated to 80 C. for 3 hours. The solvents were removed under vacuum and the residue redissolved in water, washing with diethyl ether (2). The aqueous layer was acidified to pH 4 with a aqueous 4M HCl solution and the product extracted into ethyl acetate (3). The combined organics were passed through a hydrophobic frit and concentrated under vacuum to give the product as a yellow solid.

(253) Yield: 36 mg

(254) .sup.1H NMR (ppm) (CHCl.sub.3-d): 7.49 (1H, dd, J=4.9, 1.5 Hz), 7.18-7.11 (3H, m), 6.95 (1H, s), 6.72 (1H, s), 4.25-4.19 (1H, m), 4.14-4.08 (2H, m), 3.94 (2H, t, J=6.6 Hz), 3.87 (3H, s), 3.84 (2H, dd, J=7.1, 3.7 Hz), 2.95 (2H, t, J=6.6 Hz).

(d). 9-(2,3-dihydroxypropoxy)-N((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(255) 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (23 mg) was added to a solution of intermediate 40c (33 mg), diisopropylethylamine (42 l), 1-hydroxybenzotriazole (16 mg), and D-tryptophanol (18 mg) in dry DMF (1 ml). The mixture was stirred at room temperature for 5 hours. The solvent was removed under vacuum and water was added, extracting with ethyl acetate (3). The combined organic layers were passed through a hydrophobic frit and concentrated to dryness under vacuum. The crude residue was redissolved in MeCN and purified by preparative HPLC eluting with acetonitrile and water to give the product as an off white solid.

(256) Yield: 28 mg

(257) MS (ESI) m/z: 588 (M+H).sup.+.

(258) .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.77 (1H, s), 7.68 (1H, t, J=3.3 Hz), 7.61 (1H, d, J=7.9 Hz), 7.32 (1H, d, J=8.1 Hz), 7.17-7.11 (3H, m), 7.09-6.95 (4H, m), 6.90 (2H, s), 4.97 (1H, d, J=5.1 Hz), 4.70 (2H, q, J=6.1 Hz), 4.15-4.09 (1H, m), 4.08-3.95 (1H, m), 3.92-3.89 (1H, m), 3.87-3.81 (3H, m), 3.78 (3H, s), 3.50-3.40 (2H, m), 3.42-3.38 (1H, m), 3.35-3.28 (1H, m), 2.94-2.88 (3H, m), 2.82-2.77 (1H, m).

Example 41

9-(2,3-dihydroxypropoxy)-N((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(a). ethyl 9-(allyloxy)-8-methoxy-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

(259) Example 41 was prepared in an analogous fashion as described for example 32 starting from compound 40a.

(260) .sup.1H NMR (ppm) (CHCl.sub.3-d): 7.48 (1H, dd, J=4.1, 2.3 Hz), 7.15-7.10 (3H, m), 6.89 (1H, s), 6.71 (1H, s), 6.18-6.07 (1H, m), 5.48 (1H, dd, J=17.2, 1.7 Hz), 5.32 (1H, dd, J=10.5, 1.5 Hz), 4.67 (2H, dt, J=5.4, 1.5 Hz), 4.19 (2H, q, J=7.1 Hz), 3.94 (2H, t, J=6.60 Hz), 3.89 (3H, s), 2.94 (2H, t, J=6.6 Hz), 1.21 (3H, t, J=7.1 Hz).

(261) ##STR00034##

Example 42

(R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(pyridin-3-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(a). 3-Methoxy-4-nitro-benzaldehyde

(262) A mixture of 3-hydroxy-4-nitrobenzaldehyde (51.3 g), iodomethane (38.3 ml) and potassium carbonate (85 g) in DMF (250 ml) was stirred at 60 C. for 1 h. The reaction mixture was cooled to room temperature and poured into water. The solids were collected by filtration and dried in vacuo (50 C.).

(263) Yield: 49.7 g.

(b). 4-Amino-3-methoxy-benzaldyde

(264) Iron (112 g) was added to a mixture of the product of example 42a (49.7 g) and ammonium chloride (103 g) in ethanol (500 ml) and water (500 ml). After stirring with a mechanical stirrer at 78 C. for 2 h, the reaction mixture was cooled to room temperature and extracted with diethyl ether. The combined organic layers were concentrated in vacuo and water was added to the residue. The solids were collected by filtration and dried in vacuo (50 C.).

(265) Yield: 38.3 g.

(c). 4-Bromo-3-methoxy-benzaldehyde

(266) A solution of the product of example 42b (38.3 g) in acetonitrile (600 ml) was added dropwise to a mixture of n-butyl nitrite (43.1 ml) and copper(I) bromide (63.6 g) in acetonitrile (1300 ml). After stirring for 18 h at room temperature, the reaction mixture was diluted with ethyl acetate and washed with an aqueous 1M HCl solution. The organic layer was separated and washed with brine, dried (MgSO.sub.4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel in heptane/ethyl acetate [1:1 (v/v)].

(267) Yield: 27.4 g.

(268) MS (ESI) m/z: 215, 217 (M+H).sup.+.

(d). 1-Bromo-2-methoxy-4-((E)-2-nitro-vinyl)-benzene

(269) A mixture of the product of example 42c (27.4 g), ammonium acetate (10.8 g) and nitromethane (35 ml) in acetic acid (125 ml) was stirred at 80 C. for 18 h. The reaction mixture was cooled to room temperature and poured into water. The solids were collected by filtration and dissolved in dichloromethane. The organic layer was washed with brine, dried (MgSO.sub.4), filtered and concentrated in vacuo.

(270) Yield: 29.8 g.

(e). 2-(4-Bromo-3-methoxy-phenyl)-ethylamine

(271) At 0 C. and under a nitrogen atmosphere a solution of borane-THF complex (262 ml 1 M) was added dropwise to a solution of the product of example 42d (15 g) in THF (250 ml). After the addition, the ice bath was removed. Sodium borohydride (0.11 g) was added (a slight exothermic reaction took place). After stirring for 18 h at 65 C. under a nitrogen atmosphere, the reaction mixture was cooled to room temperature and poured into an aqueous 2M HCl solution. After stirring for 1.5 h at 70 C., the reaction mixture was cooled to room temperature and extracted twice with diethyl ether. The aqueous layer was made basic with solid sodium hydroxide H until pH=10 and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO.sub.4), filtered and concentrated in vacuo.

(272) MS (ESI) m/z: 230, 232 (M+H).sup.+.

(f). N-(4-bromo-3-methoxyphenethyl)acetamide

(273) Compound 42e (15.6 g) was dissolved in DCM (200 ml). DIPEA (20.31 ml) was added and acetyl chloride (5.01 ml) was added dropwise at 0 C. under nitrogen atmosphere. The reaction mixture was allowed to warm up to ambient temperature over 1 hour. The reaction mixture was washed sequentially with a aqueous 0.2M HCl solution, a aqueous saturated NaHCO.sub.3 solution, water and brine, dried (MgSO.sub.4) and filtered. The solvent were removed under vacuum to yield a pale yellow oil which was triturated with diethylether. The solid was filtered and dried to constant mass.

(274) Yield: 14.75 g

(g). 7-bromo-6-methoxy-1-methyl-3,4-dihydroisoquinoline

(275) Phosphorus oxychloride (7.26 g) was added to a solution of compound 42f (5.42 g) in toluene (33 ml) before heating to 110 C. for 2 hours. The solution was allowed to cool to ambient temperature before being concentrated to dryness under vacuum to give a yellow residue. The crude residue was triturated with toluene (250 ml) to give product the as a pale yellow solid

(276) Yield: 8.13 g

(277) .sup.1H NMR (ppm) (DMSO-d): 8.27 (1H, s), 7.34 (1H, s), 4.04 (3H, s), 3.85-3.77 (2H, m), 3.15-3.06 (2H, m), 2.79 (3H, s).

(h). ethyl 9-bromo-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

(278) Ethyl-3-bromopyruvate (0.87 g) was added to a solution of intermediate 42g (1.0 g), potassium carbonate (5.0 g) and triethylamine (0.72 g) in acetonitrile (20 ml) and then heated to 100 C. for 2 hours. The reaction mixture was allowed to cool to ambient temperature and was then filtered through celite, washing the filter pad thoroughly with acetonitrile. The dark filtrate was concentrated to dryness to give an oil which was partitioned between ethyl acetate (20 ml) and water (20 ml). The organic phase was separated and concentrated to dryness under vacuum to give the product as a pale green oil

(279) Yield: 250 mg

(280) .sup.1H NMR (ppm) (CHCl.sub.3-d): 7.73 (1H, s), 7.31 (1H, d, J=1.62 Hz), 6.84-6.81 (1H, m), 6.79-6.74 (1H, m), 4.42-4.28 (2H, m), 4.15-4.07 (2H, m), 3.97-3.90 (3H, m), 3.09-3.01 (2H, m), 1.43-1.32 (3H, m).

(i). ethyl 8-methoxy-9-(pyridin-3-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

(281) [1,1-Bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (44 mg) was added to a degassed solution of intermediate 42h (200 mg), pyridine-3-boronic acid (104 mg) and potassium carbonate (156 mg) in 9:1 dioxane:water (5.3 ml). The reaction mixture was degassed for 15 minutes with nitrogen before sealing and then heating to 85 C. for 90 minutes. The solvents were removed under vacuum and the residue obtained was partitioned between water and ethyl acetate. The organic phase was concentrated to dryness under vacuum to give a dark oil that was purified by chromatography on silica gel eluting with petrol and increasing amounts of ethyl acetate to give the product as a colourless oil.

(282) Yield: 205 mg

(283) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.81-8.79 (1H, m), 8.58 (1H, dd, J=4.84, 1.67 Hz), 7.88-7.84 (1H, m), 7.63-7.39 (1H, m), 7.38-7.32 (2H, m), 6.85 (2H, d, J=1.97 Hz), 4.38-4.25 (2H, m), 4.17-4.08 (2H, m), 3.84 (3H, s), 3.17-3.10 (2H, m), 1.36 (3H, t, J=7.12 Hz).

(j). 8-methoxy-9-(pyridin-3-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylic Acid

(284) A aqueous 2N sodium hydroxide solution (1 ml) was added to a solution of intermediate 42i (190 mg) in ethanol (3 ml) and the mixture was then heated to 75 C. for three hours. The solvents were removed under vacuum and the residue obtained was suspended in water (5 ml) and the pH was adjusted to pH 1 with a aqueous 1 N HCl solution. A solid precipitate was filtered, washed with water and dried in air to give the product as an off white solid.

(285) Yield: 148 mg

(286) .sup.1H NMR (ppm) (DMSO-d.sub.6): 9.10 (1H, d, J=2.00 Hz), 8.85 (1H, d, J=5.53 Hz), 8.70 (1H, d, J=8.14 Hz), 8.05 (1H, dd, J=8.13, 5.53 Hz), 7.87 (1H, s), 7.49 (1H, d, J=1.65 Hz), 7.22 (1H, s), 6.94 (1H, d, J=1.66 Hz), 4.22-4.15 (2H, m), 3.92-3.87 (3H, m), 3.15 (2H, t, J=6.49 Hz).

(k). (R)N-(1-(tert-butyldimethylsilyloxy)-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(pyridin-3-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(287) 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (130 mg) was added to a solution of intermediate 42j (140 mg), 1-hydroxybenzotriazole (64 mg) and diisopropylamine (146 mg) in DMF (1.5 ml). The mixture was stirred for 5 minutes before the addition of 6b (133 mg), stirring for a further 18 hours. The reaction mixture was partitioned between ethyl acetate and water and the aqueous phase was re-extracted with ethyl acetate. The combined organic layers were washed with water and then concentrated to dryness under vacuum to give an orange oil. The crude oil was purified by chromatography on silica gel eluting with petrol and increasing amounts of ethyl acetate to give the product as a white foam.

(288) Yield: 165 mg

(289) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.79 (1H, d, J=2.21 Hz), 8.59 (1H, dd, J=4.82, 1.70 Hz), 8.07 (1H, s), 7.89-7.81 (2H, m), 7.38-7.34 (3H, m), 7.19-7.08 (4H, m), 6.83 (1H, s), 6.40 (1H, d, J=1.76 Hz), 6.12 (1H, d, J=8.52 Hz), 4.47 (1H, dd, J=8.58, 5.31 Hz), 4.15-4.07 (2H, m), 3.84 (3H, s), 3.71 (1H, dd, J=9.85, 2.99 Hz), 3.57 (1H, dd, J=9.86, 5.40 Hz), 3.22-3.05 (4H, m), 0.97 (9H, d, J=1.44 Hz), 0.08 (6H, d, J=7.63 Hz).

(l). (R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(pyridin-3-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(290) Palladium (II) acetate (1.9 mg) was added to a degassed solution of intermediate 42k (50 mg), 3-fluoroiodobenzene (26.0 mg), cesium carbonate (58.6 mg) and triphenylphosphine (4.32 mg) in dioxane (3 ml) and the mixture was degassed with nitrogen for a further 15 minutes. The reaction tube was sealed and then heated to 95 C. for 18 hours. The reaction was determined to be incomplete, hence a further aliquot of palladium (II) acetate (1.9 mg), triphenylphosphine (4.32 mg) and 3-fluoroiodobenzene (26.0 mg) were added. The mixture was degassed with nitrogen for 15 minutes, sealed and then heated to 95 C. for 4 hours. The solvents were removed under vacuum and the residue obtained was partitioned between ethyl acetate and water. The aqueous phase was re-extracted with ethyl acetate and the combined organic layers were washed with water and then concentrated to dryness giving a dark brown oil. The oil was redissolved in THF (1 ml) before the addition of tetrabutylammonium fluoride in THF (0.3 ml), stirring for 2 hours. The solvents were removed under vacuum to give a dark oil that was purified by preparative HPLC eluting with acetonitrile and water to give the target compound as a off white solid.

(291) Yield: 3.5 mg

(292) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.81 (1H, s), 8.61 (1H, s), 8.13 (1H, s), 7.89 (1H, d, J=7.90 Hz), 7.61-7.57 (1H, m), 7.43-7.31 (3H, m), 7.16-7.00 (6H, m), 6.93 (1H, d, J=2.23 Hz), 6.82 (1H, s), 6.59 (1H, s), 5.77 (1H, d, J=6.82 Hz), 4.35-4.29 (1H, m), 3.90-3.78 (5H, m), 3.69 (1H, dd, J=10.97, 3.63 Hz), 3.61 (1H, dd, J=10.97, 6.03 Hz), 3.04-2.83 (4H, m), 2.61 (1H, s).

(293) ##STR00035##

Example 43

(R)-9-ethyl-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(a). ethyl 8-methoxy-9-vinyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

(294) Tetrakis(triphenylphosphine)palladium(0) (17 mg) was added to a degassed solution of intermediate 42h (53 mg), vinylboronic acid (41 l) and potassium carbonate (37 mg) in a 10:1 mixture of DME:water (2 ml). The mixture was degassed by gently bubbling through nitrogen for a further 30 minutes before sealing under nitrogen and then heating to 90 C. for 18 hours. The reaction was allowed to cool to ambient temperature then water was added, extracting with ethyl acetate (3). The combined organic layers were passed through a hydrophobic frit and concentrated under vacuum to give a dark brown residue. The residue was purified by chromatography on silica gel eluting with petrol and increasing amounts of ethyl acetate to give product the as an orange solid.

(295) Yield: 64 mg

(296) .sup.1H NMR (ppm) (CHCl.sub.3-d): 7.63 (1H, s), 7.28 (1H, d, J=1.6 Hz), 7.01 (1H, dd, J=17.8, 11.2 Hz), 6.84 (1H, d, J=1.7 Hz), 6.69 (1H, s), 5.77 (1H, dd, J=17.7, 1.5 Hz), 5.29 (1H, dd, J=11.1, 1.5 Hz), 4.30 (2H, q, J=7.1 Hz), 4.08 (2H, t, J=6.6 Hz), 3.85 (3H, s), 3.05 (2H, t, J 20=6.5 Hz), 1.35 (3H, t, J=7.1 Hz).

(b). ethyl 9-ethyl-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

(297) 10% Palladium on carbon (50 mg) was added to a solution of intermediate 43a (62 mg) in ethanol (5 ml). The reaction vessel was flushed with nitrogen then charged with hydrogen and stirred for 72 hours. The reaction mixture was filtered through celite and the solvent was then removed under vacuum. The residue was dissolved in diethyl ether and washed with water (3). The organic layer was passed through a hydrophobic frit and then concentrated under vacuum. The residue was purified by chromatography on silica gel eluting with petrol and increasing amounts of ethyl acetate to give the product as a colourless oil/solid.

(298) Yield: 57 mg

(299) .sup.1H NMR (ppm) (CHCl.sub.3-d): 7.33 (1H, s), 7.27 (1H, d, J=1.7 Hz), 6.80 (1H, d, J=1.7 Hz), 6.66 (1H, s), 4.29 (2H, q, J=7.1 Hz), 4.07 (2H, t, J=6.6 Hz), 3.83 (3H, s), 3.03 (2H, t, J=6.6 Hz), 2.63 (2H, q, J=7.5 Hz), 1.35 (3H, t, J=7.1 Hz), 1.21 (3H, t, J=7.5 Hz).

(c). ethyl 9-ethyl-3-(3-fluorophenyl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

(300) Palladium (II) acetate (4 mg) was added to a degassed solution of intermediate 43b (57 mg), triphenylphosphine (10 mg), 1-fluoro-3-iodobenzene (22 l) and cesium carbonate (124 mg) in dioxane (2 ml). The mixture was further degassed by bubbling through a gentle stream of nitrogen for 30 minutes. The reaction tube was sealed under nitrogen and then heated to 90 C. for 16 hours. LC-MS analysis indicated the reaction was only 50% complete, hence the mixture was degassed with nitrogen for 15 minutes before the addition a further aliquot of 1-fluoro-3-iodobenzene (22 l) and palladium (II) acetate (4 mg). The mixture was degassed for a further 30 minutes before sealing under nitrogen and heating to 100 C. for 24 hours. Water was added and the product was extracted into ethyl acetate (3). The combined organic layers were passed through a hydrophobic frit and concentrated to dryness under vacuum. The residue was purified by chromatography on silica gel eluting with petrol and increasing amounts of ethyl acetate to give the product as an off white solid.

(301) Yield: 48 mg

(302) .sup.1H NMR (ppm) (CHCl.sub.3-d): 7.43-7.39 (2H, m), 7.19 (1H, dt, J=7.7, 1.2 Hz), 7.15-7.08 (2H, m), 6.93 (1H, s), 6.66 (1H, s), 4.16 (2H, q, J=7.1 Hz), 3.87 (2H, t, J=6.5 Hz), 3.84 (3H, s), 2.96 (2H, t, J=6.4 Hz), 2.66 (2H, q, J=7.5 Hz), 1.26-1.15 (6H, m).

(d). 9-ethyl-3-(3-fluorophenyl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylic Acid

(303) Sodium hydroxide (14 mg) in water (0.5 ml) was added to a solution of intermediate 43c (47 mg) in ethanol (5 ml) and the mixture heated to 80 C. for 3 hours. The solvents were removed under vacuum and the residue obtained was redissolved in water (10 ml), washing with diethyl ether. The aqueous phase was acidified to pH 4 with a aqueous 4M HCl solution and then extracted with DCM (3). The combined organic layers were passed through a hydrophobic frit and concentrated to dryness under vacuum to the give product as an off white solid.

(304) Yield: 42 mg

(305) .sup.1H NMR (ppm) (CHCl.sub.3-d): 11.00 (1H, s), 7.45-7.37 (2H, m), 7.18 (1H, d, J=7.7 Hz), 7.15-7.07 (2H, m), 6.96 (1H, s), 6.66 (1H, s), 3.91-3.81 (5H, m), 2.96 (2H, t, J=6.4 Hz), 2.65 (2H, dd, J=15.0, 7.5 Hz), 1.22 (3H, t, J=7.5 Hz).

(e). (R)-9-ethyl-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(306) 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (32 mg) was added to a solution of intermediate 43d (40 mg), diisopropylethylamine (58 l), 1-hydroxybenzotriazole (22 mg), and D-tryptophanol (25 mg) in dry DMF (1 ml), stirring for 70 hours at room temperature. The solvents were removed under vacuum and the residue obtained was partitioned between water and ethyl acetate. The aqueous phase was re-extracted with ethyl acetate (2) and the combined organic layers were passed through a hydrophobic frit and concentrated to dryness under vacuum. The crude residue was redissolved in MeCN and purified by preparative HPLC eluting with acetronitrile and water to give the target compound as an off white solid

(307) Yield: 27 mg

(308) MS (ESI) m/z: 538 (M+H).sup.+.

(309) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.04 (1H, s), 7.59 (1H, d, J=7.9 Hz), 7.37 (1H, d, J=8.1 Hz), 7.31 (1H, s), 7.27-7.19 (2H, m), 7.13 (1H, t, J=7.5 Hz), 7.08-6.96 (3H, m), 6.91 (1H, d, J=2.3 Hz), 6.65 (2H, d, J=8.3 Hz), 5.73 (1H, d, J=6.8 Hz), 4.35-4.28 (1H, m), 3.83 (3H, s), 3.78 (2H, t, J=6.5 Hz), 3.71-3.54 (2H, m), 3.16 (1H, s), 2.98-2.82 (4H, m), 2.66 (2H, q, J=7.5 Hz), 1.23 (3H, t, J=7.5 Hz).

Example 44

3-(3-fluorophenyl)-N((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(3-methylbutan-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(310) Compound 44 was prepared in an analogous fashion as described for example 43.

(311) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.00 (1H, s), 7.59 (1H, d, J=7.9 Hz), 7.37 (1H, d, J=8.1 Hz), 7.31 (1H, s), 7.24-7.19 (2H, m), 7.13 (1H, t, J=7.5 Hz), 7.07-6.97 (3H, m), 6.90 (1H, d, J=2.3 Hz), 6.72 (1H, s), 6.65 (1H, s), 5.72 (1H, d, J=6.9 Hz), 4.36-4.29 (1H, m), 3.83-3.74 (5H, m), 3.72-3.57 (2H, m), 3.10 (1H, t, J=5.5 Hz), 2.99-2.83 (5H, m), 1.89-1.82 (1H, m), 1.21 (3H, dd, J=7.1, 3.0 Hz), 0.96 (3H, dd, J=6.7, 2.6 Hz), 0.81 (3H, dd, J=6.7, 3.0 Hz).

Example 45

(R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(2-methylprop-1-enyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(312) Compound 45 was prepared in an analogous fashion as described for example 43, skipping reaction b

(313) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.11 (1H, s), 7.56 (1H, d, J=7.89 Hz), 7.35 (1H, d, J=8.83 Hz), 6.87 (1H, d, J=2.27 Hz), 6.72 (1H, s), 6.66 (1H, s), 6.29 (1H, s), 5.71 (1H, d, J=6.88 Hz), 4.36-4.27 (1H, m), 3.86-3.73 (5H, m), 3.66 (1H, d, J=10.96), 3.58 (1H, dd, J=10.94, 5.88 Hz), 3.16 (1H, s), 2.98-2.79 (4H, m), 1.97 (3H, s), 1.85 (3H, s)

Example 46

(R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(3-methyl but-2-en-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(314) Compound 46 was prepared in an analogous fashion as described for example 44, skipping reaction b.

(315) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.02 (1H, s), 7.59 (1H, d, J=7.9 Hz), 7.37 (1H, d, J=8.1 Hz), 7.24-7.10 (4H, m), 7.06-6.98 (3H, m), 6.92 (1H, d, J=2.3 Hz), 6.69 (1H, s), 6.58 (1H, s), 5.73 (1H, d, J=6.8 Hz), 4.32-4.27 (1H, m), 3.82-3.78 (5H, m), 3.70-3.56 (2H, m), 3.20-3.10 (1H, s), 2.97-2.82 (4H, m), 1.94 (3H, s), 1.87 (3H, s), 1.55 (3H, s)

(316) ##STR00036## ##STR00037##

Example 47

(R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(morpholine-4-carbonyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(a). ethyl 8-methoxy-9-(morpholine-4-carbonyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

(317) A mixture of compound 42h (105 mg), morpholine (39 l), xantphos (35 mg), palladium (II) acetate (6.7 mg) and sodium carbonate (48 mg) in toluene (2 ml) was saturated with carbon monoxide by bubbling gas through it for 20 minutes. The mixture was then heated at 80 C. overnight. The reaction mixture was diluted with water and the extracted with ethyl acetate (3). The combined organic layers were passed through a hydrophobic frit and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with DCM containing increasing amounts of methanol.

(318) Yield: 90 mg

(b). ethyl 3-(3-fluorophenyl)-8-methoxy-9-(morpholine-4-carbonyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

(319) Palladium (II) acetate (5.2 mg) was added to a degassed solution of intermediate 47a (88 mg), triphenylphosphine (12 mg), 1-fluoro-3-iodobenzene (27 l) and cesium carbonate (150 mg) in dioxane (2 ml). The mixture was further degassed by bubbling through a gentle stream of nitrogen for 30 minutes. The reaction tube was sealed under nitrogen and then heated to 80 C. for 16 hours. LC-MS analysis indicated the reaction was 50% complete, hence the mixture was degassed with nitrogen for 15 minutes before the addition a further aliquot of 1-fluoro-3-iodobenzene (22 l) and palladium (II) acetate (4 mg). The mixture was degassed for a further 30 minutes before sealing under nitrogen and heating to 80 C. for 4 hours. Water was added and the product was extracted into ethyl acetate (3). The combined organic layers were passed through a hydrophobic frit and concentrated to dryness under vacuum. The residue was purified by chromatography on silica gel eluting with petrol and increasing amounts of ethyl acetate to give the product, as an off white solid.

(320) Yield: 48 mg

(c). 3-(3-fluorophenyl)-8-methoxy-9-(morpholine-4-carbonyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylic Acid

(321) A aqueous 2N sodium hydroxide solution (0.5 ml) was added to a solution of intermediate 47b (31 mg) in ethanol (2 ml) and the mixture heated to 50 C. for 18 hours. The reaction mixture was acidified with a aqueous solution of 2M HCl and was extracted with ethyl acetate. The organic layer was washed with water and dried by passing through a hydrophobic frit and concentrated in vacuo, to yield an off-white powder.

(322) Yield: 29.6 mg

(d). (R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(morpholine-4-carbonyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(323) 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (19 mg) was added to a solution of intermediate 47c (30 mg), triethylamine (27 l), 1-hydroxybenzotriazole (9.3 mg), and D-tryptophanol (15 mg) in dry DMF (1 ml), stirring for 70 hours at room temperature. The solvents were removed under vacuum and the residue obtained was partitioned between water and ethyl acetate. The aqueous phase was re-extracted with ethyl acetate (2) and the combined organics were passed through a hydrophobic frit and concentrated to dryness under vacuum. The residue was purified by chromatography on silica gel eluting with DCM and increasing amounts of methanol (max. 10%). The pure fractions were collected, yielding in the desired product as an off-white solid.

(324) Yield: 17 mg

(325) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.14 (1H, s), 7.59 (1H, d, J=7.86 Hz), 7.42-7.35 (2H, m), 7.21-7.10 (3H, m), 7.09-7.00 (4H, m), 6.94 (1H, s), 6.73 (1H, s), 6.58 (1H, s), 5.80-5.69 (1H, m), 4.31 (1H, s), 3.89-3.74 (6H, m), 3.68 (2H, s), 3.62 (1H, s), 3.31 (2H, s), 3.18 (1H, d, J=14.81), 3.02-2.83 (4H, m)

Example 48

(R)-3-(3-fluorophenyl)-N2-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-N9,N9-dimethyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2,9-dicarboxamide

(326) Compound 48 was prepared in an analogous fashion as described for example 47.

(327) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.16 (1H, s), 7.58 (1H, d, J=7.89 Hz), 7.40-7.31 (2H, m), 7.21 (1H, s), 7.15-6.99 (4H, m), 6.94 (1H, d, J=2.29 Hz), 6.73-6.68 (1H, m), 6.53 (1H, s), 5.77 (1H, d, J=6.61 Hz), 4.30 (1H, t, J=6.40 Hz), 3.86-3.75 (4H, m), 3.72-3.65 (2H, m), 3.63-3.56 (1H, m), 3.25 (1H, s), 3.20-3.14 (3H, m), 2.99-2.82 (6H, m)

(328) TABLE-US-00001 0 50 49 51 56 52 55 53 54 x 57 x 58 x 59

Example 49

(R)N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(pyrimidin-5-yl)-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(a). ethyl 9-isopropoxy-8-methoxy-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

(329) To a solution of compound 2b (1 g) in dioxane (20 ml) were added 2-bromothiophene (775 mg), triphenylphosphine (180 mg) and cesium carbonate (2.06 g). The reaction mixture was degassed for 10 minutes under N.sub.2. Then palladium(II) acetate (80 mg) was added and the mixture was degassed for another 10 minutes under N.sub.2. The reactant was heated under reflux for 20 hours. The mixture was cooled to room temperature, diluted with ethyl acetate and filtered. The filtrate was washed with water and brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to give the crude product which was purified by chromatography on silica gel (petrol:ethyl acetate=10:1-6:1) to give the desired product

(330) Yield: 550 mg

(331) MS (ESI) m/z: 412 (M+H).sup.+.

(b). ethyl 9-hydroxy-8-methoxy-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

(332) To a solution of compound 49a (282 mg) in DCM (7 ml) was added aluminium chloride (365 mg) at 0 C. The reaction mixture was stirred at 0 C. for 2 hours. The reaction mixture was washed with water and DCM phase was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to give the desired compound the desired product.

(333) Yield: 230 mg

(334) MS (ESI) m/z: 370 (M+H).sup.+.

(335) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.99 (s, 1H), 7.74-7.75 (m, 1H), 7.20-7.22 (m, 1H), 7.17-7.19 (m, 1H), 7.05 (s, 1H), 6.86 (s, 1H), 6.77 (s, 1H), 4.04-4.09 (m, 2H), 3.87 (t, 2H, J=6.6 Hz), 3.78 (s, 3H), 2.89 (t, 2H, J=6.6 Hz), 1.13 (t, 2H, J=7.0 Hz).

(c). ethyl 8-methoxy-3-(thiophen-2-yl)-9-(trifluoromethylsulfonyloxy)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

(336) To a solution of compound 49b (20 mg) in DCM (2 ml) were added trifluoromethanesulfonic anhydride (16.8 mg) and pyridine (6.4 mg). The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was washed with water, and the DCM phase was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to give the desired compound.

(337) Yield: 23 mg

(338) MS (ESI) m/z: 502 (M+H).sup.+.

(339) 1HNMR (CDCl3 400 MHz) 7.39 (s, 1H) 7.26 (s, 1H), 7.08 (s, 1H), 7.01 (s, 1H), 6.92 (s, 1H), 6.87 (s, 1H), 4.19 (m, 2H), 3.98 (t, 2H, J=6.56 Hz), 3.92 (s, 3H), 3.01 (t, 2H, J=6.63 Hz), 1.29 (d, 5H, J=6.94 Hz), 1.21 (t, 4H, J=7.17 Hz).

(d). ethyl 8-methoxy-9-(pyrimidin-5-yl)-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

(340) To a solution of compound 49c (40 mg) in dioxane/water (5 ml/0.5 ml) was added pyrimidin-5-ylboronic acid (11.8 mg), (tetrakis(triphenylphosphine)palladium(0) (11 mg) and Na.sub.2CO.sub.3 (10 mg). The reaction mixture was heated to reflux for 2 hours. The mixture was cooled to room temperature and diluted with ethyl acetate and filtered. The filtrate was washed with water and brine. The ethyl acetate layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to give the crude product which was purified by chromatography on silica gel (petrol:ethyl acetate=6:1.fwdarw.3:1) to give the desired product.

(341) Yield: 30 mg

(342) MS (ESI) m/z: 432 (M+H).sup.+.

(343) .sup.1H NMR (ppm) (CHCl.sub.3-d): 9.18 (s, 1H), 8.94 (s, 2H), 7.64-7.69 (m, 6H), 7.53-7.57 (m, 4H), 7.44-7.48 (m, 8H), 7.25 (s, 1H), 7.13-7.15 (m, 2H), 6.97 (s, 1H), 6.86 (s, 1H), 4.15-4.21 (m, 2H), 4.00 (t, 2H, J=6.6 Hz), 3.86 (s, 3H), 3.07 (t, 2H, J=6.5 Hz), 1.22 (t, 3H, J=7.1 Hz).

(e). 8-methoxy-9-(pyrimidin-5-yl)-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylic Acid

(344) To a solution of compound 49d (25 mg) in methanol (2 ml) was added aqueous sodium hydroxide solution (0.5 ml, wt 9%). The reaction mixture was heated to 40 C. for 2 hours. The reaction mixture was acidified with a aqueous 2N HCl solution (3 ml) to pH=2 and extracted with ethyl acetate, the organic phase was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to give the desired compound.

(345) Yield: 14 mg

(346) MS (ESI) m/z: 404 (M+H).sup.+.

(f). (R)N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(pyrimidin-5-yl)-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(347) To a solution of compound 49e (14 mg) in DMF (2 ml) were added tryptophanol (9 mg), triethylamine (12 mg) and HATU (15 mg). Then the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with water and extracted into ethyl acetate. The organic phase was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to give the crude product which was purified by preparative HPLC, with acetonitrile and water as eluens to give the desired product.

(348) Yield: 11 mg

(349) LCMS (EI) (M+H).sup.+ 576

(350) .sup.1H NMR (ppm) (CHCl.sub.3-d): 9.20 (s, 1H), 8.98 (s, 2H), 8.05 (s, 1H), 7.55 (d, 1H, J=7.8 Hz), 7.46 (s, 1H), 7.38 (m, 2H), 7.08-7.18 (m, 2H), 6.94-6.95 (m, 3H), 6.82 (d, 2H, J=9.1 Hz), 5.91 (d, 1H, J=6.9 Hz), 4.33 (s, 1H), 3.86 (s, 2H), 3.85 (s, 3H), 3.66-3.70 (m, 1H), 3.55-3.59 (m, 1H), 3.04 (t, 2H, J=6.5 Hz), 2.77-2.91 (m, 2H)

Example 50

(R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(pyrimidin-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(351) Compound 50 was prepared in analogous fashion as described for example 49.

(352) MS (ESI) m/z: 588 (M+H).sup.+.

(353) .sup.1H NMR (ppm) (CHCl.sub.3-d): 9.23 (s, 1H), 9.00 (s, 2H), 8.14 (s, 1H), 7.58 (d, 1H, J=7.2 Hz), 7.42 (s, 1H), 7.36 (d, 1H, J=7.4 Hz), 7.03-7.16 (m, 5H), 6.95 (s, 1H), 6.85 (s, 1H), 6.60 (s, 1H), 5.81 (d, 1H, J=6.3 Hz), 4.31-4.32 (m, 1H), 3.86 (s, 3H), 3.85 (s, 2H), 3.69-3.72 (m, 1H), 3.59-3.64 (m, 1H), 3.03 (t, 2H, J=6.3 Hz), 2.85-2.99 (m, 2H).

Example 51

(R)-9-(2-(dimethylamino)pyrimidin-5-yl)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(354) Compound 51 was prepared in an analogous fashion as described for example 49.

(355) MS (ESI) m/z: 631 (M+H).sup.+.

(356) .sup.1H NMR (ppm) (CHCl.sub.3-d): 9.24 (s, 1H), 8.85 (s, 2H), 7.58 (d, 1H, J=7.4 Hz), 7.38 (d, 1H, J=8.3 Hz), 7.29-7.33 (m, 2H), 7.03-7.15 (m, 6H), 6.81 (s, 1H), 6.28 (s, 1H), 5.96 (d, 1H, J=4.7 Hz), 4.28 (s, 1H), 3.86 (s, 3H), 3.76-3.83 (m, 2H), 3.63-3.67 (m, 2H), 3.43 (s, 6H), 3.03-3.08 (m, 1H), 2.99 (t, 2H, J=5.5 Hz), 2.85-2.91 (m, 1H).

Example 52

(R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(1-methyl-1H-pyrazol-4-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(357) Compound 52 was prepared in analogous fashion as described for example 49.

(358) MS (ESI) m/z: 590 (M+H).sup.+.

(359) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.16 (s, 1H), 8.01 (s, 1H), 7.87 (s, 1H), 7.61 (s, 1H), 7.58 (d, 1H, J=8.1 Hz), 7.39 (d, 1H, J=8.0 Hz), 7.20 (t, 1H J=8.0 Hz), 7.13 (t, 1H, J=8.0 Hz), 7.01-7.07 (m, 3H), 6.95 (s, 1H), 6.77 (s, 1H), 6.66 (s, 1H), 5.85 (d, 1H, J=6.8 Hz), 4.33-4.36 (m, 1H), 4.02 (s, 3H), 3.92 (s, 3H), 3.81 (t, 2H, J=6.6 Hz), 3.70-3.74 (m, 1H), 3.60-3.64 (m, 1H), 2.94-2.99 (m, 3H), 2.85-2.91 (m, 1H).

Example 53

3-(3-fluorophenyl)-N((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(2-methoxypyridin-3-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(360) Compound 53 was prepared in analogous fashion as described for example 49.

(361) MS (ESI) m/z: 617 (M+H).sup.+.

(362) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.20-8.22 (m, 1H), 8.01 (s, 1H), 7.57 (d, 2H, J=5.5 Hz), 7.39 (s, 1H), 7.33 (t, 1H, J=5.4 Hz), 6.97-7.10 (m, 6H), 6.90 (s, 1H), 6.79 (s, 1H), 6.59 (s, 1H), 5.72 (d, 1H, J=5.4 Hz), 4.29-4.31 (m, 1H), 3.95 (s, 3H), 3.83 (t, 2H, J=5.4 Hz), 3.78 (s, 3H), 3.66-3.69 (m, 1H), 3.57-3.61 (m, 1H), 3.14-3.15 (m, 1H), 3.00 (t, 2H, J=6.5 Hz), 2.82-3.01 (m, 2H).

Example 54

N((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(2-methoxypyridin-3-yl)-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(363) Compound 54 was prepared in analogous fashion as described for example 49.

(364) MS (ESI) m/z: 605 (M+H).sup.+.

(365) .sup.1H NMR (ppm) (CHCl.sub.3-d): 10.73 (s, 1H), 8.17-8.18 (m, 1H), 7.56-7.67 (m, 3H), 7.36 (s, 1H), 7.28 (d, 1H, J=7.6 Hz), 7.11-7.13 (m, 1H), 7.02-7.06 (m, 5H), 6.92-6.98 (m, 1H), 6.84 (s, 1H), 4.03-4.07 (m, 1H), 3.89 (t, 2H, J=6.0 Hz), 3.82 (s, 3H), 3.73 (s, 3H), 3.02 (t, 2H, J=6.0 Hz (s, 1H), 2.84-2.89 (m, 1H), 2.70-2.75 (m, 1H).

Example 55

(R)N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(1-methyl-1H-pyrazol-4-yl)-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(366) Compound 55 was prepared in analogous fashion as described for example 49.

(367) MS (ESI) m/z: 578 (M+H).sup.+.

(368) .sup.1H NMR (ppm) (CHCl.sub.3-d): 10.74 (s, 1H), 8.12 (s, 1H), 7.94 (s, 1H), 7.78 (s, 1H), 7.65-7.66 (m, 1H), 7.56 (d, 1H, J=8 Hz), 7.29 (d, 1H, J=8.0 Hz), 7.13 (s, 2H), 7.05 (s, 5H), 7.00 (s), 6.89 (d, 1H, J=8.3 Hz), 4.09-4.11 (m, 1H), 3.88 (s, 8H), 3.38-3.42 (m, 2H), 3.28-3.32 (m, 2H), 2.98 (t, 2H, J=5.6 Hz), 2.88-2.94 (m, 1H), 2.74-2.79 (m, 1H).

Example 56

(R)-9-(2-(dimethylamino)pyrimidin-5-yl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(369) Compound 56 was prepared in analogous fashion as described for example 49.

(370) MS (ESI) m/z: 619 (M+H).sup.+.

(371) .sup.1H NMR (ppm) (CHCl.sub.3-d): 10.74 (s, 1H), 8.51 (s, 1H), 7.66 (d, 1H, J=3.6 Hz), 7.56 (d, 1H, J=8.4 Hz), 7.51 (s, 1H), 7.28 (d, 1H, J=7.8 Hz), 7.11 (s, 1H), 6.98-7.05 (m, 2H), 6.88-6.94 (m, 2H), 4.05-4.07 (m, 1H), 3.86 (t, 2H, J=6.0 Hz), 3.77 (s, 3H), 3.35-3.39 (m, 2H), 3.25-3.29 (m, 2H), 3.14 (s, 5H), 2.98 (t, 1H, J=5.7), 2.86-2.90 (m, 1H), 2.71-2.76 (m, 1H).

Example 57

(R)N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(2-methoxypyridin-4-yl)-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(372) Compound 57 was prepared in analogous fashion as described for example 49.

(373) MS (ESI) m/z: 605 (M+H).sup.+.

(374) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.33 (s, 1H), 8.17 (s, 1H), 7.52-7.55 (m, 2H), 7.34-7.39 (m, 2H), 6.013 (s, 1H), 7.28 (s, 1H), 7.07-7.18 (m, 3H), 6.89-6.94 (m, 3H), 6.83 (s, 1H), 5.97 (d, 1H, J=7.0 Hz), 4.30-4.39 (m, 1H), 4.09 (s, 3H), 3.81-3.85 (m, 8H), 3.66-3.68 (m, 1H), 3.57-3.58 (m, 1H), 3.03 (s, 2H), 2.76-2.90 (m, 2H).

Example 58

(R)N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(6-methoxypyridin-3-yl)-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(375) Compound 58 was prepared in analogous fashion as described for example 49.

(376) MS (ESI) m/z: 605 (M+H).sup.+.

(377) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.50 (s, 1H), 8.33 (s, 1H), 7.99 (d, 1H, J=6.8 Hz), 7.55 (d, 1H, J=6.9 Hz), 7.35-7.44 (m, 3H), 7.08-7.17 (m, 2H), 6.96 (d, 3H, J=3.8 Hz), 6.80 (s, 1H), 6.73 (s, 1H), 5.99 (s, 1H), 4.30-4.37 (m, 1H), 4.08 (s, 3H), 3.84-3.87 (m, 5H), 3.70 (s, 1H), 3.48-3.70 (m, 9H), 3.02 (s, 2H), 2.91-2.95 (m, 1H), 2.80-2.84 (m, 1H).

Example 59

(R)N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(1H-pyrazol-4-yl)-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(378) Compound 59 was prepared in analogous fashion as described for example 49.

(379) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.12 (s, 1H), 8.06 (s, 1H), 7.70 (s, 1H), 7.57 (d, 1H, J=7.2 Hz), 7.36-7.39 (m, 2H), 7.20 (t, 1H J=8 Hz), 7.12 (t, 1H, J=6.9 Hz), 6.92-6.96 (m, 4H), 6.79 (s, 1H), 5.90 (d, 1H, J=7.6 Hz), 4.34-4.38 (m, 1H), 3.92 (s, 3H), 3.85 (t, 2H, J=6.4 Hz), 3.67-3.71 (m, 1H), 3.56-3.59 (m, 1H), 3.00 (t, 2H, J=6.2 Hz), 2.78-2.92 (m, 2H).

(380) TABLE-US-00002 R R1 = OMe, R2 = H R1 = H, R2 = OMe 60. 63. 0 61. 64. 62. 65.

Example 60

(R)N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-7,8,9-trimethoxy-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(a). (Z)-1,2,3-trimethoxy-4-(2-nitrovinyl)benzene

(381) 2,3,4-trimethoxybenzaldehyde (20 g) was dissolved in nitromethane (50 ml). Ammonium acetate (8.25 g) was added, and the reaction was heated to 50 C. for 2 hrs. The solvents were evaporated in vacuo. The orange residue was partitioned between water and DCM. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4 filtered and concentrated in vacuo.

(382) Yield: 26.3 g

(b/c). N-(2,3,4-trimethoxyphenethyl)acetamide

(383) Lithium aluminium hydride, 2.4M in THF (69.7 ml) was diluted with tetrahydrofuran (dry) (400 ml), and heated to 65 C. in a three-necked flask under a N2 atmosphere. To this hot solution was added dropwise a solution of compound 60a (10 g) in tetrahydrofuran (dry) (150 ml), maintaining a gentle reflux, over the course of 2 hours. After addition was complete, reflux was continued for 1 h. The reaction mixture was cooled to 0 C. in an ice bath, and then the excess lithium aluminium hydride quenched by portionwise addition of sodium sulfate decahydrate (53.9 g). After quenching, 10 g anhydrous sodium sulfate was added, the reaction mixture stirred for 15 minutes, and then filtered over a Celite pad and the solvents evaporated, yielding 7.7 g clear yellow oil. The intermediate was dissolved in acetic anhydride (39.4 ml), sodium bicarbonate (3.51 g) was added and the solution stirred at room temperature for 36 hours. The reaction mixture was poured into water, and extracted with DCM twice. The combined organics were washed with a aqueous saturated NaHCO.sub.3 solution, brine, then dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The product was purified using chromatography on silica gel, methanol/DCM 1/99>7/93 gradient. The compound slowly crystallizes on standing.

(384) Yield: 3.97 g

(d). 5,6,7-trimethoxy-1-methyl-3,4-dihydroisoquinoline

(385) To a solution of compound 60c (1.8 g) in toluene (10 ml) was added dropwise phosphorus oxychloride (0.2 ml) under nitrogen atmosphere at 90 C., over a period of 1 hour. The mixture was heated at 120 C. for 2 hours and allowed to cool to room temperature overnight. The resulting HCl salt was collected by filtration and washed with ether to give the product as a brown solid

(386) Yield: 2.2 g

(e). ethyl 7,8,9-trimethoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

(387) To a mixture of 63d (2.1 g) and potassium carbonate (3.7 g) in acetonitrile (15 ml) was added dropwise ethylbromopyruvate (1.6 g). The reaction mixture was refluxed for 2 hours. The reaction was allowed to cool to ambient temperature before a saturated aqueous NaHCO.sub.3 solution was added. The aqueous phase was extracted with ethyl acetate twice. The combined organic layers were washed with brine. The organic layer was dried (MgSO.sub.4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with petrol and increasing amounts of ethyl acetate. The pure fractions of the desired product were concentrated in vacuo.

(388) Yield: 0.9 g

(f). ethyl 7,8,9-trimethoxy-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

(389) Palladium (II) acetate (7.5 mg) was added to a degassed solution of intermediate 60e (150 mg), triphenylphosphine (20 mg), phenylbromide (27 l) and cesium carbonate (200 mg) in dioxane (2 ml). The mixture was further degassed by bubbling through a gentle stream of nitrogen for 30 minutes. The reaction tube was sealed under nitrogen and then heated to 80 C. for 16 hours. LC-MS analysis indicated the reaction was 50% complete, hence the mixture was degassed with nitrogen for 15 minutes before the addition a further aliquot of 1-fluoro-3-iodobenzene (22 l) and palladium (II) acetate (4 mg). The mixture was degassed for a further 30 minutes before sealing under nitrogen and heating to 80 C. for 4 hours. Water was added and the product was extracted into ethyl acetate (3). The combined organic layers were passed through a hydrophobic frit and concentrated to dryness under vacuum. The residue was purified by chromatography on silica gel eluting with heptane and increasing amounts of ethyl acetate.

(390) Yield: 90 mg

(g). 7,8,9-trimethoxy-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylic Acid

(391) A aqueous solution of 2M sodium hydroxide (0.75 ml) was added to a solution of intermediate 60f (90 mg) in ethanol (2 ml) and the mixture heated to 50 C. for 18 hours. The reaction mixture was acidified with a aqueous solution of 2M HCl and was extracted with ethyl acetate. The organic layer was washed with water and dried by passing through a hydrophobic frit and concentrated in vacuo, to yield an off-white powder.

(392) Yield: 93 mg

(h). (R)N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-7,8,9-trimethoxy-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(393) 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (71 mg) was added to a solution of intermediate 60g (93 mg), triethylamine (102 l), 1-hydroxybenzotriazole (34 mg), cesium carbonate (200 mg) and D-tryptophanol (56 mg) in dry DMF (1 ml), stirring for 70 hours at room temperature. The solvents were removed under vacuum and the residue obtained was partitioned between water and ethyl acetate. The aqueous phase was re-extracted with ethyl acetate (2) and the combined organic layers were passed through a hydrophobic frit and concentrated to dryness under vacuum. The residue was purified by chromatography on silica gel eluting with DCM and increasing amounts of methanol (max. 10%). The pure fractions were collected.

(394) Yield: 48 mg

(395) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.04-7.96 (1H, m), 7.53 (1H, m, J=7.90 Hz), 7.35-7.1 (8H, m), 6.91 (2H, d, J=8.63 Hz), 6.82 (1H, d, J=2.32 Hz), 5.61 (1H, d, J=6.90 Hz), 4.32-4.26 (1H, m), 3.93-3.80 (9H, s), 3.73 (2H, q, J=6.61 Hz), 3.67-3.60 (1H, m), 3.53 (1H, Dt, J=11.00, 5.40 Hz), 3.11 (1H, t, J=5.56 Hz)), 3.98-3.88 (2H, m), 2.85-2.71 (2H, m)

Example 61

(R)N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-7,8,9-trimethoxy-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(396) Compound 61 was prepared in an analogous fashion as described for example 60.

(397) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.05 (1H, s), 7.57 (1H, d, J=7.90 Hz), 7.39-7.34 (2H, m), 7.2 (1H, m), 7.15-7.09 (1H, m), 6.97-6.88 (5H, m), 5.87 (1H, d, J=6.91 Hz), 4.38-4.30 (1H, m), 3.89 (10H, m), 3.80-3.71 (2H, m), 3.72-3.64 (1H, m), 3.60-3.52 (1H, Dtm), 3.09 (1H, t, J=5.51 Hz)), 2.97-2.74 (4H, m).

Example 62

(R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-7,8,9-trimethoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(398) Compound 62 was prepared in an analogous fashion as described for example 60.

(399) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.09-7.99 (1H, m), 7.57 (1H, m, J=7.89 Hz), 7.37 (1H, d, J=8.09 Hz), 7.15-7.09 (1H, m), 7.05-6.99 (3H, m), 6.89-6.85 (2H, m), 6.81 (1H, s), 5.70 (1H, d, J=6.98 Hz), 4.37-4.29 (1H, m), 3.89 (9H, s), 3.78-3.64 (3H, m), 3.59 (1H, Dd, J=10.97, 5.87 Hz), 3.08 (1H, s), 2.96-2.79 (4H, m)

Example 63

(R)N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9,10-trimethoxy-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(400) Compound 63 was prepared in an analogous fashion as described for example 60, but starting from 3,4,5-trimethoxybenzaldehyde.

(401) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.04-7.96 (1H, m), 7.55-7.50 (1H, m), 7.35-7.2 (5H, m), 7.19-7.08 (3H, m), 6.85 (1H, d, J=2.30 Hz), 6.52 (1H, s), 5.63 (1H, d, J=6.78 Hz), 4.33-4.27 (1H, m), 3.96 (3H, s), 3.93 (3H, s), 3.85 (3H, s), 3.76 (2H, t, J=6.45 Hz), 3.68-3.62 (1H, m), 3.53 (1H, Dt, J=11.00, 5.41 Hz), 3.19 (1H, t, J=5.54 Hz)), 2.92-2.72 (4H, m).

Example 64

(R)N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9,10-trimethoxy-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(402) Compound 64 was prepared in an analogous fashion as described for example 60, but starting from 3,4,5-trimethoxybenzaldehyde.

(403) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.04 (1H, s), 7.57 (1H, d, J=7.92 Hz), 7.40-7.32 (2H, m), 7.28-7.05 (6H, m), 6.96-6.91 (3H, m), 6.52 (1H, s) 5.86 (1H, d, J=6.82 Hz), 4.38-4.30 (1H, m), 3.98-3.74 (10H, m), 3.72-3.64 (1H, m), 3.57 (1H, d, J=10.07 Hz), 3.14 (1H, s), 2.94-2.76 (4H, m).

Example 65

(R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9,10-trimethoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

(404) Compound 65 was prepared in an analogous fashion as described for example 60, but starting from 3,4,5-trimethoxybenzaldehyde.

(405) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.04 (1H, s), 7.57 (1H, d, J=7.90 Hz), 7.36 (1H, d, J=8.09 Hz), 7.13-6.97 (5H, m), 6.92 (1H, d, J=2.30 Hz), 6.52 (1H, s), 6.73 (1H, d, J=6.83 Hz), 4.37-4.29 (1H, m), 3.90 (9H, s), 3.84-3.66 (3H, m), 3.60 (1H, Dd, J=10.98, 5.95 Hz), 3.16 (1H, s), 2.96-2.81 (4H, m)

(406) ##STR00052##

Example 66

(R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-5,6-dihydroimidazo[2,1-a]isoquinoline-2-carboxamide

(a). tert-butyl 3,4-dimethoxyphenethylcarbamate

(407) To a solution of compound 1a was added potassium carbonate (49.7 g). (Boc).sub.2O (52.3 g) was added dropwise in 1 hour. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and water was added. The product was extracted into ethyl acetate. The organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel eluting with heptane and increasing amounts of ethyl acetate to give the product as a pale solid.

(408) Yield: 25 g

(409) MS (ESI) m/z: 282 (M+H).sup.+.

(b). tert-butyl 2-bromo-4,5-dimethoxyphenethylcarbamate

(410) To a solution of compound 66a (1 g) in DCM (16 ml) and a aqueous saturated NaHCO.sub.3 solution (16 ml) was added dropwise bromine (0.75 g) at 0 C. and stirred for another 1 hour. The reaction mixture was stirred for an additional 2 hours at room temperature. A aqueous saturated sodium thiosulfate solution was added and the product was extracted into DCM. The organic phase was dried (MgSO.sub.4), filtered and concentrated. The crude product was purified by chromatography on silica, eluting with heptane and increasing amounts of ethyl acetate to give the compound.

(411) Yield: 1.22 g

(412) .sup.1H NMR (ppm) (CHCl.sub.3-d): 6.98 (s, 1H), 6.71 (s, 1H), 4.53-4.62 (m, 1H), 3.84 (s, 6H), 3.33 (t, 2H, J=7.2 Hz), 3.33 (t, 2H, J=7.2 Hz), 1.41 (d, 9H, J=1.2 Hz).

(c). 2-(2-bromo-4,5-dimethoxyphenyl)ethanamine

(413) To a solution of compound 66b (1.22 g) in DCM (2 ml) was added dropwise 4N HCl/ethyl acetate (20 ml) and stirred for 1 hour at room temperature. The reaction mixture was concentrated, a saturated aqueous NaHCO.sub.3 solution was added and the product was extracted into ethyl acetate. The organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated to give the crude product.

(414) Yield: 0.8 g

(415) .sup.1H NMR (ppm)(DMSO-d): 7.50-8.20 (m, 3H), 7.10 (s, 1H), 6.92 (s, 1H), 3.72 (s, 3H), 3.71 (s, 3H), 2.91-2.98 (m, 2H), 2.81-2.90 (m, 2H).

(d). (E)-ethyl 3-(3-fluorophenyl)-2-formamidoacrylate

(416) To a suspension of sodium hydride (6 g) in THF (50 ml) was added dropwise a solution of 3-fluorobenzaldehyde (6 g) and ethyl iso-cyano-acetic ester (5 g) in THF (50 ml). The reaction was stirred for 2 hours at room temperature. The reaction mixture was quenched with a aqueous saturated NH.sub.4Cl solution and the aqueous layer was extracted with ethyl acetate. The organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude product was purified by chromatography on silica gel eluting with heptane and increasing amount of ethyl acetate.

(417) Yield: 5 g

(418) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.20-8.35 (m, 1H), 6.96-7.43 (m, 6H), 4.30-4.40 (m, 2H), 1.37-1.42 (m, 3H).

(e). (Z)-ethyl 3-bromo-3-(3-fluorophenyl)-2-formamidoacrylate

(419) A solution of compound 66d (5 g) and N-bromosuccinimide (4.5 g) in carbon tetrachloride (150 ml) was heated under reflux overnight. The reaction mixture was concentrated and the residue was purified by chromatography on silica gel with heptane and increasing amounts of ethyl acetate.

(420) Yield: 3.6 g

(421) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.31 (s, 1H), 7.25-7.43 (m, 2H), 7.03-7.16 (m, 3H), 4.05 (q, 2H, J=7.2 Hz), 0.98 (t, 3H, J=7.2 Hz).

(f). (Z)-ethyl 3-bromo-3-(3-fluorophenyl)-2-isocyanoacrylate

(422) To a solution of compound 66e (5 g) in DCM (50 ml) was added triethylamine (3 eq). At 0 C. phosphorus oxychloride (12.2 g) was added dropwise in 20 min. The reaction mixture was stirred at room temperature for 2 hours. The mixture was added dropwise to a potassium carbonate (120 g, 500 ml) solution in water and extracted with DCM. The organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated to give the product as a brown oil.

(423) Yield: 3.5 g

(424) MS (ESI) m/z: 298, 300 (M+H).sup.+

(g). ethyl 1-(2-bromo-4,5-dimethoxyphenethyl)-5-(3-fluorophenyl)-1H-imidazole-4-carboxylate

(425) A solution of compound 66c and compound 69f in DMF was heated to 120 C. for 2 hours. The reaction mixture was concentrated, water was added and the product was extracted into ethyl acetate. The organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated to give the desired product.

(426) Yield: 114 mg

(427) MS (ESI) m/z: 477, 479 (M+H).sup.+

(h). ethyl 3-(3-fluorophenyl)-8,9-dimethoxy-5,6-dihydroimidazo[2,1-a]isoquinoline-2-carboxylate

(428) To a solution of compound 66g (140 mg, crude) in dimethylacetamide (3 ml) were added potassium carbonate (221 mg) and tetrakis(triphenylphosphine)palladium(0) (26 mg) under N.sub.2. The reaction was stirred at room temperature for 5 minutes. The reaction mixture was heated to 140 C. overnight. The solid was filtered off and the filtrate was concentrated. The crude product was used without purification in the next step.

(429) Yield 100 mg

(430) MS (ESI) m/z: 395 (M+H).sup.+

(i). 3-(3-fluorophenyl)-8,9-dimethoxy-5,6-dihydroimidazo[2,1-a]isoquinoline-2-carboxylic Acid

(431) To a solution of compound 66h in THF/water (2 ml/2 ml) was added lithium hydroxide (50 mg). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, water was added and extracted with ethyl acetate. The aqueous layer was acidified with concentrated HCl to pH=3 and then extracted with ethyl acetate. The organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated to give the desired product.

(432) Yield: 60 mg

(433) MS (ESI) m/z: 369 (M+H).sup.+

(j). (R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-5,6-dihydroimidazo[2,1-a]isoquinoline-2-carboxamide

(434) To a solution of compound 66i (60 mg, crude) in DMF (2 ml) were added tryptophanol (50 mg), TBTU (20 mg) and triethylamine (0.5 ml). The reaction mixture was stirred at rt for 30 minutes. The reaction mixture was concentrated the residue was purified by preparative HPLC eluting with acetonitrile and water to give the desired product.

(435) Yield: 5 mg

(436) MS (ESI) m/z: 541 (M+H).sup.+

(437) .sup.1H NMR (ppm) (CH.sub.3OH-d): 7.55-7.65 (m, 3H), 7.37-7.42 (m, 1H), 7.21-7.37 (m, 3H), 7.08-7.12 (m, 2H), 6.95-7.08 (m, 2H), 4.32-4.42 (m, 1H), 4.02 (t, 2H, J=7.6 Hz), 3.91-3.98 (m, 5H), 3.59-3.62 (m, 2H), 3.15 (t, 2H, J=7.6 Hz), 2.97-3.11 (m, 2H)

Example 67

3-(2-fluorophenyl)-N((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-5,6-dihydroimidazo[2,1-a]isoquinoline-2-carboxamide

(438) Compound 67 was prepared in analogous fashion as described for example 66.

(439) MS (ESI) m/z: 541 (M+H).sup.+

(440) .sup.1H NMR (ppm) (CH.sub.3OH-d): 7.48-7.52 (m, 3H), 7.32-7.41 (m, 1H), 7.21-7.40 (m, 3H), 7.03-7.11 (m, 2H), 6.89-6.97 (m, 2H), 4.30-4.38 (m, 1H), 3.89-3.96 (m, 2H), 3.82-3.89 (m, 6H), 3.55-3.62 (m, 2H), 3.08 (t, 2H, J=7.6 Hz), 2.92-3.05 (m, 2H)

Example 68

N((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-3-(2-methoxyphenyl)-5,6-dihydroimidazo[2,1-a]isoquinoline-2-carboxamide

(441) Compound 68 was prepared in analogous fashion as described for example 66.

(442) MS (ESI) m/z: 553 (M+H).sup.+

(443) .sup.1H NMR (ppm) (CH.sub.3OH-d): 7.45-7.57 (m, 2H), 7.11-7.32 (m, 4H), 7.02-7.10 (m, 2H), 6.75-7.01 (m, 2H), 4.45-4.48 (m, 1H), 3.81-4.10 (m, 8H), 3.72-3.85 (m, 3H), 3.45-3.60 (m, 2H), 3.08-3.18 (m, 2H), 2.92-3.05 (d, 1H, J=9.6 Hz), 2.60-2.81 (d, 1H, J=7.2 Hz). 7.40-7.52 (m, 3H), 7.19-7.42 (m, 1H), 6.99-7.15 (m, 3H), 6.82-6.98 (m, 4H), 4.24-4.40 (m, 1H), 3.73-3.93 (m, 8H), 3.72 (s, 3H), 3.42-3.52 (m, 2H), 2.95 (dd, 1H, J=7.2, 14.4 Hz), 2.85 (dd, 1H, J=7.6, 15.6 Hz)

Example 69

N((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-3-(2-methoxypyridin-3-yl)-5,6-dihydroimidazo[2,1-a]isoquinoline-2-carboxamide

(444) Compound 69 was prepared in analogous fashion as described for example 66.

(445) MS (ESI) m/z: 554 (M+H).sup.+

(446) .sup.1H NMR (ppm) (CH.sub.3OH-d): 8.20-8.32 (m, 1H), 7.46-7.65 (m, 3H), 7.17-7.37 (m, 1H), 6.85-7.05 (m, 5H), 4.27-4.48 (m, 1H), 3.75-4.02 (m, 11H), 3.52-3.62 (m, 2H), 3.05 (d, 2H, J=7.6 Hz), 2.92-3.02 (m, 2H)

(447) ##STR00053##

Example 70

N((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-3-(2-methoxyphenyl)-5,6-dihydroimidazo[1,2-h][1,7]naphthyridine-2-carboxamide

(a). 2-chloro-3-methoxypyridine

(448) To a solution of 2-chloro-pyridin-3-ol (100 g) in DMSO (1 L) was added potassium carbonate (320 g). Methyliodide was added dropwise. The reaction mixture was heated to 50 C. overnight. The reaction mixture poured into water and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated to give the desired compound.

(449) Yield: 110 g

(b). 2,3-dimethoxypyridine

(450) To a solution of 2-chloro-3-methoxy-pyridine (110 g) in DMSO (1 L) was added sodium methoxide (124 g). The reaction mixture was heated to 80 C. overnight. The reaction mixture was poured into 3 L water and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated to give the crude product.

(451) Yield: 105 g

(452) .sup.1H NMR (ppm) (CH.sub.3OH-d): 7.70 (t, 1H, J=1.2 and 5.2 Hz), 7.01 (t, 1H, J=1.2 and 8.0 Hz), 6.81 (q, 1H, J=5.2 and 7.8 Hz), 4.00 (s, 3H), 3.85 (s, 3H).

(c). 5-bromo-2,3-dimethoxypyridine

(453) To a solution of 2,3-dimethoxy-pyridine (104 g) in DCM (1 L) and a saturated aqueous solution of NaHCO.sub.3 (1.6 ml) at 0 C. was added bromine (120 g). The reaction was stirred for 2 hours at 0 C. The reaction mixture was quenched with Na.sub.2SO.sub.3 (saturated in water, 500 ml) and stirred for 30 min. The aqueous layer was extracted with DCM, and the organic phase was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude product was purified by chromatography on silica gel with heptane and increasing amounts of ethyl acetate.

(454) Yield: 100 g

(455) .sup.1H NMR (ppm) (CHCl.sub.3-d): 7.70 (d, 1H, J=2.0 Hz), 7.06 (s, 1H, J=2.0 Hz), 3.92 (s, 3H), 3.80 (s, 3H).

(d). 5,6-dimethoxynicotinaldehyde

(456) To a solution of 5-Bromo-2,3-dimethoxy-pyridine (43 g) in THF (500 ml) at 78 C. was added n-butyllithium (191 mmol). After stirring for 30 minutes at 78 C. DMF (28.8 g) was added dropwise and the reaction mixture was stirred at 78 C. for 2 hours. The reaction mixture was quenched with NH.sub.4Cl (saturated in water, 500 ml). The aqueous layer was extracted with ethyl acetate, the organic phases were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude product was purified by chromatography on silica eluting with heptane with increasing amounts of ethyl acetate.

(457) Yield: 33 g

(458) Compound 70 was further prepared in analogous fashion as described for compound 60b and example 66.

(459) MS (ESI) m/z: 554 (M+H).sup.+

(460) .sup.1H NMR (ppm) (CH.sub.3OH-d): 7.45-7.57 (m, 2H), 7.11-7.32 (m, 4H), 7.02-7.10 (m, 2H), 6.75-7.01 (m, 2H), 4.45-4.48 (m, 1H), 3.81-4.10 (m, 8H), 3.72-3.85 (m, 3H), 3.45-3.60 (m, 2H), 3.08-3.18 (m, 2H), 2.92-3.05 (d, 1H, J=9.6 Hz), 2.60-2.81 (d, 1H, J=7.2 Hz).

(461) ##STR00054##

Example 71

N((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-3-(2-methoxyphenyl)-5,6-dihydroimidazo[1,2-h][1,7]naphthyridine-2-carboxamide

(a). 2,3-dimethoxy-5-vinylpyridine

(462) To a stirred solution of compound 70c (30 g) in toluene (200 ml) were added Tetrakis(triphenylphosphine)palladium(0) (7.9 g) and tributyl(vinyl)stannane (66 g). The resulting mixture was heated to 110 C. overnight. The reaction was cooled and filtered, the filtrate was concentrated. The crude product was purified by chromatography on silica gel (petrol:ethyl acetate=20:1) to give the desired compound.

(463) Yield: 11 g

(464) .sup.1H NMR (ppm) (CHC.sub.3-d): 7.685 (d, 1H, J=0.8 Hz), 7.152 (d, 1H, J=0.8 Hz), 6.691-6.620 (m, 1H), 5.632 (d, 1H, J=8.8 Hz), 4.020 (s, 3H), 3.906 (s, 3H).

(b). 2-(5,6-dimethoxypyridin-3-yl)ethanol

(465) To a stirred solution of compound 71a (11 g) in THF (120 ml), was added borane (20 ml, 10 mol/L). The mixture was heated under reflux for 2 hours. The reaction mixture was cooled and sodium hydroxide (35.5 ml, 15% in water) was added slowly to the mixture, followed by water (15.1 ml, 30%). The resulting mixture was heated to 50 C. and stirred for 30 minutes. Extracted with ethyl acetate, washed with brine dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude product was purified by chromatography on silica gel (petrol:ethyl acetate=3:1) to give the desired compound.

(466) Yield: 3.6 g.

(467) MS (ESI) m/z: 184 (M+H).sup.+

(c). 2-(2-bromo-5,6-dimethoxypyridin-3-yl)ethanol

(468) To a solution of compound 71b (3.6 g) in DCM (30 ml) and a aqueous saturated NaHCO.sub.3 solution (30 ml) at 0 C. was added dropwise bromine (1.32 ml). The reaction was stirred for 1 hour at 0 C. and then warmed to room temperature for additional 1 hour. The reaction mixture was quenched with saturated sodium thiosulfate (saturated in water 100 ml). The aqueous layer was extracted with DCM. The organic phase was dried (MgSO.sub.4), filtered and concentrated to give the desired compound.

(469) Yield: 4.1 g

(470) MS (ESI) m/z: 262, 264 (M+H).sup.+

(d). methyl 1H-pyrrole-3-carboxylate

(471) To a solution of potassium-tert-butoxide (105 g) in THF (1.2 L) was added dropwise a solution of methyl acrylate (66 g) and toluenesulfonylmethyl isocyanide (150 g) in THF (300 ml). The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was dried (MgSO.sub.4), filtered and concentrated. The crude product was purified by chromatography on silica gel (Petrol:ethyl acetate=5:1) to give the desired compound.

(472) Yield: 40 gram

(473) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.815 (br, 1H), 7.404 (s, 1H), 6.729 (d, 1H, J=1.2 Hz), 6.621 (d, 1H, J=0.4 Hz), 3.788 (s, 3H).

(e) methyl 5-bromo-1H-pyrrole-3-carboxylate

(474) To a solution of compound 71d (40 g) in THF (60 ml) was added N-bromosuccinimide (67.6 g) portion wise at 78 C. The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was concentrated. The crude product was purified by chromatography on silica gel, eluting with (Petrol:ethyl acetate=10:1) to give the desired compound.

(475) Yield: 38 g

(476) .sup.1H NMR (ppm) (CHCl.sub.3-d): 8.625 (br, 1H), 7.364 (dd, 1H, J.sub.1=2.0 Hz J.sub.2=2.8 Hz), 6.588 (dd, 1H, J.sub.1=2.0 Hz J.sub.2=2.4 Hz), 3.808 (s, 3H).

(f) methyl 5-bromo-1-(2-(2-bromo-5,6-dimethoxypyridin-3-yl)ethyl)-1H-pyrrole-3-carboxylate

(477) To a solution of compound 71c (3.1 g) in THF (60 ml) were added triphenylphosphine (3.72 g), DIAD (2.81 ml), DIPEA (2.35 ml) and compound 71e (2.35 ml). The resulting mixture was heated under reflux for 2 hours. The reaction mixture was cooled and filtered, the filtrate was concentrated. The crude product was purified by column chromatography on silica gel eluting with (Petrol:ethyl acetate=10:1) to give the desired compound.

(478) Yield: 4 g

(479) .sup.1H NMR (ppm) (CHCl.sub.3-d): 7.170 (s, 1H), 6.567 (d, 1H, J=1.2 Hz), 6.367-6.191 (m, 1H), 4.177-4.100 (m, 2H), 3.989 (s, 3H), 3.759 (s, 3H), 3.666 (s, 3H), 3.043 (t, 2H, J=6.8 Hz).

(g) methyl 2,3-dimethoxy-5,6-dihydropyrrolo[1,2-h][1,7]naphthyridine-9-carboxylate

(480) To a solution of compound 71f (3.5 g, crude) in toluene (50 ml) were added Pd(PPh.sub.3).sub.2Cl.sub.2 (160 mg) and (n-Bu.sub.3Sn).sub.2 (2.5 ml). The resulting mixture was heated to 120 C. overnight. The reaction was cooled and filtered, the filtrate was concentrated. The crude product was purified by column chromatography on silica gel, eluting with (Petrol:ethyl acetate=10:1) to give the desired compound.

(481) Yield: 300 mg

(482) MS (ESI) m/z: 289 (M+H).sup.+

(h) methyl 8-(3-fluorophenyl)-2,3-dimethoxy-5,6-dihydropyrrolo[1,2-h][1,7]naphthyridine-9-carboxylate

(483) To a solution of compound 71g (60 mg) in dioxane (5 ml) were added triphenylphosphine (10 mg), Palladium(II) acetate (5 mg), 1-fluoro-3-iodo-benzene (93 mg) and cesium carbonate (137 mg). The resulting mixture was heated to 120 C. overnight. The reaction was cooled and filtered and the filtrate was concentrated. The crude product was purified by preparative HPLC, eluting with acetonitrile and water to give the desired compound.

(484) Yield: 25 mg

(485) MS (ESI) m/z: 383 (M+H).sup.+

(i) 8-(3-fluorophenyl)-2,3-dimethoxy-5,6-dihydropyrrolo[1,2-h][1,7]naphthyridine-9-carboxylic Acid

(486) To a solution of compound 71h (25 mg) in methanol (1 ml), water (1 ml) and THF (1 ml), was added potassium hydroxide (73 mg). The reaction mixture was heated to 60 C. overnight. The mixture was concentrated and water was added. The mixture was acidified by concentrated HCl to pH=2 and extracted with DCM. The organic phase was dried (MgSO.sub.4), filtered and concentrated to give the desired compound.

(487) Yield: 29 mg

(488) MS (ESI) m/z: 369 (M+H).sup.+

(j). N((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-3-(2-methoxyphenyl)-5,6-dihydroimidazo[1,2-h][1,7]naphthyridine-2-carboxamide

(489) To a solution of compound 71i in DCM were added compound tryptophanol (50 mg, TBTU (20 mg) and triethylamine (0.5 ml). The reaction was stirred at room temperature for 30 min. The reaction mixture was purified by preparative HPLC, eluting with acetonitrile and water to give the desired compound.

(490) Yield: 8 mg

(491) MS (ESI) m/z: 541 (M+H).sup.+

(492) .sup.1H NMR (ppm) (CHCl3-d): 7.998 (s, 1H), 7.564 (d, 1H, J=4.0 Hz), 7.361 (d, 1H, J=4.0 Hz), 7.222 (t, 1H, J=2.0 Hz), 7.198-7.119 (m, 1H), 7.053-7.011 (m, 4H), 6.931 (s, 1H), 6.857 (s, 1H), 5.860 (d, 1H, J=2.8 Hz), 4.359-4.327 (m, 1H), 4.075 (s, 3H), 3.879 (s, 3H), 3.817 (t, 2H, J=6.8 Hz), 3.727-3.611 (m, 2H), 2.997-2.859 (m, 5H).

Example 72

Antagonistic Activity of Compounds at the Human FSH Receptor Expressed in CHO Cells

(493) Antagonistic activity of the compounds at the human FSH receptor was determined in Chinese Hamster Ovary (CHO) cells stably transfected with the human FSH receptor and cotransfected with a cAMP responsive element (CRE)/promotor directing the expression of a firefly luciferase reporter gene. Binding of the compounds to the Gs protein-coupled FSH receptor will result in an increase of cAMP, which in turn will induce an increased transactivation of the luciferase reporter. The cells (7,500 cells/well of a 384 well plate) were incubated in Dulbecco' minimal essential F12 modified medium (Invitrogen), supplemented with 1 g/ml bovine insulin, 5 g/ml human apo-transferrin, 100 U/ml penicillin G and 100 g/ml streptomycin with the test compounds (concentration between 0.316 nM and 10.0 M) in duplicate together with 49 M recFSH (which, at this concentration in the absence of test compound, induces 80% of the maximal luciferase stimulation) in a humidified atmosphere (95%) at 5-7% CO.sub.2 and 37 C. The final concentration of DMSO was 1%. After 4 hours of incubation, plates were allowed to adjust to room temperature for 1 hour. Then, SteadyLite (PerkinElmer) solution was added to the wells and cells were allowed to lyse for at least 1 hour at room temperature. Subsequently, luciferase activity was measured in a luminescence counter. The signal is expressed as counts per second (cps). The IC50 (concentration of test compound causing half-maximal (50%) inhibition of the maximally attainable inhibition of the luciferase stimulation by the compound) and efficacy of the compounds were determined using the software program MathIQ (version 2.3, ID Business Solutions Limited).

(494) The compounds of all examples have an IC50 of 10.sup.5 M or lower. The compounds of examples 1-4, 9, 15, 30-32, 39, 46-48, 51 and 66-68 have an IC50 of less than 10.sup.6 M and more than 10.sup.7 M. The compounds of examples 5-8, 10-14, 16-19, 22-29, 33-38, 40-45, 49, 50, 52-65 and 70 have an IC50 of less than 10.sup.7 M.

Example 73

Functional Assay for Assessing hFSHR Antagonistic Activity of Test Compounds in Human Granulosa Cell Cultures

(495) Human granulosa cells were obtained in the course of follicular aspiration for retrieval of matured oocytes during routine IVF procedures approximately 36 hours after hCG administration to the patient. Follicular fluid was collected as one batch per patient and after oocyte removal centrifuged for 5 minutes at 350 g at room temperature (RT). The pellet was resuspended in 5 ml collagenase (0.1%) containing isolation medium, layered on 5 ml of Histopaque-1077 and centrifuged (450 g for 20 minutes, RT) to separate the granulosa cells from the erythrocytes. The granulosa cells and other mononuclear cells (e.g. lymphocytes) were obtained from the interface and washed once with isolation medium (450 g, 20 minutes). After aspiration of the supernatant, the pellet was resuspended in isolation medium and transported from the hospital to the laboratory. The granulosa cells are pelleted by centrifugation (350 g, 5 minutes) and resuspended in a small volume of culture medium with 10% fetal calf serum (FCS). To facilitate cell dispersal the suspension was subjected to gentle mechanical dissociation.

(496) Cell viability was determined by Trypan Blue exclusion and the granulosa cells were plated at a density of 25.000 viable cells/200 l/well in culture medium with 10% FCS in collagen coated 96-wells plates, and cultured at 37 C. under a humidified atmosphere supplemented with 5% CO.sub.2. Every 72 hours the cells are washed once with pre-warmed culture medium to remove dead cells, debris and non-adherent cells. Seven days after the start of the culture, the cells are washed again with culture medium. Medium was aspirated and 250 L isolation medium with isobutylmethylxanthine (IBMX) with human recombinant FSH (hrecFSH: 0 and 250 mU/mL) or with hrecFSH (250 mU/mL) in combination with test compound of example 5 was incubated for an additional 48 hours at 37 C., 5% CO.sub.2. All test conditions were performed in triplicate. Subsequently, supernatant was collected in 96 well plates. Finally 25 L supernatant was transferred to a new 96 deep-well plate and used for the determination of cAMP levels with the cAMP EIA kit (Amersham Life Sciences, cat. no RPN 225). Immediately after aspiration of the supernatant of the granulosa cells, 150 L culture medium supplemented with 10 M testosterone, was added to the wells. After 2 hours of incubation at 37 C., 5% CO.sub.2, the supernatant was collected and used for the determination of estradiol levels with an estradiol-ELISA (DRG instruments, art. no. EIA-2693). Supernatants were diluted 1:300 in Dulbecco's phosphate buffered saline (DPBS, Hyclone Cat. No. SH30028.03) and a self-made calibration curve of estradiol in DPBS was used for the determination of estradiol levels in the supernatants.