AZAINDOLE DERIVATIVES AND THEIR USE AS ERK KINASE INHIBITORS

Abstract

The present invention concerns a compound of formula (I):

##STR00001##

or one of its pharmaceutically acceptable salts, especially for use as inhibitors of the ERK kinase activity, in particular ERK2 activity.

Claims

1. A compound of formula (I): ##STR00289## or a pharmaceutically acceptable salt thereof, wherein: R.sub.1 represents a (C.sub.1-C.sub.6)alkyl group; R.sub.2 represents a (C.sub.1-C.sub.6)alkyl group, a (C.sub.3-C.sub.6)cycloalkyl group, or a (C.sub.1-C.sub.6)alkyl group substituted by one or more radicals selected from halogen atoms, cyano group, (C.sub.1-C.sub.6)alkoxy group and (C.sub.3-C.sub.6)cycloalkyl group; or R.sub.1 and R.sub.2 together with a nitrogen atom to which R.sub.1 and R.sub.2 are bound form a 3- to 6-membered heterocyclic group; and each of R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8 and R.sub.9 represent, independently of each other, a hydrogen atom, a halogen atom, a (C.sub.1-C.sub.6)alkyl group, a trifluoromethyl group or a cyano group, wherein said (C.sub.1-C.sub.6)alkyl is itself optionally substituted with a (C.sub.1-C.sub.6)alkoxy group.

2. The compound of claim 1, wherein R.sub.1 represents a methyl group.

3. The compound of claim 1, wherein R.sub.2 represents a (C.sub.1-C.sub.6)alkyl group.

4. The compound of claim 2, wherein both R.sub.1 and R.sub.2 represent a methyl group.

5. The compound of claim 1, wherein R.sub.3 represents a halogen atom, a (C.sub.1-C.sub.6)alkyl group, a trifluoromethyl group or a cyano group, wherein said (C.sub.1-C.sub.6)alkyl is itself optionally substituted with a (C.sub.1-C.sub.6)alkoxy group.

6. The compound of claim 5, wherein R.sub.3 represents a halogen atom.

7. The compound of claim 1, wherein R.sub.4 represents a hydrogen atom or a halogen atom.

8. The compound of claim 1, wherein R.sub.5 represents a hydrogen atom or a halogen atom.

9. The compound of claim 1, wherein R.sub.6 represents a hydrogen atom or a (C.sub.1-C.sub.6)alkyl group.

10. The compound of claim 1, wherein R.sub.7 represents a hydrogen atom or a halogen atom.

11. The compound of claim 1, wherein R.sub.8 represents a hydrogen atom or a halogen atom.

12. The compound of claim 1, wherein R.sub.9 represents a hydrogen atom, a halogen atom or a trifluoromethyl group.

13. The compound of claim 1, wherein the compound is selected from any one of compounds (1)-(26), as depicted in the following Table, or a pharmaceutically acceptable salt thereof: TABLE-US-00011 Com- pound No. Structures  1  2  3  4  5  6  7  8  9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26

14. A compound of formula (V), (XI) or (XII): ##STR00316## wherein: R.sub.1 represents a (C.sub.1-C.sub.6)alkyl group; R.sub.2 represents a (C.sub.1-C.sub.6)alkyl group, a (C.sub.3-C.sub.6)cycloalkyl group, or a (C.sub.1-C.sub.6)alkyl group substituted by one or more radicals selected from halogen atoms, cyano group, (C.sub.1-C.sub.6)alkoxy group and (C.sub.3-C.sub.6)cycloalkyl group; or R.sub.1 and R.sub.2 together with the nitrogen atom to which R.sub.1 and R.sub.2 are bound form a 3- to 6-membered heterocyclic group; each of R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8 and R.sub.9 represent, independently of each other, a hydrogen atom, a halogen atom, a (C.sub.1-C.sub.6)alkyl group, a trifluoromethyl group or a cyano group, wherein said (C.sub.1-C.sub.6)alkyl is itself optionally substituted with a (C.sub.1-C.sub.6)alkoxy group; Y is a halogen atom; and PG is a protecting group chosen from -Tosyl, -Mesyl, -Brosyl, -Nosyl, -Triflyl, -tert-butyloxycarbonyl, -trim ethylsilylethoxymethyl, -Trimethylsilyl, -Triisopropylsilyl.

15. The compound of claim 14, wherein the compound is selected from: ##STR00317## ##STR00318## ##STR00319## ##STR00320## ##STR00321## ##STR00322##

16. A method of inhibiting ERK kinase activity in a cell, the method comprising the step of contacting the cell with a compound selected from: (S)-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one; (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one; (S)-1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one; (S)-1-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one; (S)-1-(1-(3-bromophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one; (S)-1-(2-(dimethylamino)-1-(3-iodophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one; (S)-1-(1-(3-bromo-4-fluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one; (S)-1-(2-(dimethylamino)-1-(4-fluoro-3-iodophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one; (S)-1-(1-(3-chloro-5-fluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one; (S)-1-(2-(dimethylamino)-1-(3-fluoro-5-iodophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one; (S)-1-(1-(3-chlorophenyl)-2-((2,2-difluoroethyl)(methyl)amino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one; (S)-2-((2-(3-chlorophenyl)-2-(4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)(methyl)amino)acetonitrile; (S)-1-(1-(3-chlorophenyl)-2-((2-methoxyethyl)(methyl)amino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one; (S)-1-(1-(3-chlorophenyl)-2-(cyclopropyl(methyl)amino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one; (S)-1-(1-(3-chlorophenyl)-2-(ethyl(methyl)amino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one; (S)-1-(1-(3-chlorophenyl)-2-((cyclopropylmethyl)(methyl)amino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one; (S)-1-(1-(3,4-difluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one; (S)-1-(1-(3,5-difluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one; (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-5-fluoro-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one; (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-6-methyl-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one; 1-((S)-1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-(2-(trifluoromethyl)morpholino)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one; (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(4-fluoro-5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one; (S)-1-(1-(3-chloro-5-(methoxymethyl)phenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one; (S)-1-(2-(aziridin-1-yl)-1-(3-chlorophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one; (S)-3-(2-(dimethylamino)-1-(4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)benzonitrile; or (S)-1-(2-(dimethylamino)-1-(3-(trifluoromethyl)phenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one, or a pharmaceutically acceptable salt thereof, in an amount sufficient to inhibit the ERK kinase activity.

17. The method of claim 16, wherein the ERK kinase is ERK2 kinase.

18. The method of claim 16, further comprising treating a subject having a disease or a condition mediated by ERK kinases activity by administering to the subject an effective dose of the compound or a pharmaceutically acceptable salt thereof.

19. The method of claim 18, wherein the disease or the condition is chosen among cancers and metastases.

20. The method of claim 19, wherein the disease or the condition is chosen among glioblastomas, multiple myelomas, carcinomas, leukemia, myelodysplastic syndromes, Kaposi's sarcomas, cutaneous angiosarcomas, solid tumours, lymphomas, melanomas, bladder cancers, breast cancers, gastric cancers, colon cancers, colorectal cancers, endometrial cancers, lung cancers, including non-small-cell cancers, pancreatic cancers, prostate cancers, rectal cancers, kidney cancers, head and neck cancers, liver cancers, ovarian cancers, seminoma cancers, cancers of the respiratory tract and chest, thyroid cancers, and other tumours expressing ERK.

21. The method of claim 18, wherein the disease or the condition is chosen among a neoplastic disorder, an allergy disorder, an inflammatory disorder, an autoimmune disorder, a Plasmodium related disease, a mast cell associated disease, a graft-versus-host disease, a metabolic syndrome, a CNS related disorder, a neurodegenerative disorder, a pain condition, a substance abuse disorder, a prion disease, a heart disease, a fibrotic disease, idiopathic arterial hypertension (IPAH), and primary pulmonary hypertension (PPH).

22. A pharmaceutical composition comprising a compound of any one of formulas: ##STR00323## or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

23. The pharmaceutical composition of claim 22, wherein the pharmaceutical composition is formulated for oral administration.

24. The pharmaceutical composition of claim 23, wherein the pharmaceutical composition is a tablet or a capsule.

Description

EXAMPLES

Equipment and Analytical Methods Used for the Syntheses of Examples

[0293] Microwaves irradiation: [0294] Apparatus: CEM Discover with Synergy Software. [0295] Method: 10 mL or 30 mL sealed tube, power up to 50 W, high stirring. [0296] Flash chromatography: [0297] Apparatus: Biotage SP with auto-collector and UV detection (2 wavelengths). [0298] Normal phase columns: 10, 25 or 120 g Biotage external dry load cartridge kit, packed with Sigma-Aldrich 40-63 μm silica gel. [0299] Reverse phase column: 30 g Biotage SNAP Cartridges, KP-C18-HS. [0300] Chiral column: Daicel ChiralFlash IG 100×30 mm 20 μM. [0301] Liquid Chromatography: [0302] Apparatus: Waters alliance 2695 HPLC system with autosampler and Waters 2996 diode array detector. [0303] Reverse phase conditions: [0304] Column: Macherey-Nagel Nucleoshell RP18 plus (5 μm, 4 mm×100 mm). [0305] Column temperature: 40° C. [0306] Solvents: A (H.sub.2O 99.9%, H.sub.2CO.sub.2 0.1%); B (MeCN 99.9%, H.sub.2CO.sub.2 0.1%). [0307] Flow rate: 1 mL/min. [0308] Gradient (A/B v/v): 95/5 (t=0 min), 95/5 (t=1 min), 0/100 (t=7 min), 0/100 (t=10 min). [0309] Chiral phase conditions: [0310] Column: Daicel ChiralPak IG (Amylose-based) 20 μm, 4.6 mm×100 mm. [0311] Column temperature: 25° C. [0312] Solvents: Heptane 50%/EtOH containing 0.1% TEA 40%/DCM 10%. [0313] Flow rate: 1 mL/min. [0314] Mass Spectrometer: [0315] Apparatus: Waters Micromass ZQ (simple quad). [0316] Mass detection method: Electrospray positive mode (ESI+), mass range: 50-800 uma. [0317] Detection: 210-400 nm range. [0318] NMR Spectrometer: [0319] Apparatus: Bruker 400 MHz. [0320] Methods: .sup.1H NMR spectra performed in DMSO-d6 using DMSO-d5 as internal reference, chemical shifts expressed in parts per million (ppm), signals expressed as follows: s=singlet, d=doublet, t=triplet, q=quadruplet, sept=septuplet, dd=double doublet, dt=double triplet, m=multiplet or large singlet, br=broad, H=proton.

Example 1: Synthesis of (S)-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0321] ##STR00028##

Step 1: 4-(1H-Pyrrolo[2,3-b]pyridin-5-yl)morpholine

[0322] ##STR00029##

[0323] In 487 ml of LiHMDS (1M in THF, 487 mmol, 2.4 eq) are dissolved 947 mg (2.03 mmol, 0.01 eq) of RuPhos and 1.58 g (2.03 mmol, 0.01 eq) of RuPhos Pd G2. Then are added under argon 40 g (203 mmol, 1 eq) of 5-bromo-1H-pyrrolo[2,3-b]pyridine and 21.1 ml (244 mmol, 1.2 eq) of morpholine and the solution is heated at 66° C. for 1 h 30. The reaction mixture is then cooled to room temperature and dropped into 1.2 l of a saturated NH.sub.4Cl solution maintaining the temperature under 10° C. with an ice water bath. The mixture is stirred for 10 min at this temperature and decanted. Aqueous layer is extracted 3 times with DCM. Combined organic layers are dried over Na.sub.2SO.sub.4, filtered, and evaporated under reduced pressure to give 44.4 g of a brown solid. Crude is triturated in 200 ml of a mixture of EtOAc and hexane (3/7) for 1 h. The solid is filtrated, rinsed with 200 ml of a mixture of EtOAc and hexane (1/9) and dried under vacuum to give 38.98 g of a slightly brown powder.

[0324] Yield: 94%.

[0325] MH+: 204.3 (M+1).

Step 2: 4-(1-Tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine

[0326] ##STR00030##

[0327] 38.98 g (192 mmol, 1 eq) of 4-(1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine (described in the previous step) are dissolved in 390 ml of dry DMF, under argon. The solution is cooled to 0° C., and 11.5 g (288 mmol, 1.5 eq) of sodium hydride (60% in paraffin oil) are slowly added. The mixture is stirred for 10 min at this temperature and then 40 min at room temperature. The mixture is cooled again to 0° C., 47.5 g (249 mmol, 1.3 eq) of tosyl chloride are slowly added under argon and the reaction mixture is stirred at 0° C. for 1 h followed by 1 h at room temperature. The mixture is dropped into 800 g of ice/water and stirred for 1 h. A precipitate is obtained, which is filtrated and rinsed several times with cold water. The precipitate is then dissolved with 1.2 l of DCM, and the solution is washed 2 times with a saturated NaHCO.sub.3 solution, 2 times with water and once with brine. The organic layer is dried over Na.sub.2SO.sub.4, filtered, and evaporated under reduced pressure. Crude compound is triturated in 500 ml of a mixture of EtOAc and hexane (5/95) for 3 h. The solid is filtrated, rinsed with hexane and dried under vacuum to give 62.56 g of an off-white solid.

[0328] Yield: 91%.

[0329] MH+: 358.6 (M+1).

[0330] .sup.1H NMR (DMSO-d6, 400 MHz): δ 8.18 (d, J=2.7 Hz, 1H); 7.92 (d, J=8.3 Hz, 2H); 7.78 (d, J=4.0 Hz, 1H); 7.52 (d, J=2.7 Hz, 1H); 7.39 (d, J=8.3 Hz, 2H); 6.68 (d, J=4.0 Hz, 1H); 3.76-3.71 (m, 4H); 3.12-3.07 (m, 4H); 2.33 (s, 3H).

Step 3: 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine

[0331] ##STR00031##

[0332] 62.56 g (175 mmol, 1 eq) of 4-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine (described in the previous step) are suspended in 512 ml of Me-THF under argon. Then 48.9 g of bis(pinacolato)diboron (193 mmol, 1.1 eq), 1.88 g of 4,4′-di-tert-butylbiphenyl (7 mmol, 0.036 eq) and 2.32 g of (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (3.5 mmol, 0.018 eq) are added. The reaction is heated to reflux for 45 min under argon. The reaction mixture is then cooled to −10° C. with an ice/acetone bath and quenched carefully with MeOH (350 ml). The solution is stirred at room temperature for 15 min and evaporated under vacuum to give a brown oil. Dark oil is then dissolved in 1 l of DCM, washed 3 times with water and once with brine. Organic layer is evaporated under reduced pressure to give a black paste. 2 l of Et.sub.2O are added and the mixture is stirred for 15 min at room temperature, filtrated on Celite and evaporated under reduced pressure to give 95 g of a brown solid foam. Crude mixture is finally purified by flash chromatography using a silica gel column and an EtOAc/hexane mixture as eluent. 75.5 g of the title compound are obtained.

[0333] Yield: 89%.

[0334] MH+: 484.6 (M+1).

[0335] .sup.1H NMR (DMSO-d6, 400 MHz): δ 8.21 (d, J=2.5 Hz, 1H); 8.01 (d, J=8.3 Hz, 2H); 7.94 (s, 1H); 7.50 (d, J=2.4 Hz, 1H); 7.41 (d, J=8.0 Hz, 2H); 3.78-3.72 (m, 4H); 3.12-3.07 (m, 4H); 2.33 (s, 3H); 1.30 (s, 12H).

Step 4: 1-Fluoro-3-vinylbenzene

[0336] ##STR00032##

[0337] 5 g (40.3 mmol, 1 eq) of 3-fluorobenzaldehyde are dissolved in 50 ml of dry THE and the solution is cooled to −10° C. with an ice/acetone bath. 17.3 g (48.4 mmol, 1.2 eq) of methyltriphenylphosphonium bromide are added followed by 2.1 g (52.4 mmol, 1.3 eq) of sodium hydride (60% in paraffin oil). The suspension is then stirred at room temperature overnight under argon. The mixture is diluted with 100 ml of Et.sub.2O and the precipitate is filtrated on Celite. The filtrate is evaporated under reduced pressure to give an orange residue. Crude mixture is finally purified by flash chromatography using a silica gel column and an Et.sub.2O/pentane mixture as eluent (3/97). 1.25 g of the title compound are obtained.

[0338] Yield: 25%.

[0339] MH+: Non ionizable.

Step 5: 2-(3-Fluorophenyl)oxirane

[0340] ##STR00033##

[0341] 1.25 g (10.2 mmol, 1 eq) of 1-fluoro-3-vinylbenzene (described in the previous step) are dissolved in 6 ml of 1,4-dioxane and 18 ml of water. The solution is cooled to 0° C. and 584 μl (10.2 mmol, 1 eq) of acetic acid are added, followed by 1.99 g (11.2 mmol, 1.1 eq) of N-bromosuccinimide. Reaction mixture is stirred at 0° C. for 5 min then at room temperature for 2 h. Mixture is then cooled again to 0° C. and a solution of NaOH 2N in water (35.7 mmol, 3.5 eq) is slowly added. The solution is allowed to stir at room temperature for 1 h. Reaction mixture is concentrated under reduced pressure and aqueous resulting phase is extracted 3 times with DCM. Combined organic layers are dried over Na.sub.2SO.sub.4, filtrated and evaporated under reduced pressure. Crude mixture is purified by flash chromatography using a silica gel column and a DCM/hexane mixture as eluent (2/98). 1.02 g of the title compound are obtained.

[0342] Yield: 72%.

[0343] MH+: Non ionizable.

Step 6: 2-(Dimethylamino)-1-(3-fluorophenyl)ethan-1-ol

[0344] ##STR00034##

[0345] To a solution of 1.02 g (7.38 mmol, 1 eq) of 2-(3-fluorophenyl)oxirane (described in the previous step) in 14 ml of EtOH 96%, are added 7.38 ml (14.76 mmol, 2 eq) of a solution of dimethylamine (2M in THF). The clear resulting solution is heated under microwave irradiation at 80° C. for 30 min. Reaction mixture is then concentrated under vacuum and diluted with water. The solution is extracted 3 times with DCM. Combined organic layers are dried over Na.sub.2SO.sub.4, filtrated and evaporated under reduced pressure. Crude mixture is purified by flash chromatography using a silica gel column and a DCM/MeOH mixture as eluent. 0.927 g of the title compound are obtained.

[0346] Yield: 69%.

[0347] MH+: 322.6 (M+1).

Step 7: 2-Chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine

[0348] ##STR00035##

[0349] 0.927 g (5.03 mmol, 1 eq) of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol (described in the previous step) are dissolved in 15 ml of DCM and placed at 0° C. 2.1 ml (15.1 mmol, 3 eq) of triethylamine are added, followed by 0.781 ml (10.1 mmol, 2 eq) of mesyl chloride. The reaction is stirred at 0° C. under argon for 2 h. Water is then added and the mixture is decanted. Aqueous layer is extracted 2 times with DCM. Combined organic layers are dried over Na.sub.2SO.sub.4, filtrated and evaporated under reduced pressure. Crude compound is directly used in the next step without further purification.

[0350] Yield: Quantitative.

[0351] MH+: 202.3; 204.3 (M; M+2).

Step 8: 4-Bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one

[0352] ##STR00036##

[0353] To a mixture of 0.744 g (4.28 mmol, 1 eq) of 4-bromopyridin-2-(1H)-one and 1.39 g (4.28 mmol, 1 eq) of cesium carbonate in 10 ml of dry DMF, is added at 0° C. a solution of 1.02 g (5.08 mmol, 1.18 eq) of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine (described in the previous step) in 5 ml of dry DMF. The solution is then stirred at room temperature for 2 h. EtOAc is added, and the mixture is washed 4 times with water and once with brine. Organic layer is dried over Na.sub.2SO.sub.4, filtrated and evaporated under reduced pressure. Crude mixture is purified by flash chromatography using a deactivated silica gel column and a Hexane/EtOAc mixture as eluent. 1.31 g of the title compound are obtained.

[0354] Yield: 76%.

[0355] MH+: 339.4; 341.5 (M; M+2).

Step 9: 1-(2-(Dimethylamino)-1-(3-fluorophenyl)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0356] ##STR00037##

[0357] 1.31 g (3.86 mmol, 1 eq) of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one (described in the previous step) and 2.45 g (5.01 mmol, 1.3 eq) of 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine (described in Step 3) are dissolved in 13 ml of MeCN under argon. Then 13 ml of a solution of Na.sub.2CO.sub.3 2M are added to give a biphasic mixture which is bubbled with argon for 15 min. 135 mg (0.19 mmol, 0.05 eq) of bis(triphenylphosphine)palladium dichloride are added and the solution was bubbled with argon for another 15 min. The reaction is stirred at 70° C. for 2 h under argon. Reaction mixture is then diluted with water and EtOAc and then decanted. Aqueous layer is extracted 2 times with EtOAc. Combined organic layer are dried over Na.sub.2SO.sub.4, filtrated and evaporated under reduced pressure. Crude mixture is purified by flash chromatography using a silica gel column and a DCM/MeOH mixture as eluent. 2.05 g of the title compound are obtained.

[0358] Yield: 86%.

[0359] MH+: 616.6 (M+1).

Step 10: 1-(2-(Dimethylamino)-1-(3-fluorophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0360] ##STR00038##

[0361] 2.05 g (3.33 mmol, 1 eq) of 1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) are dissolved in 15 ml of dry THE under argon. Then 10 ml (10 mmol, 3 eq) of a solution of TBAF (1M in THF) are added and the reaction is stirred at 66° C. for 1 h under argon. Solvent is removed under reduced pressure and 100 ml of a saturated NaHCO.sub.3 solution are added. Mixture is extracted 3 times with EtOAc. Combined organic layer are dried over Na.sub.2SO.sub.4, filtrated and evaporated under reduced pressure. Crude mixture is purified by flash chromatography using a silica gel column and a DCM/MeOH mixture as eluent. 1.49 g of a yellow solid are obtained.

[0362] Yield: 96%.

[0363] MH+: 462.7 (M+1).

[0364] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.04 (br s, 1H); 8.16 (d, J=2.4 Hz, 1H); 8.09 (d, J=1.8 Hz, 1H); 7.74 (d, J=8.0 Hz, 1H); 7.70 (d, J=2.5 Hz, 1H); 7.45-7.36 (m, 1H); 7.30-7.18 (m, 2H); 7.18-7.10 (m, 1H); 6.72-6.64 (m, 2H); 6.27-6.16 (m, 1H); 3.84-3.73 (m, 4H); 3.32-3.22 (m, 1H); 3.20-3.08 (m, 4H); 2.80-2.69 (m, 1H); 2.21 (s, 6H).

Step 11: (S)-1-(2-(Dimethylamino)-1-(3-fluorophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0365] ##STR00039##

[0366] Enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and an Hexane/EtOH/DCM/0.1% TEA mixture as the mobile phase. First fraction to be eluted is the (−) (R)-enantiomer, followed by the (+) (S)-enantiomer with ee >98%. 275 mg of the title compound are obtained starting from 1.49 g of racemate.

[0367] MH+: 462.7 (M+1).

[0368] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.04 (br s, 1H); 8.16 (d, J=2.4 Hz, 1H); 8.09 (d, J=1.8 Hz, 1H); 7.74 (d, J=8.0 Hz, 1H); 7.70 (d, J=2.5 Hz, 1H); 7.45-7.36 (m, 1H); 7.30-7.18 (m, 2H); 7.18-7.10 (m, 1H); 6.72-6.64 (m, 2H); 6.27-6.16 (m, 1H); 3.84-3.73 (m, 4H); 3.32-3.22 (m, 1H); 3.20-3.08 (m, 4H); 2.80-2.69 (m, 1H); 2.21 (s, 6H).

Example 2: Synthesis of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0369] ##STR00040##

Step 1: 1-Chloro-3-vinylbenzene

[0370] ##STR00041##

[0371] The compound is obtained by the procedure described in Example 1, Step 4, starting from 10 g (71.1 mmol) of 3-chlorobenzaldehyde instead of 3-fluorobenzaldehyde. 4.05 g of the title compound are obtained.

[0372] Yield: 41%.

[0373] MH+: Non ionizable.

Step 2: 2-(3-Chlorophenyl)oxirane

[0374] ##STR00042##

[0375] The compound is obtained by the procedure described in Example 1, Step 5, starting from 4.05 g (29.2 mmol) of 1-chloro-3-vinylbenzene (described in the previous step) instead of 1-fluoro-3-vinylbenzene. 3.85 g of the title compound are obtained.

[0376] Yield: 85%.

[0377] MH+: Non ionizable.

Step 3: 1-(3-Chlorophenyl)-2-(dimethylamino)ethan-1-ol

[0378] ##STR00043##

[0379] The compound is obtained by the procedure described in Example 1, Step 6, starting from 4.15 g (26.9 mmol) of 2-(3-chlorophenyl)oxirane (described in the previous step) instead of 2-(3-fluorophenyl)oxirane. 4.06 g of the title compound are obtained.

[0380] Yield: 76%.

[0381] MH+: 200.2; 202.3 (M; M+2).

Step 4: 2-Chloro-2-(3-chlorophenyl)-N,N-dimethylethan-1-amine

[0382] ##STR00044##

[0383] The compound is obtained by the procedure described in Example 1, Step 7, starting from 4.06 g (20.3 mmol) of 1-(3-chlorophenyl)-2-(dimethylamino)ethan-1-ol (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 4.41 g of the title compound are obtained.

[0384] Yield: 99%.

[0385] MH+: 218.4; 220.4 (M; M+2).

Step 5: 4-Bromo-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)pyridin-2(1H)-one

[0386] ##STR00045##

[0387] The compound is obtained by the procedure described in Example 1, Step 8, starting from 4.41 g (20.3 mmol) of 2-chloro-2-(3-chlorophenyl)-N,N-dimethylethan-1-amine (described in the previous step) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 5.02 g of the title compound are obtained.

[0388] Yield: 70%.

[0389] MH+: 355.2; 357.2 (M; M+2).

Step 6: 1-(1-(3-Chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0390] ##STR00046##

[0391] The compound is obtained by the procedure described in Example 1, Step 9, starting from 2 g (5.6 mmol) of 4-bromo-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)pyridin-2(1H)-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 2.68 g of the title compound are obtained.

[0392] Yield: 75%.

[0393] MH+: 632.8; 634.8 (M; M+2).

Step 7: 1-(1-(3-Chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0394] ##STR00047##

[0395] The compound is obtained by the procedure described in Example 1, Step 10, starting from 2.68 g (4.2 mmol) of 1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 617 mg of racemate are obtained.

[0396] Yield: 30%.

[0397] MH+: 478.5; 480.6 (M; M+2).

[0398] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.06 (br s, 1H); 8.17 (d, J=2.4 Hz, 1H); 8.10 (d, J=2.3 Hz, 1H); 7.76 (d, J=8.0 Hz, 1H); 7.70 (d, J=2.4 Hz, 1H); 7.47 (s, 1H); 7.44-7.32 (m, 3H); 6.72-6.65 (m, 2H); 6.23-6.13 (m, 1H); 3.84-3.73 (m, 4H); 3.34-3.23 (m, 1H); 3.20-3.08 (m, 4H); 2.78-2.67 (m, 1H); 2.21 (s, 6H).

Step 8: (S)-1-(1-(3-Chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0399] ##STR00048##

[0400] Enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and an Hexane/EtOH/DCM/0.1% TEA mixture as the mobile phase. First fraction to be eluted is the (−) (R)-enantiomer, followed by the (+) (S)-enantiomer with ee >98%. 227 mg of the title compound are obtained starting from 617 mg of racemate.

[0401] MH+: 478.5; 480.6 (M; M+2).

[0402] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.06 (br s, 1H); 8.17 (d, J=2.4 Hz, 1H); 8.10 (d, J=2.3 Hz, 1H); 7.76 (d, J=8.0 Hz, 1H); 7.70 (d, J=2.4 Hz, 1H); 7.47 (s, 1H); 7.44-7.32 (m, 3H); 6.72-6.65 (m, 2H); 6.23-6.13 (m, 1H); 3.84-3.73 (m, 4H); 3.34-3.23 (m, 1H); 3.20-3.08 (m, 4H); 2.78-2.67 (m, 1H); 2.21 (s, 6H).

Example 3: Synthesis of (S)-1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0403] ##STR00049##

Step 1: 1,3-Dichloro-5-vinylbenzene

[0404] ##STR00050##

[0405] The compound is obtained by the procedure described in Example 1, Step 4, starting from 2.00 g (11.4 mmol) of 3,5-dichlorobenzaldehyde instead of 3-fluorobenzaldehyde. 495 mg of the title compound are obtained.

[0406] Yield: 25%.

[0407] MH+: Non ionizable.

Step 2: 2-(3,5-Dichlorophenyl)oxirane

[0408] ##STR00051##

[0409] The compound is obtained by the procedure described in Example 1, Step 5, starting from 495 mg (2.86 mmol) of 1,3-dichloro-5-vinylbenzene (described in the previous step) instead of 1-fluoro-3-vinylbenzene. 433 mg of the title compound are obtained.

[0410] Yield: 80%.

[0411] MH+: Non ionizable.

Step 3: 1-(3,5-Dichlorophenyl)-2-(dimethylamino)ethan-1-ol

[0412] ##STR00052##

[0413] The compound is obtained by the procedure described in Example 1, Step 6, starting from 433 mg (2.29 mmol) of 2-(3,5-dichlorophenyl)oxirane (described in the previous step) instead of 2-(3-fluorophenyl)oxirane. 455 mg of the title compound are obtained.

[0414] Yield: 85%.

[0415] MH+: 234.3; 236.3 (M; M+2).

Step 4: 2-Chloro-2-(3,5-dichlorophenyl)-N,N-dimethylethan-1-amine

[0416] ##STR00053##

[0417] The compound is obtained by the procedure described in Example 1, Step 7, starting from 455 mg (1.94 mmol) of 1-(3,5-dichlorophenyl)-2-(dimethylamino)ethan-1-ol (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 521 mg of the title compound are obtained.

[0418] Yield: Quantitative.

[0419] MH+: 252.3; 254.4 (M; M+2).

Step 5: 4-Bromo-1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)pyridin-2(1H)-one

[0420] ##STR00054##

[0421] The compound is obtained by the procedure described in Example 1, Step 8, starting from 521 mg (2.06 mmol) of 2-chloro-2-(3,5-dichlorophenyl)-N,N-dimethylethan-1-amine (described in the previous step) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 276 mg of the title compound are obtained.

[0422] Yield: 36%.

[0423] MH+: 389.5; 391.5; 393.5 (M; M+2; M+4).

Step 6: 1-(1-(3,5-Dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0424] ##STR00055##

[0425] The compound is obtained by the procedure described in Example 1, Step 9, starting from 276 mg (0.71 mmol) of 4-bromo-1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)pyridin-2(1H-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H-one. 365 mg of the title compound are obtained.

[0426] Yield: 77%.

[0427] MH+: 666.9; 668.8 (M; M+2).

Step 7: 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0428] ##STR00056##

[0429] 365 mg (0.55 mmol) of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) are suspended in 10 ml of DMSO and 1.37 ml (2.74 mmol, 5 eq) of a solution of NaOH 2N are slowly added. The mixture is stirred at room temperature for 2 h then cooled to 0° C. with an ice/water bath and quenched carefully with a saturated NH.sub.4Cl solution. Cold water is added and a white precipitate crashes out, which is filtrated, rinsed several times with water and dried under vacuum.

[0430] Crude mixture is finally purified by flash chromatography using a silica gel column and a DCM/MeOH mixture as eluent. 226 mg of a slightly yellow solid are obtained.

[0431] Yield: 80%.

[0432] MH+: 512.7; 514.6 (M; M+2).

[0433] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.06 (br s, 1H); 8.17 (d, J=2.5 Hz, 1H); 8.11 (d, J=2.8 Hz, 1H); 7.79 (d, J=7.3 Hz, 1H); 7.71 (d, J=2.5 Hz, 1H); 7.59-7.55 (m, 1H); 7.46 (d, J=1.8 Hz, 2H); 6.74-6.66 (m, 2H); 6.17-6.08 (m, 1H); 3.83-3.73 (m, 4H); 3.34-3.23 (m, 1H); 3.20-3.09 (m, 4H); 2.80-2.70 (m, 1H); 2.21 (s, 6H).

Step 8: (S)-1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0434] ##STR00057##

[0435] Enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and an Hexane/EtOH/DCM/0.1% TEA mixture as the mobile phase. First fraction to be eluted is the (−) (R)-enantiomer, followed by the (+) (S)-enantiomer with ee >98%. 25 mg of the title compound are obtained.

[0436] MH+: 512.7; 514.6 (M; M+2).

[0437] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.06 (br s, 1H); 8.17 (d, J=2.5 Hz, 1H); 8.11 (d, J=2.8 Hz, 1H); 7.79 (d, J=7.3 Hz, 1H); 7.71 (d, J=2.5 Hz, 1H); 7.59-7.55 (m, 1H); 7.46 (d, J=1.8 Hz, 2H); 6.74-6.66 (m, 2H); 6.17-6.08 (m, 1H); 3.83-3.73 (m, 4H); 3.34-3.23 (m, 1H); 3.20-3.09 (m, 4H); 2.80-2.70 (m, 1H); 2.21 (s, 6H).

Example 4: Synthesis of (S)-1-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0438] ##STR00058##

Step 1: 1,2-Dichloro-4-vinylbenzene

[0439] ##STR00059##

[0440] The compound is obtained by the procedure described in Example 1, Step 4, starting from 2.00 g (11.4 mmol) of 3,4-dichlorobenzaldehyde instead of 3-fluorobenzaldehyde. 850 mg of the title compound are obtained.

[0441] Yield: 43%.

[0442] MH+: Non ionizable.

Step 2: 2-(3,4-Dichlorophenyl)oxirane

[0443] ##STR00060##

[0444] The compound is obtained by the procedure described in Example 1, Step 5, starting from 850 mg (4.91 mmol) of 1,2-dichloro-4-vinylbenzene (described in the previous step) instead of 1-fluoro-3-vinylbenzene. 630 mg of the title compound are obtained.

[0445] Yield: 68%.

[0446] MH+: Non ionizable.

Step 3: 1-(3,4-Dichlorophenyl)-2-(dimethylamino)ethan-1-ol

[0447] ##STR00061##

[0448] The compound is obtained by the procedure described in Example 1, Step 6, starting from 630 mg (3.33 mmol) of 2-(3,4-dichlorophenyl)oxirane (described in the previous step) instead of 2-(3-fluorophenyl)oxirane. 692 mg of the title compound are obtained.

[0449] Yield: 89%.

[0450] MH+: 234.3; 236.2 (M; M+2).

Step 4: 2-Chloro-2-(3,4-dichlorophenyl)-N,N-dimethylethan-1-amine

[0451] ##STR00062##

[0452] The compound is obtained by the procedure described in Example 1, Step 7, starting from 692 mg (2.96 mmol) of 1-(3,4-dichlorophenyl)-2-(dimethylamino)ethan-1-ol (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 760 mg of the title compound are obtained.

[0453] Yield: Quantitative.

[0454] MH+: 252.2; 254.2 (M; M+2).

Step 5: 4-Bromo-1-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)pyridin-2(1H)-one

[0455] ##STR00063##

[0456] The compound is obtained by the procedure described in Example 1, Step 8, starting from 760 mg (3.01 mmol) of 2-chloro-2-(3,4-dichlorophenyl)-N,N-dimethylethan-1-amine (described in the previous step) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 553 mg of the title compound are obtained.

[0457] Yield: 47%.

[0458] MH+: 389.4; 391.3 (M; M+2).

Step 6: 1-(1-(3,4-Dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0459] ##STR00064##

[0460] The compound is obtained by the procedure described in Example 1, Step 9, starting from 276 mg (0.71 mmol) of 4-bromo-1-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)pyridin-2(1H)-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 334 mg of the title compound are obtained.

[0461] Yield: 71%.

[0462] MH+: 666.6; 668.4 (M; M+2).

Step 7: 1-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0463] ##STR00065##

[0464] The compound is obtained by the procedure described in Example 3, Step 7, starting from 334 mg (0.50 mmol) of 1-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 199 mg of racemate are obtained.

[0465] Yield: 77%.

[0466] MH+: 512.5; 514.5 (M; M+2).

[0467] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.08 (br s, 1H); 8.17 (d, J=2.5 Hz, 1H); 8.11 (d, J=2.9 Hz, 1H); 7.76 (d, J=7.2 Hz, 1H); 7.69 (d, J=2.1 Hz, 2H); 7.64 (d, J=8.4 Hz, 1H); 7.39-7.33 (m, 1H); 6.73-6.66 (m, 2H); 6.20-6.10 (m, 1H); 3.82-3.73 (m, 4H); 3.33-3.23 (m, 1H); 3.18-3.09 (m, 4H); 2.79-2.69 (m, 1H); 2.20 (s, 6H).

Step 8: (S)-1-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0468] ##STR00066##

[0469] Enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and an Hexane/EtOH/DCM/0.1% TEA mixture as the mobile phase. First fraction to be eluted is the (−) (R)-enantiomer, followed by the (+) (S)-enantiomer with ee >98%. 39 mg of the title compound are obtained starting from 199 mg of the racemate.

[0470] MH+: 512.5; 514.5 (M; M+2).

[0471] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.08 (br s, 1H); 8.17 (d, J=2.5 Hz, 1H); 8.11 (d, J=2.9 Hz, 1H); 7.76 (d, J=7.2 Hz, 1H); 7.69 (d, J=2.1 Hz, 2H); 7.64 (d, J=8.4 Hz, 1H); 7.39-7.33 (m, 1H); 6.73-6.66 (m, 2H); 6.20-6.10 (m, 1H); 3.82-3.73 (m, 4H); 3.33-3.23 (m, 1H); 3.18-3.09 (m, 4H); 2.79-2.69 (m, 1H); 2.20 (s, 6H).

Example 5: Synthesis of (S)-1-(1-(3-bromophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0472] ##STR00067##

Step 1: 2-(3-Bromophenyl)oxirane

[0473] ##STR00068##

[0474] The compound is obtained by the procedure described in Example 1, Step 5, starting from 2 g (11 mmol) of 1-bromo-3-vinylbenzene instead of 1-fluoro-3-vinylbenzene. 2.12 g of the title compound are obtained.

[0475] Yield: 98%.

[0476] MH+: Non ionizable.

Step 2: 1-(3-Bromophenyl)-2-(dimethylamino)ethan-1-ol

[0477] ##STR00069##

[0478] The compound is obtained by the procedure described in Example 1, Step 6, starting from 2.12 g (10.7 mmol) of 2-(3-bromophenyl)oxirane (described in the previous step) instead of 2-(3-fluorophenyl)oxirane. 2.11 g of the title compound are obtained.

[0479] Yield: 97%.

[0480] MH+: 244.3; 246.4 (M; M+2).

Step 3: 2-(3-Bromophenyl)-2-chloro-N,N-dimethylethan-1-amine

[0481] ##STR00070##

[0482] The compound is obtained by the procedure described in Example 1, Step 7, starting from 2.11 g (8.6 mmol) of 1-(3-bromophenyl)-2-(dimethylamino)ethan-1-ol (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 2.30 g of the title compound are obtained.

[0483] Yield: Quantitative.

[0484] MH+: 262.4; 264.3 (M; M+2).

Step 4: 4-Bromo-1-(1-(3-bromophenyl)-2-(dimethylamino)ethyl)pyridin-2(1H)-one

[0485] ##STR00071##

[0486] The compound is obtained by the procedure described in Example 1, Step 8, starting from 2.30 g (20.3 mmol) of 2-(3-bromophenyl)-2-chloro-N,N-dimethylethan-1-amine (described in the previous step) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 1.85 g of the title compound are obtained.

[0487] Yield: 52%.

[0488] MH+: 399.3; 401.4 (M; M+2).

Step 5: 1-(1-(3-Bromophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0489] ##STR00072##

[0490] The compound is obtained by the procedure described in Example 1, Step 9, starting from 1.85 g (4.6 mmol) of 4-bromo-1-(1-(3-bromophenyl)-2-(dimethylamino)ethyl)pyridin-2(1H)-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 2.72 g of the title compound are obtained.

[0491] Yield: 88%.

[0492] MH+: 676.8; 678.8 (M; M+2).

Step 6: 1-(1-(3-bromophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0493] ##STR00073##

[0494] The compound is obtained by the procedure described in Example 3, Step 7, starting from 1.04 g (1.54 mmol) of 1-(1-(3-bromophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 681 mg of racemate are obtained.

[0495] Yield: 85%.

[0496] MH+: 522.6; 524.5 (M; M+2).

[0497] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.04 (br s, 1H); 8.17 (d, J=2.5 Hz, 1H); 8.09 (s, 1H); 7.75 (d, J=8.0 Hz, 1H); 7.70 (d, J=2.5 Hz, 1H); 7.62-7.57 (m, 1H); 7.53-7.47 (m, 1H); 7.42-7.37 (m, 1H); 7.33 (t, J=7.8 Hz, 1H); 6.72-6.65 (m, 2H); 6.20-6.12 (m, 1H); 3.83-3.73 (m, 4H); 3.34-3.24 (m, 1H); 3.20-3.08 (m, 4H); 2.78-2.68 (m, 1H); 2.21 (s, 6H).

Step 7: (S)-1-(1-(3-bromophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0498] ##STR00074##

[0499] Enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and an Hexane/EtOH/DCM/0.1% TEA mixture as the mobile phase. First fraction to be eluted is the (−) (R)-enantiomer, followed by the (+) (S)-enantiomer with ee >98%. 292 mg of the title compound are obtained starting from 681 mg of the racemate.

[0500] MH+: 522.6; 524.5 (M; M+2).

[0501] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.04 (br s, 1H); 8.17 (d, J=2.5 Hz, 1H); 8.09 (s, 1H); 7.75 (d, J=8.0 Hz, 1H); 7.70 (d, J=2.5 Hz, 1H); 7.62-7.57 (m, 1H); 7.53-7.47 (m, 1H); 7.42-7.37 (m, 1H); 7.33 (t, J=7.8 Hz, 1H); 6.72-6.65 (m, 2H); 6.20-6.12 (m, 1H); 3.83-3.73 (m, 4H); 3.34-3.24 (m, 1H); 3.20-3.08 (m, 4H); 2.78-2.68 (m, 1H); 2.21 (s, 6H).

Example 6: Synthesis of (S)-1-(2-(dimethylamino)-1-(3-iodophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0502] ##STR00075##

Step 1: 1-Iodo-3-vinylbenzene

[0503] ##STR00076##

[0504] The compound is obtained by the procedure described in Example 1, Step 4, starting from 5 g (21.5 mmol) of 3-iodobenzaldehyde instead of 3-fluorobenzaldehyde. 3.20 g of the title compound are obtained.

[0505] Yield: 65%.

[0506] MH+: Non ionizable.

Step 2: 2-(3-Iodophenyl)oxirane

[0507] ##STR00077##

[0508] The compound is obtained by the procedure described in Example 1, Step 5, starting from 3.20 g (13.91 mmol) of 1-iodo-3-vinylbenzene (described in the previous step) instead of 1-fluoro-3-vinylbenzene. 2.78 g of the title compound are obtained.

[0509] Yield: 81%.

[0510] MH+: Non ionizable.

Step 3: 2-(Dimethylamino)-1-(3-iodophenyl)ethan-1-ol

[0511] ##STR00078##

[0512] The compound is obtained by the procedure described in Example 1, Step 6, starting from 2.78 g (26.9 mmol) of 2-(3-iodophenyl)oxirane (described in the previous step) instead of 2-(3-fluorophenyl)oxirane. 2.54 g of the title compound are obtained.

[0513] Yield: 77%.

[0514] MH+: 292.2 (M+1).

Step 4: 2-Chloro-2-(3-iodophenyl)-N,N-dimethylethan-1-amine

[0515] ##STR00079##

[0516] The compound is obtained by the procedure described in Example 1, Step 7, starting from 1.25 g (4.3 mmol) of 2-(dimethylamino)-1-(3-iodophenyl)ethan-1-ol (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 1.59 g of the title compound are obtained.

[0517] Yield: Quantitative.

[0518] MH+: 310.3; 312.3 (M; M+2).

Step 5: 1-(2-(Dimethylamino)-1-(3-iodophenyl)ethyl)-4-iodopyridin-2(1H)-one

[0519] ##STR00080##

[0520] To a mixture of 1.04 g (4.70 mmol, 1 eq) of 4-iodopyridin-2-(1H)-one and 1.68 g (5.20 mmol, 1.1 eq) of cesium carbonate in 10 ml of dry DMF, is added at 0° C. a solution of 1.59 g (5.14 mmol, 1 eq) of 2-chloro-2-(3-iodophenyl)-N,N-dimethylethan-1-amine (described in the previous step) in 5 ml of dry DMF. The solution is then stirred at room temperature for 1 h 30. EtOAc is added, and the mixture is washed 4 times with water and once with brine. Organic layer is dried over Na.sub.2SO.sub.4, filtrated and evaporated under reduced pressure. Crude mixture is purified by flash chromatography using a deactivated silica gel column and an Hexane/EtOAc mixture as eluent. 1.11 g of the title compound are obtained.

[0521] Yield: 52%.

[0522] MH+: 495.6 (M+1).

Step 6: 1-(2-(Dimethylamino)-1-(3-iodophenyl)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0523] ##STR00081##

[0524] The compound is obtained by the procedure described in Example 1, Step 9, starting from 1.11 g (22.5 mmol) of 1-(2-(dimethylamino)-1-(3-iodophenyl)ethyl)-4-iodopyridin-2(1H)-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 589 mg of the title compound are obtained.

[0525] Yield: 80%.

[0526] MH+: 724.5 (M+1).

Step 7: 1-(2-(Dimethylamino)-1-(3-iodophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0527] ##STR00082##

[0528] The compound is obtained by the procedure described in Example 3, Step 7, starting from 875 mg (1.21 mmol) of 1-(2-(dimethylamino)-1-(3-iodophenyl)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 674 mg of racemate are obtained.

[0529] Yield: 97%.

[0530] MH+: 570.5 (M+1).

[0531] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.06 (br s, 1H); 8.17 (d, J=2.5 Hz, 1H); 8.10 (d, J=2.9 Hz, 1H); 7.79-7.73 (m, 2H); 7.72-7.64 (m, 2H); 7.44-7.38 (m, 1H); 7.17 (t, J=7.8 Hz, 1H); 6.72-6.65 (m, 2H); 6.18-6.09 (m, 1H); 3.85-3.73 (m, 4H); 3.34-3.24 (m, 1H); 3.20-3.08 (m, 4H); 2.73-2.64 (m, 1H); 2.20 (s, 6H).

Step 8: (S)-1-(2-(Dimethylamino)-1-(3-iodophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0532] ##STR00083##

[0533] Enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and an Hexane/EtOH/DCM/0.1% TEA mixture as the mobile phase. First fraction to be eluted is the (−) (R)-enantiomer, followed by the (+) (S)-enantiomer with ee >98%. 262 mg of the title compound are obtained starting from 674 mg of the racemate.

[0534] MH+: 570.5 (M+1).

[0535] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.06 (br s, 1H); 8.17 (d, J=2.5 Hz, 1H); 8.10 (d, J=2.9 Hz, 1H); 7.79-7.73 (m, 2H); 7.72-7.64 (m, 2H); 7.44-7.38 (m, 1H); 7.17 (t, J=7.8 Hz, 1H); 6.72-6.65 (m, 2H); 6.18-6.09 (m, 1H); 3.85-3.73 (m, 4H); 3.34-3.24 (m, 1H); 3.20-3.08 (m, 4H); 2.73-2.64 (m, 1H); 2.20 (s, 6H).

Example 7: Synthesis of (S)-1-(1-(3-bromo-4-fluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0536] ##STR00084##

Step 1: 2-Bromo-1-fluoro-4-vinylbenzene

[0537] ##STR00085##

[0538] The compound is obtained by the procedure described in Example 1, Step 4, starting from 2.61 g (12.9 mmol) of 3-bromo-4-fluorobenzaldehyde instead of 3-fluorobenzaldehyde. 1.37 g of the title compound are obtained.

[0539] Yield: 53%.

[0540] MH+: Non ionizable.

Step 2: 2-(3-Bromo-4-fluorophenyl)oxirane

[0541] ##STR00086##

[0542] The compound is obtained by the procedure described in Example 1, Step 5, starting from 1.37 g (6.81 mmol) of 2-bromo-1-fluoro-4-vinylbenzene (described in the previous step) instead of 1-fluoro-3-vinylbenzene. 1.13 g of the title compound are obtained.

[0543] Yield: 76%.

[0544] MH+: Non ionizable.

Step 3: 1-(3-Bromo-4-fluorophenyl)-2-(dimethylamino)ethan-1-ol

[0545] ##STR00087##

[0546] The compound is obtained by the procedure described in Example 1, Step 6, starting from 1.13 g (5.21 mmol) of 2-(3-bromo-4-fluorophenyl)oxirane (described in the previous step) instead of 2-(3-fluorophenyl)oxirane. 1.05 g of the title compound are obtained.

[0547] Yield: 77%.

[0548] MH+: 262.2; 264.3 (M; M+2).

Step 4: 2-(3-Bromo-4-fluorophenyl)-2-chloro-N,N-dimethylethan-1-amine

[0549] ##STR00088##

[0550] The compound is obtained by the procedure described in Example 1, Step 7, starting from 1.05 g (4.00 mmol) of 1-(3-bromo-4-fluorophenyl)-2-(dimethylamino)ethan-1-ol (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 1.30 g of the title compound are obtained.

[0551] Yield: Quantitative.

[0552] MH+: 280.3; 282.3 (M; M+2).

Step 5: 4-Bromo-1-(1-(3-bromo-4-fluorophenyl)-2-(dimethylamino)ethyl)pyridin-2(1H)-one

[0553] ##STR00089##

[0554] The compound is obtained by the procedure described in Example 1, Step 8, starting from 1.30 g (4.64 mmol) of 2-(3-bromo-4-fluorophenyl)-2-chloro-N,N-dimethylethan-1-amine (described in the previous step) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 733 mg of the title compound are obtained.

[0555] Yield: 38%.

[0556] MH+: 417.3; 419.3; 421.2 (M; M+2; M+4).

Step 6: 1-(1-(3-Bromo-4-fluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0557] ##STR00090##

[0558] The compound is obtained by the procedure described in Example 1, Step 9, starting from 733 mg (1.74 mmol) of 4-bromo-1-(1-(3-bromo-4-fluorophenyl)-2-(dimethylamino)ethyl)pyridin-2(1H)-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 1.00 g of the title compound are obtained.

[0559] Yield: 82%.

[0560] MH+: 694.6; 696.5 (M; M+2).

Step 7: 1-(1-(3-bromo-4-fluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0561] ##STR00091##

[0562] The compound is obtained by the procedure described in Example 3, Step 7, starting from 640 mg (0.92 mmol) of 1-(1-(3-bromo-4-fluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 464 mg of racemate are obtained.

[0563] Yield: 93%.

[0564] MH+: 540.5; 542.4 (M; M+2).

[0565] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.06 (br s, 1H); 8.17 (d, J=2.5 Hz, 1H); 8.10 (s, 1H); 7.80-7.73 (m, 2H); 7.69 (d, J=2.5 Hz, 1H); 7.48-7.41 (m, 1H); 7.38 (t, J=8.7 Hz, 1H); 6.72-6.66 (m, 2H); 6.21-6.12 (m, 1H); 3.83-3.74 (m, 4H); 3.34-3.24 (m, 1H); 3.18-3.08 (m, 4H); 2.77-2.67 (m, 1H); 2.20 (s, 6H).

Step 8: (S)-1-(1-(3-bromo-4-fluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0566] ##STR00092##

[0567] Enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and an Hexane/EtOH/DCM/0.1% TEA mixture as the mobile phase. First fraction to be eluted is the (−) (R)-enantiomer, followed by the (+) (S)-enantiomer with ee >98%. 206 mg of the title compound are obtained starting from 464 mg of the racemate.

[0568] MH+: 540.5; 542.4 (M; M+2).

[0569] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.06 (br s, 1H); 8.17 (d, J=2.5 Hz, 1H); 8.10 (s, 1H); 7.80-7.73 (m, 2H); 7.69 (d, J=2.5 Hz, 1H); 7.48-7.41 (m, 1H); 7.38 (t, J=8.7 Hz, 1H); 6.72-6.66 (m, 2H); 6.21-6.12 (m, 1H); 3.83-3.74 (m, 4H); 3.34-3.24 (m, 1H); 3.18-3.08 (m, 4H); 2.77-2.67 (m, 1H); 2.20 (s, 6H).

Example 8: Synthesis of (S)-1-(2-(dimethylamino)-1-(4-fluoro-3-iodophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0570] ##STR00093##

Step 1: 1-Fluoro-2-iodo-4-vinylbenzene

[0571] ##STR00094##

[0572] The compound is obtained by the procedure described in Example 1, Step 4, starting from 3.5 g (14.0 mmol) of 4-fluoro-3-iodobenzaldehyde instead of 3-fluorobenzaldehyde. 2.13 g of the title compound are obtained.

[0573] Yield: 61%.

[0574] MH+: Non ionizable.

Step 2: 2-(4-Fluoro-3-iodophenyl)oxirane

[0575] ##STR00095##

[0576] The compound is obtained by the procedure described in Example 1, Step 5, starting from 2.13 g (8.58 mmol) of 1-fluoro-2-iodo-4-vinylbenzene (described in the previous step) instead of 1-fluoro-3-vinylbenzene. 1.99 g of the title compound are obtained.

[0577] Yield: 88%.

[0578] MH+: Non ionizable.

Step 3: 2-(Dimethylamino)-1-(4-fluoro-3-iodophenyl)ethan-1-ol

[0579] ##STR00096##

[0580] The compound is obtained by the procedure described in Example 1, Step 6, starting from 1.99 g (7.54 mmol) of 2-(4-fluoro-3-iodophenyl)oxirane (described in the previous step) instead of 2-(3-fluorophenyl)oxirane. 1.57 g of the title compound are obtained.

[0581] Yield: 67%.

[0582] MH+: 310.5 (M+1).

Step 4: 2-Chloro-2-(4-fluoro-3-iodophenyl)-N,N-dimethylethan-1-amine

[0583] ##STR00097##

[0584] The compound is obtained by the procedure described in Example 1, Step 7, starting from 1.57 g (5.08 mmol) of 2-(dimethylamino)-1-(4-fluoro-3-iodophenyl)ethan-1-ol (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 1.64 g of the title compound are obtained.

[0585] Yield: 98%.

[0586] MH+: 328.4 (M+1).

Step 5: 1-(2-(Dimethylamino)-1-(4-fluoro-3-iodophenyl)ethyl)-4-iodopyridin-2(1H)-one

[0587] ##STR00098##

[0588] The compound is obtained by the procedure described in Example 6, Step 5, starting from 1.57 g (5.08 mmol) of 2-chloro-2-(4-fluoro-3-iodophenyl)-N,N-dimethylethan-1-amine (described in the previous step) instead of 2-chloro-2-(3-iodophenyl)-N,N-dimethylethan-1-amine. 555 mg of the title compound are obtained.

[0589] Yield: 22%.

[0590] MH+: 513.5 (M+1).

Step 6: 1-(2-(Dimethylamino)-1-(4-fluoro-3-iodophenyl)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0591] ##STR00099##

[0592] The compound is obtained by the procedure described in Example 1, Step 9, starting from 555 mg (1.08 mmol) of 1-(2-(dimethylamino)-1-(4-fluoro-3-iodophenyl)ethyl)-4-iodopyridin-2(1H)-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 780 mg of the title compound are obtained.

[0593] Yield: 97%.

[0594] MH+: 742.8 (M+1).

Step 7: 1-(2-(dimethylamino)-1-(4-fluoro-3-iodophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0595] ##STR00100##

[0596] The compound is obtained by the procedure described in Example 3, Step 7, starting from 760 mg (1.02 mmol) of 1-(2-(dimethylamino)-1-(4-fluoro-3-iodophenyl)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 240 mg of racemate are obtained followed by 87 mg of the title compound after chiral separation ((+) (S)-enantiomer).

[0597] Yield: 40%.

[0598] MH+: 588.4 (M+1).

[0599] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.06 (br s, 1H); 8.16 (d, J=2.5 Hz, 1H); 8.10 (s, 1H); 7.91-7.85 (m, 1H); 7.75 (d, J=8.0 Hz, 1H); 7.69 (d, J=2.6 Hz, 1H); 7.49-7.41 (m, 1H); 7.26 (t, J=8.3 Hz, 1H); 6.72-6.64 (m, 2H); 6.19-6.08 (m, 1H); 3.84-3.72 (m, 4H); 3.34-3.24 (m, 1H); 3.18-3.08 (m, 4H); 2.73-2.65 (m, 1H); 2.20 (s, 6H).

Step 8: (S)-1-(2-(dimethylamino)-1-(4-fluoro-3-iodophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0600] ##STR00101##

[0601] Enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and an Hexane/EtOH/DCM/0.1% TEA mixture as the mobile phase. First fraction to be eluted is the (−) (R)-enantiomer, followed by the (+) (S)-enantiomer with ee >98%. 87 mg of the title compound are obtained starting from 240 mg of the racemate.

[0602] MH+: 588.4 (M+1).

[0603] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.06 (br s, 1H); 8.16 (d, J=2.5 Hz, 1H); 8.10 (s, 1H); 7.91-7.85 (m, 1H); 7.75 (d, J=8.0 Hz, 1H); 7.69 (d, J=2.6 Hz, 1H); 7.49-7.41 (m, 1H); 7.26 (t, J=8.3 Hz, 1H); 6.72-6.64 (m, 2H); 6.19-6.08 (m, 1H); 3.84-3.72 (m, 4H); 3.34-3.24 (m, 1H); 3.18-3.08 (m, 4H); 2.73-2.65 (m, 1H); 2.20 (s, 6H).

Example 9: Synthesis of (S)-1-(1-(3-chloro-5-fluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0604] ##STR00102##

Step 1: 1-Chloro-3-fluoro-5-vinylbenzene

[0605] ##STR00103##

[0606] The compound is obtained by the procedure described in Example 1, Step 4, starting from 5 g (31.5 mmol) of 3-chloro-5-fluorobenzaldehyde instead of 3-fluorobenzaldehyde. 3.07 g of the title compound are obtained.

[0607] Yield: 62%.

[0608] MH+: Non ionizable.

Step 2: 2-(3-Chloro-5-fluorophenyl)oxirane

[0609] ##STR00104##

[0610] The compound is obtained by the procedure described in Example 1, Step 5, starting from 3.07 g (20 mmol) of 1-chloro-3-fluoro-5-vinylbenzene (described in the previous step) instead of 1-fluoro-3-vinylbenzene. 1.55 g of the title compound are obtained.

[0611] Yield: 46%.

[0612] MH+: Non ionizable.

Step 3: 1-(3-Chloro-5-fluorophenyl)-2-(dimethylamino)ethan-1-ol

[0613] ##STR00105##

[0614] The compound is obtained by the procedure described in Example 1, Step 6, starting from 300 mg (1.74 mmol) of 2-(3-chloro-5-fluorophenyl)oxirane (described in the previous step) instead of 2-(3-fluorophenyl)oxirane. 136 mg of the title compound are obtained.

[0615] Yield: 36%.

[0616] MH+: 218.4; 220.4 (M; M+2).

Step 4: 2-Chloro-2-(3-chloro-5-fluorophenyl)-N,N-dimethylethan-1-amine

[0617] ##STR00106##

[0618] The compound is obtained by the procedure described in Example 1, Step 7, starting from 136 mg (0.62 mmol) of 1-(3-chloro-5-fluorophenyl)-2-(dimethylamino)ethan-1-ol (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 145 mg of the title compound are obtained.

[0619] Yield: 98%.

[0620] MH+: 236.2; 238.2 (M; M+2).

Step 5: 4-Bromo-1-(1-(3-chloro-5-fluorophenyl)-2-(dimethylamino)ethyl)pyridin-2(1H)-one

[0621] ##STR00107##

[0622] The compound is obtained by the procedure described in Example 1, Step 8, starting from 145 mg (0.61 mmol) of 2-chloro-2-(3-chloro-5-fluorophenyl)-N,N-dimethylethan-1-amine (described in the previous step) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 90 mg of the title compound are obtained.

[0623] Yield: 39%.

[0624] MH+: 373.3; 375.5 (M; M+2).

Step 6: 1-(1-(3-Chloro-5-fluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0625] ##STR00108##

[0626] The compound is obtained by the procedure described in Example 1, Step 9, starting from 90 mg (0.24 mmol) of 4-bromo-1-(1-(3-chloro-5-fluorophenyl)-2-(dimethylamino)ethyl)pyridin-2(1H)-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H-one. 94 mg of the title compound are obtained.

[0627] Yield: 60%.

[0628] MH+: 650.5; 652.6 (M; M+2).

Step 7: 1-(1-(3-Chloro-5-fluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0629] ##STR00109##

[0630] 94 mg (0.14 mmol) of 1-(1-(3-chloro-5-fluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) are suspended in 5 ml of MeCN and 2.5 ml of a Na.sub.2CO.sub.3 2M solution. The mixture is stirred at 120° C. under microwave irradiation in a sealed tube (150 W) for 1 h. The mixture is cooled to room temperature, diluted with EtOAc and washed 3 times with water. Organic layer is dried over Na.sub.2SO.sub.4, filtrated and evaporated under reduced pressure. Crude product is finally purified by flash chromatography using a silica gel column and a DCM/MeOH mixture as eluent. 16 mg of a white solid are obtained.

[0631] Yield: 23%.

[0632] MH+: 588.7 (M+1).

[0633] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.06 (br s, 1H); 8.17 (d, J=2.5 Hz, 1H); 8.11 (s, 1H); 7.77 (d, J=7.6 Hz, 1H); 7.70 (d, J=2.6 Hz, 1H); 7.43-7.36 (m, 1H); 7.34-7.24 (m, 2H); 6.74-6.67 (m, 2H); 6.20-6.11 (m, 1H); 3.83-3.73 (m, 4H); 3.34-3.23 (m, 1H); 3.19-3.09 (m, 4H); 2.81-2.71 (m, 1H); 2.21 (s, 6H).

Step 8: (S)-1-(1-(3-Chloro-5-fluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0634] ##STR00110##

[0635] Enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and an Hexane/EtOH/DCM/0.1% TEA mixture as the mobile phase. First fraction to be eluted is the (−) (R)-enantiomer, followed by the (+) (S)-enantiomer with ee >98%. 5 mg of the title compound are obtained starting from 16 mg of the racemate.

[0636] MH+: 588.7 (M+1).

[0637] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.06 (br s, 1H); 8.17 (d, J=2.5 Hz, 1H); 8.11 (s, 1H); 7.77 (d, J=7.6 Hz, 1H); 7.70 (d, J=2.6 Hz, 1H); 7.43-7.36 (m, 1H); 7.34-7.24 (m, 2H); 6.74-6.67 (m, 2H); 6.20-6.11 (m, 1H); 3.83-3.73 (m, 4H); 3.34-3.23 (m, 1H); 3.19-3.09 (m, 4H); 2.81-2.71 (m, 1H); 2.21 (s, 6H).

Example 10: Synthesis of (S)-1-(2-(dimethylamino)-1-(3-fluoro-5-iodophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0638] ##STR00111##

Step 1: 1-Fluoro-3-iodo-4-vinylbenzene

[0639] ##STR00112##

[0640] The compound is obtained by the procedure described in Example 1, Step 4, starting from 2 g (7.96 mmol) of 3-fluoro-5-iodobenzaldehyde instead of 3-fluorobenzaldehyde. 873 mg of the title compound are obtained.

[0641] Yield: 44%.

[0642] MH+: Non ionizable.

Step 2: 2-(3-Fluoro-5-iodophenyl)oxirane

[0643] ##STR00113##

[0644] The compound is obtained by the procedure described in Example 1, Step 5, starting from 873 mg (3.5 mmol) of 1-fluoro-3-iodo-4-vinylbenzene (described in the previous step) instead of 1-fluoro-3-vinylbenzene. 432 mg of the title compound are obtained.

[0645] Yield: 47%.

[0646] MH+: Non ionizable.

Step 3: 2-(Dimethylamino)-1-(3-fluoro-5-iodophenyl)ethan-1-ol

[0647] ##STR00114##

[0648] The compound is obtained by the procedure described in Example 1, Step 6, starting from 376 mg (1.40 mmol) of 2-(3-fluoro-5-iodophenyl)oxirane (described in the previous step) instead of 2-(3-fluorophenyl)oxirane. 295 mg of the title compound are obtained.

[0649] Yield: 67%.

[0650] MH+: 310.3 (M+1).

Step 4: 2-Chloro-2-(3-fluoro-5-iodophenyl)-N,N-dimethylethan-1-amine

[0651] ##STR00115##

[0652] The compound is obtained by the procedure described in Example 1, Step 7, starting from 351 mg (1.14 mmol) of 2-(dimethylamino)-1-(3-fluoro-5-iodophenyl)ethan-1-ol (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 328 mg of the title compound are obtained.

[0653] Yield: 88%.

[0654] MH+: 388.3 (M+1).

Step 5: 1-(2-(Dimethylamino)-1-(3-fluoro-5-iodophenyl)ethyl)-4-iodopyridin-2(1H)-one

[0655] ##STR00116##

[0656] The compound is obtained by the procedure described in Example 6, Step 5, starting from 328 mg (0.85 mmol) of 2-chloro-2-(3-fluoro-5-iodophenyl)-N,N-dimethylethan-1-amine (described in the previous step) instead of 2-chloro-2-(3-iodophenyl)-N,N-dimethylethan-1-amine. 236 mg of the title compound are obtained.

[0657] Yield: 54%.

[0658] MH+: 513.2 (M+1).

Step 6: 1-(2-(Dimethylamino)-1-(3-fluoro-5-iodophenyl)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0659] ##STR00117##

[0660] The compound is obtained by the procedure described in Example 1, Step 9, starting from 236 mg (0.46 mmol) of 1-(2-(dimethylamino)-1-(3-fluoro-5-iodophenyl)ethyl)-4-iodopyridin-2(1H)-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 340 mg of the title compound are obtained.

[0661] Yield: 99%.

[0662] MH+: 742.5 (M+1).

Step 7: 1-(2-(dimethylamino)-1-(3-fluoro-5-iodophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0663] ##STR00118##

[0664] The compound is obtained by the procedure described in Example 3, Step 7, starting from 207 mg (0.28 mmol) of 1-(2-(dimethylamino)-1-(3-fluoro-5-iodophenyl)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 97 mg of racemate are obtained.

[0665] Yield: 59%.

[0666] MH+: 588.6 (M+1).

[0667] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.06 (br s, 1H); 8.17 (d, J=2.5 Hz, 1H); 8.10 (s, 1H); 7.77 (d, J=7.8 Hz, 1H); 7.71 (d, J=2.6 Hz, 1H); 7.64-7.57 (m, 2H); 7.35-7.28 (m, 1H); 6.74-6.67 (m, 2H); 6.17-6.08 (m, 1H); 3.83-3.74 (m, 4H); 3.34-3.22 (m, 1H); 3.19-3.08 (m, 4H); 2.78-2.68 (m, 1H); 2.20 (s, 6H).

Step 8: (S)-1-(2-(dimethylamino)-1-(3-fluoro-5-iodophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0668] ##STR00119##

[0669] Enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and an Hexane/EtOH/DCM/0.1% TEA mixture as the mobile phase. First fraction to be eluted is the (−) (R)-enantiomer, followed by the (+) (S)-enantiomer with ee >98%. 2.9 mg of the title compound are obtained.

[0670] MH+: 588.6 (M+1).

[0671] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.06 (br s, 1H); 8.17 (d, J=2.5 Hz, 1H); 8.10 (s, 1H); 7.77 (d, J=7.8 Hz, 1H); 7.71 (d, J=2.6 Hz, 1H); 7.64-7.57 (m, 2H); 7.35-7.28 (m, 1H); 6.74-6.67 (m, 2H); 6.17-6.08 (m, 1H); 3.83-3.74 (m, 4H); 3.34-3.22 (m, 1H); 3.19-3.08 (m, 4H); 2.78-2.68 (m, 1H); 2.20 (s, 6H).

Example 11: Synthesis of (S)-1-(1-(3-chlorophenyl)-2-((2,2-difluoroethyl)(methyl)amino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0672] ##STR00120##

Step 1: 1-(3-Chlorophenyl)-2-((2,2-difluoroethyl)(methyl)amino)ethan-1-ol

[0673] ##STR00121##

[0674] The compound is obtained by the procedure described in Example 1, Step 6, starting from 500 mg (3.23 mmol) of 2-(3-chlorophenyl)oxirane (described in example 2 step 2) instead of 2-(3-fluorophenyl)oxirane, and 843 mg (6.46 mmol) of (2,2-difluoroethyl)(methyl)amine hydrochloride instead of dimethylamine. 277 mg of the title compound are obtained.

[0675] Yield: 34%.

[0676] MH+: 250.4; 252.3 (M; M+2).

Step 2: 2-Chloro-2-(3-chlorophenyl)-N-(2,2-difluoroethyl)-N-methylethan-1-amine

[0677] ##STR00122##

[0678] The compound is obtained by the procedure described in Example 1, Step 7, starting from 277 mg (1.10 mmol) of 1-(3-chlorophenyl)-2-((2,2-difluoroethyl)(methyl)amino)ethan-1-ol (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 302 mg of the title compound are obtained.

[0679] Yield: Quantitative.

[0680] MH+: 268.4; 270.3 (M; M+2).

Step 3: 4-Bromo-1-(1-(3-chlorophenyl)-2-((2,2-difluoroethyl)(methyl)amino)ethyl)pyridin-2(1H)-one

[0681] ##STR00123##

[0682] The compound is obtained by the procedure described in Example 1, Step 8, starting from 302 mg (1.10 mmol) of 2-chloro-2-(3-chlorophenyl)-N-(2,2-difluoroethyl)-N-methylethan-1-amine (described in the previous step) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 197 mg of the title compound are obtained.

[0683] Yield: 44%.

[0684] MH+: 405.4; 407.4; 409.3 (M; M+2; M+4).

Step 4: 1-(1-(3-Chlorophenyl)-2-((2,2-difluoroethyl)(methyl)amino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0685] ##STR00124##

[0686] The compound is obtained by the procedure described in Example 1, Step 9, starting from 197 mg (0.49 mmol) of 4-bromo-1-(1-(3-chlorophenyl)-2-((2,2-difluoroethyl)(methyl)amino)ethyl)pyridin-2(1H)-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 341 mg of the title compound are obtained.

[0687] Yield: Quantitative.

[0688] MH+: 682.6; 684.0 (M; M+2).

Step 5: 1-(1-(3-Chlorophenyl)-2-((2,2-difluoroethyl)(methyl)amino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0689] ##STR00125##

[0690] The compound is obtained by the procedure described in Example 3, Step 7, starting from 341 mg (0.49 mmol) of 1-(1-(3,4-difluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 137 mg of racemate are obtained.

[0691] Yield: 51%.

[0692] MH+: 528.5; 530.5 (M; M+2).

[0693] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.04 (br s, 1H); 8.17 (d, J=2.6 Hz, 1H); 8.11 (d, J=2.9 Hz, 1H); 7.73 (d, J=8.1 Hz, 1H); 7.70 (d, J=2.6 Hz, 1H); 7.50-7.46 (m, 1H); 7.43-7.33 (m, 3H); 6.73-6.67 (m, 2H); 6.24-6.17 (m, 1H); 6.06 (dt, J=55.8 and 4.3 Hz, 1H); 3.83-3.74 (m, 4H); 3.50-3.41 (m, 1H); 3.18-3.08 (m, 5H); 2.99-2.79 (m, 2H); 2.37 (s, 3H).

Step 6: (S)-1-(1-(3-Chlorophenyl)-2-((2,2-difluoroethyl)(methyl)amino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0694] ##STR00126##

[0695] Enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and an Hexane/EtOH/DCM/0.1% TEA mixture as the mobile phase. First fraction to be eluted is the (−) (R)-enantiomer, followed by the (+) (S)-enantiomer with ee >98%. 19 mg of the title compound are obtained starting from 137 mg of the racemate.

[0696] MH+: 528.5; 530.5 (M; M+2).

[0697] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.04 (br s, 1H); 8.17 (d, J=2.6 Hz, 1H); 8.11 (d, J=2.9 Hz, 1H); 7.73 (d, J=8.1 Hz, 1H); 7.70 (d, J=2.6 Hz, 1H); 7.50-7.46 (m, 1H); 7.43-7.33 (m, 3H); 6.73-6.67 (m, 2H); 6.24-6.17 (m, 1H); 6.06 (dt, J=55.8 and 4.3 Hz, 1H); 3.83-3.74 (m, 4H); 3.50-3.41 (m, 1H); 3.18-3.08 (m, 5H); 2.99-2.79 (m, 2H); 2.37 (s, 3H).

Example 12: Synthesis of (S)-2-((2-(3-chlorophenyl)-2-(4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)(methyl)amino)acetonitrile

[0698] ##STR00127##

Step 1: 2-((2-(3-Chlorophenyl)-2-hydroxyethyl)(methyl)amino)acetonitrile

[0699] ##STR00128##

[0700] The compound is obtained by the procedure described in Example 1, Step 6, starting from 500 mg (3.23 mmol) of 2-(3-chlorophenyl)oxirane (described in example 2 step 2) instead of 2-(3-fluorophenyl)oxirane, and 688 mg (6.46 mmol) of 2-(methylamino)acetonitrile hydrochloride instead of dimethylamine. 398 mg of the title compound are obtained.

[0701] Yield: 55%.

[0702] MH+: 225.4; 227.1 (M; M+2).

Step 2: 2-((2-Chloro-2-(3-chlorophenyl)ethyl)(methyl)amino)acetonitrile

[0703] ##STR00129##

[0704] The compound is obtained by the procedure described in Example 1, Step 7, starting from 398 mg (1.77 mmol) of 2-((2-(3-chlorophenyl)-2-hydroxyethyl)(methyl)amino)acetonitrile (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 430 mg of the title compound are obtained.

[0705] Yield: Quantitative.

[0706] MH+: 243.3; 245.2 (M; M+2).

Step 3: 2-((2-(4-Bromo-2-oxopyridin-1(2H)-yl)-2-(3-chlorophenyl)ethyl)(methyl)amino)acetonitrile

[0707] ##STR00130##

[0708] The compound is obtained by the procedure described in Example 1, Step 8, starting from 430 mg (1.77 mmol) of 2-((2-chloro-2-(3-chlorophenyl)ethyl)(methyl)amino)acetonitrile (described in the previous step) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 205 mg of the title compound are obtained.

[0709] Yield: 30%.

[0710] MH+: 380.4; 382.3; 384.3 (M; M+2; M+4).

Step 4: 2-((2-(3-Chlorophenyl)-2-(4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)(methyl)amino)acetonitrile

[0711] ##STR00131##

[0712] The compound is obtained by the procedure described in Example 1, Step 9, starting from 205 mg (0.54 mmol) of 2-((2-(4-bromo-2-oxopyridin-1(2H)-yl)-2-(3-chlorophenyl)ethyl)(methyl)amino)acetonitrile (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 346 mg of the title compound are obtained.

[0713] Yield: 98%.

[0714] MH+: 657.6; 659.6 (M; M+2).

Step 5: 2-((2-(3-Chlorophenyl)-2-(4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)(methyl)amino)acetonitrile

[0715] ##STR00132##

[0716] The compound is obtained by the procedure described in Example 3, Step 7, starting from 346 mg (0.52 mmol) of 2-((2-(3-chlorophenyl)-2-(4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)(methyl)amino)acetonitrile (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 150 mg of racemate are obtained.

[0717] Yield: 56%.

[0718] MH+: 503.5; 505.5 (M; M+2).

[0719] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.07 (br s, 1H); 8.17 (d, J=2.5 Hz, 1H); 8.11 (s, 1H); 7.73 (d, J=8.1 Hz, 1H); 7.70 (d, J=2.6 Hz, 1H); 7.51-7.47 (m, 1H); 7.46-7.34 (m, 3H); 6.74-6.68 (m, 2H); 6.26-6.17 (m, 1H); 3.84-3.73 (m, 6H); 3.52-3.41 (m, 1H); 3.18-3.09 (m, 4H); 3.00-2.90 (m, 1H); 2.33 (s, 3H).

Step 6: (S)-2-((2-(3-Chlorophenyl)-2-(4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)(methyl)amino)acetonitrile

[0720] ##STR00133##

[0721] Enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and an Hexane/EtOH/DCM/0.1% TEA mixture as the mobile phase. First fraction to be eluted is the (−) (R)-enantiomer, followed by the (+) (S)-enantiomer with ee >98%. 58 mg of the title compound are obtained starting from 150 mg of the racemate.

[0722] MH+: 503.5; 505.5 (M; M+2).

[0723] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.07 (br s, 1H); 8.17 (d, J=2.5 Hz, 1H); 8.11 (s, 1H); 7.73 (d, J=8.1 Hz, 1H); 7.70 (d, J=2.6 Hz, 1H); 7.51-7.47 (m, 1H); 7.46-7.34 (m, 3H); 6.74-6.68 (m, 2H); 6.26-6.17 (m, 1H); 3.84-3.73 (m, 6H); 3.52-3.41 (m, 1H); 3.18-3.09 (m, 4H); 3.00-2.90 (m, 1H); 2.33 (s, 3H).

Example 13: Synthesis of (S)-1-(1-(3-chlorophenyl)-2-((2-methoxyethyl)(methyl)amino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0724] ##STR00134##

Step 1: 1-(3-Chlorophenyl)-2-((2-methoxyethyl)(methyl)amino)ethan-1-ol

[0725] ##STR00135##

[0726] The compound is obtained by the procedure described in Example 1, Step 6, starting from 400 mg (2.59 mmol) of 2-(3-chlorophenyl)oxirane (described in example 2 step 2) instead of 2-(3-fluorophenyl)oxirane, and 462 mg (5.18 mmol) of N-(2-methoxyethyl)methylamine instead of dimethylamine. 470 mg of the title compound are obtained.

[0727] Yield: 74%.

[0728] MH+: 244.4; 246.2 (M; M+2).

Step 2: 2-Chloro-2-(3-chlorophenyl)-N-(2-methoxyethyl)-N-methylethan-1-amine

[0729] ##STR00136##

[0730] The compound is obtained by the procedure described in Example 1, Step 7, starting from 470 mg (1.93 mmol) of 1-(3-chlorophenyl)-2-((2-methoxyethyl)(methyl)amino)ethan-1-ol (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 552 mg of the title compound are obtained.

[0731] Yield: Quantitative.

[0732] MH+: 262.4; 264.3 (M; M+2).

Step 3: 4-Bromo-1-(1-(3-chlorophenyl)-2-((2-methoxyethyl)(methyl)amino)ethyl)pyridin-2(1H)-one

[0733] ##STR00137##

[0734] The compound is obtained by the procedure described in Example 1, Step 8, starting from 506 mg (1.92 mmol) of 2-chloro-2-(3-chlorophenyl)-N-(2-methoxyethyl)-N-methylethan-1-amine (described in the previous step) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 525 mg of the title compound are obtained.

[0735] Yield: 68%.

[0736] MH+: 399.3; 401.4; 403.2 (M; M+2; M+4).

Step 4: 1-(1-(3-Chlorophenyl)-2-((2-methoxyethyl)(methyl)amino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0737] ##STR00138##

[0738] The compound is obtained by the procedure described in Example 1, Step 9, starting from 262 mg (0.66 mmol) of 4-bromo-1-(1-(3-chlorophenyl)-2-((2-methoxyethyl)(methyl)amino)ethyl)pyridin-2(1H-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H-one. 421 mg of the title compound are obtained.

[0739] Yield: 95%.

[0740] MH+: 676.7; 678.0 (M; M+2).

Step 5: 1-(1-(3-Chlorophenyl)-2-((2-methoxyethyl)(methyl)amino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0741] ##STR00139##

[0742] The compound is obtained by the procedure described in Example 3, Step 7, starting from 421 mg (0.62 mmol) of 1-(1-(3-chlorophenyl)-2-((2-methoxyethyl)(methyl)amino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 240 mg of racemate are obtained.

[0743] Yield: 74%.

[0744] MH+: 522.6; 524.6 (M; M+2).

[0745] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.08 (br s, 1H); 8.17 (d, J=2.5 Hz, 1H); 8.12 (s, 1H); 7.75 (d, J=7.8 Hz, 1H); 7.70 (d, J=2.5 Hz, 1H); 7.49-7.45 (m, 1H); 7.43-7.30 (m, 3H); 6.73-6.67 (m, 2H); 6.23-6.14 (m, 1H); 3.83-3.73 (m, 4H); 3.45-3.31 (m, 3H); 3.20 (s, 3H); 3.18-3.09 (m, 4H); 3.00-2.91 (m, 1H); 2.65-2.57 (m, 2H); 2.26 (s, 3H).

Step 6: (S)-1-(1-(3-Chlorophenyl)-2-((2-methoxyethyl)(methyl)amino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0746] ##STR00140##

[0747] Enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and an Hexane/EtOH/DCM/0.1% TEA mixture as the mobile phase. First fraction to be eluted is the (−) (R)-enantiomer, followed by the (+) (S)-enantiomer with ee >98%. 56 mg of the title compound are obtained starting from 240 mg of the racemate.

[0748] MH+: 522.6; 524.6 (M; M+2).

[0749] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.08 (br s, 1H); 8.17 (d, J=2.5 Hz, 1H); 8.12 (s, 1H); 7.75 (d, J=7.8 Hz, 1H); 7.70 (d, J=2.5 Hz, 1H); 7.49-7.45 (m, 1H); 7.43-7.30 (m, 3H); 6.73-6.67 (m, 2H); 6.23-6.14 (m, 1H); 3.83-3.73 (m, 4H); 3.45-3.31 (m, 3H); 3.20 (s, 3H); 3.18-3.09 (m, 4H); 3.00-2.91 (m, 1H); 2.65-2.57 (m, 2H); 2.26 (s, 3H).

Example 14: Synthesis of (S)-1-(1-(3-chlorophenyl)-2-(cyclopropyl(methyl)amino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0750] ##STR00141##

Step 1: 1-(3-Chlorophenyl)-2-(cyclopropyl(methyl)amino)ethan-1-ol

[0751] ##STR00142##

[0752] The compound is obtained by the procedure described in Example 1, Step 6, starting from 400 mg (2.59 mmol) of 2-(3-chlorophenyl)oxirane (described in example 2 step 2) instead of 2-(3-fluorophenyl)oxirane, and 557 mg (5.18 mmol) of N-cyclopropylmethylamine hydrochloride instead of dimethylamine. 412 mg of the title compound are obtained.

[0753] Yield: 70%.

[0754] MH+: 226.4; 228.3 (M; M+2).

Step 2: N-(2-Chloro-2-(3-chlorophenyl)ethyl)-N-methylcyclopropanamine

[0755] ##STR00143##

[0756] The compound is obtained by the procedure described in Example 1, Step 7, starting from 402 mg (1.78 mmol) of 1-(3-chlorophenyl)-2-(cyclopropyl(methyl)amino)ethan-1-ol (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 505 mg of the title compound are obtained.

[0757] Yield: 58%.

[0758] MH+: 244.3; 246.3 (M; M+2).

Step 3: 4-Bromo-1-(1-(3-chlorophenyl)-2-(cyclopropyl(methyl)amino)ethyl)pyridin-2(1H)-one

[0759] ##STR00144##

[0760] The compound is obtained by the procedure described in Example 1, Step 8, starting from 505 mg (2.07 mmol) of N-(2-chloro-2-(3-chlorophenyl)ethyl)-N-methylcyclopropanamine (described in the previous step) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 253 mg of the title compound are obtained.

[0761] Yield: 32%.

[0762] MH+: 381.3; 383.3; 385.3 (M; M+2; M+4).

Step 4: 1-(1-(3-Chlorophenyl)-2-(cyclopropyl(methyl)amino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0763] ##STR00145##

[0764] The compound is obtained by the procedure described in Example 1, Step 9, starting from 253 mg (0.66 mmol) of 4-bromo-1-(1-(3-chlorophenyl)-2-(cyclopropyl(methyl)amino)ethyl)pyridin-2(1H)-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H-one. 210 mg of the title compound are obtained.

[0765] Yield: 48%.

[0766] MH+: 658.4; 659.7; 660.6 (M; M+1; M+2).

Step 5: 1-(1-(3-Chlorophenyl)-2-(cyclopropyl(methyl)amino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0767] ##STR00146##

[0768] The compound is obtained by the procedure described in Example 3, Step 7, starting from 210 mg (0.32 mmol) of 1-(1-(3-chlorophenyl)-2-(cyclopropyl(methyl)amino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 146 mg of racemate are obtained.

[0769] Yield: 91%.

[0770] MH+: 504.6; 506.5 (M; M+2).

[0771] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.08 (br s, 1H); 8.17 (d, J=2.5 Hz, 1H); 8.12 (s, 1H); 7.77 (d, J=8.1 Hz, 1H); 7.69 (d, J=2.5 Hz, 1H); 7.50-7.46 (m, 1H); 7.43-7.33 (m, 3H); 6.72-6.65 (m, 2H); 6.30-6.20 (m, 1H); 3.83-3.74 (m, 4H); 3.53-3.41 (m, 1H); 3.18-3.10 (m, 4H); 3.08-2.99 (m, 1H); 2.32 (s, 3H); 1.78-1.69 (m, 1H); 0.45-0.36 (m, 2H); 0.25-0.14 (m, 2H).

Step 6: (S)-1-(1-(3-Chlorophenyl)-2-(cyclopropyl(methyl)amino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0772] ##STR00147##

[0773] Enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and an Hexane/EtOH/DCM/0.1% TEA mixture as the mobile phase. First fraction to be eluted is the (−) (R)-enantiomer, followed by the (+) (S)-enantiomer with ee >98%. 38 mg of the title compound are obtained starting from 146 mg of the racemate.

[0774] MH+: 504.6; 506.5 (M; M+2).

[0775] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.08 (br s, 1H); 8.17 (d, J=2.5 Hz, 1H); 8.12 (s, 1H); 7.77 (d, J=8.1 Hz, 1H); 7.69 (d, J=2.5 Hz, 1H); 7.50-7.46 (m, 1H); 7.43-7.33 (m, 3H); 6.72-6.65 (m, 2H); 6.30-6.20 (m, 1H); 3.83-3.74 (m, 4H); 3.53-3.41 (m, 1H); 3.18-3.10 (m, 4H); 3.08-2.99 (m, 1H); 2.32 (s, 3H); 1.78-1.69 (m, 1H); 0.45-0.36 (m, 2H); 0.25-0.14 (m, 2H).

Example 15: Synthesis of (S)-1-(1-(3-chlorophenyl)-2-(ethyl(methyl)amino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0776] ##STR00148##

Step 1: 1-(3-Chlorophenyl)-2-(ethyl(methyl)amino)ethan-1-ol

[0777] ##STR00149##

[0778] The compound is obtained by the procedure described in Example 1, Step 6, starting from 400 mg (2.59 mmol) of 2-(3-chlorophenyl)oxirane (described in example 2 step 2) instead of 2-(3-fluorophenyl)oxirane, and 495 mg (5.18 mmol) of N-methylethanamine hydrochloride instead of dimethylamine. 103 mg of the title compound are obtained.

[0779] Yield: 19%.

[0780] MH+: 214.3; 216.2 (M; M+2).

Step 2: 2-Chloro-2-(3-chlorophenyl)-N-ethyl-N-methylethan-1-amine

[0781] ##STR00150##

[0782] The compound is obtained by the procedure described in Example 1, Step 7, starting from 103 mg (0.48 mmol) of 1-(3-chlorophenyl)-2-(ethyl(methyl)amino)ethan-1-ol (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 125 mg of the title compound are obtained.

[0783] Yield: Quantitative.

[0784] MH+: 232.3; 234.2 (M; M+2).

Step 3: 4-Bromo-1-(1-(3-chlorophenyl)-2-(ethyl(methyl)amino)ethyl)pyridin-2(1H)-one

[0785] ##STR00151##

[0786] The compound is obtained by the procedure described in Example 1, Step 8, starting from 125 mg (0.54 mmol) of 2-chloro-2-(3-chlorophenyl)-N-ethyl-N-methylethan-1-amine (described in the previous step) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 78 mg of the title compound are obtained.

[0787] Yield: 39%.

[0788] MH+: 369.4; 371.3; 373.3 (M; M+2; M+4).

Step 4: 1-(1-(3-Chlorophenyl)-2-(ethyl(methyl)amino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0789] ##STR00152##

[0790] The compound is obtained by the procedure described in Example 1, Step 9, starting from 78 mg (0.21 mmol) of 4-bromo-1-(1-(3-chlorophenyl)-2-(ethyl(methyl)amino)ethyl)pyridin-2(1H)-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H-one. 128 mg of the title compound are obtained.

[0791] Yield: 94%.

[0792] MH+: 646.7; 648.6 (M; M+2).

Step 5: 1-(1-(3-Chlorophenyl)-2-(ethyl(methyl)amino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0793] ##STR00153##

[0794] The compound is obtained by the procedure described in Example 3, Step 7, starting from 128 mg (0.20 mmol) of 1-(1-(3-chlorophenyl)-2-(ethyl(methyl)amino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 45 mg of racemate are obtained.

[0795] Yield: 46%.

[0796] MH+: 492.6; 494.6 (M; M+2).

[0797] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.03 (br s, 1H); 8.16 (d, J=2.6 Hz, 1H); 8.09 (s, 1H); 7.74 (d, J=8.0 Hz, 1H); 7.70 (d, J=2.6 Hz, 1H); 7.49-7.45 (m, 1H); 7.43-7.34 (m, 3H); 6.71-6.66 (m, 2H); 6.22-6.15 (m, 1H); 3.82-3.74 (m, 4H); 3.34-3.24 (m, 1H); 3.17-3.10 (m, 4H); 2.91-2.83 (m, 1H); 2.51-2.40 (m, 2H); 2.21 (s, 3H); 0.95 (t, J=7.1 Hz, 3H).

Step 6: (S)-1-(1-(3-Chlorophenyl)-2-(ethyl(methyl)amino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0798] ##STR00154##

[0799] Enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and an Hexane/EtOH/DCM/0.1% TEA mixture as the mobile phase. First fraction to be eluted is the (−) (R)-enantiomer, followed by the (+) (S)-enantiomer with ee >98%. 16 mg of the title compound are obtained starting from 45 mg of the racemate.

[0800] MH+: 492.6; 494.6 (M; M+2).

[0801] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.03 (br s, 1H); 8.16 (d, J=2.6 Hz, 1H); 8.09 (s, 1H); 7.74 (d, J=8.0 Hz, 1H); 7.70 (d, J=2.6 Hz, 1H); 7.49-7.45 (m, 1H); 7.43-7.34 (m, 3H); 6.71-6.66 (m, 2H); 6.22-6.15 (m, 1H); 3.82-3.74 (m, 4H); 3.34-3.24 (m, 1H); 3.17-3.10 (m, 4H); 2.91-2.83 (m, 1H); 2.51-2.40 (m, 2H); 2.21 (s, 3H); 0.95 (t, J=7.1 Hz, 3H).

Example 16: Synthesis of (S)-1-(1-(3-chlorophenyl)-2-((cyclopropylmethyl)(methyl)amino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0802] ##STR00155##

Step 1: 1-(3-Chlorophenyl)-2-((cyclopropylmethyl)(methyl)amino)ethan-1-ol

[0803] ##STR00156##

[0804] The compound is obtained by the procedure described in Example 1, Step 6, starting from 400 mg (2.59 mmol) of 2-(3-chlorophenyl)oxirane (described in example 2 step 2) instead of 2-(3-fluorophenyl)oxirane, and 630 mg (5.18 mmol) of 1-cyclopropyl-N-methylmethanamine hydrochloride instead of dimethylamine. 183 mg of the title compound are obtained.

[0805] Yield: 29%.

[0806] MH+: 240.4; 242.2 (M; M+2).

Step 2: 2-Chloro-2-(3-chlorophenyl)-N-(cyclopropylmethyl)-N-methylethan-1-amine

[0807] ##STR00157##

[0808] The compound is obtained by the procedure described in Example 1, Step 7, starting from 183 mg (0.76 mmol) of 1-(3-chlorophenyl)-2-((cyclopropylmethyl)(methyl)amino)ethan-1-ol (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 220 mg of the title compound are obtained.

[0809] Yield: Quantitative.

[0810] MH+: 258.4; 260.2 (M; M+2).

Step 3: 4-Bromo-1-(1-(3-chlorophenyl)-2-((cyclopropylmethyl)(methyl)amino)ethyl)pyridin-2(1H)-one

[0811] ##STR00158##

[0812] The compound is obtained by the procedure described in Example 1, Step 8, starting from 220 mg (0.85 mmol) of 2-chloro-2-(3-chlorophenyl)-N-(cyclopropylmethyl)-N-methylethan-1-amine (described in the previous step) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 115 mg of the title compound are obtained.

[0813] Yield: 34%.

[0814] MH+: 395.4; 397.4; 399.3 (M; M+2; M+4).

Step 4: 1-(1-(3-Chlorophenyl)-2-((cyclopropylmethyl)(methyl)amino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0815] ##STR00159##

[0816] The compound is obtained by the procedure described in Example 1, Step 9, starting from 115 mg (0.29 mmol) of 4-bromo-1-(1-(3-chlorophenyl)-2-((cyclopropylmethyl)(methyl)amino)ethyl)pyridin-2(1H)-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 144 mg of the title compound are obtained.

[0817] Yield: 73%.

[0818] MH+: 672.7; 674.7 (M; M+2).

Step 5: 1-(1-(3-Chlorophenyl)-2-((cyclopropylmethyl)(methyl)amino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0819] ##STR00160##

[0820] The compound is obtained by the procedure described in Example 3, Step 7, starting from 144 mg (0.21 mmol) of 1-(1-(3-chlorophenyl)-2-((cyclopropylmethyl)(methyl)amino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 68 mg of racemate are obtained.

[0821] Yield: 61%.

[0822] MH+: 518.7; 520.6 (M; M+2).

[0823] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.03 (br s, 1H); 8.14 (d, J=2.5 Hz, 1H); 8.09 (s, 1H); 7.71 (d, J=7.3 Hz, 1H); 7.69 (d, J=2.6 Hz, 1H); 7.49-7.45 (m, 1H); 7.42-7.32 (m, 3H); 6.71-6.64 (m, 2H); 6.24-6.16 (m, 1H); 3.83-3.74 (m, 4H); 3.36-3.26 (m, 1H); 3.17-3.09 (m, 4H); 2.99-2.91 (m, 1H); 2.31 (d, J=6.6 Hz, 2H); 2.29 (s, 3H); 0.88-0.78 (m, 1H); 0.48-0.38 (m, 2H); 0.09-0.03 (m, 2H).

Step 6: (S)-1-(1-(3-Chlorophenyl)-2-((cyclopropylmethyl)(methyl)amino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0824] ##STR00161##

[0825] Enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and an Hexane/EtOH/DCM/0.1% TEA mixture as the mobile phase. First fraction to be eluted is the (−) (R)-enantiomer, followed by the (+) (S)-enantiomer with ee >98%. 29 mg of the title compound are obtained starting from 68 mg of the racemate.

[0826] MH+: 518.7; 520.6 (M; M+2).

[0827] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.03 (br s, 1H); 8.14 (d, J=2.5 Hz, 1H); 8.09 (s, 1H); 7.71 (d, J=7.3 Hz, 1H); 7.69 (d, J=2.6 Hz, 1H); 7.49-7.45 (m, 1H); 7.42-7.32 (m, 3H); 6.71-6.64 (m, 2H); 6.24-6.16 (m, 1H); 3.83-3.74 (m, 4H); 3.36-3.26 (m, 1H); 3.17-3.09 (m, 4H); 2.99-2.91 (m, 1H); 2.31 (d, J=6.6 Hz, 2H); 2.29 (s, 3H); 0.88-0.78 (m, 1H); 0.48-0.38 (m, 2H); 0.09-0.03 (m, 2H).

Example 17: Synthesis of (S)-1-(1-(3,4-difluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0828] ##STR00162##

Step 1: 1,2-Difluoro-4-vinylbenzene

[0829] ##STR00163##

[0830] The compound is obtained by the procedure described in Example 1, Step 4, starting from 2.5 g (17.6 mmol) of 3,4-difluorobenzaldehyde instead of 3-fluorobenzaldehyde. 1.38 g of the title compound are obtained.

[0831] Yield: 56%.

[0832] MH+: Non ionizable.

Step 2: 2-(3,4-Difluorophenyl)oxirane

[0833] ##STR00164##

[0834] The compound is obtained by the procedure described in Example 1, Step 5, starting from 1.38 g (9.85 mmol) of 1,2-difluoro-4-vinylbenzene (described in the previous step) instead of 1-fluoro-3-vinylbenzene. 884 mg of the title compound are obtained.

[0835] Yield: 57%.

[0836] MH+: Non ionizable.

Step 3: 1-(3,4-Difluorophenyl)-2-(dimethylamino)ethan-1-ol

[0837] ##STR00165##

[0838] The compound is obtained by the procedure described in Example 1, Step 6, starting from 884 mg (5.66 mmol) of 2-(3,4-difluorophenyl)oxirane (described in the previous step) instead of 2-(3-fluorophenyl)oxirane. 784 mg of the title compound are obtained.

[0839] Yield: 69%.

[0840] MH+: 202.2 (M+1).

Step 4: 2-Chloro-2-(3,4-difluorophenyl)-N,N-dimethylethan-1-amine

[0841] ##STR00166##

[0842] The compound is obtained by the procedure described in Example 1, Step 7, starting from 784 mg (3.90 mmol) of 1-(3,4-difluorophenyl)-2-(dimethylamino)ethan-1-ol (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 770 mg of the title compound are obtained.

[0843] Yield: 90%.

[0844] MH+: 220.3; 222.1 (M; M+2).

Step 5: 4-Bromo-1-(1-(3,4-difluorophenyl)-2-(dimethylamino)ethyl)pyridin-2(1H)-one

[0845] ##STR00167##

[0846] The compound is obtained by the procedure described in Example 1, Step 8, starting from 770 mg (3.51 mmol) of 2-chloro-2-(3,4-difluorophenyl)-N,N-dimethylethan-1-amine (described in the previous step) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 560 mg of the title compound are obtained.

[0847] Yield: 45%.

[0848] MH+: 357.3; 359.3 (M; M+2).

Step 6: 1-(1-(3,4-Difluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0849] ##STR00168##

[0850] The compound is obtained by the procedure described in Example 1, Step 9, starting from 560 mg (1.57 mmol) of 4-bromo-1-(1-(3,4-difluorophenyl)-2-(dimethylamino)ethyl)pyridin-2(1H)-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 685 mg of the title compound are obtained.

[0851] Yield: 69%.

[0852] MH+: 634.5 (M+1).

Step 7: 1-(1-(3,4-Difluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0853] ##STR00169##

[0854] The compound is obtained by the procedure described in Example 3, Step 7, starting from 685 mg (1.08 mmol) of 1-(1-(3,4-difluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 400 mg of racemate are obtained.

[0855] Yield: 77%.

[0856] MH+: 480.6 (M+1).

[0857] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.03 (br s, 1H); 8.17 (d, J=2.6 Hz, 1H); 8.08 (d, J=2.9 Hz, 1H); 7.73 (d, J=8.1 Hz, 1H); 7.69 (d, J=2.6 Hz, 1H); 7.56-7.50 (m, 1H); 7.46-7.39 (m, 1H); 7.25-7.20 (m, 1H); 6.70-6.65 (m, 2H); 6.20-6.14 (m, 1H); 3.81-3.74 (m, 4H); 3.28-3.21 (m, 1H); 3.17-3.09 (m, 4H); 2.79-2.70 (m, 1H); 2.21 (s, 6H).

Step 8: (S)-1-(1-(3,4-Difluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0858] ##STR00170##

[0859] Enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and an Hexane/EtOH/DCM/0.1% TEA mixture as the mobile phase. First fraction to be eluted is the (−) (R)-enantiomer, followed by the (+) (S)-enantiomer with ee >98%. 16 mg of the title compound are obtained.

[0860] MH+: 480.6 (M+1).

[0861] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.03 (br s, 1H); 8.17 (d, J=2.6 Hz, 1H); 8.08 (d, J=2.9 Hz, 1H); 7.73 (d, J=8.1 Hz, 1H); 7.69 (d, J=2.6 Hz, 1H); 7.56-7.50 (m, 1H); 7.46-7.39 (m, 1H); 7.25-7.20 (m, 1H); 6.70-6.65 (m, 2H); 6.20-6.14 (m, 1H); 3.81-3.74 (m, 4H); 3.28-3.21 (m, 1H); 3.17-3.09 (m, 4H); 2.79-2.70 (m, 1H); 2.21 (s, 6H).

Example 18: Synthesis of (S)-1-(1-(3,5-difluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0862] ##STR00171##

Step 1: 1,3-Difluoro-5-vinylbenzene

[0863] ##STR00172##

[0864] The compound is obtained by the procedure described in Example 1, Step 4, starting from 2.5 g (17.6 mmol) of 3,5-difluorobenzaldehyde instead of 3-fluorobenzaldehyde. 0.52 g of the title compound are obtained.

[0865] Yield: 21%.

[0866] MH+: Non ionizable.

Step 2: 2-(3,5-Difluorophenyl)oxirane

[0867] ##STR00173##

[0868] The compound is obtained by the procedure described in Example 1, Step 5, starting from 0.52 g (3.71 mmol) of 1,3-difluoro-5-vinylbenzene (described in the previous step) instead of 1-fluoro-3-vinylbenzene. 226 mg of the title compound are obtained.

[0869] Yield: 39%.

[0870] MH+: Non ionizable.

Step 3: 1-(3,5-Difluorophenyl)-2-(dimethylamino)ethan-1-ol

[0871] ##STR00174##

[0872] The compound is obtained by the procedure described in Example 1, Step 6, starting from 226 mg (1.45 mmol) of 2-(3,5-difluorophenyl)oxirane (described in the previous step) instead of 2-(3-fluorophenyl)oxirane. 120 mg of the title compound are obtained.

[0873] Yield: 41%.

[0874] MH+: 202.2 (M+1).

Step 4: 2-Chloro-2-(3,5-difluorophenyl)-N,N-dimethylethan-1-amine

[0875] ##STR00175##

[0876] The compound is obtained by the procedure described in Example 1, Step 7, starting from 120 mg (0.60 mmol) of 1-(3,5-difluorophenyl)-2-(dimethylamino)ethan-1-ol (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 105 mg of the title compound are obtained.

[0877] Yield: 80%.

[0878] MH+: 220.3; 221.1 (M; M+2).

Step 5: 4-Bromo-1-(1-(3,5-difluorophenyl)-2-(dimethylamino)ethyl)pyridin-2(1H)-one

[0879] ##STR00176##

[0880] The compound is obtained by the procedure described in Example 1, Step 8, starting from 105 mg (0.48 mmol) of 2-chloro-2-(3,5-difluorophenyl)-N,N-dimethylethan-1-amine (described in the previous step) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 57 mg of the title compound are obtained.

[0881] Yield: 33%.

[0882] MH+: 3573; 359.3 (M; M+2).

Step 6: 1-(1-(3,5-Difluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0883] ##STR00177##

[0884] The compound is obtained by the procedure described in Example 1, Step 9, starting from 57 mg (0.16 mmol) of 4-bromo-1-(1-(3,5-difluorophenyl)-2-(dimethylamino)ethyl)pyridin-2(1H-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H-one. 65 mg of the title compound are obtained.

[0885] Yield: 64%.

[0886] MH+: 634.5 (M+1).

Step 7: 1-(1-(3,5-Difluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0887] ##STR00178##

[0888] The compound is obtained by the procedure described in Example 3, Step 7, starting from 65 mg (0.10 mmol) of 1-(1-(3,5-difluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 12 mg of racemate are obtained.

[0889] Yield: 25%.

[0890] MH+: 480.5 (M+1).

[0891] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.05 (br s, 1H); 8.16 (d, J=2.6 Hz, 1H); 8.10 (s, 1H); 7.75 (d, J=8.0 Hz, 1H); 7.70 (d, J=2.6 Hz, 1H); 7.22-7.16 (m, 1H); 7.16-7.10 (m, 2H); 6.73-6.66 (m, 2H); 6.21-6.14 (m, 1H); 3.84-3.74 (m, 4H); 3.31-3.22 (m, 1H); 3.17-3.10 (m, 4H); 2.81-2.72 (m, 1H); 2.21 (s, 6H).

Step 8: (S)-1-(1-(3,5-Difluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0892] ##STR00179##

[0893] Enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and an Hexane/EtOH/DCM/0.1% TEA mixture as the mobile phase. First fraction to be eluted is the (−) (R)-enantiomer, followed by the (+) (S)-enantiomer with ee >98%. 3 mg of the title compound are obtained starting from 12 mg of the racemate.

[0894] MH+: 480.5 (M+1).

[0895] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.05 (br s, 1H); 8.16 (d, J=2.6 Hz, 1H); 8.10 (s, 1H); 7.75 (d, J=8.0 Hz, 1H); 7.70 (d, J=2.6 Hz, 1H); 7.22-7.16 (m, 1H); 7.16-7.10 (m, 2H); 6.73-6.66 (m, 2H); 6.21-6.14 (m, 1H); 3.84-3.74 (m, 4H); 3.31-3.22 (m, 1H); 3.17-3.10 (m, 4H); 2.81-2.72 (m, 1H); 2.21 (s, 6H).

Example 19: Synthesis of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-5-fluoro-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0896] ##STR00180##

Step 1: 4-Bromo-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-5-fluoropyridin-2(1H)-one

[0897] ##STR00181##

[0898] The compound is obtained by the procedure described in Example 1, Step 8, starting from 220 mg (1.15 mmol) of 4-bromo-5-fluoro-1H-pyridin-2-one instead of 4-bromopyridin-2-(1H)-one, and 250 mg (1.15 mmol) of 2-chloro-2-(3-chlorophenyl)-N,N-dimethylethan-1-amine (described in example 2 step 4) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 145 mg of the title compound are obtained.

[0899] Yield: 34%.

[0900] MH+: 373.3; 375.3; 377.2 (M; M+2; M+4).

Step 2: 1-(1-(3-Chlorophenyl)-2-(dimethylamino)ethyl)-5-fluoro-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0901] ##STR00182##

[0902] The compound is obtained by the procedure described in Example 1, Step 9, starting from 145 mg (0.39 mmol) of 4-bromo-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-5-fluoropyridin-2(1H)-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 211 mg of the title compound are obtained.

[0903] Yield: 84%.

[0904] MH+: 650.5; 651.9; 652.7 (M; M+1; M+2).

Step 3: 1-(1-(3-Chlorophenyl)-2-(dimethylamino)ethyl)-5-fluoro-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0905] ##STR00183##

[0906] The compound is obtained by the procedure described in Example 3, Step 7, starting from 211 mg (0.32 mmol) of 1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-5-fluoro-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 95 mg of racemate are obtained.

[0907] Yield: 59%.

[0908] MH+: 496.5; 498.5 (M; M+2).

[0909] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.16 (br s, 1H); 8.19 (d, J=2.6 Hz, 1H); 8.12 (d, J=7.7 Hz, 1H); 7.92 (d, J=2.8 Hz, 1H); 7.63-7.59 (m, 1H); 7.54-7.51 (m, 1H); 7.44-7.36 (m, 3H); 6.67 (d, J=7.7 Hz, 1H); 6.18-6.10 (m, 1H); 3.82-3.73 (m, 4H); 3.43-3.35 (m, 1H); 3.16-3.08 (m, 4H); 2.72-2.63 (m, 1H); 2.22 (s, 6H).

Step 4: (S)-1-(1-(3-Chlorophenyl)-2-(dimethylamino)ethyl)-5-fluoro-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0910] ##STR00184##

[0911] Enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and an Hexane/EtOH/DCM/0.1% TEA mixture as the mobile phase. First fraction to be eluted is the (−) (R)-enantiomer, followed by the (+) (S)-enantiomer with ee >98%. 34 mg of the title compound are obtained starting from 95 mg of the racemate.

[0912] MH+: 496.5; 498.5 (M; M+2).

[0913] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.16 (br s, 1H); 8.19 (d, J=2.6 Hz, 1H); 8.12 (d, J=7.7 Hz, 1H); 7.92 (d, J=2.8 Hz, 1H); 7.63-7.59 (m, 1H); 7.54-7.51 (m, 1H); 7.44-7.36 (m, 3H); 6.67 (d, J=7.7 Hz, 1H); 6.18-6.10 (m, 1H); 3.82-3.73 (m, 4H); 3.43-3.35 (m, 1H); 3.16-3.08 (m, 4H); 2.72-2.63 (m, 1H); 2.22 (s, 6H).

Example 20: Synthesis of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-6-methyl-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0914] ##STR00185##

Step 1: 4-Bromo-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-6-methylpyridin-2(1H)-one

[0915] ##STR00186##

[0916] The compound is obtained by the procedure described in Example 1, Step 8, starting from 216 mg (1.15 mmol) of 4-bromo-6-methylpyridin-2(1H)-one instead of 4-bromopyridin-2-(1H)-one, and 250 mg (1.15 mmol) of 2-chloro-2-(3-chlorophenyl)-N,N-dimethylethan-1-amine (described in Example 2, Step 4) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 40 mg of the title compound are obtained.

[0917] Yield: 9%.

[0918] MH+: 369.3; 371.3; 373.2 (M; M+2; M+4).

Step 2: 1-(1-(3-Chlorophenyl)-2-(dimethylamino)ethyl)-6-methyl-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0919] ##STR00187##

[0920] The compound is obtained by the procedure described in Example 1, Step 9, starting from 40 mg (0.39 mmol) of 4-bromo-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-6-methylpyridin-2(1H)-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 78 mg of the title compound are obtained.

[0921] Yield: Quantitative.

[0922] MH+: 646.6; 648.4 (M; M+2).

Step 3: 1-(1-(3-Chlorophenyl)-2-(dimethylamino)ethyl)-6-methyl-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0923] ##STR00188##

[0924] The compound is obtained by the procedure described in Example 3, Step 7, starting from 78 mg (0.12 mmol) of 1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-6-methyl-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 12 mg of racemate are obtained.

[0925] Yield: 20%.

[0926] MH+: 492.5; 494.5 (M; M+2).

[0927] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.05 (br s, 1H); 8.17 (m, 1H); 8.06 (m, 1H); 7.80-7.64 (m, 1H); 7.47-7.18 (m, 4H); 6.77-6.53 (m, 1H); 6.50-6.40 (m, 1H); 5.40-5.30 (m, 1H); 3.87-3.71 (m, 4H); 3.33-3.21 (m, 1H); 3.21-3.07 (m, 4H); 2.90-2.78 (m, 1H); 2.54 (s, 3H); 2.26 (s, 6H).

Step 4: (S)-1-(1-(3-Chlorophenyl)-2-(dimethylamino)ethyl)-6-methyl-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0928] ##STR00189##

[0929] Enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and an Heptane/EtOH/DCM/0.1% TEA mixture as the mobile phase. First fraction to be eluted is the (−) (R)-enantiomer, followed by the (+) (S)-enantiomer with ee >98%. 4 mg of the title compound are obtained starting from 12 mg of the racemate.

[0930] MH+: 492.5; 494.5 (M; M+2).

[0931] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.05 (br s, 1H); 8.17 (m, 1H); 8.06 (m, 1H); 7.80-7.64 (m, 1H); 7.47-7.18 (m, 4H); 6.77-6.53 (m, 1H); 6.50-6.40 (m, 1H); 5.40-5.30 (m, 1H); 3.87-3.71 (m, 4H); 3.33-3.21 (m, 1H); 3.21-3.07 (m, 4H); 2.90-2.78 (m, 1H); 2.54 (s, 3H); 2.26 (s, 6H).

Example 21: Synthesis of 1-((S)-1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-(2-(trifluoromethyl)morpholino)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0932] ##STR00190##

Step 1: 4-(1H-Pyrrolo[2,3-b]pyridin-5-yl)-2-(trifluoromethyl)morpholine

[0933] ##STR00191##

[0934] The compound is obtained by the procedure described in Example 1, Step 1, starting from 119 mg (0.62 mmol) of 2-(trifluoromethyl)morpholine hydrochloride instead of morpholine. 161 mg of the title compound are obtained.

[0935] Yield: Quantitative.

[0936] MH+: 272.4 (M+1).

Step 2: 4-(1-Tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(trifluoromethyl)morpholine

[0937] ##STR00192##

[0938] The compound is obtained by the procedure described in Example 1, Step 2, starting from 161 mg (0.59 mmol) of 4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(trifluoromethyl)morpholine (described in the previous step) instead of 4-(1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine. 305 mg of the title compound are obtained.

[0939] Yield: Quantitative.

[0940] MH+: 426.6 (M+1).

Step 3: 4-(3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(trifluoromethyl)morpholine

[0941] ##STR00193##

[0942] The compound is obtained by the procedure described in Example 1, Step 3, starting from 305 mg (0.72 mmol) of 4-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(trifluoromethyl)morpholine (described in the previous step) instead of 4-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine. 330 mg of the title compound are obtained.

[0943] Yield: 84%.

[0944] MH+: 552.5 (M+1).

Step 4: 1-(1-(3-Chlorophenyl)-2-(dimethylamino)ethyl)-4-(1-tosyl-5-(2-(trifluoromethyl)morpholino)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0945] ##STR00194##

[0946] The compound is obtained by the procedure described in Example 1, Step 9, starting from 160 mg (0.29 mmol) of 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(trifluoromethyl)morpholine (described in the previous step) instead of 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine, and 103 mg (0.29 mmol) of 4-bromo-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)pyridin-2(1H)-one (described in Example 2, Step 5) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 155 mg of the title compound are obtained.

[0947] Yield: 76%.

[0948] MH+: 700.6; 701.9; 702.7 (M; M+1; M+2).

Step 5: 1-(1-(3-Chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-(2-(trifluoromethyl)morpholino)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0949] ##STR00195##

[0950] The compound is obtained by the procedure described in Example 3, Step 7, starting from 155 mg (0.22 mmol) of 1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(1-tosyl-5-(2-(trifluoromethyl)morpholino)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 73 mg of racemate are obtained.

[0951] Yield: 60%.

[0952] MH+: 546.6; 548.6 (M; M+2).

[0953] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.10 (br s, 1H); 8.21 (d, J=2.5 Hz, 1H); 8.12 (s, 1H); 7.83 (d, J=2.5 Hz, 1H); 7.76 (d, J=7.4 Hz, 1H); 7.49-7.44 (m, 1H); 7.44-7.33 (m, 3H); 6.76-6.66 (m, 2H); 6.23-6.13 (m, 1H); 4.46-4.33 (m, 1H); 4.15-4.05 (m, 1H); 3.91-3.78 (m, 1H); 3.78-3.63 (m, 1H); 3.54-3.44 (m, 1H); 3.32-3.23 (m, 1H); 2.96-2.79 (m, 2H); 2.79-2.69 (m, 1H); 2.21 (s, 6H).

Step 6: 1-((S)-1-(3-Chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-(2-(trifluoromethyl)morpholino)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0954] ##STR00196##

[0955] Enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and an Hexane/EtOH/DCM/0.1% TEA mixture as the mobile phase. First fraction to be eluted is the (−) (R)-enantiomer, followed by the (+) (S)-enantiomer with ee >98%. 30 mg of the title compound are obtained starting from 73 mg of the racemate.

[0956] MH+: 546.6; 548.6 (M; M+2).

[0957] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.10 (br s, 1H); 8.21 (d, J=2.5 Hz, 1H); 8.12 (s, 1H); 7.83 (d, J=2.5 Hz, 1H); 7.76 (d, J=7.4 Hz, 1H); 7.49-7.44 (m, 1H); 7.44-7.33 (m, 3H); 6.76-6.66 (m, 2H); 6.23-6.13 (m, 1H); 4.46-4.33 (m, 1H); 4.15-4.05 (m, 1H); 3.91-3.78 (m, 1H); 3.78-3.63 (m, 1H); 3.54-3.44 (m, 1H); 3.32-3.23 (m, 1H); 2.96-2.79 (m, 2H); 2.79-2.69 (m, 1H); 2.21 (s, 6H).

Example 22: Synthesis of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(4-fluoro-5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0958] ##STR00197##

Step 1: 4-(4-Fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine

[0959] ##STR00198##

[0960] The compound is obtained by the procedure described in Example 1, Step 1, starting from 145 mg (0.67 mmol) of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridine instead of 5-bromo-1H-pyrrolo[2,3-b]pyridine. 35 mg of the title compound are obtained.

[0961] Yield: 23%.

[0962] MH+: 222.3 (M+1).

Step 2: 4-(4-Fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine

[0963] ##STR00199##

[0964] The compound is obtained by the procedure described in Example 1, Step 2, starting from 35 mg (0.16 mmol) of 4-(4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine (described in the previous step) instead of 4-(1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine. 53 mg of the title compound are obtained.

[0965] Yield: 53%.

[0966] MH+: 376.4 (M+1).

Step 3: 4-(4-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine

[0967] ##STR00200##

[0968] The compound is obtained by the procedure described in Example 1, Step 3, starting from 53 mg (0.14 mmol) of 4-(4-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine (described in the previous step) instead of 4-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine. 22 mg of the title compound are obtained.

[0969] Yield: 31%.

[0970] MH+: 502.5 (M+1).

Step 4: 1-(1-(3-Chlorophenyl)-2-(dimethylamino)ethyl)-4-(4-fluoro-5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0971] ##STR00201##

[0972] The compound is obtained by the procedure described in Example 1, Step 9, starting from 22 mg (0.044 mmol) of 1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(4-fluoro-5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine, and 16 mg (0.044 mmol) of 4-bromo-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)pyridin-2(1H)-one (described in Example 2, Step 5) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 17 mg of the title compound are obtained.

[0973] Yield: 61%.

[0974] MH+: 700.6; 701.9; 702.8 (M; M+1; M+2).

Step 5: 1-(1-(3-Chlorophenyl)-2-(dimethylamino)ethyl)-4-(4-fluoro-5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0975] ##STR00202##

[0976] The compound is obtained by the procedure described in Example 3, Step 7, starting from 17 mg (0.026 mmol) of 1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(4-fluoro-5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 5 mg of racemate are obtained.

[0977] Yield: 42%.

[0978] MH+: 496.6; 498.5 (M; M+2)

Step 6: (S)-1-(1-(3-Chlorophenyl)-2-(dimethylamino)ethyl)-4-(4-fluoro-5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0979] ##STR00203##

[0980] Enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and an Hexane/EtOH/DCM/0.1% TEA mixture as the mobile phase. First fraction to be eluted is the (−) (R)-enantiomer, followed by the (+) (S)-enantiomer with ee >98%. 2 mg of the title compound are obtained starting from 5 mg of the racemate.

[0981] MH+: 496.6; 498.5 (M; M+2)

Example 23: Synthesis of (S)-1-(1-(3-chloro-5-(methoxymethyl)phenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0982] ##STR00204##

Step 1: 3-Chloro-5-(methoxymethyl)benzonitrile

[0983] ##STR00205##

[0984] 500 mg (2.98 mmol, 1 eq) of 3-chloro-5-cyanobenzyl alcohol are dissolved in 30 ml of dry DMF and the solution is cooled to 0° C. with an ice/water bath. 155 mg (3.88 mmol, 1.3 eq) of sodium hydride (60% in paraffin oil) are slowly added and the slurry is stirred for 15 min. Then, 441 μL (8.95 mmol) of methyl iodide are then added at 0° C. and the mixture is stirred for another 30 min. The mixture is diluted with 100 ml of Et.sub.2O, washed 3 times with water and once with brine. Organic layer is dried over Na.sub.2SO.sub.4, filtered, and evaporated under reduced pressure to give 664 mg of the crude compound which is purified by flash chromatography using a silica gel column and an Et.sub.2O/hexane mixture as eluent. 497 mg of the title compound are obtained.

[0985] Yield: 92%.

[0986] MH+: 182.2 (M+1).

Step 2: 3-Chloro-5-(methoxymethyl)benzaldehyde

[0987] ##STR00206##

[0988] 437 mg (2.40 mmol, 1 eq) of 3-chloro-5-(methoxymethyl)benzonitrile (described in the previous step) are dissolved in a mixture of 1.25 ml of pyridine, 1.25 mL of acetic acid and 1.25 mL of water. The solution is cooled to 0° C. and 2.04 g (19.25 mmol, 8 eq) of NaH.sub.2PO.sub.2 monohydrate are added, followed by a small amount of Ni Raney (50% in water). The reaction is stirred for 1 h at 0° C. and at room temperature for another 3 h. The mixture is filtrated on Celite and the precipitate is rinsed several times with EtOAc. Combined filtrates are washed with a saturated NaHCO.sub.3 solution and the organic layer is dried over Na.sub.2SO.sub.4, filtered, and evaporated under reduced pressure. Crude compound is finally purified by flash chromatography using a silica gel column and an EtOAc/hexane mixture as eluent. 278 mg of the title compound are obtained.

[0989] Yield: 59%.

[0990] MH+: 185.2; 187.1 (M+1; M+3).

Step 3: 1-Chloro-3-(methoxymethyl)-5-vinylbenzene

[0991] ##STR00207##

[0992] The compound is obtained by the procedure described in Example 1, Step 4, starting from 278 mg (1.50 mmol) of 3-chloro-5-(methoxymethyl)benzaldehyde (described in the previous step) instead of 3-fluorobenzaldehyde. 100 mg of the title compound are obtained.

[0993] Yield: 36%.

[0994] MH+: Non ionizable.

Step 4: 2-(3-Chloro-5-(methoxymethyl)phenyl)oxirane

[0995] ##STR00208##

[0996] The compound is obtained by the procedure described in Example 1, Step 5, starting from 100 mg (0.55 mmol) of 1-chloro-3-(methoxymethyl)-5-vinylbenzene (described in the previous step) instead of 1-fluoro-3-vinylbenzene. 66 mg of the title compound are obtained.

[0997] Yield: 60%.

[0998] MH+: Non ionizable.

Step 5: 1-(3-Chloro-5-(methoxymethyl)phenyl)-2-(dimethylamino)ethan-1-ol

[0999] ##STR00209##

[1000] The compound is obtained by the procedure described in Example 1, Step 6, starting from 66 mg (0.33 mmol) of 2-(3-chloro-5-(methoxymethyl)phenyl)oxirane (described in the previous step) instead of 2-(3-fluorophenyl)oxirane. 58 mg of the title compound are obtained.

[1001] Yield: 71%.

[1002] MH+: 244.3; 246.2 (M; M+2).

Step 6: 2-Chloro-2-(3-chloro-5-(methoxymethyl)phenyl)-N,N-dimethylethan-1-amine

[1003] ##STR00210##

[1004] The compound is obtained by the procedure described in Example 1, Step 7, starting from 58 mg (0.24 mmol) of 1-(3-chloro-5-(methoxymethyl)phenyl)-2-(dimethylamino)ethan-1-ol (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 70 mg of the title compound are obtained.

[1005] Yield: Quantitative.

[1006] MH+: 262.3; 264.3 (M; M+2).

Step 7: 1-(1-(3-Chloro-5-(methoxymethyl)phenyl)-2-(dimethylamino)ethyl)-4-iodopyridin-2(1H)-one

[1007] ##STR00211##

[1008] The compound is obtained by the procedure described in Example 6, Step 5, starting from 70 mg (0.27 mmol) of 2-chloro-2-(3-chloro-5-(methoxymethyl)phenyl)-N,N-dimethylethan-1-amine (described in the previous step) instead of 2-chloro-2-(3-iodophenyl)-N,N-dimethylethan-1-amine. 35 mg of the title compound are obtained.

[1009] Yield: 33%.

[1010] MH+: 448.2; 450.3 (M; M+2).

Step 8: 1-(1-(3-Chloro-5-(methoxymethyl)phenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[1011] ##STR00212##

[1012] The compound is obtained by the procedure described in Example 1, Step 9, starting from 136 mg (0.30 mmol) of 1-(1-(3-chloro-5-(methoxymethyl)phenyl)-2-(dimethylamino)ethyl)-4-iodopyridin-2(1H)-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 168 mg of the title compound are obtained.

[1013] Yield: 81%.

[1014] MH+: 676.5; 678.5 (M; M+2).

Step 9: 1-(1-(3-Chloro-5-(methoxymethyl)phenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[1015] ##STR00213##

[1016] The compound is obtained by the procedure described in Example 3, Step 7, starting from 150 mg (0.22 mmol) of 1-(1-(3-chloro-5-(methoxymethyl)phenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 57 mg of racemate are obtained.

[1017] Yield: 49%.

[1018] MH+: 522.5; 524.7 (M; M+2).

[1019] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.06 (br s, 1H); 8.17 (d, J=2.5 Hz, 1H); 8.10 (s, 1H); 7.76 (d, J=8.1 Hz, 1H); 7.70 (d, J=2.6 Hz, 1H); 7.42-7.37 (m, 1H); 7.33-7.27 (m, 2H); 6.73-6.65 (m, 2H); 6.22-6.12 (m, 1H); 4.40 (s, 2H); 3.83-3.73 (m, 4H); 3.43-3.35 (m, 1H); 3.29 (s, 3H); 3.18-3.08 (m, 4H); 2.75-2.64 (m, 1H); 2.20 (s, 6H).

Step 10: (S)-1-(1-(3-Chloro-5-(methoxymethyl)phenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[1020] ##STR00214##

[1021] Enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and an Hexane/EtOH/DCM/0.1% TEA mixture as the mobile phase. First fraction to be eluted is the (−) (R)-enantiomer, followed by the (+) (S)-enantiomer with ee >98%. 24 mg of the title compound are obtained starting from 57 mg of the racemate.

[1022] MH+: 522.5; 524.7 (M; M+2).

[1023] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.06 (br s, 1H); 8.17 (d, J=2.5 Hz, 1H); 8.10 (s, 1H); 7.76 (d, J=8.1 Hz, 1H); 7.70 (d, J=2.6 Hz, 1H); 7.42-7.37 (m, 1H); 7.33-7.27 (m, 2H); 6.73-6.65 (m, 2H); 6.22-6.12 (m, 1H); 4.40 (s, 2H); 3.83-3.73 (m, 4H); 3.43-3.35 (m, 1H); 3.29 (s, 3H); 3.18-3.08 (m, 4H); 2.75-2.64 (m, 1H); 2.20 (s, 6H).

Example 24: Synthesis of (S)-1-(2-(aziridin-1-yl)-1-(3-chlorophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[1024] ##STR00215##

Step 1: 2-(Aziridin-1-yl)-1-(3-chlorophenyl)ethan-1-ol

[1025] ##STR00216##

[1026] To a solution of 450 mg (3.88 mmol, 2 eq) of 2-chloroethanamine hydrochloride in 1 ml of water, is added a solution of 310 mg (7.76 mmol, 4 eq) of sodium hydroxide in 1 ml of water. The resulting mixture is stirred at 50° C. for 45 min. Then a solution of 300 mg (1.94 mmol, 1 eq) of 2-(3-chlorophenyl)oxirane (described in Example 2, Step 2) in 3 ml of 1,4-dioxane is added. The mixture is stirred at 50° C. for 4 h. Reaction is then diluted with water and extracted with DCM. Combined organic layers are washed 3 times with water, dried over Na.sub.2SO.sub.4, filtered, and evaporated under reduced pressure. Crude compound is used in the next step without further purification. 460 mg of the title compound are obtained.

[1027] Yield: Quantitative.

[1028] MH+: 198.1; 200.1 (M; M+2).

Step 2: 1-(2-Bromo-2-(3-chlorophenyl)ethyl)aziridine

[1029] ##STR00217##

[1030] To a solution of 165 mg (0.83 mmol, 1 eq) of 2-(aziridin-1-yl)-1-(3-chlorophenyl)ethan-1-ol (described in the previous step) in 3 ml of dry DCM, placed at 0° C. with an ice/water bath, are added dropwise 129 μl (1.67 mmol, 2 eq) of thionyl bromide. The resulting mixture is allowed to reach room temperature over the night. Then reaction mixture is directly purified by flash chromatography using a silica gel column and an DCM/MeOH mixture as eluent. 176 mg of the title compound are obtained.

[1031] Yield: 76%.

[1032] MH+: 260.2; 262.2; 264.1 (M; M+2; M+4).

Step 3: 1-(2-(Aziridin-1-yl)-1-(3-chlorophenyl)ethyl)-4-bromopyridin-2(1H)-one

[1033] ##STR00218##

[1034] The compound is obtained by the procedure described in Example 1, Step 8, starting from 166 mg (0.64 mmol) of 1-(2-bromo-2-(3-chlorophenyl)ethyl)aziridine (described in the previous step) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 77 mg of the title compound are obtained.

[1035] Yield: 34%.

[1036] MH+: 353.3; 355.3; 357.2 (M; M+2; M+4).

Step 4: 1-(2-(Aziridin-1-yl)-1-(3-chlorophenyl)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[1037] ##STR00219##

[1038] The compound is obtained by the procedure described in Example 1, Step 9, starting from 77 mg (0.23 mmol) of 1-(2-(aziridin-1-yl)-1-(3-chlorophenyl)ethyl)-4-bromopyridin-2(1H)-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 69 mg of the title compound are obtained.

[1039] Yield: 48%.

[1040] MH+: 630.6; 631.9; 632.7 (M; M+1; M+2).

Step 5: 1-(2-(Aziridin-1-yl)-1-(3-chlorophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[1041] ##STR00220##

[1042] The compound is obtained by the procedure described in Example 3, Step 7, starting from 69 mg (0.11 mmol) of 1-(2-(aziridin-1-yl)-1-(3-chlorophenyl)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 32 mg of racemate are obtained.

[1043] Yield: 61%.

[1044] MH+: 476.5; 478.5 (M; M+2).

[1045] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.03 (br s, 1H); 8.17 (d, J=2.5 Hz, 1H); 8.03 (s, 1H); 7.67 (d, J=2.6 Hz, 1H); 7.52 (d, J=7.2 Hz, 1H); 7.30-7.22 (m, 2H); 7.21-7.12 (m, 2H); 6.67-6.63 (m, 1H); 6.55-6.50 (m, 1H); 4.11-4.00 (m, 2H); 3.84-3.74 (m, 4H); 3.19-3.10 (m, 4H); 2.77-2.58 (m, 3H); 1.83-1.74 (m, 2H).

Step 6: (S)-1-(2-(Aziridin-1-yl)-1-(3-chlorophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[1046] ##STR00221##

[1047] Enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and an Hexane/IPA/0.1% TEA mixture as the mobile phase. First fraction to be eluted is the (−) (R)-enantiomer, followed by the (+) (S)-enantiomer with ee >98%. 14 mg of the title compound are obtained starting from 32 mg of the racemate.

[1048] MH+: 476.5; 478.5 (M; M+2).

[1049] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.03 (br s, 1H); 8.17 (d, J=2.5 Hz, 1H); 8.03 (s, 1H); 7.67 (d, J=2.6 Hz, 1H); 7.52 (d, J=7.2 Hz, 1H); 7.30-7.22 (m, 2H); 7.21-7.12 (m, 2H); 6.67-6.63 (m, 1H); 6.55-6.50 (m, 1H); 4.11-4.00 (m, 2H); 3.84-3.74 (m, 4H); 3.19-3.10 (m, 4H); 2.77-2.58 (m, 3H); 1.83-1.74 (m, 2H).

Example 25: Synthesis of (S)-3-(2-(dimethylamino)-1-(4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)benzonitrile

[1050] ##STR00222##

Step 1: 3-Vinylbenzonitrile

[1051] ##STR00223##

[1052] The compound is obtained by the procedure described in Example 1, Step 4, starting from 0.5 g (3.8 mmol) of 3-cyanobenzaldehyde instead of 3-fluorobenzaldehyde. 180 mg of the title compound are obtained.

[1053] Yield: 37%.

[1054] MH+: Non ionizable.

Step 2: 3-(Oxiran-2-yl)benzonitrile

[1055] ##STR00224##

[1056] The compound is obtained by the procedure described in Example 1, Step 5, starting from 180 mg (1.39 mmol) of 3-vinylbenzonitrile (described in the previous step) instead of 1-fluoro-3-vinylbenzene. 136 mg of the title compound are obtained.

[1057] Yield: 67%.

[1058] MH+: Non ionizable.

Step 3: 3-(2-(Dimethylamino)-1-hydroxyethyl)benzonitrile

[1059] ##STR00225##

[1060] The compound is obtained by the procedure described in Example 1, Step 6, starting from 136 mg (0.94 mmol) of 3-(oxiran-2-yl)benzonitrile (described in the previous step) instead of 2-(3-fluorophenyl)oxirane. 156 mg of the title compound are obtained.

[1061] Yield: 88%.

[1062] MH+: 191.2 (M+1).

Step 4: 3-(1-Chloro-2-(dimethylamino)ethyl)benzonitrile

[1063] ##STR00226##

[1064] The compound is obtained by the procedure described in Example 1, Step 7, starting from 156 mg (0.82 mmol) of 3-(2-(dimethylamino)-1-hydroxyethyl)benzonitrile (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 188 mg of the title compound are obtained.

[1065] Yield: Quantitative.

[1066] MH+: 209.2; 211.1 (M; M+2).

Step 5: 3-(1-(4-Bromo-2-oxopyridin-1(2H)-yl)-2-(dimethylamino)ethyl)benzonitrile

[1067] ##STR00227##

[1068] The compound is obtained by the procedure described in Example 1, Step 8, starting from 171 mg (0.82 mmol) of 3-(1-chloro-2-(dimethylamino)ethyl)benzonitrile (described in the previous step) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 109 mg of the title compound are obtained.

[1069] Yield: 38%.

[1070] MH+: 346.4; 348.4 (M; M+2).

Step 6: 3-(2-(Dimethylamino)-1-(4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)benzonitrile

[1071] ##STR00228##

[1072] The compound is obtained by the procedure described in Example 1, Step 9, starting from 109 mg (0.31 mmol) of 3-(1-(4-bromo-2-oxopyridin-1(2H)-yl)-2-(dimethylamino)ethyl)benzonitrile (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H-one. 138 mg of the title compound are obtained.

[1073] Yield: 70%.

[1074] MH+: 623.7 (M+1).

Step 7: 3-(2-(Dimethylamino)-1-(4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)benzonitrile

[1075] ##STR00229##

[1076] The compound is obtained by the procedure described in Example 3, Step 7, starting from 138 mg (0.22 mmol) of 3-(2-(dimethylamino)-1-(4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)benzonitrile (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 32 mg of racemate are obtained.

[1077] Yield: 30%.

[1078] MH+: 469.7 (M+1).

[1079] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.07 (br s, 1H); 8.17 (d, J=2.5 Hz, 1H); 8.10 (s, 1H); 7.93-7.88 (m, 1H); 7.82-7.74 (m, 2H); 7.73-7.67 (m, 2H); 7.58 (t, J=7.8 Hz, 1H); 6.74-6.66 (m, 2H); 6.25-6.15 (m, 1H); 3.84-3.73 (m, 4H); 3.34-3.24 (m, 1H); 3.18-3.08 (m, 4H); 2.83-2.72 (m, 1H); 2.21 (s, 6H).

Step 8: (S)-3-(2-(Dimethylamino)-1-(4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)benzonitrile

[1080] ##STR00230##

[1081] Enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and an Hexane/EtOH/DCM/0.1% TEA mixture as the mobile phase. First fraction to be eluted is the (−) (R)-enantiomer, followed by the (+) (S)-enantiomer with ee >98%. 8 mg of the title compound are obtained starting from 32 mg of racemate.

[1082] MH+: 469.7 (M+1).

[1083] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.07 (br s, 1H); 8.17 (d, J=2.5 Hz, 1H); 8.10 (s, 1H); 7.93-7.88 (m, 1H); 7.82-7.74 (m, 2H); 7.73-7.67 (m, 2H); 7.58 (t, J=7.8 Hz, 1H); 6.74-6.66 (m, 2H); 6.25-6.15 (m, 1H); 3.84-3.73 (m, 4H); 3.34-3.24 (m, 1H); 3.18-3.08 (m, 4H); 2.83-2.72 (m, 1H); 2.21 (s, 6H).

Example 26: Synthesis of (S)-1-(2-(dimethylamino)-1-(3-(trifluoromethyl)phenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[1084] ##STR00231##

Step 1: 1-(Trifluoromethyl)-3-vinylbenzene

[1085] ##STR00232##

[1086] The compound is obtained by the procedure described in Example 1, Step 4, starting from 0.5 g (2.87 mmol) of 3-(trifluoromethyl)benzaldehyde instead of 3-fluorobenzaldehyde. 295 mg of the title compound are obtained.

[1087] Yield: 60%.

[1088] MH+: Non ionizable.

Step 2: 2-(3-(Trifluoromethyl)phenyl)oxirane

[1089] ##STR00233##

[1090] The compound is obtained by the procedure described in Example 1, Step 5, starting from 295 mg (1.71 mmol) of 1-(trifluoromethyl)-3-vinylbenzene (described in the previous step) instead of 1-fluoro-3-vinylbenzene. 176 mg of the title compound are obtained.

[1091] Yield: 55%.

[1092] MH+: Non ionizable.

Step 3: 2-(Dimethylamino)-1-(3-(trifluoromethyl)phenyl)ethan-1-ol

[1093] ##STR00234##

[1094] The compound is obtained by the procedure described in Example 1, Step 6, starting from 176 mg (0.94 mmol) of 1-(trifluoromethyl)-3-vinylbenzene (described in the previous step) instead of 2-(3-fluorophenyl)oxirane. 183 mg of the title compound are obtained.

[1095] Yield: 84%.

[1096] MH+: 234.4 (M+1).

Step 4: 2-Chloro-N,N-dimethyl-2-(3-(trifluoromethyl)phenyl)ethan-1-amine

[1097] ##STR00235##

[1098] The compound is obtained by the procedure described in Example 1, Step 7, starting from 183 mg (0.78 mmol) of 2-(dimethylamino)-1-(3-(trifluoromethyl)phenyl)ethan-1-ol (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 203 mg of the title compound are obtained.

[1099] Yield: Quantitative.

[1100] MH+: 252.2; 254.2 (M; M+2).

Step 5: 4-Bromo-1-(2-(dimethylamino)-1-(3-(trifluoromethyl)phenyl)ethyl)pyridin-2(1H)-one

[1101] ##STR00236##

[1102] The compound is obtained by the procedure described in Example 1, Step 8, starting from 197 mg (0.78 mmol) of 2-chloro-N,N-dimethyl-2-(3-(trifluoromethyl)phenyl)ethan-1-amine (described in the previous step) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 126 mg of the title compound are obtained.

[1103] Yield: 41%.

[1104] MH+: 389.4; 391.3 (M; M+2).

Step 6: 1-(2-(Dimethylamino)-1-(3-(trifluoromethyl)phenyl)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[1105] ##STR00237##

[1106] The compound is obtained by the procedure described in Example 1, Step 9, starting from 126 mg (0.32 mmol) of 4-bromo-1-(2-(dimethylamino)-1-(3-(trifluoromethyl)phenyl)ethyl)pyridin-2(1H)-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 178 mg of the title compound are obtained.

[1107] Yield: 83%.

[1108] MH+: 666.7 (M+1).

Step 7: 1-(2-(Dimethylamino)-1-(3-(trifluoromethyl)phenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[1109] ##STR00238##

[1110] The compound is obtained by the procedure described in Example 3, Step 7, starting from 178 mg (0.26 mmol) of 1-(2-(dimethylamino)-1-(3-(trifluoromethyl)phenyl)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 106 mg of racemate are obtained.

[1111] Yield: 77%.

[1112] MH+: 512.6 (M+1).

[1113] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.07 (br s, 1H); 8.17 (d, J=2.5 Hz, 1H); 8.11 (s, 1H); 7.83-7.78 (m, 1H); 7.78-7.74 (m, 1H); 7.73-7.65 (m, 3H); 7.61 (t, J=7.7 Hz, 1H); 6.74-6.66 (m, 2H); 6.30-6.20 (m, 1H); 3.83-3.73 (m, 4H); 3.38-3.28 (m, 1H); 3.18-3.09 (m, 4H); 2.82-2.72 (m, 1H); 2.22 (s, 6H).

Step 8: (S)-1-(2-(Dimethylamino)-1-(3-(trifluoromethyl)phenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[1114] ##STR00239##

[1115] Enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and an Hexane/EtOH/DCM/0.1% TEA mixture as the mobile phase. First fraction to be eluted is the (−) (R)-enantiomer, followed by the (+) (S)-enantiomer with ee >98%. 41 mg of the title compound are obtained starting from 106 mg of racemate.

[1116] MH+: 512.6 (M+1).

[1117] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.07 (br s, 1H); 8.17 (d, J=2.5 Hz, 1H); 8.11 (s, 1H); 7.83-7.78 (m, 1H); 7.78-7.74 (m, 1H); 7.73-7.65 (m, 3H); 7.61 (t, J=7.7 Hz, 1H); 6.74-6.66 (m, 2H); 6.30-6.20 (m, 1H); 3.83-3.73 (m, 4H); 3.38-3.28 (m, 1H); 3.18-3.09 (m, 4H); 2.82-2.72 (m, 1H); 2.22 (s, 6H).

Example 27: Synthesis of comparative compound (S)-1-(2-amino-1-(3-chlorophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (Compound A)

[1118] ##STR00240##

Step 1: 2-(3-Chlorophenyl)-2-((trimethylsilyl)oxy)acetonitrile

[1119] ##STR00241##

[1120] To a solution of 5 g (36 mmol, 1 eq) of 3-chlorobenzaldehyde in 50 ml of dry DCM under argon, are added 399 mg (36 mmol, 1 eq) of DABCO, followed by 4.45 ml (36 mmol, 1 eq) of trimethylsilyl cyanide and the resulting mixture is stirred at 40° C. for 2 h. Reaction mixture is then diluted with DCM and washed 2 times with water and once with brine. Organic layer is dried over Na.sub.2SO.sub.4, filtered, and evaporated under reduced pressure. Crude compound is used in the next step without further purification. 7.80 g of the title compound are obtained.

[1121] Yield: 91%.

[1122] MH+: Non ionizable.

Step 2: 2-Amino-1-(3-chlorophenyl)ethan-1-ol

[1123] ##STR00242##

[1124] To a solution of 7.80 g (33 mmol, 1 eq) of 2-(3-chlorophenyl)-2-((trimethylsilyl)oxy)acetonitrile (described in the previous step) in 80 ml of dry Et.sub.2O, placed at 0° C. with an ice/water bath, are added in portions 1.85 g (49 mmol, 1.5 eq) of LiAlH.sub.4. The resulting mixture is stirred at 0° C. for 1 h. Then ice is slowly added into the reaction at 0° C. until no more gas is formed and finally 100 ml of water are added. The mixture is stirred at room temperature for 30 min, the precipitate is filtrated on Celite and washed 2 times with Et.sub.2O. Filtrate is decanted and aqueous layer is extracted 2 times with Et.sub.2O. Combined organic layers are dried over Na.sub.2SO.sub.4, filtered, and evaporated under reduced pressure. Crude compound is used in the next step without further purification. 5.95 g of the title compound are obtained.

[1125] Yield: Quantitative.

[1126] MH+: 172.3; 174.3 (M; M+2).

Step 3: Tert-butyl (2-(3-chlorophenyl)-2-hydroxyethyl)carbamate

[1127] ##STR00243##

[1128] To a solution of 5.95 g (35 mmol, 1 eq) of 2-amino-1-(3-chlorophenyl)ethan-1-ol (described in the previous step) in 60 ml of THF, are added 8.32 g (38 mmol, 1.1 eq) of di-tert-butyl dicarbonate and the resulting mixture is stirred at room temperature for 1 h. Solvent is then removed under reduced pressure and the mixture is diluted with 100 ml of EtOAc. Organic layer is washed 2 times with water and once with brine, dried over Na.sub.2SO.sub.4, filtered, and evaporated under reduced pressure. Crude mixture is purified by flash chromatography using a silica gel column and a DCM/MeOH mixture as eluent. 6.78 g of the title compound are obtained.

[1129] Yield: 72%.

[1130] MH+: 272.6; 274.7 (M; M+2).

Step 4: 2-((Tert-butoxycarbonyl)amino)-1-(3-chlorophenyl)ethyl methanesulfonate

[1131] ##STR00244##

[1132] The compound is obtained by the procedure described in Example 1, Step 7, starting from 6.78 g (25 mmol) of tert-butyl (2-(3-chlorophenyl)-2-hydroxyethyl)carbamate (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 9.28 g of the title compound are obtained.

[1133] Yield: Quantitative.

[1134] MH+(dimer): 700.2; 702.2 (M; M+2).

Step 5: Tert-butyl (2-(4-bromo-2-oxopyridin-1(2H)-yl)-2-(3-chlorophenyl)ethyl)carbamate

[1135] ##STR00245##

[1136] The compound is obtained by the procedure described in Example 1, Step 8, starting from 8.73 g (25 mmol) of 2-((tert-butoxycarbonyl)amino)-1-(3-chlorophenyl)ethyl methanesulfonate (described in the previous step) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 5.56 g of the title compound are obtained.

[1137] Yield: 52%.

[1138] MH+: 427.7; 429.7; 431.7 (M; M+2; M+4).

Step 6: Tert-butyl (2-(3-chlorophenyl)-2-(4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)carbamate

[1139] ##STR00246##

[1140] 2.8 g (6.50 mmol, 1 eq) of tert-butyl (2-(4-bromo-2-oxopyridin-1(2H)-yl)-2-(3-chlorophenyl)ethyl)carbamate (described in the previous step), 3.16 g (6.50 mmol, 1 eq) of 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine (described in Example 1, Step 3) and 905 mg (6.50 mmol, 1 eq) of K.sub.2CO.sub.3 are placed in 140 ml of MeCN under argon. The mixture is bubbled with argon for 15 min and 459 mg (0.65 mmol, 0.1 eq) of bis(triphenylphosphine)palladium dichloride are added. The mixture is bubbled for another 15 min and then the reaction is stirred at 80° C. for 1 h under argon. Reaction mixture is diluted with 140 ml of EtOAc and washed 3 times with water. Organic layer is dried over Na.sub.2SO.sub.4, filtrated and evaporated under reduced pressure. Crude mixture is purified by flash chromatography using a silica gel column and a DCM/MeOH mixture as eluent. 4.79 g of the title compound are obtained.

[1141] Yield: Quantitative.

Step 7: Tert-butyl (2-(3-chlorophenyl)-2-(4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)carbamate

[1142] ##STR00247##

[1143] The compound is obtained by the procedure described in Example 9, Step 7, starting from 1.0 g (1.4 mmol) of tert-butyl (2-(3-chlorophenyl)-2-(4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)carbamate (described in the previous step) instead of 1-(1-(3-chloro-5-fluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 644 mg of racemate are obtained.

[1144] Yield: 82%.

[1145] MH+: 550.6; 552.6 (M; M+2).

Step 8: 1-(2-Amino-1-(3-chlorophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[1146] ##STR00248##

[1147] To a solution of 644 mg (1.17 mmol, 1 eq) of tert-butyl (2-(3-chlorophenyl)-2-(4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)carbamate (described in the previous step) in 6 ml of DCM, placed at 0° C. with an ice/water bath, are added 3 ml of trifluoroacetic acid. The solution is stirred at 0° C. for 1 h 30, then solvent is removed under reduced pressure and the mixture is diluted with 100 ml of a saturated NaHCO.sub.3 solution. The solution is extracted 3 times with DCM. Combined organic layers are dried over Na.sub.2SO.sub.4, filtered, and evaporated under reduced pressure. Crude mixture is purified by flash chromatography using a C18 column and a water/MeOH mixture as eluent. 340 mg of the title compound are obtained.

[1148] Yield: 64%.

[1149] MH+: 450.7; 452.7 (M; M+2).

[1150] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.06 (br s, 1H); 8.17 (d, J=2.5 Hz, 1H); 8.09 (s, 1H); 7.75 (d, J=8.1 Hz, 1H); 7.70 (d, J=2.6 Hz, 1H); 7.44-7.29 (m, 4H); 6.74-6.67 (m, 2H); 5.90 (t, J=7.5 Hz, 1H); 3.84-3.72 (m, 4H); 3.34-3.25 (m, 2H); 3.18-3.09 (m, 4H); 1.60 (br s, 2H).

Step 9: (S)-1-(2-Amino-1-(3-chlorophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[1151] ##STR00249##

[1152] Enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and an Hexane/EtOH/DCM/0.1% TEA mixture as the mobile phase. First fraction to be eluted is the (−) (R)-enantiomer, followed by the (+) (S)-enantiomer with ee >98%. 33 mg of the title compound are obtained starting from 120 mg of racemate.

[1153] MH+: 450.7; 452.7 (M; M+2).

[1154] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.06 (br s, 1H); 8.17 (d, J=2.5 Hz, 1H); 8.09 (s, 1H); 7.75 (d, J=8.1 Hz, 1H); 7.70 (d, J=2.6 Hz, 1H); 7.44-7.29 (m, 4H); 6.74-6.67 (m, 2H); 5.90 (t, J=7.5 Hz, 1H); 3.84-3.72 (m, 4H); 3.34-3.25 (m, 2H); 3.18-3.09 (m, 4H); 1.60 (br s, 2H).

Example 28: Synthesis of comparative compound (S)-1-(1-(3,4-dichlorophenyl)-2-(methylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (Compound B)

[1155] ##STR00250##

Step 1: 2-(3,4-Dichlorophenyl)-2-((trimethylsilyl)oxy)acetonitrile

[1156] ##STR00251##

[1157] The compound is obtained by the procedure described in Example 27, Step 1, starting from 2.5 g (14.3 mmol) of 3,4-dichlorobenzaldehyde instead of 3-chlorobenzaldehyde. 3.70 g of the title compound are obtained.

[1158] Yield: 94%.

[1159] MH+: Non ionizable.

Step 2: 2-Amino-1-(3,4-dichlorophenyl)ethan-1-ol

[1160] ##STR00252##

[1161] The compound is obtained by the procedure described in Example 27, Step 2, starting from 3.70 g (13.5 mmol) of 2-(3,4-dichlorophenyl)-2-((trimethylsilyl)oxy)acetonitrile (described in the previous step) instead of 2-(3-chlorophenyl)-2-((trimethylsilyl)oxy)acetonitrile. 1.66 g of the title compound are obtained.

[1162] Yield: 60%.

[1163] MH+: 206.1; 208.2; 210.1 (M; M+2; M+4).

Step 3: Tert-butyl (2-(3,4-dichlorophenyl)-2-hydroxyethyl)carbamate

[1164] ##STR00253##

[1165] The compound is obtained by the procedure described in Example 27, Step 3, starting from 1.66 g (8.03 mmol) of 2-amino-1-(3,4-dichlorophenyl)ethan-1-ol (described in the previous step) instead of 2-amino-1-(3-chlorophenyl)ethan-1-ol. 2.55 g of the title compound are obtained.

[1166] Yield: Quantitative.

[1167] MH+: 306.3; 308.3 (M; M+2).

Step 4: 2-((Tert-butoxycarbonyl)amino)-1-(3,4-dichlorophenyl)ethyl methanesulfonate

[1168] ##STR00254##

[1169] The compound is obtained by the procedure described in Example 1, Step 7, starting from 2.46 g (8.03 mmol) of tert-butyl (2-(3,4-dichlorophenyl)-2-hydroxyethyl)carbamate (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 3.23 g of the title compound are obtained.

[1170] Yield: Quantitative.

[1171] MH+(dimer): 767.5; 769.4; 771.6 (M; M+2; M+4).

Step 5: Tert-butyl (2-(4-bromo-2-oxopyridin-1(2H)-yl)-2-(3,4-dichlorophenyl)ethyl)carbamate

[1172] ##STR00255##

[1173] The compound is obtained by the procedure described in Example 1, Step 8, starting from 3.09 g (8.03 mmol) of 2-((tert-butoxycarbonyl)amino)-1-(3,4-dichlorophenyl)ethyl methanesulfonate (described in the previous step) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 1.74 g of the title compound are obtained.

[1174] Yield: 47%.

[1175] MH+: 461.3; 463.3; 465.2 (M; M+2; M+4).

Step 6: Tert-butyl (2-(4-bromo-2-oxopyridin-1(2H)-yl)-2-(3,4-dichlorophenyl)ethyl)(methyl)carbamate

[1176] ##STR00256##

[1177] To a solution of 840 mg (1.82 mmol, 1 eq) of tert-butyl (2-(4-bromo-2-oxopyridin-1(2H)-yl)-2-(3,4-dichlorophenyl)ethyl)carbamate (described in the previous step) in 9 ml of dry DMF, placed at 0° C. with an ice/water bath, are added under argon 87 mg (2.18 mmol, 1.2 eq) of sodium hydride (60% in paraffin oil), followed by 170 μl (2.73 mmol, 1.5 eq) of methyl iodide. The solution is stirred at 0° C. for 1 h 30, then the mixture is diluted with 100 ml of EtOAc. The solution is washed 4 times with water and once with brine. Organic layer is dried over Na.sub.2SO.sub.4, filtered, and evaporated under reduced pressure. Crude mixture is purified by flash chromatography using a silica gel column and a EtOAc/Hexane mixture as eluent. 750 mg of the title compound are obtained.

[1178] Yield: 86%.

[1179] MH+: 475.4; 477.3; 479.3 (M; M+2; M+4).

Step 7: Tert-butyl (2-(3,4-dichlorophenyl)-2-(4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)(methyl)carbamate

[1180] ##STR00257##

[1181] The compound is obtained by the procedure described in Example 1, Step 9, starting from 750 mg (1.57 mmol) of tert-butyl (2-(4-bromo-2-oxopyridin-1(2H)-yl)-2-(3,4-dichlorophenyl)ethyl)(methyl)carbamate (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 1.27 g of the title compound are obtained.

[1182] Yield: Quantitative.

[1183] MH+: 753.4; 755.2 (M; M+2).

Step 8: Tert-butyl (2-(3,4-dichlorophenyl)-2-(4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)(methyl)carbamate

[1184] ##STR00258##

[1185] The compound is obtained by the procedure described in Example 9, Step 7, starting from 1.27 g (1.69 mmol) of tert-butyl (2-(3,4-dichlorophenyl)-2-(4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)(methyl)carbamate (described in the previous step) instead of 1-(1-(3-chloro-5-fluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 730 mg of racemate are obtained.

[1186] Yield: 72%.

[1187] MH+: 598.7; 600.5 (M; M+2).

Step 9: 1-(1-(3,4-Dichlorophenyl)-2-(methylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[1188] ##STR00259##

[1189] The compound is obtained by the procedure described in Example 27, Step 8, starting from 730 mg (1.20 mmol) of tert-butyl (2-(3,4-dichlorophenyl)-2-(4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)(methyl)carbamate (described in the previous step) instead of tert-butyl (2-(3-chlorophenyl)-2-(4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)carbamate. 543 mg of racemate are obtained.

[1190] Yield: 89%.

[1191] MH+: 498.6; 500.5 (M; M+2).

[1192] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.08 (br s, 1H); 8.17 (d, J=2.5 Hz, 1H); 8.10 (d, J=2.6 Hz, 1H); 7.76 (d, J=7.3 Hz, 1H); 7.69 (d, J=2.5 Hz, 1H); 7.66-7.61 (m, 2H); 7.37-7.30 (m, 1H); 6.74-6.66 (m, 2H); 6.08-5.98 (m, 1H); 3.84-3.73 (m, 4H); 3.34-3.24 (m, 1H); 3.22-3.14 (m, 1H); 3.14-3.09 (m, 4H); 2.30 (s, 3H); 1.94 (br s, 1H).

Step 10: (S)-1-(1-(3,4-Dichlorophenyl)-2-(methylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[1193] ##STR00260##

[1194] Enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and an Hexane/EtOH/DCM/0.1% TEA mixture as the mobile phase. First fraction to be eluted is the (−) (R)-enantiomer, followed by the (+) (S)-enantiomer with ee >98%. 54 mg of the title compound are obtained starting from 150 mg of racemate.

[1195] MH+: 498.6; 500.5 (M; M+2).

[1196] .sup.1H NMR (DMSO-d6, 400 MHz): δ 12.08 (br s, 1H); 8.17 (d, J=2.5 Hz, 1H); 8.10 (d, J=2.6 Hz, 1H); 7.76 (d, J=7.3 Hz, 1H); 7.69 (d, J=2.5 Hz, 1H); 7.66-7.61 (m, 2H); 7.37-7.30 (m, 1H); 6.74-6.66 (m, 2H); 6.08-5.98 (m, 1H); 3.84-3.73 (m, 4H); 3.34-3.24 (m, 1H); 3.22-3.14 (m, 1H); 3.14-3.09 (m, 4H); 2.30 (s, 3H); 1.94 (br s, 1H).

[1197] The following table illustrates the chemical structures of compounds according to the invention:

TABLE-US-00001 TABLE 1 Chemical structure of compounds of the invention N.sup.o Structures  1 [00261]  2 [00262]  3 [00263]  4 [00264]  5 [00265]  6 [00266]  7 [00267]  8 [00268]  9 [00269] 10 [00270] 11 [00271] 12 [00272] 13 [00273] 14 [00274] 15 [00275] 16 [00276] 17 [00277] 18 [00278] 19 [00279] 20 [00280] 21 [00281] 22 [00282] 23 [00283] 24 [00284] 25 [00285] 26 [00286]

TABLE-US-00002 TABLE 2 Chemical structure of comparative compounds A [00287] B [00288]

[1198] Comparative compounds A and B are disclosed in WO 2017/085230, but their synthesis was not described.

[1199] Comparative compounds A and B are not part of the present invention since none of R.sub.1 and R.sub.2 in the general formula (I) of the invention can represent a hydrogen atom.

[1200] The Examples 33 and 34 below demonstrate that the compounds of the invention are surprisingly superior to the comparative compounds A and B from the prior art.

Example 29: ERK2 (MAPK1) Enzymatic Assay

[1201] To assess the capacity of compounds to inhibit ERK2 enzymatic activity, Z′-Lyte biochemical assay from Life technologies was used according to manufacturer's instructions. Briefly, black 384-well plates containing 100 nl of 100× compound solution in 100% DMSO, 2.4 μl kinase buffer, 5 μl 2×MAPK1 (ERK2)/Ser/Thr 03 mixture and 2.5 μl 4×ATP solution were used. Plates were shaken for 30 seconds and incubated for 60 minutes at room temperature. Then, 5 μl of a 1:1024 dilution of Development Reagent A was added. Plates were shaken for 30 seconds and incubated for 60 minutes at room temperature. A plate reader was used to read fluorescence. In this assay, ERK2 enzyme was used at a concentration of 0.4 μg/ml (5.74 nM) at ATP Km (100 μM). Kinase buffer consisted of 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl.sub.2, 1 mM EGTA. Compounds IC.sub.50 were determined with a 3-fold serial dilution (10 point titrations in duplicate).

[1202] ERK2 inhibitory activity of selected compounds (“ERK2 IC.sub.50”) is reported in Table 3 below:

TABLE-US-00003 TABLE 3 Compounds ERK2 IC.sub.50 (nM) Compound no1 (S) 1.2 Compound no2 (S) 2.1 Compound no3 (S) 3.2 Compound no4 (S) 3.1 Compound no5 (S) 4.5 Compound no6 (S) 2.4 Compound no7 (S) 4.1 Compound no8 (S) 2.2 Compound no9 (racemate) 7.7 Compound no10 (racemate) 5.1 Compound no15 (S) 3.5 Compound no17 (S) 2.7 Compound no22 (S) 4.0 Compound no23 (S) 4.5

[1203] All tested compounds exhibit a capacity to inhibit ERK2 enzymatic activity.

[1204] Indeed, all the compounds have an IC.sub.50 value lower than 10 nM and most of them have an IC.sub.50 value lower than 5 nM.

Example 30: Cell Line Proliferation Assay

[1205] A cell line assay was used to determine the capacity of compounds to inhibit cell proliferation. A375 cells (malignant melanoma) were grown to near 80% confluence and seeded at 3000 cells per 100 μl per well in DMEM with 10% FBS in 96-well flat bottom plates. Cells were incubated for 24 hours at 37° C. under 5% CO.sub.2. 100 μl compound solutions were added to cells and incubated for 72 hours at 37° C. Total volume of media was 200 μl per well. Compounds were screened in 0.15% DMSO (final) using 10 titration points in duplicate. Negative control wells consisted of vehicle only (0.15% DMSO in 10% FBS DMEM). After 72 hours of compound treatment, SDS 1% (final) was added to positive control wells for 15 minutes at 37° C. Then, medium was discarded and replaced by 100 μl per well of a MTT solution (3-[4.5-dimethylthiazol-2-yl]-2.5-diphenyltetrazolium bromide) (Sigma, Cat #M5655) at 0.5 mg/ml in 10% FBS DMEM. Cells were incubated for 4 hours at 37° C. MTT reaction was stopped and homogenized by the addition of 100 μl per well of SDS 10% 0.01M HCl. After 16 hours at 37° C., absorbance was measured at 570 nm in a Bio-Tek plate reader (PowerWave HT). Percent of proliferation inhibition was calculated using negative controls (0.15% DMSO) as 0% growth inhibition and positive controls (1% SDS) as 100% growth inhibition. IC.sub.50 values (concentration inducing a half-maximal growth inhibition) were determined by non-linear regression analysis of the inhibition curve generated by mean replicate values (using a sigmoid dose-response with variable Hill Slope and constraining the top to a constant value of 100 and the bottom to a value between 0 and 50). Analysis was performed using GraphPad Prism software.

[1206] Cell proliferation inhibitory activity of selected compounds (“A375 IC.sub.50”) is reported in Table 4 below:

TABLE-US-00004 TABLE 4 Compounds MTT A375 IC.sub.50 (nM) Compound no1 (S) 107 Compound no2 (S) 35 Compound no3 (S) 132 Compound no4 (S) 72 Compound no5 (S) 77 Compound no6 (S) 42 Compound no7 (S) 53 Compound no8 (S) 64 Compound no9 (S) 188 Compound no10 (S) 116 Compound no11 (S) 229 Compound no12 (S) 7 Compound no13 (S) 262 Compound no14 (S) 420 Compound no15 (S) 51 Compound no16 (S) 162 Compound no17 (S) 103 Compound no18 (S) 371 Compound no19 (S) 303 Compound no20 (S) 825 Compound no21 (S) 199 Compound no22 (S) 77 Compound no23 (S) 8 Compound no24 (S) 96 Compound no25 (S) 156 Compound no26 (S) 15

[1207] All tested compounds exhibit a capacity to inhibit A375 cell proliferation.

[1208] Indeed, all the compounds have an IC.sub.50 value lower than 1 μM and most of them have an IC.sub.50 value lower than 500 nM.

Example 31: hERG Channel Inhibition Assay

[1209] Evaluation of hERG channel inhibition of selected compounds have been performed. Compounds were used as a 10 mM stock in DMSO before dilution in HEPES-buffered saline to 30 μM. 6-point concentration-response curves were generated using 3.16-fold serial dilutions from the top test concentration. Electrophysiological recordings were made from a Chinese Hamster Ovary cell line stably expressing the full-length ion channel. Single cell ionic currents were measured in whole-cell configuration at room temperature (21-23° C.) using a Patchliner (Nanion Technologies). The internal solution for hERG contained (mM): 120 KF, 20 KCl, 10 EGTA, 10 HEPES and was buffered to pH 7.3. The external solution (HEPES-buffered saline, HEPES-buffered saline) contained (mM): 138 NaCl, 4.5 KCl, 1.8 CaCl.sub.2), 1.0 MgCl.sub.2, 10 HEPES, 10 glucose, buffered to pH 7.4. Voltage protocol is given below. Currents were measured from the step and referenced to the holding current. Compounds were then incubated for 2 minutes to achieve steady state prior to addition of the next concentration.

TABLE-US-00005 Channel hERG Holding potential (mV) −80  Step potential (mV) +40, 2 s then −40 for 2 s Frequency (Pulse applied every X seconds) 10 Cell background CHO

[1210] hERG channel inhibition properties of selected compounds (“hERG IC.sub.50”) is reported in Table 5 below:

TABLE-US-00006 TABLE 5 Compounds hERG IC.sub.50 (μM) Compound no1 (S) >30 Compound no2 (S) 10.9 Compound no3 (S) >30 Compound no4 (S) >30 Compound no5 (S) 20.5 Compound no6 (S) 11.1 Compound no7 (S) 13.3 Compound no8 (S) 9.6

[1211] All tested compounds exhibit a safe hERG profile with patch clamp assay.

[1212] Indeed, all the compounds have an IC.sub.50 value higher than 9.6 μM.

Example 32: CYP 3A4 Inhibition Assay

[1213] To assess the capacity of compounds to inhibit CYP 3A4 enzymatic activity, the test compounds (0.1 μM-25 μM) were incubated with cryopreserved human hepatocytes for 10 min in the presence of the specific CYP3A4 probe substrate, midazolam. 1-Hydroxymidazolam was monitored by LC-MS/MS and a decrease in the formation of the metabolite compared to the vehicle control was used to calculate an IC.sub.50 value.

[1214] CYP 3A4 inhibitory activity of selected compounds (“CYP 3A4 IC.sub.50”) is reported in Table 6 below:

TABLE-US-00007 TABLE 6 Compounds CYP 3A4 IC.sub.50 (μM) Comparative compound A (S) 0.74 Compound no1 (S) 17.2 Compound no2 (S) 7.8 Compound no3 (S) 10.0 Compound no4 (S) 12.2 Compound no5 (S) 9.5 Compound no6 (S) 6.6 Compound no7 (S) 19.5 Compound no8 (S) 10.9

[1215] All tested compounds according to the invention exhibit a low inhibition of CYP 3A4. Indeed, all the compounds have an IC.sub.50 value greater than 5 μM.

[1216] By contrast, the comparative compound A has an IC.sub.50 value of 0.74 μM. Comparative compound A is therefore a highly potent inhibitor of CYP 3A4.

Example 33: Kinase Panel

[1217] To assess the kinase selectivity of compounds, Z′-Lyte biochemical assay, and Adapta/Lanthascreen binding assays from Life technologies were used according to manufacturer's instructions. Pourcentages of inhibition at 500 nM of test compounds were performed towards 58 kinases: ABL1, ACVR1B (ALK4), AKT2 (PKB beta), AMPK (A1/B2/G3), AURKA (Aurora A), AXL, BRAF, BTK, CAMK2B (CaMKII beta), CDK2/cyclin A, CHEK1 (CHK1), CLK1, CSNK1A1 (CK1 alpha 1), CSNK2A1 (CK2 alpha 1), DAPK3 (ZIPK), DYRK1A, EGFR (ErbB1), EPHB3, ERBB2 (HER2), FGFR2, FLT3, FRAP1 (mTOR), GSK3B (GSK3 beta), IGF1R, IKBKB (IKK beta), INSR, IRAK4, JAK2, KDR (VEGFR2), KIT, LCK, MAP2K1 (MEK1), MAPK10 (JNK3), MAPK11 (p38 beta), MAPKAPK2, MARK2, MET (cMet), NEK2, NTRK1 (TRKA), PAK2 (PAK65), PDGFRB (PDGFR beta), PDK1 Direct, PHKG2, PIK3CA/PIK3R.sub.1 (p110 alpha/p85 alpha), PIM1, PLK1, PRKACA (PKA), PRKCA (PKC alpha), PTK2 (FAK), RET, ROCK1, RPS6KA1 (RSK1), RPS6KB1 (p70S6K), SRC, STK3 (MST2), SYK, TEK (Tie2), TYRO3 (RSE). The concentration of ATP was used at apparent Km for all kinases except for MAPK10 (JNK3) which was at 100 mM and for BRAF and MAP2K1 (MEK1) which are binding assays.

[1218] The results are reported in Table 7 below:

TABLE-US-00008 TABLE 7 Kinase panel @500 nM @500 nM Compounds hits > 80% hits > 50% Comparative compound A (S) 15/58  26/58  Comparative compound B (S) 10/58  20/58  Compound no1 (S) 1/58 2/58 Compound no2 (S) 1/58 10/58  Compound no3 (S) 1/58 6/58 Compound no4 (S) 1/58 5/58 Compound no5 (S) 1/58 7/58 Compound no7 (S) 1/58 4/58 Compound no8 (S) 1/58 7/58

[1219] All tested compounds according to the invention exhibit a favorable kinase selectivity score in the representative kinase panel. Indeed, for each compound, only 1 kinase over 58 was inhibited with a percentage of inhibition higher than 80%, and 10 kinases at most were inhibited with a percentage of inhibition higher than 50%.

[1220] By contrast, comparative compounds A and B exhibit a poor selectivity score. Indeed, comparative compounds A and B inhibited respectively 15/58 and 10/58 kinases with a percentage of inhibition higher than 80%, and 26/58 and 20/58 kinases with a percentage of inhibition higher than 50%.

Example 34: Permeability Assay

[1221] Caco 2 cell lines were used for the in vitro transport studies and were obtained from ATCC. Cells were split every other day at a split ratio of 1:3-1:5 and grown in Dulbecco's Modified Eagle Medium (GlutaMAX I, 4,500 mg/L D-glucose, sodium pyruvate.) supplemented with 10% FBS in the presence of antibiotics. For transport studies, cells were seeded onto polycarbonate Transwell filter membranes (Millipore) at a density of 60,000 cells/well. After 24 h post seeding, changed medium and cultured for another 21 days before transport experiments. For transport studies, donor solutions were prepared by diluting the stock solutions of test compounds in transport medium (HBSS buffer with 10 mM HEPES, pH 7.4). Receiver solutions were the same HBSS buffer with 10 mM HEPES, pH 7.4. The transport of test compounds (5 μM) was measured in duplicate in two directions [apical to basolateral (A.fwdarw.B) and basolateral to apical (B.fwdarw.A)].

[1222] The permeability coefficient for membrane transport of test compounds was determined using the following equation: Papp (cm/sec)=(Vr/C0) (1/S) (dC/dt); Papp=apparent permeability, Vr=volume of medium in the receiver chamber, C0=PAR of the test drug in the receiver chamber, S=surface area of monolayer, dC/dt=drug PAR in the receiver chamber with time).

[1223] Efflux Ratio was defined as: Efflux Ratio=Papp B-A/Papp A-B Bioanalysis was done on LC-MS/MS.

[1224] The results are reported in Table 8 below:

TABLE-US-00009 TABLE 8 Caco-2 permeability assay Papp A-B Compounds (10.sup.−6 cm/s) Efflux Ratio Comparative compound A (S) 3.7 5.1 Comparative compound B (S) 8.3 5.9 Compound no1 (S) 21.2 3.2 Compound no2 (S) 34.9 0.7 Compound no3 (S) 38.2 1.0 Compound no4 (S) 53.9 0.9 Compound no6 (S) 27.9 1.3 Compound no7 (S) 36.9 1.4 Compound no8 (S) 47.4 0.6 Compound no9 (S) 14 3 Compound no10 (S) 27 1

[1225] All tested compounds according to the invention exhibit excellent Caco-2 permeability parameters.

[1226] Indeed, all the compounds have a Papp A-B value higher than 10.10.sup.−6 cm/s and most of them have a value higher than 20.10.sup.−6 cm/s. Moreover, all the compounds have an Efflux Ratio lower than 3.2, and most of them have a value lower than 2.

[1227] By contrast, comparative compounds A and B exhibit poor Caco-2 permeability parameters, with low Papp A-B values (lower than 10.10.sup.−6 cm/s) and high Efflux Ratios (higher than 3).

Example 35: PK Experiments

[1228] To determine their absolute oral bioavailability, compounds were suspended in a 0.5% CMC vehicle and administered to a group of 5-6 weeks old male BalbC mice. For intravenous injection, a single 1 mg/kg dose was injected in tail vein and blood was collected at 0.12, 0.25, 0.5, 1, 2, 4, 8 and 24 h after injection. For oral route, a single 20 mg/kg dose was administered, and blood was collected at 0.25, 0.5, 1, 2, 4, 8, 10 and 24 h after gavage. Plasma separated from blood samples was stored at −20° C. until analysis. Vials containing the study samples were retrieved and thawed to room temperature. A volume of 50 μl of sample was added to 200 μl of acetronitrile containing internal standard (tolbutamide; 25 ng/mL) and vortexed for 5 min and centrifuged at 14000 rpm for 5 min at 4° C. 200 μl of supernatant was separated and transferred to HPLC vial for analysis. For prodrug pharmacokinetics, only parent drug was dosed by HPLC.

[1229] The results are reported in Table 9 below:

TABLE-US-00010 TABLE 9 PK experiments @20 mpk PO; @1 mpk IV Oral C.sub.max bioavailability (ng/ml) T.sub.1/2 Compounds (%) (μM) (h) Compound no2 (S) 9.3 641 (1.3) 0.9 Compound no4 (S) 21.8 995 (1.9) 3.07 Compound no5 (S) 9.2 1 731 (3.3) 1.83 Compound no6 (S) 14.4 1 486 (2.6) 1.16 Compound no7 (S) 13.7 1 209 (2.2) 1.06 Compound no8 (S) 8.9 736 (1.3) 1.35

[1230] All tested compounds according to the invention exhibit good PK parameters.

[1231] Indeed, all the compounds have an oral bioavailability upper than 8.9 which will permit to reach the target concentration of the molecule into the plasma.