CONDENSED PYRROLES AS NOVEL BROMODOMAIN INHIBITORS

Abstract

Compounds of formula (1) or (2) and their use in the treatment of diseases or conditions for which a bromodomain inhibitor is indicated.

##STR00001##

Claims

1. A compound of formula (1) or formula (2) ##STR00055## wherein A, B, C and D, which may be the same or different, independent of one another represent —C(R7Rs)-, —C(R9R10)-C(R11R12)-, —N(R13)-, -0- or —S— with the proviso that the total number of ring atoms of the ring comprising ring members A, B, C and D is 7 to 9, R1 is selected from the group consisting of OH, OR3, NH2, NHR4 and NRsR6 R2 is a substituted or unsubstituted alkyl group with 1 to 8 carbon atoms or a substituted or unsubstituted alkoxy group with 1 to 8 carbon atoms in which one or more of the hydrogen atoms may be optionally replaced by halogen, R3 and R4, independent of each other, represent an alkyl group with 1 to 6 carbon atoms or a substituted or unsubstituted alkylaryl, aryl or heteroaryl group, Rs and R6, independent of each other, represent an alkyl group with 1 to 6 carbon atoms or a substituted or unsubstituted aryl or heteroaryl group or form together with the nitrogen atom to which they are attached, a six- or seven membered, substituted or unsubstituted heterocyclic ring, R7 to R13, independent of each other, represent hydrogen, hydroxyl, substituted or unsubstituted alkyl groups with 1 to 4 carbon atoms, substituted or unsubstituted alkoxy groups with 1 to 4 carbon atoms and substituted or unsubstituted hydroxyalkyl groups with 1 to 4 carbon atoms or wherein two of R7 to R13 located at adjacent atoms, form together a chemical bond or a ring, R14 represents a substituted or unsubstituted aryl or heteroaryl group, and R1s and R16, independent of each other, are hydrogen or a C1 to C4-alkyl group.

2. The compound of formula (1) or (2) in accordance with claim 1 wherein A, B, C and D and Care —(CR?Rs)-.

3. The compound of formula (1) or (2) in accordance with claim 2 wherein R2 is an alkyl group or a haloalkyl group with 1 to 4 carbon atoms.

4. The compound of formula (1) in accordance with claim 3 wherein R1 is a group NHR4 wherein R4 is as defined in claim 1.

5. The compound of formula (1) in accordance with claim 4 wherein R4 is a substituted or unsubstituted aryl group, in particular a substituted or unsubstituted phenyl group.

6. The compound of formula (1) in accordance with claim 5 wherein R4 is represented by formula (3) ##STR00056## wherein * represents the site of attachment to the nitrogen atom, R11 is hydroxyl or an alkoxy group with 1 to 4 carbon atoms and R1s is NR19R2o wherein R19 and R2o, independent of each other, represent an alkyl group with 1 to 4 carbon atoms, a substituted or unsubstituted aryl ring or together with the nitrogen atom to which they are attached form a substituted or unsubstituted heterocyclic ring with 4 to 7 ring atoms.

7. The compound of formula (1) in accordance with claim 3 wherein R1 is a group —OR3 wherein R3 is as defined in claim 1.

8. The compound of formula (1) in accordance with claim 4 represented by formula (1″) ##STR00057##

9. The compound of formula (2) in accordance with claim 3 wherein R14 is a substituted or unsubstituted phenyl group or a substituted or unsubstituted oxadiazole group.

10. The compound of formula (2) in accordance with claim 9 wherein R2 is an alkyl group with 1 to 4 carbon atoms.

11. The compound of formula (2) in accordance with claim 10 wherein R14 is a substituted or unsubstituted phenyl or oxadiazole group.

12. The compound of formula (2) in accordance with claim 11 wherein R16 is hydrogen.

13. The compound of formula (1) in accordance with claim 6 represented by formula (4), formula (5), formula (6) or formula (7) ##STR00058## wherein A, B, C, D, R2 and R1s are as defined in claim 1, R21 and R22, independent of each other, are hydrogen, C1-C4 alkyl or form together a chemical bond, R23, R2s and R2s, independent of each other, are hydrogen or C1 to C4 alkyl, R24, R27 and R29, independent of each other, are C1-C4 alkyl or C2-C4-carboxyl, and R26 is hydrogen or C1 to C4 alkyl.

14. The compound of formula (1) or (2) in accordance with claim 13 for use in the treatment of diseases or conditions for which a bromodomain inhibitor is indicated.

15. Use of a compound of formula (1) or (2) in accordance with claim 13 as bromodomain inhibitor.

16. Use of a compound of formula (1) or (2) as defined in claim 13 or a pharmaceutically acceptable salt thereof in the treatment of diseases or conditions selected from chronic autoimmune or inflammatory conditions, cancer or viral diseases, for the inhibition of the proliferation of leukemia cells, for the treatment of obesity, for the treatment of kidney malfunctions, as a male contraceptive, or for the treatment of diseases caused by parasites such as malaria or leishmaniasis.

17. A pharmaceutical composition comprising at least one compound of formula (1) or (2) as defined in claim 13 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

18. A combination pharmaceutical product comprising at least one compound of formula (1) or (2) as defined in claim 13 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients together with one or more other pharmaceutically active ingredients.

Description

EXAMPLES

[0108] General Procedures

[0109] Reagents and solvents were obtained from commercial sources and used without any further purification.

[0110] Column chromatography was accomplished using MACHEREY-NAGEL silica gel 60® (230-400 mesh). Thin layer chromatography was performed on aluminum plates pre-coated with silica gel (MERCK, 60F254), which were visualized by UV fluorescence (λ.sub.max=254 nm) and/or by staining with ninhydrin in ethanol (EtOH).

[0111] .sup.1H and .sup.13C NMR Spectroscopy

[0112] NMR spectra were acquired on a BRUKER Avance 400 spectrometer (400

[0113] MHz and 100.6 MHz for .sup.1H and .sup.13C respectively) or a Bruker 500 DRX NMR spectrometer with TBI probe head (499.6 MHz and 125.6 MHz for .sup.1H and .sup.13C respectively) at a temperature of 303 K unless specified. Chemical shifts are reported in parts per million (ppm) relative to residual solvent. Data for .sup.1H NMR are described as following: chemical shift (δ in ppm), multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad signal), coupling constant (Hz), integration. Data for .sup.13C NMR are described in terms of chemical shift (δ in ppm).

[0114] High Resolution Mass Spectrometry (HR-MS) data were obtained on a THERMO SCIENTIFIC Advantage and a THERMO SCIENTIFIC instrument (Atmospheric Pressure Chemical Ionization (APCI)/methanol (MeOH): spray voltage 4-5 kV, ion transfer tube: 250-300° C., vaporizer: 300-400° C.).

Example 1 Synthesis of 3-methyl-4-oxo-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrrole-1-carboxylic acid

[0115] General Synthesis Scheme

##STR00015## ##STR00016##

[0116] Reaction conditions: i) Benzyl bromide (BnBr), sodium hydride (NaH), THF, room temperature (room temperature, hereinafter referred to as rt), 93%; ii) N-Bromosuccinimide (NBS), triphenylphosphine (PPh.sub.3), dichloromethane (CH.sub.2Cl.sub.2), −78° C. to rt, 89%; iii) Ethyl acetoacetate, NaH, n-butyllithium (BuLi), −20° C. to rt, 76%; iv) sodium nitrite (NaNO.sub.2), acetic acid (AcOH)/H.sub.2O, 0° C. to rt, 96%; v) Pentane-2,4-dione, Zn, AcOH, sodium acetate (AcONa), 90° C., 63%; vi) H.sub.2, palladium on charcoal (Pd/C), ethyl acetate (EtOAc)/(MeOH), rt, 67%; vii) (COCl).sub.2, triethylamine multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad signal), coupling constant (Hz), integration. Data for .sup.13C NMR are described in terms of chemical shift (δ in ppm).

[0117] High Resolution Mass Spectrometry (HR-MS) data were obtained on a THERMO SCIENTIFIC Advantage and a THERMO SCIENTIFIC instrument (Atmospheric Pressure Chemical Ionization (APCI)/methanol (MeOH): spray voltage 4-5 kV, ion transfer tube: 250-300° C., vaporizer: 300-400° C.).

Example 1 Synthesis of 3-methyl-4-oxo-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrrole-1-carboxylic acid

[0118] General Synthesis Scheme

##STR00017## ##STR00018##

[0119] Reaction conditions: i) Benzyl bromide (BnBr), sodium hydride (NaH), THF, room temperature (room temperature, hereinafter referred to as rt), 93%; ii) N-Bromosuccinimide (NBS), triphenylphosphine (PPh.sub.3), dichloromethane (CH.sub.2Cl.sub.2), −78° C. to rt, 89%; iii) Ethyl acetoacetate, NaH, n-butyllithium (BuLi), −20° C. to rt, 76%; iv) sodium nitrite (NaNO.sub.2), acetic acid (AcOH)/H.sub.2O, 0° C. to rt, 96%; v) Pentane-2,4-dione, Zn, AcOH, sodium acetate (AcONa), 90° C., 63%; vi) H.sub.2, palladium on charcoal (Pd/C), ethyl acetate (EtOAc)/(MeOH), rt, 67%; vii) (COCl).sub.2, triethylamine (NEt.sub.3), DMSO, NEt.sub.3, CH.sub.2Cl.sub.2, −78° C. to rt, 100%; viii) p-toluene sulfonic acid (PTSA).H.sub.2O, toluene (PhMe), 110° C., 56%; ix) H.sub.2, Pd/C, EtOAc/MeOH, rt, 98%; x) NaOH, EtOH/H.sub.2O, reflux, then HCl, 0° C., 71%

##STR00019##

[0120] 2-(benzyloxy)ethan-1-ol (Compound I). To a suspension of NaH (10.2 g, 0.25 mmol, 1.05 equiv) in dry THF (152 mL) ethylene glycol (250 g, 2.42 mol, 10 equiv) was added dropwise at 0 C. The reaction mixture was first stirred at rt for 30 min and afterwards benzylbromide (48 mL, 0.24 mol, 1.0 equiv) was added at 0 C. The mixture was stirred for 12 h at rt and afterwards quenched with saturated ammonium chloride (NH.sub.4Cl) solution. The aqueous phase was extracted three times with diethyl ether (Et.sub.2O). The combined organic layers were washed with H.sub.2O, brine, dried over sodium sulfate (Na.sub.2SO.sub.4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (20-100% EtOAc in petroleum ether (hereinafter referred to as PE) to afford the desired compound as a light yellow oil (56.7 g, 373 mmol, 93%).

[0121] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 0.39-7.27 (m, 5H), 4.56 (s, 2H), 3.79-3.69 (m, 2H), 3.61-3.54 (m, 2H), 2.61-2.50 (m, 1H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ 138.0, 128.4, 127.8, 127.7, 73.2, 71.5, 61.8; R.sub.f: 0.39 (40% AcOEt in PE).

##STR00020##

[0122] ((2-bromoethoxy)methyl)benzene (Compound II). To a solution of NBS (17.7 g, 99.3 mol, 1 equiv.) in CH.sub.2Cl.sub.2 (200 mL) was added dropwise a solution of PPh.sub.3 (26.1 g, 99.3 mol, 1 equiv.) in CH.sub.2Cl.sub.2 (140 mL) at −78° C. The solution was stirred for 1 h, then a solution of 2-(benzyloxy)ethan-1-ol (14.4 g, 94.6 mmol, 1 equiv.) in CH.sub.2Cl.sub.2 (100 mL) was added dropwise. The solution was allowed to return to rt and after one hour, the reaction was quenched using MeOH (10 mL) and PhMe (150 mL). The solution was evaporated, water was added and the aqeuous phase was extracted three times with EtOAc. The combined organics were washed with brine, dried over Na.sub.2SO.sub.4 and evaporated. The residue was purified on silica gel column eluting with 10% EtOAc in cyclohexane to afford the desired product (18.1 g, 84.1 mol, 89%) as a light yellow oil.

[0123] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.41-7.28 (m, 5H), 4.60 (s, 2H), 3.80 (t, J=6.2 Hz, 2H), 3.50 (t, J=6.2 Hz, 2H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ 137.8, 128.5, 127.9, 127.8, 73.2, 70.0, 30.5; R.sub.f: 0.85 (20% AcOEt in CyH)

##STR00021##

[0124] Ethyl 6-(benzyloxy)-3-oxohexanoate (Compound III). Ethyl acetoacetate (32 mL, 252 mmol, 1.0 equiv) was added dropwise to a suspension of NaH (5.55 g, 278 mmol, 1.1 equiv, 60% w/w) in dry THF (500 mL) at −20 C. The reaction mixture was stirred for 1 h, then BuLi in hexane (2.5 M, 112 mL, 278 mmol, 1.1 equiv) was added dropwise. After 1 h, ((2-bromoethoxy)methyl)benzene (65.1 g, 302 mmol, 1.0 equiv) was added and the reaction mixture was allowed to return to rt and stirred overnight. A saturated NH.sub.4Cl solution was added and the organic phase was evaporated. The aqueous phase was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and evaporated. The residue was purified by column chromatography eluting with 10-100% EtOAc in PE to afford the desired compound as an orange liquid (50.5 g, 191 mmol, 76%). .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.41-7.28 (m, 5H), 4.50 (s, 2H), 4.20 (q, J=7.1 Hz, 2H), 3.51 (t, J=6.1 Hz, 2H), 3.45 (s, 2H), 2.68 (t, J=7.1 Hz, 2H), 1.99-1.89 (m, 2H), 1.29 (t, J=7.1 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ 202.6, 167.3, 138.5, 128.5, 127.7, 127.7, 73.0, 69.1, 61.4, 49.5, 39.8, 23.8, 14.2; HRMS (ESI): calcd. for C.sub.15H.sub.20O.sub.4Na [M+Na].sup.+: 287.1254, found: 287.1254; R.sub.f: 0.30 (20% AcOEt in cyclohexane (CyH)).

##STR00022##

[0125] Ethyl (Z)-6-(benzyloxy)-2-(hydroxyimino)-3-oxohexanoate (Compound IV). To a solution of ethyl-6-(benzyloxy)-3-oxohexanoate (63.0 g, 238 mmol, 1.0 equiv) in AcOH (240 mL) at 0 C, was added dropwise a solution of NaNO.sub.2 (32.9 g, 477 mmol, 2.0 equiv) in H.sub.2O (125 mL). The mixture was then allowed to return to rt, and stirred overnight. Water was added and the aqueous phase was extracted four times with ethyl acetate (EA). The combined organic layers were washed three times with saturated Na.sub.2CO.sub.3 solution, brine and dried over Na.sub.2SO.sub.4 to afford the desired compound as a yellow oil (67.0 g, 229 mmol, 96%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.51 (s, 1H), 7.42-7.26 (m, 5H), 4.53 (s, 2H), 4.35 (q, J=7.1 Hz, 2H), 3.55 (td, J=6.1, 1.7 Hz, 2H), 2.87 (dt, J=35.4, 7.2 Hz, 2H), 2.09-1.78 (m, 2H), 1.33 (t, J=7.1 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ 195.6, 161.9, 150.6, 137.5, 128.5, 127.9, 127.9, 73.0, 69.2, 62.2, 34.4, 23.6, 14.0; HRMS (ESI): calcd. for C.sub.15H.sub.19NO.sub.5Na [M+Na].sup.+: 316.1155, found: 316.1155; R.sub.f: 0.63 (33% AcOEt in CyH).

##STR00023##

[0126] Ethyl 4-acetyl-3-(3-(benzyloxy)propyl)-5-methyl-1-H-pyrrole-2-carboxylate (Compound V). To a solution of ethyl (Z)-6-(benzyloxy)-2-(hydroxyimino)-3-oxohexanoate (28.1 g, 95.9 mmol, 0.8 equiv.) and pentane-2,4-dione (12.0 g, 120 mmol, 1 equiv.) in AcOH (274 mL) was added AcONa (39.3 g, 479 mmol, 4 equiv.). The solution was heated to 90° C. and Zn (10.5 g, 161 mmol, 3 equiv.) was added portionwise. The mixture was then heated to 90° C. for 1 h, filtered and evaporated. The residue was dissolved in water and the aqueous phase was extracted three times with EtOAc. The combined organics were washed with brine, dried over Na.sub.2SO.sub.4 and evaporated. The residue was purified on silica gel column eluting with 10-50% EtOAc in cyclohexane to give the desired product (20.9 g, 60.7 mmol, 63%) as a colorless solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.48 (s, 1H), 7.40-7.27 (m, 5H), 4.51 (s, 2H), 4.31 (q, J=7.2 Hz, 2H), 3.55 (t, J=6.6 Hz, 2H), 3.21-3.07 (m, 2H), 2.52 (s, 3H), 2.46 (s, 3H), 1.93-1.78 (m, 2H), 1.33 (t, J=7.1 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ 195.3, 161.7, 138.9, 138.0, 134.2, 128.3, 127.6, 127.4, 123.1, 118.0, 72.8, 70.5, 60.5, 31.4, 31.1, 22.7, 15.3, 14.4; HRMS (ESI): calcd. for C.sub.20H.sub.25NO.sub.4Na [M+Na].sup.+: 366.1676, found: 366.1676; R.sub.f: 0.49 (40% EtOAc in cyclohexane (CyH)).

##STR00024##

[0127] Ethyl 4-acetyl-3-(3-hydroxypropyl)-5-methyl-1H-pyrrole-2-carboxylate (Compound VI). To a solution of ethyl 4-acetyl-3-(3-(benzyloxy)propyl)-5-methyl-1H-pyrrole-2-carboxylate (2.40 g, 6.99 mmol, 1 equiv.) in EtOAc and MeOH (28 mL, 1:1) under argon, was added Pd/C (580 mg, 5% w/w). The solution was put under H.sub.2 (1 atm) and stirred overnight at rt. The mixture was filtered over celite, evaporated and purified on silica gel column eluting with 50-100% EtOAc in CyH to afford the desired product (1.19 g, 4.70 mmol, 67%) as a light yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.92 (s, 1H), 4.31 (q, J=7.2 Hz, 2H), 3.53 (dd, J=6.1, 5.3 Hz, 2H), 3.36 (br s, 1H), 3.15 (t, J=6.9 Hz, 2H), 2.54 (s, 3H), 2.44 (s, 3H), 1.89-1.72 (m, 2H), 1.34 (t, J=7.1 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ 195.8, 161.6, 138.1, 134.5, 123.2, 118.4, 61.1, 60.6, 33.5, 31.1, 21.3, 15.5, 14.4; HRMS (ESI): calcd. for C.sub.13H.sub.19NO.sub.4Na [M+Na].sup.+: 276.1206, found: 276.1206; R.sub.f: 0.42 (80% EtOAc in CyH).

##STR00025##

[0128] Ethyl 4-acetyl-5-methyl-3-(3-oxopropyl)-1H-pyrrole-2-carboxylate (Compound VII). To a solution of DMSO (374 μl, 3.16 mmol, 2 equiv.) in dry CH.sub.2Cl.sub.2 (10 mL) was added (0001).sub.2 (203 μl, 2.37 mmol, 1.5 equiv.) at −78° C. dropwise. The mixture was stirred at −78° C. for 15 min, then a solution of ethyl 4-acetyl-3-(3-hydroxypropyl)-5-methyl-1H-pyrrole-2-carboxylate (400 mg, 1.58 mmol, 1 equiv.) in dry CH.sub.2Cl.sub.2 (5.8 mL) was added dropwise. After 30 min, NEt.sub.3 (1.10 mL, 7.90 mmol, 5 equiv.) was added. The mixture was stirred 30 min at −78° C., then, was allowed to return to rt. The solution was evaporated and water was added. The aqueous phase was extracted three times with EtOAc and evaporated to afford after fast purification on silica gel column (20-100% EtOAc in cyclohexane), the desired product (397 mg, 1.58 mmol, 100%) as a colorless oil. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.81 (t, J=2.0 Hz, 1H), 9.07 (s, 1H), 4.33 (q, J=7.1 Hz, 2H), 3.40 (dd, J=8.0, 7.1 Hz, 2H), 2.74-2.65 (m, 2H), 2.44 (s, 3H), 1.35 (t, J=7.1 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ 202.7, 194.7, 161.1, 137.2, 132.8, 123.1, 118.4, 60.7, 44.8, 31.2, 19.1, 15.7, 14.5; HRMS (ESI): calcd. for C.sub.13H.sub.16NO.sub.4 [M−H].sup.−: 250.1085, found: 250.1085; R.sub.f: 0.50 (50% AcOEt in CyH).

##STR00026##

[0129] Ethyl 3-methyl-4-oxo-2,4,7,8-tetrahydrocyclohepta[c]pyrrole-1-carboxylate (Compound 9). To a solution of ethyl 4-acetyl-5-methyl-3-(3-oxopropyl)-1H-pyrrole-2-carboxylate (7.30 g, 29.1 mmol, 1 equiv.) in PhMe (291 mL) was added PTSA monohydrate (2.76 g, 14.5 mmol, 0.5 equiv.). The mixture was heated to reflux for 3 h, cooled to rt, evaporated. Concentrated NaHCO.sub.3 solution was added and the aqueous phase was extracted three times with EtOAc. The combined organics were washed with brine, dried over Na.sub.2SO.sub.4 and evaporated. The residue was purified on silica gel column eluting with 20-50% EtOAc in CyH to afford the desired product (3.79 g, 16.2 mmol, 56%) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.32 (s, 1H), 6.66 (dt, J=12.1, 6.0 Hz, 1H), 6.16 (dt, J=12.3, 1.5 Hz, 1H), 4.35 (q, J=7.1 Hz, 2H), 3.33-3.23 (m, 2H), 2.59 (d, J=0.6 Hz, 3H), 2.52 (ddt, J=10.5, 5.9, 1.6 Hz, 2H), 1.39 (t, J=7.1 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ 188.7, 161.5, 143.8, 140.7, 134.4, 132.5, 123.5, 115.9, 60.5, 28.0, 24.4, 14.8, 14.6; HRMS (ESI): calcd. for C.sub.13H.sub.16NO.sub.3 [M+H].sup.+: 234.1125, found: 234.1125.

##STR00027##

[0130] Ethyl 3-methyl-4-oxo-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrrole-1-carboxylate (Compound 8). To a solution of ethyl 3-methyl-4-oxo-2,4,7,8-tetrahydrocyclohepta[c]pyrrole-1-carboxylate (3.50 g, 15.0 mmol, 1 equiv.) in EtOAc/MeOH (150 mL, 1:1) under argon was added Pd/C (700 mg, 5% w/w). The reaction was stirred at rt for 16 h under H.sub.2. After filtration and purification on silica gel column (20-60% EtOAc in CyH), to obtain the desired compound as a white solid (3.46 g, 14.7 mmol, 98%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.62 (s, 1H), 4.32 (q, J=7.1 Hz, 2H), 3.25-3.07 (m, 2H), 2.70-2.57 (m, 2H), 2.51 (s, 3H), 1.89-1.72 (m, 4H), 1.35 (t, J=7.1 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ 200.0, 161.8, 138.7, 134.2, 123.5, 116.6, 60.4, 42.0, 25.3, 23.4, 21.9, 14.5, 13.8; HRMS (ESI): calcd. for C.sub.13H.sub.16NO.sub.3 [M−H].sup.−: 234.1136, found: 234.1136; R.sub.f: 0.47 (30% AcOEt in CyH).

##STR00028##

[0131] 3-methyl-4-oxo-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrrole-1-carboxylic acid (Compound VIII). To a solution of ethyl 3-methyl-4-oxo-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrrole-1-carboxylate (1.15 g, 4.89 mmol, 1 equiv.) was dissolved in EtOH and aqueous 2M NaOH (48.9 mL, 1:1). The mixture was heated at reflux overnight, cooled at 0° C. and neutralized until pH 1 using concentrated aqueous HCl (12M). The resulting precipitate was filtered and recrystallised using CHCl.sub.3 to afford the desired product (723 mg, 3.49 mmol, 71%) as a white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.44 (s, 1H), 11.81 (s, 1H), 3.13 (td, J=6.2, 5.3, 2.9 Hz, 2H), 2.55-2.50 (m, 1H), 2.36 (s, 2H), 1.75-1.65 (m, 4H); .sup.13C NMR (126 MHz, DMSO-d.sub.6) δ 198.4, 162.3, 138.0, 133.0, 122.3, 116.6, 41.3, 24.8, 22.3, 21.2, 13.1; HRMS (APCI): calcd. for C.sub.11H.sub.14NO.sub.3 [M+H].sup.+: 208.0968, found: 208.0968; R.sub.f: 0.63 (100% AcOEt+2% AcOH).

Example 2. Synthesis of 3-amino-N,N-diethyl-4-methoxybenzenesulfonamide

[0132] General Synthetic Scheme

##STR00029##

[0133] Reaction conditions: i) HNO.sub.3, H.sub.2SO.sub.4, 0° C., 60%; ii) diethylamine (Et.sub.2NH), CH.sub.2Cl.sub.2, 0° C. to rt, 99%; iii) H.sub.2, Pd/C, MeOH/AcOEt, rt, 96%

[0134] CH.sub.2Cl.sub.2); R.sub.f: 0.38 (60% AcOEt in CyH)

##STR00030##

[0135] 4-methoxy-3-nitrobenzenesulfonyl chloride (Compound IX). To a solution of 4-methoxybenzenesulfonyl chloride (6.18 g, 29.9 mmol, 1 equiv.) in H.sub.2SO.sub.4 (30 mL) at 0° C., was added HNO.sub.3 (1.91 mL, 44.8 mmol, 1.5 equiv.). After 2 h, the solution was poured into ice/water and extracted with Et.sub.2O. The organic phase was washed with water, brine, dried over Na.sub.2SO.sub.4 and evaporated to afford the desired product (4.53 g, 18.0 mmol, 60%) as a white solid. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 8.51 (d, J=2.5 Hz, 1H), 8.21 (dd, J=9.0, 2.4 Hz, 1H), 7.31 (d, J=9.1 Hz, 1H), 4.11 (s, 3H); .sup.13C NMR (126 MHz, CDCl.sub.3) δ 157.7, 139.2, 135.9, 132.8, 125.5, 114.5, 57.6; R.sub.f: 0.19 (33% AcOEt in CyH).

##STR00031##

[0136] N,N-diethyl-4-methoxy-3-nitrobenzenesulfonamide (Compound X). To a solution of 4-methoxy-3-nitrobenzenesulfonyl chloride (4.53 g, 18.0 mmol, 1 equiv.) in CH.sub.2Cl.sub.2 (36 mL) at 0° C., was added diethylamine (9.31 mL, 54.0 mmol, 3 equiv.) dropwise. The solution was then stirred at rt for 16 h, washed with 1M HCl, brine, dried over Na.sub.2SO.sub.4 and evaporated. The residue was purified on silica gel column eluting with 20-80% EtOAc in CyH to afford the desired product (5.15 g, 17.9 mmol, 99%) as a light yellow solid. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 8.23 (d, J=2.3 Hz, 1H), 7.95 (dd, J=8.8, 2.3 Hz, 1H), 7.19 (d, J=8.9 Hz, 1H), 4.02 (s, 3H), 3.23 (q, J=7.1 Hz, 4H), 1.13 (t, J=7.2 Hz, 6H); .sup.13C NMR (126 MHz, CDCl.sub.3) δ 155.4, 139.2, 132.8, 132.7, 124.8, 114.0, 57.1, 42.2, 14.2; HRMS (ESI): calcd. for C.sub.11H.sub.17N.sub.2O.sub.5 [M+H].sup.+: 289.0855, found: 289.0855; R.sub.f: 0.40 (100% CH.sub.2Cl.sub.2); R.sub.f: 0.38 (60% AcOEt in CyH).

##STR00032##

Example 3. Synthesis of N-(5-(N,N-diethylsulfamoyl)-2-methoxyphenyl)-3-methyl-4-oxo-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrrole-1-carboxamide

[0137] ##STR00033##

[0138] Reaction conditions: i) HCTU, DIEA, DMF, 0° C. to 100° C., 64%

##STR00034##

[0139] N-(5-(N,N-diethylsulfamoyl)-2-methoxyphenyl)-3-methyl-4-oxo-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrrole-1-carboxamide (Compound 11). To a solution of 3-methyl-4-oxo-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrrole-1-carboxylic acid (100 mg, 0.48 mmol, 1 equiv.) and 3-amino-N,N-diethyl-4-methoxybenzenesulfonamide (155 mg, 0.60 mmol, 1.25 equiv.) in dry DMF (1.9 mL) at −0° C., were added diisopropylethylamine (DIEA) (0.42 mL, 2.41 mmol, 5 equiv.) and HCTU (2-(6-Chloro-1h-benzotriazol-1-yl),1,1,3,3-tetramethylaminium-hexafluorophopsphate) (250 mg, 0.60 mmol, 1.25 equiv.). The reaction was allowed to warm at rt. After 4 h, the mixture was heated at 100° C. for 16 h. Then, DMF was evaporated. Water was added and the aqueous phase was extracted three times with EtOAc. The combined organics were washed with 1H HCl, saturated Na.sub.2CO.sub.3, brine, dried over Na.sub.2SO.sub.4. Purification on silica gel column eluting with 20-100% EtOAc in cyclohexane to afford the desired product (139 mg, 0.31 mmol, 64%) as a light yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.13 (s, 1H), 8.84 (d, J=2.3 Hz, 1H), 8.22 (s, 1H), 7.52 (dd, J=8.5, 2.3 Hz, 1H), 6.93 (d, J=8.7 Hz, 1H), 3.98 (s, 3H), 3.22 (q, J=7.1 Hz, 4H), 3.15-3.06 (m, 2H), 2.72-2.62 (m, 2H), 2.49 (d, J=0.5 Hz, 3H), 2.00-1.80 (m, 4H), 1.11 (t, J=7.2 Hz, 6H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ 199.5, 159.8, 150.6, 138.6, 132.8, 128.1, 127.9, 123.5, 123.2, 120.7, 118.1, 109.6, 56.5, 42.2, 41.9, 25.8, 24.5, 21.8, 14.3, 13.7; HRMS (ESI): calcd. for C.sub.22H.sub.29N.sub.3O.sub.5SNa [M+Na].sup.+: 470.1720, found: 470.1720; R.sub.f: 0.57 (66% AcOEt in CyH).

Example 4. Synthesis of 2-methoxy-5-(morpholinosulfonyl)aniline

[0140] ##STR00035##

[0141] Reaction conditions: i) Morpholine, CH.sub.2Cl.sub.2, 0° C. to rt, 87%; ii) H.sub.2, Pd/C, MeOH/AcOEt, rt, 91%

##STR00036##

[0142] 4-((4-methoxy-3-nitrophenyl)sulfonyl)morpholine (Compound XII). The compound was synthesized as reported for N,N-diethyl-4-methoxy-3-nitrobenzenesulfonamide (morpholine was used instead of diethylamine), to afford the desired compound (3.14 g, 10.4 mmol, 87%) as a light yellow solid.

[0143] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.20 (d, J=2.3 Hz, 1H), 8.00 (dd, J=8.9, 2.3 Hz, 1H), 7.61 (d, J=9.0 Hz, 1H), 4.04 (s, 3H), 3.68-3.60 (m, 4H), 2.96-2.88 (m, 4H); .sup.13C NMR (101 MHz, DMSO) δ 155.2, 138.9, 133.4, 126.3, 124.6, 115.4, 65.2, 57.4, 45.7; HRMS (ESI): calcd. for C.sub.11H.sub.14N.sub.2O.sub.6SNa [M+Na].sup.+: 325.0465, found: 325.0465; R.sub.f: 0.35 (60% AcOEt in CyH).

##STR00037##

[0144] 2-methoxy-5-(morpholinosulfonyl)aniline (Compound XIII). The compound was synthesized as reported for 3-amino-N,N-diethyl-4-methoxybenzenesulfonamide in MeOH/EtOAc (1:1, 50 mL), to afford the desired compound (1.89 g, 6.94 mmol, 91%) as a light yellow solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.04-6.94 (m, 2H), 6.88 (dt, J=8.4, 2.1 Hz, 1H), 3.84 (d, J=1.6 Hz, 3H), 3.60 (t, J=4.8 Hz, 4H), 2.84-2.74 (m, 4H); .sup.13C NMR (126 MHz, DMSO-d.sub.6) δ 149.6, 138.3, 125.8, 116.2, 111.5, 109.9, 65.3, 55.6, 45.9; HRMS (ESI): calcd. for C.sub.11H.sub.16N.sub.2O.sub.4SNa [M+Na].sup.+: 295.0723, found: 295.0723; R.sub.f: 0.72 (80% AcOEt in CyH).

Example 5. Synthesis of N-(2-methoxy-5-(morpholinosulfonyl)phenyl)-3-methyl-4-oxo-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrrole-1-carboxamide

[0145] ##STR00038##

[0146] Reaction conditions: i) O-(1H-6-Chlorobenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU), N,N-Diisopropylethylamine (DIEA), DMF, 0° C. to 100° C., 38%

##STR00039##

[0147] N-(2-methoxy-5-(morpholinosulfonyl)phenyl)-3-methyl-4-oxo-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrrole-1-carboxamide. The compound was synthesized as reported for N-(5-(N,N-diethylsulfamoyl)-2-methoxyphenyl)-3-methyl-4-oxo-2,4,5,6,7,8-hexahydrocyclohepta[c]-pyrrole-1-carboxamide, to afford the desired compound (84 mg, 0.18 mmol, 38%) as a light yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.90 (s, 1H), 8.83 (d, J=2.3 Hz, 1H), 8.25 (s, 1H), 7.48 (dd, J=8.6, 2.3 Hz, 1H), 7.01 (d, J=8.7 Hz, 1H), 4.02 (s, 3H), 3.77-3.65 (m, 4H), 3.13-3.07 (m, 2H), 3.05-2.98 (m, 4H), 2.71-2.66 (m, 2H), 2.50 (s, 3H), 2.01-1.85 (m, 4H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ 199.5, 159.8, 151.1, 138.7, 128.3, 127.8, 127.7, 124.0, 123.6, 120.7, 118.9, 109.8, 66.2, 56.6, 46.2, 41.9, 25.9, 24.7, 21.8, 13.8; HRMS (ESI): calcd. for C.sub.22H.sub.27N.sub.3O.sub.6SNa [M+Na].sup.+: 484.1513, found: 484.1513; R.sub.f: 0.19 (66% AcOEt in CyH).

Example 6. Synthesis of 2-methoxy-5-((4-methylpiperazin-1-yl)sulfonyl)aniline

[0148] ##STR00040##

[0149] Reaction conditions: i) N-Methylpiperazine, CH.sub.2Cl.sub.2, 0° C. to rt, 87%; ii) H.sub.2, Pd/C, MeOH/AcOEt, rt, 91%

##STR00041##

[0150] 2-methoxy-5-((4-methylpiperazin-1-yl)sulfonyl)aniline (Compound XV). The compound was synthesized as reported for 3-amino-N,N-diethyl-4-methoxybenzenesulfonamide in MeOH/EtOAc (1:1, 50 mL), to afford the desired compound (1.66 g, 5.82 mmol, 92%) as a light yellow solid. HRMS (ESI): calcd. for C.sub.12H.sub.20N.sub.3O.sub.3S [M+H].sup.+: 286.1220, found: 286.1220.

Example 7. Synthesis of N-(2-methoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-3-methyl-4-oxo-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrrole-1-carboxamide

[0151] ##STR00042##

[0152] Reaction conditions: i) HCTU, DIEA, DMF, 0° C. to 100° C., 41%

##STR00043##

[0153] N-(2-methoxy-5-(4-methylpiperazin-1-yl)sulfonyl)phenyl)-3-methyl-4-oxo-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrrole-1-carboxamide (Compound 14). The compound was synthesized as reported for N-(5-(N,N-diethylsulfamoyl)-2-methoxyphenyl)-3-methyl-4-oxo-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrrole-1-carboxamide, to afford the desired compound (94 mg, 0.20 mmol, 41%) as a light yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.98 (s, 1H), 8.83 (d, J=2.3 Hz, 1H), 8.23 (s, 1H), 7.47 (dd, J=8.6, 2.3 Hz, 1H), 6.98 (d, J=8.7 Hz, 1H), 4.00 (s, 3H), 3.14-2.99 (m, 6H), 2.73-2.62 (m, 2H), 2.49 (d, J=0.4 Hz, 3H), 2.45 (t, J=5.0 Hz, 4H), 2.24 (s, 3H), 2.00-1.81 (m, 4H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ 199.5, 159.7, 151.0, 138.6, 128.3, 127.9, 127.7, 123.9, 123.6, 120.8, 118.8, 109.7, 56.6, 54.2, 46.1, 45.8, 41.9, 25.9, 24.6, 21.8, 13.8; HRMS (ESI): calcd. for C.sub.23H.sub.31N.sub.4O.sub.5S [M+H].sup.+: 475.2010, found: 475.2010; R.sub.f: 0.05 (66% AcOEt in CyH); R.sub.f: 0.36 (12% MeOH in CH.sub.2Cl.sub.2+0.1% NEt.sub.3).

Example 8. Synthesis of 5-(azepan-1-ylsulfonyl)-2-methoxyaniline

[0154] ##STR00044##

[0155] Reaction conditions: i) Azepane, CH.sub.2Cl.sub.2, 0° C. to rt, 94%; ii) H.sub.2, Pd/C, MeOH/AcOEt, rt, 95%

##STR00045##

[0156] 1-((4-methoxy-3-nitrophenyl)sulfonyl)azepane (Compound XVI). The compound was synthesized as reported for N,N-diethyl-4-methoxy-3-nitrobenzenesulfonamide (azepane was used instead of diethylamine), to afford the desired compound (3.52 g, 11.2 mmol, 94%) as a light yellow solid. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 8.23 (d, J=2.3 Hz, 1H), 7.95 (dd, J=8.8, 2.3 Hz, 1H), 7.19 (d, J=8.9 Hz, 1H), 4.03 (s, 3H), 3.32-3.19 (m, 4H), 1.72 (ddddd, J=9.9, 8.1, 6.7, 3.3, 2.2 Hz, 4H), 1.63-1.53 (m, 4H); .sup.13C NMR (126 MHz, CDCl.sub.3) δ 155.4, 139.3, 132.6, 132.0, 124.7, 113.9, 57.1, 48.4, 29.2, 26.9; HRMS (ESI): calcd. for C.sub.13H.sub.19N.sub.2O.sub.5S [M+H].sup.+: 315.1009, found: 315.1009; R.sub.f: 0.56 (60% AcOEt in CyH).

##STR00046##

[0157] 5-(azepan-1-ylsulfonyl)-2-methoxyaniline (Compound XVII). The compound was synthesized as reported for 3-amino-N,N-diethyl-4-methoxybenzenesulfonamide in MeOH/EtOAc (1:1, 50 mL), to afford the desired compound (1.72 g, 6.05 mmol, 95%) as a light yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.85 (s, 3H), 7.68 (d, J=2.3 Hz, 1H), 7.50 (dd, J=8.6, 2.4 Hz, 1H), 7.22 (dd, J=8.7, 1.1 Hz, 1H), 3.91 (s, 3H), 3.24-3.12 (m, 4H), 1.72-1.42 (m, 8H); .sup.13C NMR (101 MHz, DMSO-d.sub.6) δ 153.2, 131.0, 127.0, 123.8, 118.8, 111.8, 56.3, 47.6, 28.4, 26.3; HRMS (ESI): calcd. for C.sub.13H.sub.21N.sub.2O.sub.3S [M+H].sup.+: 285.1287, found: 285.1287; R.sub.f: 0.48 (40% AcOEt in PE).

Example 9. Synthesis of N-(5-(azepan-1-ylsulfonyl)-2-methoxyphenyl)-3-methyl-4-oxo-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrrole-1-carboxamide

[0158] ##STR00047##

[0159] Reaction conditions: i) HCTU, DIEA, DMF, 0° C. to 100° C., 73%

##STR00048##

[0160] N-(5-(azepan-1-ylsulfonyl)-2-methoxyphenyl)-3-methyl-4-oxo-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrrole-1-carboxamide (Compound 12). The compound was synthesized as reported for N-(5-(N,N-diethylsulfamoyl)-2-methoxyphenyl)-3-methyl-4-oxo-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrrole-1-carboxamide, to afford the desired compound (167 mg, 0.35 mmol, 73%) as a light yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.07 (s, 1H), 8.83 (d, J=2.3 Hz, 1H), 8.23 (s, 1H), 7.51 (dd, J=8.6, 2.3 Hz, 1H), 6.94 (d, J=8.6 Hz, 1H), 3.99 (s, 3H), 3.31-3.23 (m, 4H), 3.12-3.07 (m, 2H), 2.72-2.63 (m, 2H), 2.49 (d, J=0.5 Hz, 3H), 1.99-1.82 (m, 4H), 1.68 (dtt, J=10.9, 4.7, 2.4 Hz, 4H), 1.61-1.52 (m, 4H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ 199.5, 159.8, 150.6, 138.6, 132.1, 128.1, 127.9, 123.5, 123.1, 120.8, 117.9, 109.6, 56.5, 48.4, 41.9, 29.2, 27.0, 25.8, 24.5, 21.8, 13.7; HRMS (ESI): calcd. for C.sub.24H.sub.31N.sub.3O.sub.5SNa [M+Na].sup.+: 496.1877, found: 496.1877; R.sub.f: 0.40 (66% AcOEt in CyH).

Example 10—Synthesis of Compound 23

[0161] ##STR00049##

2-Bromo-1-chloro-4-nitrobenzene

[0162] NBS (14.1 g, 79.2 mmol, 1.2equiv) were added portionwise to a solution of 4-chloronitrobenzene (10.4 g, 66.0 mmol, 1.0 equiv) in conc. H.sub.2SO.sub.4 (30 mL over 45 min at 60° C. After 2 h the reaction mixture was poured on ice. The precipitated solids were filtered off, washed first with H.sub.2O and then with pentane. The remaining solid was dried under reduced pressure to obtain the desired product as a yellowish solid (11.3 g, 47.7 mmol, 72%). Mp: 53-54° C.

[0163] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=7.63 (d, J=8.8 Hz, 1H), 8.12 (dd, J=8.8 Hz, J=2.6 Hz, 1H), 8.50 (d, J=2.6 Hz, 1H). .sup.13C-NMR (101 MHz, CDCl.sub.3): δ=123.3, 123.4, 127.5, 128.9, 130.9, 141.9.

2-(2-Chloro-5-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0164] A suspension of 2-(3,5-dinitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (100 mg, 423 mmol, 1.0 equiv), KOAc (81 mg, 825 mmol, 2.0 equiv.), B.sub.2(pin).sub.2 (120 mg, 465 mmol, 1.1 equiv.), Pd(dppf)Cl.sub.2 (9.3 mg, 12.7 mmol, 3 mol %) in degassed dioxane (1.2 mL) and DMSO (20 μL) was stirred overnight at 90° C. The solvent was removed under reduced pressure and an aqueous solution of NaOH (2M) was added, the mixture was stirred for 10 min, filtered and washed two times with Et.sub.2O. The aqueous phase was acidified with conc. HCl and afterwards three times extracted with EA. The organic phase was dried over Na.sub.2SO.sub.4 and evaporated to obtain the title compound as a yellowish solid (63.1 mg, 0.222 mmol, 52%). Mp: 89-92° C.

[0165] .sup.1H-NMR (500 MHz, CDCl.sub.3): δ=1.39 (s, 14H), 7.51 (d, J=8.8 Hz, 1H), 8.18 (dd, J=8.8, 2.8 Hz, 1H), 8.55 (d, J=2.9 Hz, 1H). .sup.13C-NMR (101 MHz, CDCl.sub.3): δ=25.0, 85.1, 126.6, 130.6, 131.5, 132.6, 146.1, 146.7. HRMS (neg. APCI): [M+O.sub.2].sup.− calc. for C.sub.12H.sub.15NO.sub.6BCl: 315.0686; found: 315.0688.

1-bromo-3-methyl-5,6,7,8-tetrahydrocyclohepta[c]pyrrol-4(2H)-one

[0166] General synthetic scheme

##STR00050##

[0167] Pyridine (0.54 mL, 6.76 mmol, 5 equiv.) followed by pyridinium tribromide (648 mg, 2.03 mmol, 1.5 equiv.) were added to a solution of 3-methyl-4-oxo-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrrole-1-carboxylic acid (280 mg, 1.35 mmol, 1 equiv.) in CH.sub.2Cl.sub.2 (13.5 mL) at 0° C. The mixture was allowed to return to room temperature and stirred overnight. Aqueous hydrochloric acid (HCl, 0.5M) was added and the organic phase was collected, dried over Na.sub.2SO.sub.4 and evaporated. Purification on flash chromatography column afford the desired product (159 mg, 0.66 mmol, 49%) as a colourless solid, which decomposes at room temperature.

[0168] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.67 (s, 1H), 2.71-2.64 (m, 4H), 2.49 (d, J=0.5 Hz, 3H), 1.92-1.70 (m, 4H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ 200.1, 137.2, 123.9, 121.1, 96.0, 41.8, 25.1, 24.2, 22.3, 13.9, HRMS (ESI): calcd. for C.sub.10H.sub.13NOBr [M+H].sup.+: 242.0175, found: 242.0175; R.sub.f: 0.45 (33% AcOEt in cyclohexane).

##STR00051##

1-(2-Chloro-5-nitrophenyl)-3-methyl-5,6,7,8-tetrahydrocyclohepta[c]pyrrol-4(2H)-one

[0169] A mixture of 1-bromo-3-methyl-5,6,7,8-tetrahydrocyclohepta[c]pyrrol-4(2H)-one (73 mg, 0.30 mmol, 1.0 equiv.), 2-(2-Chloro-5-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.13 g, 0.45 mmol, 1.5 equiv.), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (18 mg, 0.06 mmol, 0.02 equiv.), Pd.sub.2dba.sub.3 (14 mg, 15 μmol, 0.05 equiv.), K.sub.3PO.sub.4 (0.19 g, 0.90 mmol, 3.0 equiv.) in degassed dioxane/H.sub.2O (1.5 mL) was stirred 3.75 h at 70° C., then filtered over celite and evaporated. The residue was purified by column chromatography (10-85% EA in PE) to afford the desired product (34 mg, 0.11 mmol, 35%) as a light yellow solid. Mp: 198-199° C.

[0170] .sup.1H-NMR (500 MHz, CDCl.sub.3): δ=1.80-1.95 (m, 4H), 2.58 (s, 3H), 2.67-2.73 (m, 4H), 7.64 (d, J=8.8 Hz, 1H), 8.12 (d, J=8.8 Hz, J=2.7 Hz, 1H), 8.19 (d, J=2.7 Hz, 1H), 8.38 (br. s, 1H). .sup.13C-NMR (126 MHz, CDCl.sub.3): δ=14.0, 22.2, 23.9, 25.6, 42.0, 121.0, 122.0, 123.3, 125.7, 126.9, 131.3, 132.7, 136.2, 140.2, 146.6, 200.1. HRMS (pos. ESI): [M+H].sup.+ calc. for C.sub.16H.sub.15O.sub.3N.sub.2Cl: 319.0844; found: 319.0842.

1-(5-Amino-2-chlorophenyl)-3-methyl-5,6,7,8-tetrahydrocyclohepta[c]pyrrol-4(2M-one (Compound 23)

[0171] To a solution of 1-(2-chloro-5-nitrophenyl)-3-methyl-5,6,7,8-tetrahydrocyclohepta[c]pyrrol-4(2H)-one (33 mg, 0.11 mmol, 1.0 equiv.) and NH.sub.4Cl (12 mg, 0.23 mmol, 2.0 equiv.) in EtOH/H.sub.2O (4:1, 2.3 mL) Fe powder (22 mg, 0.40 mmol, 3.5 equiv.) was added. The mixture was stirred under reflux for 4 h, afterwards filtered first over cotton, then celite. EtOH was evaporated, water was added and the aqueous phase was three times extracted with EA. The combined organic phases were washed with brine, dried over Na.sub.2SO.sub.4 and evaporated. The residue was purified by reversed phase column chromatography (MeCN/H.sub.2O) to afford the desired product as a colourless solid (23 mg, 0.79 mmol, 69%). Mp: 169-171° C.

[0172] .sup.1H-NMR (500 MHz, CDCl.sub.3): δ=1.79-1.92 (m, 4H), 2.54 (d, J=0.5 Hz, 3H), 2.63-2.75 (m, 4H), 3.60-3.83 (m, 2H), 6.54-6.62 (m, 2H), 7.18-7.23 (m, 1H), 8.27 (s, 1H). .sup.13C-NMR (126 MHz, CDCl.sub.3): δ=13.9, 22.2, 23.8, 25.7, 42.0, 115.7, 118.3, 121.5, 122.5, 123.4, 123.6, 130.8, 131.5, 134.7, 145.2, 220.3. HRMS (pos. ESI): [M+H].sup.+ calc. for C.sub.16H.sub.18ON.sub.2Cl: 289.1102; found: 289.1101.

Example 11—Synthesis of Compound (24)

[0173] ##STR00052##

1-(1H-indol-6-yl)-3-methyl-5,6,7,8-tetrahydrocyclohepta[c]pyrrol-4(2H)-one (Compound 24)

[0174] To 1-bromo-3-methyl-5,6,7,8-tetrahydrocyclohepta[c]pyrrol-4(2H)-one (50 mg, 0.21 mmol, 1 equiv.), (1H-indol-6-yl)boronic acid (50 mg, 0.31 mmol, 1.5 equiv.), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (24 mg, 0.02 mmol, 0.1 equiv.), Pd.sub.2dba.sub.3 (19 mg, 0.02 mmol, 0.1 equiv.), K.sub.3PO.sub.4 (131 mg, 0.62 mmol, 3 equiv.) degassed dioxane/H.sub.2O (2.1 mL) under argon was added. The mixture was stirred at 60° C. for 16 h, then filtered on celite and evaporated. The mixture was purified on silica gel column eluting with 30-70% EtOAc in PE to afford the desired product (37 mg, 0.13 mmol, 64%) as a light yellow solid.

[0175] .sup.1H NMR (500 MHz, MeOD-d.sub.4) δ 7.58 (dd, J=8.2, 0.7 Hz, 1H), 7.45-7.36 (m, 1H), 7.20 (d, J=3.1 Hz, 1H), 7.08 (dd, J=8.2, 1.5 Hz, 1H), 6.45 (dd, J=3.2, 0.9 Hz, 1H), 2.90-2.84 (m, 2H), 2.67-2.62 (m, 2H), 2.49 (s, 3H), 1.90-1.72 (m, 4H); .sup.13C NMR (126 MHz, MeOD-d.sub.4) δ 202.4, 136.7, 135.9, 128.9, 127.2, 126.4, 125.5, 121.9, 121.2, 120.7, 120.1, 110.7, 101.9, 41.8, 26.3, 23.8, 22.7, 13.5; R.sub.f: 0.25 (40% AcOEt in cyclohexane).

Example 12—Synthesis of Compounds (26) and (27)

[0176] ##STR00053## ##STR00054##

2-((Dimethylamino)methylene)cycloheptane-1,3-dione (Step I)

[0177] To a solution of cycloheptane-1,3-dione (7.61 g, 60.3 mmol, 1.0 equiv.) in dry DCM (86 mL) N,N-dimethylformamide dimethyl acetal (10.5 mL, 9.34 g, 78.4 mmol, 1.3 equiv.) was added. The mixture was stirred at room temperature overnight, evaporated and purified by column chromatography (8% MeOH in DCM) to afford the desired product (9.49 g, 52.4 mmol, 87%) as a yellow solid. Mp: 91-92° C.

[0178] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=1.83 (m.sub.c, 4H), 2.56 (m.sub.c, 4H), 2.78 (s, 3H), 3.27 (s, 3H), 7.69 (s, 1H). .sup.13C-NMR (101 MHz, CDCl.sub.3): δ=22.3, 40.6, 43.3, 48.0, 112.9, 159.6, 200.1

2,7-Dioxacycloheptane-1-carbaldehyde (Step II)

[0179] To a solution of 2-((dimethylamino)methylene)-cycloheptane-1,3-dione (9.49 g, 52.3 mmol, 1.0 equiv.) in THF (70 mL) aqueous HCl (1%, 260 mL) was added. The solution was stirred for 3 h at room temperature, THF was removed and the aqueous phase was extracted three times with EA. The combined organic phases were washed with water, brine, dried over Na.sub.2SO.sub.4 and evaporated to afford the desired product (7.52 g, 48.8 mmol, 93%) as a light orange oil. .sup.1H-NMR (500 MHz, CDCl.sub.3): δ=1.86-1.95 (m, 4H), 2.64-2.70 (m, 2H), 2.74-2.78 (m, 2H), 9.29 (br. s, 1H). .sup.13C-NMR (126 MHz, CDCl.sub.3): δ=21.2, 22.1, 36.2, 41.1, 117.3, 190.3, 198.4, 199.2. HRMS (neg. APCI): [M−H].sup.− calc. for C.sub.8H.sub.9O.sub.3: 153.0557; found: 153.0558.

Methyl 4-oxo-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrrole-1-carboxylate (Step III)

[0180] Dimethyl 2-(hydroxy-imino)malonate (10.2 g, 63.5 mmol, 1.35 equiv), 2,7-dioxocycloheptane-1-carbaldehyde (7.25 g, 47.0 mmol, 1.0 equiv) and NaOAc (13.5 g, 165 mmol, 3.5 equiv.) were dissolved in AcOH (157 mL) and heated to 90° C. Zn (12.3 g, 188 mmol, 4.0 equiv) was added portionwise. The reaction mixture was stirred for 5 h at 95° C., poured on ice and the aqueous phase was extracted three times with EA. The combined organic layers were washed twice with NaOH, then brine, dried over Na.sub.2SO.sub.4 and evaporated. The residue was purified by column chromatography (33-40% EA in PE) to afford the desired product as a colourless solid (2.64 g, 12.8 mmol, 27%). Mp: 129-132° C.

[0181] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=1.80-1.97 (m, 4H), 2.69 (m.sub.c, 2H), 3.19 (m.sub.c, 2H), 3.87 (s, 3H), 7.50 (d, J=3.5 Hz, 1H), 9.62 (br. s, 1H). .sup.13C-NMR (101 MHz, CDCl.sub.3): δ=22.2, 24.4, 25.9, 42.2, 51.6, 119.6, 126.0, 127.9, 132.9, 161.9, 199.2. HRMS (pos. APCI): [M+H].sup.+ calc. for C.sub.11H.sub.13NO.sub.3: 208.0968; found: 208.0969.

Methyl 4-oxo-3-propyl-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrrole-1-carboxylate and Methyl 3-butyl-4-oxo-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrrole-1-carboxylate (Step IV)

[0182] Methyl 4-oxo-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrrole-1-carboxylate (0.95 g, 4.6 mmol, 1.0 equiv), 1-bromopropane (0.83 mL, 1.1 g, 9.1 mmol, 2.0 equiv), norbornene (0.86 g, 9.1 mmol, 2.0 equiv), KHCO.sub.3 (1.4 g, 14 mmol, 3.0 equiv) and PdCl.sub.2(MeCN).sub.2 (87 mg, 0.34 mmol, 0.01 equiv.) were stirred in DMA (3.4 mL) and heated to 90° C. overnight. After cooling to room temperature the mixture was filtered through a pad of celite, which was rinsed three times with Et.sub.2O. The filtrate was washed with H.sub.2O and the aqueous phase was extracted two times with Et.sub.2O. The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and evaporated. The residue was purified by column chromatography (25% EA in PE) to afford the desired as a yellow solid (0.75 g, 3.0 mmol, 66%). Mp: 125-127° C.,

[0183] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=0.97 (t, J=7.3 Hz, 3H), 1.60-1.75 (m, 2H), 1.80-1.91 (m, 4H), 2.62-2.70 (m, 2H), 2.86-2.95 (m, 2H), 3.13-3.23 (m, 1H), 3.86 (s, 3H), 8.85 (s, 1H).sup.13C-NMR (101 MHz, CDCl.sub.3): δ=14.0, 22.0, 22.0, 23.4, 25.3, 29.7, 42.2, 51.5, 77.5, 116.5, 123.3, 134.4, 142.8, 161.9, 199.8 HRMS (pos. ESI): [M+H].sup.+ calc. for C.sub.14H.sub.20NO.sub.3: 250.1438; found: 250.1438.

[0184] For methyl 3-butyl-4-oxo-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrrole-1-carboxylate 1-bromobutane (0.97 mL, 1.2 g, 9.1 mmol, 2.0 equiv) was used instead of 1-bromopropane. The desired product was obtained as a yellow solid (0.78 g, 3.0 mmol, 59%). Mp: 123-125° C., .sup.1H-NMR (500 MHz, CDCl.sub.3): δ=0.93 (t, J=7.3 Hz, 3H), 1.38 (dq, J=14.7, 7.3 Hz, 2H), 1.55-1.66 (m, 2H), 1.79-1.88 (m, 4H), 2.61-2.69 (m, 2H), 2.88-2.95 (m, 2H), 3.14-3.21 (m, 2H), 3.86 (s, 3H), 8.97 (s, 1H). .sup.13C-NMR (126 MHz, CDCl.sub.3): δ=14.0, 21.9, 22.7, 23.3, 25.3, 27.5, 30.9, 42.1, 51.5, 116.5, 123.1, 134.5, 143.1, 162.0, 199.9. HRMS (pos. ESI): [M+H].sup.+ calc. for C.sub.15H.sub.22NO.sub.3: 264.1594; found: 264.1596.

4-Oxo-3-propyl-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrrole-1-carboxylic acid and (Step V)

[0185] LiOH.H.sub.2O (1.3 g, 30 mmol, 10 equiv) was added to a solution of methyl 4-oxo-3-propyl-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrrole-1-carboxylate (0.75 g, 3.0 mmol, 1.0 equiv) in a mixture of THF/H.sub.2O/MeOH (30 mL, 1:1:1). The reaction mixture was stirred at rt overnight. The organic solvents were evaporated and the aqueous phase was acidified with conc. HCl, extracted three times with EA, dried over Na.sub.2SO.sub.4 and concentrated in vacuo to obtain the desired product as a colourless solid (0.69 g, 2.9 mmol, 97%). Mp: 182-187° C.,

[0186] .sup.1H-NMR (500 MHz, Acetone-d.sub.6): δ=0.90 (t, J=7.4 Hz, 3H), 1.59-1.69 (m, 2H), 1.77-1.85 (m, 4H), 2.54-2.64 (m, 2H), 2.85-2.96 (m, 2H), 3.18-3.29 (m, 2H), 10.77 (s, 1H). .sup.13C-NMR (126 MHz, Acetone-d.sub.6): δ=14.1, 22.5, 23.4, 26.0, 29.5, 42.4, 117.3, 123.5, 134.5, 143.4, 162.4, 199.0. HRMS (neg. APCI): [M−H].sup.− calc. for C.sub.13H.sub.16NO.sub.3: 234.1136; found: 234.1130.

4-Oxo-3-butyl-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrrole-1-carboxylic acid (Step V)

[0187] LiOH.H.sub.2O (1.2 g, 30 mmol, 10 equiv) was added to a solution of methyl 4-oxo-3-butyl-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrrole-1-carboxylate (0.78 g, 3.0 mmol, 1.0 equiv) in a mixture of THF/H.sub.2O/MeOH (30 mL, 1:1:1). The reaction mixture was stirred at rt overnight. The organic solvents were evaporated and the aqueous phase was acidified with conc. HCl, extracted three times with EA, dried over Na.sub.2SO.sub.4 and concentrated in vacuo to obtain the desired product as a colourless solid (0.20 g, 0.79 mmol, 27%). Mp: 134-139° C.

[0188] .sup.1H-NMR (500 MHz, Acetone-d.sub.6): δ=0.90 (t, J=7.4 Hz, 3H), 1.28-1.39 (m, 2H), 1.55-1.64 (m, 2H), 1.76-1.85 (m, 4H), 2.55-2.62 (m, 2H), 2.90-2.99 (m, 2H), 3.20-3.27 (m, 2H), 10.79 (s, 1H). .sup.13C-NMR (126 MHz, Acetone-d.sub.6): δ=14.1, 22.5, 23.2, 23.4, 26.0, 27.4, 32.4, 42.4, 117.5, 123.4, 134.4, 143.5, 162.8, 199.0. HRMS (neg. APCI): [M+H]+ calc. for C.sub.14H.sub.18NO.sub.3: 248.1292; found: 248.1291.

1-Bromo-3-propyl-5,6,7,8-tetrahydrocyclohepta[c]pyrrol-4(2H)-one

[0189] Pyridine (1.0 mL, 0.98 g, 13 mmol, 5.0 equiv) and PyHBr.sub.3 (1.2 g, 3.6 mmol, 1.5 equiv) were added to a solution of 4-oxo-3-propyl-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrrole-1-carboxylic acid (0.57 g, 2.4 mmol, 1.0 equiv) in DCM (24 mL) at 0° C. The reaction mixture was stirred at rt for 4.5 h. Aqueous HCl (0.5 M) was added and the phases were separated. The organic phase was dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified via column chromatography (5-9% EA in pentane) to obtain the desired product as a colourless solid which turns black and decomposes at rt (0.43 g, 1.6 mmol, 66%). The product was used without further characterisation due to it's instability. HRMS (pos. ESI): [M+H].sup.+ calc. for C.sub.12H.sub.17NOBr: 270.0488; found: 270.0489.

1-Bromo-3-butyl-5,6,7,8-tetrahydrocyclohepta[c]pyrrol-4(2H)-one

[0190] Pyridine (0.28 mL, 0.27 g, 3.4 mmol, 5.0 equiv) and PyHBr.sub.3 (0.33 g, 1.0 mmol, 1.5 equiv) were added to a solution of 4-oxo-3-butyl-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrrole-1-carboxylic acid (0.17 g, 0.68 mmol, 1.0 equiv) in DCM (7.0 mL) at 0° C. The reaction mixture was stirred at rt for 4.5 h. Aqueous HCl (0.5 M) was added and the phases were separated. The organic phase was dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified via column chromatography (5-6% EA in pentane) to obtain the desired product as a colourless solid which turns black and decomposes at rt (79 mg, 0.28 mmol, 41%). The product was used without further characterisation due to it's instability. HRMS (pos. ESI): [M+H].sup.+ calc. for C.sub.13H.sub.19NOBr: 284.0645; found: 284.0643.

1-(2-Chloro-5-nitrophenyl)-3-propyl-5,6,7,8-tetrahydrocyclohepta[c]pyrrol-4(2H)-one

[0191] To 1-bromo-3-propyl-5,6,7,8-tetrahydrocyclohepta[c]pyrrol-4(2H)-one (100 mg, 0.37 mmol, 1.0 equiv.), 2-(2-Chloro-5-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.16 g, 0.56 mmol, 1.5 equiv.), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (22 mg, 74 μmol, 0.02 equiv.), Pd.sub.2dba.sub.3 (17 mg, 19 μmol, 0.05 equiv.), K.sub.3PO.sub.4 (0.24 g, 1.1 mmol, 3.0 equiv.) in degassed dioxane/H.sub.2O (1.9 mL) was stirred 2.5 h at 70° C., then filtered over celite and evaporated. The residue was purified by column chromatography (3-85% EA in PE) to afford the desired product (25 mg, 73 μmol, 20%) as a light yellow solid. Mp: 68-70° C.

[0192] .sup.1H-NMR (500 MHz, CDCl.sub.3): δ=0.98 (t, J=7.4, 7.4 Hz, 3H), 1.61-1.75 (m, 2H), 1.77-1.93 (m, 4H), 2.64-2.72 (m, 4H), 2.89-2.99 (m, 2H), 7.63 (d, J=8.8 Hz, 1H), 8.10 (dd, J=8.8, 2.7 Hz, 1H), 8.19 (d, J=2.7 Hz, 1H), 8.65 (s, 1H). .sup.13C-NMR (126 MHz, CDCl.sub.3): δ=14.0, 22.1, 22.4, 23.8, 25.5, 29.6, 42.0, 121.1, 121.4, 123.2, 125.6, 127.0, 131.3, 132.7, 140.3, 140.8, 146.6, 200.0. HRMS (pos. ESI): [M+H].sup.+ calc. for C.sub.18H.sub.20N.sub.2O.sub.3Cl: 347.1157; found: 347.1160.

1-(2-Chloro-5-nitrophenyl)-3-butyl-5,6,7,8-tetrahydrocyclohepta[c]pyrrol-4(2H)-one

[0193] A mixture of 1-bromo-3-butyl-5,6,7,8-tetrahydrocyclohepta[c]pyrrol-4(2H)-one (0.8 g, 0.28 mmol, 1.0 equiv.), 2-(2-Chloro-5-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.12 g, 0.42 mmol, 1.5 equiv.), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (16 mg, 56 μmol, 0.02 equiv.), Pd.sub.2dba.sub.3 (13 mg, 14 μmol, 0.05 equiv.), K.sub.3PO.sub.4 (0.18 g, 0.85 mmol, 3.0 equiv.) in degassed dioxane/H.sub.2O (1.4 mL) was stirred 2.5 h at 70° C., then filtered over celite and evaporated. The residue was purified by reversed phase column chromatography (MeCN/H.sub.2O) to afford the desired product (12 mg, 33 μmol, 12%) as a yellow oil.

[0194] .sup.1H-NMR (500 MHz, CDCl.sub.3): δ=0.94 (t, J=7.3 Hz, 3H), 1.41 (dq, J=14.7, 7.4 Hz, 2H), 1.61-1.69 (m, 2H), 1.81-1.95 (m, 4H), 2.69 (ddd, J=7.6, 4.4, 1.8 Hz, 4H), 2.94-3.03 (m, 2H), 7.64 (d, J=8.8 Hz, 1H), 8.11 (dd, J=8.8, 2.7 Hz, 1H), 8.19 (d, J=2.7 Hz, 1H), 8.44 (s, 1H). .sup.13C-NMR (126 MHz, CDCl.sub.3): δ=14.1, 22.1, 22.7, 23.8, 25.6, 27.4, 31.2, 42.1, 121.0, 121.5, 123.2, 125.7, 126.9, 131.3, 132.7, 140.2, 140.9, 146.6, 199.9. HRMS (neg. ESI): [M−H].sup.− calc. for C.sub.19H.sub.20N.sub.2O.sub.3Cl: 359.1168; found: 359.1165.

1-(5-Amino-2-chlorophenyl)-3-propyl-5,6,7,8-tetrahydrocyclohepta[c]pyrrol-4(2H)-one (Compound 26)

[0195] To a solution of 1-(2-chloro-5-nitrophenyl)-3-propyl-5,6,7,8-tetrahydrocyclohepta[c]pyrrol-4(2H)-one (25 mg, 72 μmol, 1.0 equiv.) and NH.sub.4Cl (7.7 mg, 0.14 mmol, 2.0 equiv.) in EtOH/H.sub.2O (4:1, 1.4 mL) Fe powder (14 mg, 0.25 mmol, 3.5 equiv.) was added. The mixture was stirred under reflux for 4 h, afterwards filtered first over cotton, then celite. EtOH was evaporated, water was added and the aqueous phase was three times extracted with EA. The combined organic phases were washed with brine, dried over Na.sub.2SO.sub.4 and evaporated. The residue was purified by reversed phase column chromatography (MeCN/H.sub.2O) to afford the desired product as a yellow oil (15 mg, 47 μmol, 66%).

[0196] .sup.1H-NMR (500 MHz, CDCl.sub.3): δ=0.98 (t, J=7.3 Hz, 4H), 1.63-1.73 (m, 2H), 1.76-1.92 (m, 4H), 2.64-2.68 (m, 2H), 2.68-2.72 (m, 2H), 2.90-2.97 (m, 2H), 6.58-6.63 (m, 2H), 7.18-7.23 (m, 1H), 8.37 (s, 1H). .sup.13C-NMR (126 MHz, CDCl.sub.3): δ=14.1, 22.3, 22.3, 23.7, 25.7, 29.7, 42.1, 115.8, 118.4, 121.0, 122.5, 123.5, 123.7, 130.8, 131.6, 139.3, 145.2, 200.2. HRMS (pos. ESI): [M+H].sup.+ calc. for C.sub.18H.sub.22N.sub.2OCl: 317.1415; found: 317.1422.

[0197] 1-(5-Amino-2-chlorophenyl)-3-butyl-5,6,7,8-tetrahydrocyclohepta[c]pyrrol-4(2H)-one (Compound 27). To a solution of 1-(2-chloro-5-nitrophenyl)-3-butyl-5,6,7,8-tetrahydrocyclohepta[c]pyrrol-4(2H)-one (12 mg, 33 μmol, 1.0 equiv.) and NH.sub.4Cl (3.5 mg, 66 μmol, 2.0 equiv.) in EtOH/H.sub.2O (4:1, 0.67 mL) Fe powder (6.5 mg, 0.12 mmol, 3.5 equiv.) was added. The mixture was stirred under reflux for 4 h, afterwards filtered first over cotton, then celite. EtOH was evaporated, water was added and the aqueous phase was three times extracted with EA. The combined organic phases were washed with brine, dried over Na.sub.2SO.sub.4 and evaporated. The residue was purified by reversed phase column chromatography (MeCN/H.sub.2O) to afford the desired product as a yellow oil (6.6 mg, 20 μmol, 60%). .sup.1H-NMR (500 MHz, CDCl.sub.3): δ=0.93 (t, J=7.3 Hz, 3H), 1.40 (h, J=7.4 Hz, 2H), 1.58-1.69 (m, 2H), 1.76-1.92 (m, 4H), 2.63-2.74 (m, 4H), 2.93-3.00 (m, 2H), 6.56-6.68 (m, 2H), 7.21 (d, J=8.3 Hz, 1H), 8.30 (s, 1H). .sup.13C-NMR (126 MHz, CDCl.sub.3): δ=14.1, 22.3, 22.7, 23.8, 25.7, 27.5, 31.2, 42.1, 115.8, 118.5, 120.9, 122.6, 123.5, 123.7, 130.9, 131.6, 139.6, 145.1, 200.2. HRMS (pos. ESI): [M+H].sup.+ calc. for C.sub.19H.sub.24N.sub.2OCl: 331.1572; found: 331.1576.

[0198] Protein Preparation, Crystallization and Structure Determination

[0199] BRD4-BD1 was expressed and purified as described previously (Filippakopoulos et al, (2012), Cell 149(1): 241-231) with the exception of the final buffer for crystallization and ITC analysis (20 mM Hepes/NaOH pH 7.5, 150 mM NaCl). Crystals were grown in the presence of 3.5 M Na-Formate (pH 7.5) at a protein concentration of 10 mg/ml and a ligand concentration of 2 mM added directly to the protein prior to crystallization from a 100 mM stock solution in DMSO. Data were collected at 100K using either a Rigaku HF-007 rotating anode X-ray generator equipped with VariMaxHF optics and a Saturn944 CCD detector or a mar345 image plate respectively at λ=1.54179 Å or at the PXI beamline at the Swiss Light Source at λ=1.000 Å with a Pilatus detector. Data processing and reduction was done with iMOSFLM (Leslie AGW PH (2007), Evolving Methods for Macromolecular Crystallography 245, 41.51), POINTLESS, and SCALA (Kabsch W (2010) Xds. Acta crystallographica. Section D, Biological crystallography 66(Pt 2):125-132; Bruker (2008) SADABS, SAINT and XPREP (Bruker AXS Inc., Madison, Wis., USA); Collaborative Computational Project N (1994) The CCP4 suite: programs for protein crystallography, Acta crystallographica, Section D, Biological crystallography 50(Pt 5):760-763), or with XDS, XSCALE, XDSCONV (Evans P (2006), Scaling and assessment of data quality, Acta crystallographica, Section D, Biological crystallography 62(Pt 1):72-82), and XPREP (Evans P R (2011), An introduction to data reduction: space-group determination, scaling and intensity statistics, Acta crystallographica, Section D, Biological crystallography 67(Pt 4):282-292).

[0200] BRD4.ligand complexes crystallized in space group P2.sub.12.sub.12.sub.1. The structures were solved by molecular replacement with PHASER (McCoy A J, et al. (2007), Phaser crystallographic software, Journal of applied crystallography 40(Pt 4):658-674) with apoBRD4 as search model (internal data) yielding one molecule per asymmetric unit. Compounds were modelled into 2Fo-Fc electron density maps using AFITT-CL (version 2.1.0, OpenEye Scientific Software, Inc., Santa Fe, NM, USA.) Model building and real space refinement was done with COOT (Murshudov G N, Vagin A A, & Dodson E J (1997), Refinement of macromolecular structures by the maximum-likelihood method, Acta crystallographica. Section D, Biological crystallography 53(Pt 3):240-255) reciprocal space refinement against the calculated data was done with Refmac5, as implemented in the CCP4 suite (Murshudov G N, et al. (2011), REFMAC5 for the refinement of macromolecular crystal structures, Acta crystallographica. Section D, Biological crystallography 67(Pt 4):355-367; Vaguine A A, Richelle J, & Wodak S J (1999), SFCHECK: a unified set of procedures for evaluating the quality of macromolecular structure-factor data and their agreement with the atomic model, Acta crystallographica, Section D, Biological crystallography 55(Pt 1):191-205). Final structure validation was done with procheck/sfcheck (Wlodek S, Skillman A G, & Nicholls A (2006), Automated ligand placement and refinement with a combined force field and shape potential, Acta crystallographica, Section D, Biological crystallography 62(Pt 7):741-749).

[0201] Isothermal Titration Calorimetry

[0202] ITC experiments for the determination of the dissociation constant K.sub.d were done with a Microcal VP-ITC microcalorimeter (GE Healthcare) at 25° C. using ligand concentrations between 10 and 50 μM in the sample cell and BRD4 concentrations between 120 and 600 μM in the injection syringe. Data were obtained in discrete titration experiments with an injection volume of 12 μl per injection. Subsequently, the heats per injection were calculated as integrals and after normalization against the molar concentrations plotted against the molar ratio as implemented in Microcal Origin. Finally, data were fitted according to a single set of sites binding model with

[00001]$\begin{array}{cc}Q={\mathrm{nM}}_t\times \Delta {\mathrm{HV}}_0\times \frac{1}{2}\times \left(1+\frac{X_t}{{\mathrm{nM}}_t}+\frac{1}{{\mathrm{nKM}}_t}-\sqrt{{\left(1+\frac{X_t}{{\mathrm{nM}}_t}+\frac{1}{{\mathrm{nKM}}_t}\right)}^2-\frac{4X_t}{{\mathrm{nM}}_t}}\right)& \left(1\right)\end{array}$

[0203] as function to calculate the overall sum of heat of the titration and with

[00002]$\begin{array}{cc}\Delta Q\left(i\right)=Q\left(i\right)+\frac{{\mathrm{dV}}_i}{V_0}\times \left(\frac{Q\left(i\right)+Q\left(i-1\right)}{2}\right)-Q\left(i-1\right)& \left(2\right)\end{array}$

[0204] (According to Microcal's manual “ITC Data Analysis in Origin” (September 1998)) as function describing the sum of heat of each individual injection. A correction term was included to compensate for displacement of volume of the sample cell in the course of subsequent injections according to the manufacturer's manual “ITC Data Analysis in Origin” (Microcal).

[0205] The dissociation constant K.sub.d, is commonly used to describe the affinity between a ligand L and a protein, i.e. how tightly a ligand binds to a particular protein. The dissociation constant has molar units which correspond to the concentration of ligand at which the binding site on a particular protein is half occupied, i.e. the concentration of the ligand at which the concentration of protein with ligand bound equals the concentration of protein with no ligand bound. The smaller the dissociation constant, the higher the affinity between ligand and protein.

[0206] Table 1 shows the dissociation constants K.sub.D for two bromodomains (BRD4(1) and BRPF1B) as well as the concentration of the respective compound required to reduce the population of a culture of HL-60 cells by 50% (GI.sub.50)

TABLE-US-00001 TABLE 1 Cpd. of K.sub.D BRD4(1) K.sub.D BRPF1B GI50.sub.HL60 formula (nM) (nM) (nM)  1″ 6410 5080 n.d.  8 4562 1050 n.d.  9 8281 2050 n.d. 11 143.9 n.d. 1360 12 176.7 n.d. 570 13 77.8 n.d. 170 14 259.6 n.d. 2080 15 47.3 n.d. n.d. 16 417.2 n.d. n.d. 18 72.2 n.d. n.d. 19 n.d. 910 n.d. 20 n.d. 567 n.d. 21 n.d. 1990 n.d. 22 n.d. 2310 n.d. 23 n.d. 166 n.d. 24 n.d. 639 n.d. 25 n.d. 713 n.d. 26 6900 7000 n.d. 27 >10000 >10000 (n.d. = not determined)

[0207] Bromodomain Profiling

[0208] Bromodomain profiling was carried out on the basis of BROMOscan™. This platform accounted for the indirect determination of the dissociation constants between 19 bromodomains and the compound of formula (13), by binding competition against a reference immobilized ligand.

[0209] The overall structure of the complex of the compound of formula (13) and BRD4-BD1 revealed the already well-characterized bromodomain fold with a bundle of four α-helices, interconnected by three loops of different length. The termini of the helices bundle are flanked by elongational loops, which tightly pack against the protein core producing a compact and rather rigid structure.

[0210] The compound of formula (13) is bound in a pocket located at the end of the longitudinal axis running through the helix bundle which points towards the N-terminus. Consequently, it occupies the same pocket as the native K.sub.ac substrate.

[0211] Moreover, it mimics the K.sub.ac interaction with BRD4-BD1 by positioning the 4-acyl substitution in the pyrrole ring toward the highly conserved Asn140, thus engaging in hydrogen bond interactions with Asn140 and the equally conserved water molecule that bridges to the conserved Tyr97. The pyrrole ring is located deep in the recognition pocket, and complements the hydrophobic pocket defined by the four conserved waters with a 5-methyl substitution. The surface complementarity between the ligand and the recognition pocket is further achieved by the 3-ethyl substitution in the pyrrole ring. The presence of the heteroatom in the core of the compound of formula (I″) allows for a key hydrogen-bond donor interaction with the proline's backbone in position 82. Such interaction has not been described previously, and may have an important role in fixating the compound in the recognition site.

[0212] Apart from this major determinant of ligand recognition by BRD4-BD1, the compound of formula (13) also explores another patch of interactions.

[0213] The phenylsulphonamide moiety is placed along the ZA channel, such that a T-shaped CH-π interaction with Trp81 is established, whereby a perfect orthogonal orientation of both aromatic systems is created with Trp81 directly pointing towards the centre of the phenyl moiety of the compound of formula (13). Such interactions have already been reported in other drug-protein interactions. In addition, Leu92 serves as lid from the opposing side and together with Trp81 it forms a special configuration which will be referred to hereinafter as WL trap.

[0214] Compounds that bind the bromodomain prevent its binding to the immobilized ligand thus reducing the amount of protein captured. Conversely, molecules that do not bind the bromodomain have no effect on the amount of protein captured. Hits are identified by measuring the amount of bromodomain captured in test versus control samples.

[0215] Protocol Description

[0216] Bromodomain assays for Kd determination: T7 phage strains displaying bromodomains were grown in parallel in 24-well blocks in an E. coli host derived from the BL21 strain. E. coli were grown to log-phase and infected with T7 phage from a frozen stock (multiplicity of infection=0.4) and incubated with shaking at 32° C. until lysis (90-150 minutes). The lysates were centrifuged (5,000×g) and filtered (0.2 μm) to remove cell debris. Streptavidin-coated magnetic beads were treated with biotinylated small molecule or acetylated peptide ligands for 30 minutes at room temperature to generate affinity resins for bromodomain assays. The liganded beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and to reduce non-specific phage binding. Binding reactions were assembled by combining bromodomains, liganded affinity beads, and test compounds in 1× binding buffer (17% SeaBlock, 0.33×PBS, 0.04% Tween 20, 0.02% BSA, 0.004% Sodium azide, 7.4 mM DTT). Test compounds were prepared as 1000× stocks in 100% DMSO. Kds were determined using an 11-point 3-fold compound dilution series with one DMSO control point. All compounds for Kd measurements are distributed by acoustic transfer (non-contact dispensing) in 100% DMSO. The compounds were then diluted directly into the assays such that the final concentration of DMSO was 0.09%. All reactions performed in polypropylene 384-well plates. Each was a final volume of 0.02 ml. The assay plates were incubated at room temperature with shaking for 1 hour and the affinity beads were washed with wash buffer (1×PBS, 0.05% Tween 20). The beads were then re-suspended in elution buffer (1×PBS, 0.05% Tween 20, 2 μM non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The bromodomain concentration in the eluates was measured by qPCR.

[0217] Compound Handling for Kd determination: An 11-point 3-fold serial dilution of each test compound was prepared in 100% DMSO at 1000× final test concentration. All compounds for Kd measurements are distributed by acoustic transfer (non-contact dispensing) in 100% DMSO. The compounds were then diluted directly into the assays such that the final concentration of DMSO was 0.09%. Most Kds were determined using a compound top concentration=10,000 nM. If the initial Kd determined was <0.169 nM (the lowest concentration tested), the measurement was repeated with a serial dilution starting at a lower top concentration.

[0218] Binding Constants (Kds): Binding constants (Kds) were calculated with a standard dose-response curve using the Hill equation:

[00003]$\mathrm{Response}=\frac{\mathrm{Background}+\mathrm{Signal}-\mathrm{Background}}{1+\left({\mathrm{Kd}}^{\mathrm{Hill}\mathrm{Slope}}\text{/}{\mathrm{Dose}}^{\mathrm{Hill}\mathrm{Slope}}\right)}$

[0219] The Hill Slope was set to −1. Curves were fitted using a non-linear least square fit with the Levenberg-Marquardt algorithm.

[0220] The results are given in Table 2 and Table 3.

TABLE-US-00002 TABLE 2 Compound 23 11 12 13 14 15 16 Bromodomain- Kd Kd Kd Kd Kd Kd Kd (Gene symbol) (nM) (nM) (nM) (nM) (nM) (nM) (nM) ATAD2A >10000 n.d. n.d. n.d. n.d. n.d. n.d. ATAD2B >10000 n.d. n.d. n.d. n.d. n.d. n.d. BAZ2A 1900 n.d. n.d. n.d. n.d. n.d. n.d. BAZ2B 1800 n.d. n.d. n.d. n.d. n.d. n.d. BRD1 3100 n.d. n.d. n.d. n.d. n.d. n.d. BRD2(1) 130 n.d. n.d. 45 n.d. n.d. n.d. BRD2(1, 2) 84 n.d. n.d. n.d. n.d. n.d. n.d. BRD2(2) 200 n.d. n.d. 290 n.d. n.d. n.d. BRD3(1) 170 n.d. n.d. 100 n.d. n.d. n.d. BRD3(1, 2) 100 n.d. n.d. n.d. n.d. n.d. n.d. BRD3(2) 330 n.d. n.d. 140 n.d. n.d. n.d. BRD4(1) 250 85 170 60 300 82 150 BRD4(1, 2) 160 n.d. n.d. n.d. n.d. n.d. n.d. BRD4(2) 270 n.d. n.d. 220 n.d. n.d. n.d. BRD4(short-iso.) 180 n.d. n.d. n.d. n.d. n.d. n.d. BRD7 430 250 310 85 160 440 5.5 BRD8(1) 2600 n.d. n.d. n.d. n.d. n.d. n.d. BRD8(2) >10000 n.d. n.d. n.d. n.d. n.d. n.d. BRD9 67 160 530 67 68 300 4.3 BRDT(1) 240 n.d. n.d. 670 n.d. n.d. n.d. BRDT(1, 2) 420 n.d. n.d. n.d. n.d. n.d. n.d. BRDT(2) 620 n.d. n.d. 1000 n.d. n.d. n.d. BRPF1 130 420 2500 520 320 1800 1300 BRPF3 6000 n.d. n.d. n.d. n.d. n.d. n.d. CECR2 970 1100 8100 n.d. 240 580 760 CREBBP 420 n.d. n.d. n.d. n.d. n.d. n.d. EP300 1200 2100 9000 n.d. 1800 3500 990 FALZ 2600 n.d. n.d. n.d. n.d. n.d. n.d. GCN5L2 >10000 n.d. n.d. n.d. n.d. n.d. n.d. PBRM1(2) 4200 n.d. n.d. n.d. n.d. n.d. n.d. PBRM1(5) 3800 n.d. n.d. n.d. n.d. n.d. n.d. PCAF >10000 n.d. n.d. n.d. n.d. n.d. n.d. SMARCA2 >10000 n.d. n.d. n.d. n.d. n.d. n.d. SMARCA4 >10000 n.d. n.d. n.d. n.d. n.d. n.d. TAF1(2) 4100 n.d. n.d. n.d. n.d. n.d. n.d. TAF1L(2) 6800 n.d. n.d. n.d. n.d. n.d. n.d. TRIM24 1400 n.d. n.d. n.d. n.d. n.d. n.d. (Bromo.) TRIM24(PHD, 5300 n.d. n.d. n.d. n.d. n.d. n.d. Bromo.) TRIM33(PHD, 7700 n.d. n.d. n.d. n.d. n.d. n.d. Bromo.) WRD9(2) >10000 n.d. n.d. n.d. n.d. n.d. n.d.

TABLE-US-00003 TABLE 3 (Results for compounds 23, 26 and 27) Compound Bromodomain 23 26 27 (Gene Symbol) Kd (nM) Kd (nM) Kd (nm) BRD4(1) 250 6900 >10000 BRD7 430 1100 >10000 BRD9 67 150 800 BRDT(1) 240 6100 >10000 BRPF1 130 7000 >10000 CECR2 970 >10000 >10000

[0221] The results show that the compounds of formula (26) and (27) have a higher selectivity for certain bromodomains evaluated compared to the compound of formula (23) which, in turn, shows a very good activity as inhibitor (as evidenced by low values for Kd) for all bromodomains evaluated in Table 3.

[0222] Bromodomain assays for % Ctrl determination: T7 phage strains displaying bromodomains were grown in parallel in 24-well blocks in an E. coli host derived from the BL21 strain. E. coli were grown to log-phase and infected with T7 phage from a frozen stock (multiplicity of infection=0.4) and incubated with shaking at 32° C. until lysis (90-150 minutes). The lysates were centrifuged (5,000×g) and filtered (0.2 μm) to remove cell debris. Streptavidin-coated magnetic beads were treated with biotinylated small molecule or acetylated peptide ligands for 30 minutes at room temperature to generate affinity resins for bromodomain assays. The liganded beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and to reduce non-specific phage binding. Binding reactions were assembled by combining bromodomains, liganded affinity beads, and test compounds in 1× binding buffer (16% SeaBlock, 0.32×PBS, 0.02% BSA, 0.04% Tween 20, 0.004% Sodium azide, 7.9 mM DTT). Test compounds were prepared as 1000× stocks in 100% DMSO and subsequently diluted 1:25 in monoethylene glycol (MEG). The compounds were then diluted directly into the assays such that the final concentrations of DMSO and MEG were 0.1% and 2.4%, respectively. All reactions were performed in polypropylene 384-well plates in a final volume of 0.02 ml. The assay plates were incubated at room temperature with shaking for 1 hour and the affinity beads were washed with wash buffer (1×PBS, 0.05% Tween 20). The beads were then re-suspended in elution buffer (1×PBS, 0.05% Tween 20, 2 μM non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The bromodomain concentration in the eluates was measured by qPCR.

[0223] The compounds were screened at a concentration of 10 000 nM and results for primary screen binding are reported as % of control where lower numbers indicate a stronger binding

[0224] The % Ctrl values were determined as follows:

% Ctrl=[(test compound signal-positive control signal)/(negative control signal-positive control signal)]×100

[0225] where test compound was the compound of formula (13), negative control was DMSO and positive control was the control compound

[0226] Table 3 shows the results for a group of 32 bromodomains:

TABLE-US-00004 TABLE 3 Target bromodomain % Ctrl @ 10 000 nM ATAD2A 94 ATAD2B 97 BAZ2A 24 BAZ2B 6.8 BRD1 26 BRD2(1) 0 BRD2(2) 0.1 BRD3(1) 0.05 BRD3(2) 0 BRD4(1) 0 BRD4(2) 0 BRD7 0 BRD9 0 BRDT(1) 0 BRDT(2) 0.65 BRPF1 0.15 BRPF3 35 CECR2 1.3 CREBBP 4.7 EP300 1.4 FALZ 6.8 GCN5L2 44 PBRM1(2) 75 PBRM1(5) 90 PCAF 20 SMARCA2 83 SMARCA4 71 TAF1(2) 7.4 TAF1L(2) 40 TRIM24(PHD, Bromo) 82 TRIM33(PHD, Bromo) 60 WDR9(2) 81

[0227] The results show that the compounds showed very good to average binding affinity to a variety of bromodomains (less than 35% Ctrl).

[0228] The results indicate that the compounds in accordance with the present invention provide a promising starting point for the development of novel potent bromodomain inhibitors.

[0229] Plasmodium falciparum Inhibitor Treatment for 72 Hours (One Replication Cycle)

[0230] P. falciparum cultures were treated for 72 hours with 100 μm of compounds (19) to (22), (24) and (25) or DMSO as control. The cultures were stained for DNA content with fluorescent dye Hoechst 33342 (20 μm) and for RNA content with thiazole orange (1 μm). The double negative population represented uninfected erythrocytes (devoid of DNA and low in RNA content) whereas the P. falciparum infected erythrocytes were gated as early ring, mid trophozoite and late schizont stages based on their DNA and RNA content. The degree of parasitemia was determined by flow cytometry after 72 hours of drug treatment and the compounds in accordance with the present invention yielded a lower degree of parasitemia than the control with the compound of formula (24) being particularly effective in this regard in each of the stages (early ring, mid trophozoite and schizont).