COMPOUNDS FOR TREATING DISORDERS SENSITIVE TO SEROTONINERGIC REGULATION CONTROLLED BY THE 5-HT1A RECEPTORS

Abstract

The invention concerns compounds that possess a high affinity at 5-HT.sub.1A receptors and an agonist efficacy, as measured by Emax values from a cellular activation assay, that is higher than that of the compounds described in prior art. The capacity of the compounds of the invention to activate an effector protein complex is higher than that the most efficacious agonist described in prior art. Compounds of the invention also exhibit an exceptionally high selectivity (Ki ratio greater than 1000-fold) with respect, in particular, to dopamine D2 receptors and adrenergic receptors of the alpha1 subtype. This selectivity which constitutes a great advantage since it means that the compounds will avoid inducing (central and peripheral) effects associated with activating or inhibiting such receptors.

Claims

1. Compound according to formula (I): ##STR00013## or a pharmaceutically acceptable salt and/or solvate thereof, wherein: X represents a halo, in particular Cl or F; Y represents O, S or NH, in particular O or S; and Ar is selected from the group consisting of aryl, heterocycloalkyl-fused aryl or heteroaryl, said group being optionally substituted.

2. Compound according to claim 1, wherein: X represents a halo, in particular Cl or F; Y represents O, S or N H, in particular O or S; and Ar is selected from the group consisting of aryl, heterocycloalkyl-fused aryl or heteroaryl, said group being optionally substituted with one or several, preferably one or two, groups selected from: halo, ORi , NR.sub.2R.sub.3, NR.sub.4COR.sub.5, NR.sub.6C(0)OR.sub.7,SR.sub.8, S(0)R.sub.9, S0.sub.2Rio, S0.sub.2NRn R.sub.12, OCOR13, C0.sub.2Ri.sub.4, CONR.sub.15R.sub.16, OC0.sub.2Ri.sub.7, OCONR.sub.18Ri9, COR.sub.20, CF.sub.3, nitro (N0.sub.2), cyano (CN) or a group consisting of -(C C.sub.6)alkyl group preferably methyl, heteroaryl preferably pyrazole and heterocycloalkyl preferably pyrrolidine; with R-i to R.sub.20 being, independently of one another, H, (d-C6)alkyl group preferably H, methyl or ethyl.

3. A pharmaceutical composition comprising the compound according to claim 1.

4. A method of treating depression, which comprises administering a compound according to claim 1 to a patient in need thereof.

5. A method of treating major depressive disorders, which comprises administering a compound according to claim 1 to a patient in need thereof.

6. A method of treating bipolar type major depression according to the DSM IV, which comprises administering a compound according to claim 1 to a patient in need thereof.

7. A method of treating depression with severity evaluated with a score of more than 26 using the HAMD (Hamilton Depression Scale) scale, or with a score of more than 35 on the MADRS (Montgomery and Asberg Depression Rating Scale) scale, which comprises administering a compound according to claim 1 to a patient in need thereof.

8. A method of treating movement disorders, which comprises administering a compound according to claim 1 to a patient in need thereof.

9. A method of treating L-DOPA-induced dyskinesia, which comprises administering a compound according to claim 1 to a patient in need thereof.

10. A method of treating anxiety, which comprises administering a compound according to claim 1 to a patient in need thereof.

11. Pharmaceutical compositions containing, as active ingredient, a compound according to claim 1, in combination with one or more inert carriers or other pharmaceutically acceptable vehicles.

12. A pharmaceutical composition comprising the compound to claim 2.

13. A method of treating depression, which comprises administering a compound according to claim 2 to a patient in need thereof.

14. A method of treating major depressive disorders, which comprises administering a compound according to claim 2 to a patient in need thereof.

15. A method of treating bipolar type major depression according to the DSM IV, which comprises administering a compound according to claim 2 to a patient in need thereof.

16. The method according to claim 6, wherein the bipolar type major depression according to the DSM IV is a major recurrent depressive disorder.

17. The method according to claim 15, wherein the bipolar type major depression according to the DSM IV is a major recurrent depressive disorder.

18. A method of treating depression with severity evaluated with a score of more than 26 using the HAMD (Hamilton Depression Scale) scale, or with a score of more than 35 on the MADRS (Montgomery and Asberg Depression Rating Scale) scale, which comprises administering a compound according to claim 2 to a patient in need thereof.

19. A method of treating movement disorders, which comprises administering a compound according to claim 2 to a patient in need thereof.

20. A method of treating anxiety, which comprises administering a compound according to claim 2 to a patient in need thereof.

Description

INTERMEDIATE COMPOUNDS

Starting Materials of Formula IVa:

IVa-1

1-(3,4-dichlorobenzoyl)piperidin-4-one

[0116] The title compound was prepared starting from the 3,4-dichlorobenzoyl chloride.

[0117] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.58 (d, J=1.8 Hz, 1 H), 7.52 (d, J=8.2 Hz, 1 H), 7.31 (dd, J=2.1, 8.2 Hz, 1 H), 3.86 (br. s., 4 H), 2.51 (br. s., 4 H)

[0118] MS: 272 [M+H.sup.+].

IVa-2

1-(3-chloro-4-fluorobenzoyl)piperidin-4-one

[0119] The title compound was prepared starting from the 3-chloro-4-fluorobenzoyl chloride.

[0120] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.56 (dd, J=2.1, 6.9 Hz, 1 H), 7.37 (ddd, J=2.2, 4.6, 8.4 Hz, 1 H), 7.25-7.17 (m, 1 H), 3.87 (br. s., 4 H), 2.51 (br. s., 4 H)

[0121] .sup.19F NMR (282 MHz, CDCl.sub.3) : 111.50 (s, 1F)

[0122] MS: 256 [M+H.sup.+].

Starting Materials of Formula IIIa:

IIIa-1

6-(3,4-dichlorobenzoyl)-1-oxa-6-azaspiro[2.5]octane-2-carbonitrile

[0123] The title compound was prepared starting from the compound of formula (IVa-1)

[0124] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.59-7.45 (m, 2 H), 7.31-7.19 (m, 1 H), 4.44-4.15 (m, 1 H), 3.82-3.49 (m, 3 H), 3.41 (s, 1 H), 1.99-1.37 (m, 4 H)

[0125] .sup.13C NMR (75 MHz, CDCl.sub.3) : 168.2, 134.9, 134.6, 133.2, 130.8, 129.2, 126.3, 115.2, 63.1, 60.4, 47.1, 21.0, 14.2

[0126] MS: 311 [M+H.sup.+].

IIIa-2

6-(3-chloro-4-fluorobenzoyl)-1-oxa-6-azaspiro[2.5]octane-2-carbonitrile

[0127] The title compound was prepared starting from the compound of formula (IVa-2)

[0128] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.52 (dd, J=2.1, 6.7 Hz, 1 H), 7.38-7.29 (m, 1 H), 7.24-7.14 (m, 1 H), 4.35-3.70 (m, 2 H), 3.67-3.49 (m, 2 H), 3.41 (s, 1 H), 2.20-1.69 (m, 4 H)

[0129] MS: 295 [M+H.sup.+].

Starting Materials of Formula IIa:

IIa-1

2-(1-(3,4-dichlorobenzoyl)-4-fluoropiperidin-4-yl)-2-hydroxyacetonitrile

[0130] The title compound was prepared starting from the compound of formula (IIIa-1)

[0131] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.54-7.49 (m, 2 H), 7.26-7.22 (m, 1 H), 4.65 (br. s., 1 H), 4.39 (d, J=12.6 Hz, 1 H), 4.29-4.05 (m, 1 H), 3.76 (br. s., 1 H), 3.49 (s, 2 H), 2.21-1.57 (m, 4 H)

[0132] .sup.19F NMR (282 MHz, CDCl.sub.3) : 170.77 (s, 1F)

[0133] MS: 330 [M+H.sup.+].

IIa-2

2-(1-(3-chloro-4-fluorobenzoyl)-4-fluoropiperidin-4-yl)-2-hydroxyacetonitrile

[0134] The title compound was prepared starting from the compound of formula (IIIa-2)

[0135] .sup.1H NMR (300 MHz, CDCl.sub.3) :7.49 (dd, J=2.1, 6.7 Hz,

[0136] 1 H), 7.34-7.27 (m, 1 H), 7.24-7.17 (m, 1 H), 4.65 (br. s., 1 H), 4.40 (d, J=12.6 Hz, 1 H), 3.75 (br. s., 1 H), 3.51-3.03 (m, 2 H), 2.19-1.65 (m, 4 H)

[0137] .sup.13C NMR (75 MHz, CDCl.sub.3) : 168.5, 159.1, 132.0, 129.8, 127.1, 121.8, 117.0, 116.6, 94.5, 92.1, 66.9, 66.5

[0138] MS: 315 [M+H.sup.+].

Starting Materials of Formula IIb-A, B, C, D, E, F

Starting Materials of Formula IIb-A:

[0139] Starting Materials of Formula Boc-IIb-A.

Boc-IIb-A-1

tert-butyl [2-(pyridazin-4-yloxy)ethyl]carbamate

[0140] The title compound was prepared starting from the pyridazin-4-ol.

[0141] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.88 (d, J=3.1 Hz, 1 H), 7.68 (d, J=7.7 Hz, 1 H), 6.42 (dd, J=3.2, 7.8 Hz, 1 H), 4.13 (t, J=5.4 Hz, 2 H), 3.53 (q, J=6.0 Hz, 2 H), 1.42 (s, 9 H).

[0142] MS: 240 [M+H.sup.+]

Boc-IIb-A-2

tert-butyl [2-(pyrimidin-5-yloxy)ethyl]carbamate

[0143] The title compound was prepared starting from the pyrimidin-5-ol.

[0144] .sup.1H NMR (300 MHz, CDCl.sub.3) : 8.86 (s, 1 H), 8.41 (s, 2 H), 4.13 (t, J=5.1 Hz, 2 H), 3.57 (q, J=5.4 Hz, 2 H), 1.85-1.71 (m, 1 H), 1.44 (s, 9 H).

[0145] MS: 240 [M+H.sup.+]

[0146] Starting Materials of Formula IIb-A

IIb-A-1

2-(pyridazin-4-yloxy)ethanamine hydrochloride

[0147] The title compound was prepared starting from the compound of formula (Boc-IIb-A-1)

[0148] 1H NMR (300 MHz, DMSO-d.sub.6) : 8.69 (d, J=7.4 Hz, 1 H), 8.43 (br. s., 3 H), 8.24 (d, J=3.1 Hz, 1 H), 6.88 (dd, J=3.2, 7.6 Hz, 1 H), 4.51 (t, J=5.8 Hz, 2 H), 3.34-3.22 (m, 2 H).

[0149] MS: 140 [M+H.sup.+]

IIb-A-2

2-(pyrimidin-5-yloxy)ethanamine hydrochloride

[0150] The title compound was prepared starting from the compound of formula (Boc-IIb-A-2)

[0151] 1H NMR (300 MHz, CD.sub.3OD) : 9.09 (s, 1 H), 8.92 (br. s., 2 H), 4.55 (t, J=4.0 Hz, 2 H), 3.48 (br. s., 2 H) NH protons not detected

[0152] MS: 140 [M+H.sup.+]

Starting Materials of Formula IIb-B:

[0153] Starting Materials of Formula Boc-IIb-B.

Boc-IIb-B-1

tert-butyl {2-[(6-fluoropyridin-2-yl)oxy]ethyl}carbamate

[0154] The title compound was prepared starting from 2,6-difluoropyridine.

[0155] 1H NMR (300 MHz, CDCl.sub.3) : 7.65 (q, J=8.2 Hz, 1 H), 6.60 (dd, J=1.7, 8.1 Hz, 1 H), 6.47 (dd, J=2.4, 7.8 Hz, 1 H), 4.92 (br. s., 1 H), 4.36-4.28 (m, 2 H), 3.51 (q, J=5.2 Hz, 2 H), 1.44 (s, 9 H).

[0156] MS: 257 [M+H.sup.+]

Boc-IIb-B-2

tert-butyl [2-(pyrazin-2-yloxy)ethyl]carbamate

[0157] The title compound was prepared starting from 2-bromopyrazine.

[0158] MS: 240 [M+H.sup.+]

Boc-IIb-B-3

tert-butyl (2-((4-methoxypyridin-2-yl)oxy)ethyl)carbamate

[0159] The title compound was prepared starting from 2-fluoro-4-methoxypyridine.

[0160] MS: 269 [M+H.sup.+]

[0161] Starting Materials of Formula IIb-B.

IIb-B-1

2-[(6-fluoropyridin-2-yl)oxy]ethanamine hydrochloride

[0162] The title compound was prepared starting from the compound of formula (Boc-IIb-B-1)

[0163] 1H NMR (300 MHz, DMSO-d.sub.6) : 8.28 (br. s., 3 H), 7.96-7.86 (m, 1 H), 6.76 (dt, J=2.1, 7.6 Hz, 2 H), 4.42-4.35 (m, 2 H), 3.18 (t, J=5.4 Hz, 2 H).

[0164] MS: 157 [M+H.sup.+]

IIb-B-2

2-(pyrazin-2-yloxy)ethanamine hydrochloride

[0165] The title compound was prepared starting from the compound of formula (Boc-IIb-B-2)

[0166] 1H NMR (300 MHz, DMSO-d.sub.6) : 8.27 (s, 1 H), 8.17 (s, 2 H), 4.21 (t, J=5.8 Hz, 2 H), 2.87 (t, J=5.9 Hz, 2 H).

[0167] MS: 240 [M+H.sup.+]

IIb-B-3

2-((4-methoxypyridin-2-yl)oxy)ethanamine

[0168] The title compound was prepared starting from the compound of formula (Boc-IIb-B-3)

[0169] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.77 (m, 1 H), 7.20 (m, 1 H), 6.69 (m, 1 H), 4.25 (t, J=5.3 Hz, 2 H), 3.80 (s, 3 H), 3.05 (t, J=5.3 Hz, 2 H), 2.00 (s, 2 H)

[0170] MS: 169 [M+H.sup.+]

Starting Materials of Formula IIb-C:

[0171] Starting Materials of Formula 1-Boc-IIb-C

1-Boc-IIb-C-1

tert-butyl {2-[(6-fluoropyridin-2-yl)oxy]ethyl}carbamate

[0172] The title compound was prepared starting from 2,6-difluoropyridine.

[0173] 1H NMR (300 MHz, CDCl.sub.3) : 7.65 (q, J=8.2 Hz, 1 H), 6.60 (dd, J=1.7, 8.1 Hz, 1 H), 6.47 (dd, J=2.4, 7.8 Hz, 1 H), 4.92 (br. s., 1 H), 4.36-4.28 (m, 2 H), 3.51 (q, J=5.2 Hz, 2 H), 1.44 (s, 9 H). MS: 257 [M+H.sup.+]

1-Boc-IIb-C-2

tert-butyl {2-[(6-fluoro-5-methylpyridin-2-yl)oxy]ethyl}carbamate

[0174] The title compound was prepared starting from 2,6-difluoro-3-methylpyridine.

[0175] MS: 271 [M+H.sup.+]

[0176] Starting Materials of Formula Boc-IIb-C [0177] Starting amines of formula Ccommercially available: [0178] Pyrrolidine (C-1) [0179] Pyrazole (C-2) [0180] N-methylmethanamine (C-3) [0181] N-ethylethanamine (C-4) [0182] N-methyl-1-phenylmethanamine (C-5)

Boc-IIb-C-1

tert-butyl (2-{[6-(pyrrolidin-1-yl)pyridin-2-yl]oxy}ethyl)carbamate

[0183] The title compound was prepared starting from the compounds of formula (1-Boc-IIb-C-1) and (C-1)

[0184] 1H NMR (300 MHz, CD.sub.3OD) : 7.34 (t, J=8.0 Hz, 1 H), 5.93 (d, J=9.7 Hz, 2 H), 4.26 (t, J=5.6 Hz, 2 H), 3.44-3.35 (m, 6 H), 2.02-1.94 (m, 4 H), 1.42 (s, 9 H), 1.28 (s, 1 H).

[0185] MS: 308 [M+H.sup.+]

Boc-IIb-C-2

tert-butyl (2-{[6-(1H-pyrazol-1-yl)pyridin-2-yl]oxy}ethyl)carbamate

[0186] The title compound was prepared starting from the compounds of formula (1-Boc-IIb-C-1) and (C-2)

[0187] 1H NMR (300 MHz, CDCl.sub.3) : 8.48 (d, J=2.6 Hz, 1 H), 7.74-7.68 (m, 1 H), 7.62 (d, J=2.1 Hz, 1 H), 7.53 (d, J=8.5 Hz, 1 H), 6.63 (dd, J=0.6, 8.1 Hz, 1 H), 6.44 (dd, J=1.5, 2.6 Hz, 1 H), 5.09-4.96 (m,1 H), 4.42 (t, J=5.3 Hz, 2 H), 3.57 (q, J=5.5 Hz, 2 H), 1.45 (s, 9 H). MS: 305 [M+H.sup.+]

Boc-IIb-C-3

tert-butyl (2-{[6-(dimethylamino)pyridin-2-yl]oxy}ethyl)carbamate

[0188] The title compound was prepared starting from the compounds of formula (1-Boc-IIb-C-1) and (C-3)

[0189] MS: 282 [M+H.sup.+]

Boc-IIb-C-4

tert-butyl (2-{[6-(diethylamino)pyridin-2-yl]oxy}ethyl)carbamate

[0190] The title compound was prepared starting from the compounds of formula (1-Boc-IIb-C-1) and (C-4)

[0191] MS: 310 [M+H.sup.+]

Boc-IIb-C-5

tert-butyl (2-((6-(benzyl(methyl)amino)-5-methylpyridin-2-yl)oxy)ethyl)carbamate

[0192] The title compound was prepared starting from the compounds of formula (1-Boc-IIb-C-2) and (C-5)

[0193] MS: 372 [M+H.sup.+]

Boc-IIb-C-6

tert-butyl (2-((6-(benzyl(methyl)amino)pyridin-2-yl)oxy)ethyl)carbamate

[0194] The title compound was prepared starting from the compounds of formula (1-Boc-IIb-C-1) and (C-5)

[0195] MS: 358 [M+H.sup.+]

[0196] Starting Materials of Formula IIb-C

IIb-C-1

2-{[6-(pyrrolidin-1-yl)pyridin-2-yl]oxy}ethanamine hydrochloride

[0197] The title compound was prepared starting from the compound of formula (Boc-IIb-C-1).

[0198] 1H NMR (300 MHz, DMSO-d.sub.6) : 8.25 (br. s., 3 H), 7.43 (t, J=8.0 Hz, 1 H), 5.98 (t, J=8.3 Hz, 2 H), 4.38 (t, J=5.4 Hz, 2 H), 3.41-3.29 (m, 4 H), 3.20-3.09 (m, 2 H), 1.97-1.85 (m, 4 H).

[0199] MS: 308 [M+H.sup.+]

IIb-C-2

2-{[6-(1H-pyrazol-1-yl)pyridin-2-yl]oxy}ethanamine hydrochloride

[0200] The title compound was prepared starting from the compound of formula (Boc-IIb-C-2).

[0201] 1H NMR (300 MHz, CD.sub.3OD) : 8.60 (d, J=2.1 Hz, 1 H), 7.87 (t, J=8.0 Hz, 1 H), 7.77 (d, J=1.0 Hz, 1 H), 7.52 (d, J=7.7 Hz, 1 H), 6.83 (d, J=8.2 Hz, 1 H), 6.55 (dd, J=1.7, 2.7 Hz, 1 H), 4.67-4.62 (m, 2 H), 3.45-3.38 (m, 2 H) NH protons not detected

[0202] MS: 308 [M+H.sup.+]

IIb-C-3

6-(2-aminoethoxy)-N,N-dimethylpyridin-2-amine hydrochloride

[0203] The title compound was prepared starting from the compound of formula (Boc-IIb-C-3).

[0204] MS: 308 [M+H.sup.+]

IIb-C-4

6-(2-aminoethoxy)-N,N-diethylpyridin-2-amine hydrochloride

[0205] The title compound was prepared starting from the compound of formula (Boc-IIb-C-4).

[0206] MS: 308 [M+H.sup.+]

IIb-C-5

6-(2-aminoethoxy)-N-benzyl-N,3-dimethylpyridin-2-amine hydrochloride

[0207] The title compound was prepared starting from the compound of formula (Boc-IIb-C-5).

[0208] MS: 308 [M+H.sup.+]

IIb-C-6

6-(2-aminoethoxy)-N-benzyl-N-methylpyridin-2-amine hydrochloride

[0209] The title compound was prepared starting from the compound of formula (Boc-IIb-C-6).

[0210] MS: 308 [M+H.sup.+]

Starting Materials of Formula IIb-D

[0211] Starting Materials of Formula Boc-IIb-D

Boc-IIb-D-1

tert-butyl (2-(2-(methylamino)phenoxy)ethyl)carbamate

[0212] The title compound was prepared starting from the 2-(methylamino)phenol and tert-butyl (2-hydroxyethyl)carbamate

[0213] .sup.1H NMR (300 MHz, CDCl.sub.3) : 6.98-6.84 (m, 1 H), 6.78-6.70 (m, 1 H), 6.63 (ddd, J=1.5, 7.6, 14.4 Hz, 2 H), 4.95 (br. s., 1 H), 4.04 (t, J=5.3 Hz, 2 H), 3.55 (q, J=5.3 Hz, 2 H), 2.86 (s, 3 H), 1.45 (s, 9 H) NH-Boc proton not detected

[0214] MS: 267 [M+H.sup.+]

[0215] Starting Materials of Formula IIb-D

IIb-D-1

2-(2-aminoethoxy)-N-methylaniline

[0216] The title compound was prepared starting from the compound of formula (Boc-IIb-D-1).

[0217] .sup.1H NMR (300 MHz, CDCl.sub.3) : 6.95-6.86 (m, 1 H), 6.81-6.72 (m, 1 H), 6.64 (ddd, J=1.8, 7.5, 14.8 Hz, 2 H), 4.02 (t, J=5.3 Hz, 2 H), 3.10 (t, J=5.3 Hz, 2 H), 2.87 (s, 3 H), 1.89 (br. s., 3 H)

[0218] MS: 167 [M+H.sup.+]

Starting Materials of Formula IIb-E

[0219] Starting Materials of Formula Br-IIb-E

Br-IIb-E-1

tert-butyl (3-(2-bromoethoxy)phenyl)(methyl)carbamate

[0220] The title compound was prepared starting from the tert-butyl (3-hydroxyphenyl)carbamate, 1,2-dibromoethane and iodomethane

[0221] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.26-7.18 (m, 1 H), 6.90-6.80 (m, 2 H), 6.72 (dd, J=1.8, 8.2 Hz, 1 H), 4.28 (t, J=6.4 Hz, 2 H), 3.63 (t, J=6.2 Hz, 2 H), 3.24 (s, 3 H), 1.46 (s, 9 H)

[0222] MS: 330 [M+H.sup.+]

[0223] Starting Materials of Formula IIb-E

IIb-E-1

3-(2-aminoethoxy)-N-methylaniline

[0224] The title compound was prepared starting from the compound of formula (Br-IIb-E-1).

[0225] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.25-7.17 (m, 1 H), 6.85-6.79 (m, 2 H), 6.75-6.69 (m, 1 H), 3.97 (t, J=5.0 Hz, 2 H), 3.24 (s, 3 H), 3.07 (t, J=5.3 Hz, 2 H), 1.48 (br. s., 2 H), 1.45 (s, 9 H)

[0226] MS: 266 [M+H.sup.+]

Starting Materials of Formula IIb-F

[0227] Starting Materials of Formula Pre-IIb-F

Pre-IIb-F-1

6-fluoro-N-methylpyridin-2-amine

[0228] The title compound was prepared starting from 2,6-difluoropirydine and methanamine

[0229] .sup.1H NMR (300MH, CDCl.sub.3) : 7.53-7.42 (m, 1 H), 6.18 (dd, J=2.3, 8.2 Hz, 1 H), 6.13 (dd, J=2.3, 8.2 Hz, 1 H), 4.77 (br. s., 1 H), 2.90 (d, J=4.1 Hz, 3 H)

[0230] .sup.19F NMR (282 MHz, CDCl.sub.3) : 70.08 (s, 1 F)

[0231] MS: 127 [M+H.sup.+]

Pre-IIb-F-2

6-fluoro-N,N-dimethylpyridin-2-amine

[0232] The title compound was prepared starting from 2,6-difluoropirydine and dimetyhylamine

[0233] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.54-7.42 (m, 1 H), 6.27 (dd, J=2.3, 8.2 Hz, 1 H), 6.08 (dd, J=2.9, 7.6 Hz, 1 H), 3.06 (s, 6 H)

[0234] .sup.19F NMR (282 MHz, CDCl.sub.3) : 69.03 (s, 1 F)

[0235] MS: 141 [M+H.sup.+]

Pre-IIb-F-3

N-(6-fluoropyridin-2-yl)acetamide

[0236] The title compound was prepared starting from 2,6-difluoropirydine and acetamide

[0237] .sup.1H NMR (300 MHz, CDCl.sub.3) : 8.06 (d, J=8.2 Hz, 2 H), 7.78 (q, J=7.8 Hz, 1 H), 6.65 (dd, J=2.3, 7.6 Hz, 1 H), 2.20 (s, 3 H)

[0238] MS: 155 [M+H.sup.+]

[0239] Starting Materials of Formula IIb-F

IIb-F-1

6-(2-aminoethoxy)-N-methylpyridin-2-amine

[0240] The title compound was prepared starting from the compound of formula Pre-IIb-F1 and ethanolamine

[0241] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.40-7.31 (m, 1 H), 6.02 (d, J=8.2 Hz, 1 H), 5.93 (d, J=7.6 Hz, 1 H), 4.41 (br. s., 1 H), 4.22 (t, J=5.3 Hz, 2 H), 3.03 (t, J=5.3 Hz, 2 H), 2.86 (br. s., 3 H), 1.69 (br. s., 2 H)

[0242] MS: 168 [M+H.sup.+]

IIb-F-2

6-(2-aminoethoxy)-N,N-dimethylpyridin-2-amine

[0243] The title compound was prepared starting from the compound of formula Pre-IIb-F2 and ethanolamine

[0244] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.36 (t, J=7.9 Hz, 1 H), 6.01 (dd, J=7.9, 9.1 Hz, 2 H), 4.33-4.25 (m, 2 H), 3.09-2.99 (m, 8 H), 1.46 (s, 2 H)

[0245] MS: 182 [M+H.sup.+]

IIb-F-3

N-(6-(2-aminoethoxy)pyridin-2-yl)acetamide

[0246] The title compound was prepared starting from the compound of formula Pre-IIb-F3 and ethanolamine

[0247] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.83 (br. s., 1 H), 7.72 (d, J=7.0 Hz, 1 H), 7.57 (t, J=7.9 Hz, 1 H), 6.47 (d, J=8.8 Hz, 1 H), 4.27-4.16 (m, 2 H), 3.09-2.99 (m, 2 H), 2.19 (s, 3 H), 1.52 (s, 2 H)

[0248] MS: 196 [M+H.sup.+]

[0249] The preparation of compound (I) from compounds IIa and IIb is depicted in the FIG. 2 FScheme 6.

[0250] The cyanohydrin of formula IIa (1.0 eq, 0.478 mmol) was dissolved in methanol (5 mL) at room temperature, 1,4-diaza-bicyclo[2.2.2]octane (12.5 eq, 5.97 mmol) was added in one portion, followed by appropriate amine of formula IIb (1.6 eq , 0.764 mmol), 4A molecular sieves (1.04 g), sodium cyanoborohydride (7.8eq, 3.73 mmol), and iron sulfate (FeSO4.7H2O) (1.2 eq, 0.526 mmol). Mixture stirred at room temperature until the cyanohydrin was consumed. After stirring for 72 hours, mixture filtered to remove insoluble material, concentrated in vacuo to remove methanol and subsequently quenched with brine. The Aqueous was extracted with ethyl acetate three times, organics combined and dried over magnesium sulfate, filtered and concentrated to crude product. Purification via flash chromatography (5% methanol/ethyl acetate) yielded pure product as a colorless oil. The yield of compounds (I) was in the range of 28-98%, and HPLC purity in the range of 95-100%.

[0251] According to the above general procedure, various compounds of formula (I) according to the invention were prepared and are depicted in the example section.

[0252] Compound (I) can also be prepared starting from their Boc-protected intermediates (i.e. compound 75) according to FIG. 2 KScheme 11 depicting the general synthesis.

[0253] The appropriate product of formula IIb-E (1 eq., 0.15 mmol) was poured with 1M hydrochloric acid in ethyl acetate (5 mL), and stirred for 24 h. Then, the mixture was filtered giving pure hydrochloride as a white-gray solid. (yield 71%).

[0254] Compound (I) can also be prepared starting from their benzyl intermediates (i.e. compound 49 and 50) according to FIG. 2 GScheme 7 depicting the general synthesis.

[0255] The appropriate compound of formula (Benzyl-I) (0.100 g, 0.189 mmol) was dissolved in ethanol (2 mL) and added to a round bottom flask containing 10% Pd/C (0.100 g) under nitrogen gas. Cyclohexene (1 mL) was then added and mixture warmed to 90 C. with stirring. After 72 hours, mixture was cooled to room temperature, filtered over celite, and filtrate concentrated in vacuo to yield crude product as an orange oil. Crude was purified via flash chromatography (ethyl acetate/hexanes/trimethylamine 3:6:1) to yield pure product as a light tan solid (22% yield).

[0256] The invention also extends to additive salts from compounds of aforementioned formula I, with pharmaceutically acceptable mineral or organic acids.

[0257] More particularly, the present invention target some of the 1-48 numbered compounds of formula (I) selected in the group consisting of:

Compound 1

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-phenoxyethyl)amino)methyl)piperidin-1-yl)methanone

[0258] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-1).

[0259] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.48 (dd, J=2.1, 7.2 Hz, 1 H), 7.33-7.26 (m, 3 H), 7.22-7.13 (m, 1 H), 6.99-6.86 (m, 3 H), 4.51 (br. s., 1 H), 4.07 (t, J=5.1 Hz, 2 H), 3.71-3.53 (m, 1 H), 3.22 (br. s., 2 H), 3.03 (t, J=5.1 Hz, 2 H), 2.92-2.77 (m, 2 H), 2.01 (br. s., 2 H), 1.67 (br. s., 3 H)

[0260] .sup.19F NMR (282 MHz, CDCl.sub.3) : 112.63 (s, 1F), 166.48 (s, 1F)

[0261] .sup.13C NMR (75 MHz, CDCl.sub.3) : 168.1, 158.7, 157.1, 132.9, 129.7, 129.5, 127.1, 121.6, 121.4, 120.9, 116.9, 116.6, 114.5, 95.5, 93.2, 67.2, 57.5, 57.2, 49.3

[0262] MS: 409 [M+H.sup.+]

Compound 2

N-(3-(2-(((1-(3-chloro-4-fluorobenzoyl)-4-fluoropiperidin-4-yl)methyl)amino)ethoxy)phenyl)acetamide

[0263] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-2).

[0264] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.89 (br. s., 1 H), 7.46 (dd, J=2.1, 6.9 Hz, 1 H), 7.35-7.31 (m, 1 H), 7.30-7.24 (m, 1 H), 7.21-7.11 (m, 2 H), 6.92 (d, J=8.0 Hz, 1 H), 6.61 (dd, J=2.1, 8.2 Hz, 1 H), 5.86-5.58 (m, 5 H), 4.48 (br. s., 1 H), 4.03 (t, J=5.1 Hz, 2 H), 3.58 (br. s., 1 H), 3.42 -3.10 (m, 2 H), 3.00 (t, J=5.0 Hz, 2 H), 2.89-2.76 (m, 2 H), 2.13 (s, 3 H), 2.03 (br. s., 2 H), 1.63 (br. s., 3 H)

[0265] .sup.13C NMR (75 MHz, CDCl.sub.3) : 173.0, 168.1, 160.4, 159.2, 157.1, 139.4, 132.8, 129.6, 127.1, 121.5, 116.8, 112.2, 110.2, 106.4, 95.4, 93.2, 67.3, 57.3, 57.0, 49.2, 22.6

[0266] MS: 466 [M+H.sup.+]

Compound 3

N-(3-(2-(((1-(3,4-dichlorobenzoyl)-4-fluoropiperidin-4-yl)methyl)amino)ethoxy)phenyl)acetamide

[0267] The title compound was prepared starting from the compound (IIa-1) and amine (IIb-2)

[0268] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.56-7.45 (m, 2 H), 7.34 (br. s., 1 H), 7.23 (dd, J=1.9, 8.1 Hz, 1 H), 7.10-6.97 (m, 1 H), 6.89 (d, J=7.2 Hz, 1 H), 6.65 (d, J=7.4 Hz, 1 H), 6.26-6.11 (m, 1 H), 4.52 (br. s., 1 H), 4.05 (t, J=5.0 Hz, 2 H), 3.57 (br. s., 1 H), 3.47-3.09 (m, 2 H), 3.06-2.97 (m, 2 H), 2.90-2.77 (bd, 2 H), 2.16 (s, 3 H), 1.84-1.45 (m, 5 H)

[0269] MS: 483 [M+H.sup.+]

Compound 4

(3-chloro-4-fluorophenyl)(4-(((2-(3-chlorophenoxy)ethyl)amino)methyl)-4-fluoropiperidin-1-yl)methanone

[0270] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-3)

[0271] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.48 (dd, J=2.1, 6.9 Hz, 1 H), 7.33-7.26 (m, 1 H), 7.18 (dt, J=5.1, 8.3 Hz, 2 H), 6.96-6.91 (m, 1 H), 6.90 (t, J=2.1 Hz, 1 H), 6.78 (ddd, J=0.8, 2.4, 8.3 Hz, 1 H), 4.52 (br. s., 1 H), 4.04 (t, J=5.0 Hz, 2 H), 3.60 (br. s., 1 H), 3.37 (br. s., 2 H), 3.02 (t, J=5.1 Hz, 2 H), 2.90-2.77 (m, 2 H), 2.02 (br. s., 2 H), 1.63 (s, 3 H)

[0272] .sup.13C NMR (75 MHz, CDCl.sub.3) : 168.1, 160.5, 159.5, 157.1, 134.9, 132.9, 130.2, 129.7, 127.0, 121.1, 116.8, 114.9, 113.0, 95.5, 93.2, 67.6, 57.5, 57.2, 49.1

[0273] MS: 443 [M+H.sup.+]

Compound 5

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-(3-fluorophenoxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0274] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-4)

[0275] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.48 (dd, J=2.1, 6.9 Hz, 1 H), 7.33-7.26 (m, 1 H), 7.24-7.13 (m, 2 H), 6.67 (tdd, J=1.0, 2.0, 9.5 Hz, 2 H), 6.64-6.58 (m, 1 H), 4.51 (br. s., 1 H), 4.04 (t, J=5.0 Hz, 2 H), 3.60 (br. s., 1 H), 3.46-3.10 (m, 2 H), 3.03 (t, J=5.1 Hz, 2 H), 2.90-2.77 (m, 2 H), 2.01 (br. s., 2 H), 1.63 (br. s., 3 H)

[0276] .sup.13C NMR (75 MHz, CDCl.sub.3) : 168.1, 165.2, 162.0, 160.2, 157.1, 132.9, 130.0, 127.1, 121.5, 116.8, 110.2, 107.7, 102.2, 95.5, 93.2, 67.7, 57.5, 57.2, 49.1

[0277] MS: 427 [M+H.sup.+]

Compound 6

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-(2-methoxyphenoxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0278] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-5)

[0279] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.48 (dd, J=2.1, 6.9 Hz, 1 H), 7.32-7.26 (m, 1 H), 7.20-7.13 (m, 1 H), 6.98-6.85 (m, 4 H), 4.50 (br. s., 1 H), 4.12 (t, J=5.3 Hz, 2 H), 3.84 (s, 3 H), 3.60 (br. s., 1 H), 3.45-3.13 (m, 2 H), 3.04 (t, J=5.3 Hz, 2 H), 2.91-2.79 (m, 2 H), 2.10-1.92 (m, 2 H), 1.70 (br. s., 3 H)

[0280] .sup.19F NMR (282 MHz, CDCl.sub.3) : 112.66 (s, 1F), 166.26 (s, 1F)

[0281] .sup.13C NMR (75 MHz, CDCl.sub.3) : 168.0, 160.4, 157.1, 149.8, 148.2, 133.0, 129.7, 127.1, 121.6, 120.9, 116.8, 114.2, 111.9, 95.5, 93.2, 69.0, 57.4, 57.1, 55.8, 49.3

[0282] MS: 439 [M+H.sup.+]

Compound 7

(3,4-dichlorophenyl)(4-fluoro-4-(((2-(2-methoxyphenoxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0283] The title compound was prepared starting from the compound (IIa-1) and amine (IIb-5)

[0284] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.53-7.45 (m, 2 H), 7.23 (dd, J=1.8, 8.2 Hz, 1 H), 6.99-6.84 (m, 4 H), 4.51 (br. s., 1 H), 4.12 (t, J=5.3 Hz, 2 H), 3.84 (s, 3 H), 3.57 (br. s., 1 H), 3.46-3.10 (m, 2 H), 3.04 (t, J=5.1 Hz, 2 H), 2.91-2.78 (m, 2 H), 2.00 (br. s., 2 H), 1.77 (br. s., 3 H)

[0285] .sup.13C NMR (75 MHz, CDCl.sub.3) : 167.9, 149.7, 148.2, 135.7, 134.1, 133.0, 130.6, 129.1, 126.2, 121.6, 120.9, 114.2, 111.9, 95.5, 93.2, 69.0, 57.3, 55.8, 49.3, 29.7

[0286] MS: 455 [M+H.sup.+]

Compound 8

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-(3-methoxyphenoxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0287] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-6)

[0288] .sup.1H NMR (300 MHz, CDCl.sub.3) 5: 7.48 (dd, J=2.1, 6.9 Hz, 1 H), 7.33-7.26 (m, 1 H), 7.21-7.13 (m, 2 H), 6.54-6.48 (m, 2 H), 6.47-6.45 (m, 1 H), 4.52 (br. s., 1 H), 4.05 (t, J=5.1 Hz, 2 H), 3.78 (s, 3 H), 3.59 (br. s., 1 H), 3.45-3.11 (m, 2 H), 3.02 (t, J=5.0 Hz, 2 H), 2.91-2.76 (m, 2 H), 2.01 (br. s., 2 H), 1.71 (br. s., 3 H)

[0289] .sup.13C NMR (75 MHz, CDCl.sub.3) : 168.1, 160.8, 160.4, 160.0, 157.1, 132.9, 129.8, 127.1, 121.5, 116.8, 106.6, 106.4, 101.0, 95.5, 93.2, 67.3, 57.4, 57.1, 55.3, 49.3

[0290] MS: 439 [M+H.sup.+]

Compound 9

(3,4-dichlorophenyl)(4-fluoro-4-(((2-(3-methoxyphenoxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0291] The title compound was prepared starting from the compound (IIa-1) and amine (IIb-6)

[0292] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.53-7.47 (m, 2 H), 7.23 (dd, J=1.8, 8.2 Hz, 1 H), 7.18 (t, J=8.1 Hz, 1 H), 6.56-6.43 (m, 3 H), 4.51 (br. s., 1 H), 4.05 (t, J=5.1 Hz, 2 H), 3.79 (s, 3 H), 3.60 (br. s., 1 H), 3.38 (br. s., 2 H), 3.02 (t, J=5.0 Hz, 2 H), 2.90-2.78 (m, 2 H), 2.01 (br. s., 2 H), 1.59 (br. s., 3 H)

[0293] MS: 455 [M+H.sup.+]

Compound 10

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-(4-methoxyphenoxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0294] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-7)

[0295] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.48 (dd, J=2.1, 6.9 Hz, 1 H), 7.33-7.26 (m, 1 H), 7.22-7.14 (m, 1 H), 6.83 (s, 4 H), 4.50 (br. s., 1 H), 4.01 (t, J=5.1 Hz, 2 H), 3.76 (s, 3 H), 3.60 (br. s., 1 H), 3.44-3.13 (m, 2 H), 3.00 (t, J=5.1 Hz, 2 H), 2.90-2.78 (m, 2 H), 2.02 (s, 2 H), 1.64 (br. s., 3 H)

[0296] .sup.13C NMR (75 MHz, CDCl.sub.3) : 168.1, 160.4, 157.1, 153.4, 132.9, 129.7, 127.1, 121.5, 116.8, 115.5, 114.7, 95.5, 93.2, 68.0, 57.5, 57.2, 55.7, 49.4

[0297] MS: 439 [M+H.sup.+]

Compound 11

(3,4-dichlorophenyl)(4-fluoro-4-(((2-(4-methoxyphenoxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0298] The title compound was prepared starting from the compound (IIa-1) and amine (IIb-7)

[0299] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.54-7.44 (m, 2 H), 7.23 (dd, J=2.1, 8.2 Hz, 1 H), 6.83 (s, 4 H), 4.52 (br. s., 1 H), 4.01 (t, J=5.1 Hz, 2 H), 3.76 (s, 3 H), 3.57 (br. s., 1 H), 3.45-3.10 (m, 2 H), 3.00 (t, J=5.0 Hz, 2 H), 2.88-2.77 (m, 2 H), 2.02 (m, 2 H), 1.61 (br. s., 3 H)

[0300] .sup.19F NMR (282 MHz, CDCl.sub.3) : 166.50 (s, 1F)

[0301] .sup.13C NMR (75 MHz, CDCl.sub.3) : 167.9, 154.0, 152.9, 135.7, 134.1, 133.0, 130.6, 129.1, 126.2, 115.5, 114.6, 95.5, 93.2, 68.0, 57.5, 57.2, 55.7, 49.4

[0302] MS: 455 [M+H.sup.+]

Compound 12

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-(2-(methylthio)phenoxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0303] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-8)

[0304] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.48 (dd, J=2.1, 6.9 Hz, 1 H), 7.32-7.26 (m, 1 H), 7.20-7.07 (m, 3 H), 7.01-6.94 (m, 1 H), 6.83 (d, J=8.2 Hz, 1 H), 4.51 (br. s., 1 H), 4.13 (t, J=5.0 Hz, 2 H), 3.58 (br. s., 1 H), 3.45-3.13 (m, 2 H), 3.07 (t, J=5.0 Hz, 2 H), 2.94-2.82 (m, 2 H), 2.41 (s, 3 H), 2.10-1.92 (m, 2 H), 1.75 (br. s., 3 H)

[0305] .sup.13C NMR (75 MHz, CDCl.sub.3) : 168.0, 160.4, 157.1, 155.2, 133.0, 129.7, 127.6, 127.1, 125.6, 121.6, 121.4, 116.8, 111.6, 95.5, 93.2, 68.5, 57.4, 57.1, 49.1, 14.4

[0306] MS: 455 [M+H.sup.+]

Compound 13

((3,4-dichlorophenyl)(4-fluoro-4-(((2-(2-(methylthio)phenoxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0307] The title compound was prepared starting from the compound (IIa-1) and amine (IIb-8)

[0308] .sup.1H-NMR (300 MHz, CDCl.sub.3) : 7.51-7.48 (m., 2H), 7.26-7.24 (m., 1H), 7.13-7.10 (m., 2H), 7.00-6.96 (m., 1H), 6.85-6.83 (m., 1H), 4.52-4.50 (m., 1H), 4.16-4.13 (t., J=5.1 Hz, 2H), 3.58-3.10 (m., 3H), 3.09-3.07 (t., J=5.3 Hz, 2H), 2.92-2.87 (d., J=19.9 Hz, 2H), 2.42 (s., 3H), 2.01 (br s., 2H) 1,69-1.24 (m., 3H).

[0309] MS: 471 [M+H.sup.+]

Compound 14

(3-chloro-4-fluorophenyl)(4-(((2-((2,3-dihydrobenzo[b][1,4]dioxin-5-yl)oxy)ethyl)amino)methyl)-4-fluoropiperidin-1-yl)methanone

[0310] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-9)

[0311] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.48 (dd, J=2.1, 6.9 Hz, 1 H), 7.32-7.26 (m, 1 H), 7.21-7.14 (m, 1 H), 6.78-6.71 (m, 1 H), 6.53 (ddd, J=1.3, 8.2, 10.8 Hz, 2 H), 4.50 (br. s., 1 H), 4.32-4.27 (m, 2 H), 4.27-4.23 (m, 2 H), 4.16-4.07 (m, 2 H), 3.60 (br. s., 1 H), 3.34 (br. s., 2 H), 3.05 (t, J=5.3 Hz, 2 H), 2.91-2.78 (m, 2 H), 2.02 (s, 2 H), 1.63 (br. s., 3 H)

[0312] MS: 467 [M+H.sup.+]

Compound 15

(3,4-dichlorophenyl)(4-(((2-((2,3-dihydrobenzo[b][1,4]dioxin-5-yl)oxy)ethyl)amino)methyl)-4-fluoropiperidin-1-yl)methanone

[0313] The title compound was prepared starting from the compound (IIa-1) and amine (IIb-9)

[0314] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.53-7.46 (m, 2 H), 7.23 (dd, J=1.8, 8.2 Hz, 1 H), 6.78-6.71 (m, 1 H), 6.52 (ddd, J=1.4, 8.3, 10.8 Hz, 2 H), 4.51 (br. s., 1 H), 4.31-4.27 (m, 2 H), 4.27-4.23 (m, 2 H), 4.11 (t, J=5.4 Hz, 2 H), 3.56 (br. s., 1 H), 3.45-3.11 (m, 2 H), 3.04 (t, J=5.1 Hz, 2 H), 2.90-2.79 (m, 2 H), 2.08-1.92 (m, 2 H), 1.67 (br. s., 3 H)

[0315] .sup.19F NMR (282 MHz, CDCl.sub.3) : 166.28 (s, 1F)

[0316] .sup.13C NMR (75 MHz, CDCl.sub.3) : 167.9, 148.2, 144.4, 135.7, 134.1, 133.9, 133.0, 130.6, 129.1, 126.2, 120.2, 110.5, 106.3, 95.5, 93.2, 69.0, 64.4, 64.2, 57.3, 49.2

[0317] MS: 483 [M+H.sup.+]

Compound 16

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-(quinolin-8-yloxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0318] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-10)

[0319] .sup.1H NMR (300 MHz, CDCl.sub.3) : 8.92 (dd, J=1.8, 4.1 Hz, 1 H), 8.15 (dd, J=1.7, 8.3 Hz, 1 H), 7.50 -7.38 (m, 4 H), 7.28 (dd, J=2.1, 4.6 Hz, 1 H), 7.19-7.12 (m, 1 H), 7.09 (dd, J=1.7, 7.3 Hz, 1 H), 4.50 (br. s., 1 H), 4.34 (t, J=5.3 Hz, 2 H), 3.58 (br. s., 1 H), 3.39-3.13 (m, 4 H), 2.98-2.86 (m, 2 H), 2.06-1.97 (m, 2 H), 1.66 (br. s., 3 H)

[0320] .sup.13C NMR (75 MHz, CDCl.sub.3) : 168.0, 160.4, 157.1, 154.5, 149.2, 140.2, 136.1, 132.9, 129.7, 129.5, 127.1, 126.7, 121.7, 120.1, 116.7, 109.4, 95.5, 93.2, 68.7, 57.4, 57.1, 49.1

[0321] MS: 460 [M+H.sup.+]

Compound 17

(3,4-dichlorophenyl)(4-fluoro-4-(((2-(quinolin-8-yloxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0322] The title compound was prepared starting from the compound (IIa-1) and amine (IIb-10)

[0323] .sup.1H-NMR (300 MHz, CDCl.sub.3) : 7.52-7.41 (m, 5H), 7.27 (m, 2H), 7.26-7.19 (m, 1H), 7.12-7.09 (m, 1H), 4.52 (m, 1H), 4.72-4.43 (t, J=5.1 Hz, 2H), 3.55 (m, 1H), 3.37 (m, 1H), 3.26-3.23 (t, J=5.2 Hz, 2H), 3.17 (m, 1H), 2.95-2.90 (d, J=19.9 Hz, 2H), 2.01 (br s, 2H) 1,69-1.24 (m, 3H).

[0324] MS: 477 [M+H.sup.+]

Compound 18

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-(pyridin-2-yloxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0325] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-11)

[0326] .sup.1H NMR (300 MHz, CDCl.sub.3) : 8.16-8.08 (m, 1 H), 7.61-7.52 (m, 1 H), 7.47 (dd, J=1.8, 7.0 Hz, 1 H), 7.33-7.26 (m, 1 H), 7.20-7.12 (m, 1 H), 6.90-6.82 (m, 1 H), 6.77-6.68 (m, 1 H), 4.50 (br. s., 1 H), 4.42-4.33 (m, 2 H), 3.57 (br. s., 1 H), 3.46-3.06 (m, 2 H), 3.02 (t, J=5.3 Hz, 2 H), 2.91-2.73 (m, 2 H), 2.01 (br. s., 2 H), 1.87-1.52 (m, 3 H)

[0327] .sup.19F NMR (282 MHz, CDCl.sub.3) : 112.63 (s, 1F), 166.52 (s, 1F)

[0328] .sup.13C NMR (75 MHz, CDCl.sub.3) : 168.0, 163.6, 160.4, 157.1, 146.8, 138.6, 132.9, 129.7, 127.1, 121.5, 116.8, 111.0, 95.5, 93.2, 65.1, 57.4, 57.1, 49.2

[0329] MS: 410 [M+H.sup.+]

Compound 19

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-(pyridin-3-yloxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0330] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-12)

[0331] .sup.1H NMR (300 MHz, CDCl.sub.3) : 8.32 (td, J=1.0, 1.7 Hz, 1 H), 8.25-8.21 (m, 1 H), 7.48 (dd, J=2.1, 6.9 Hz, 1 H), 7.33-7.26 (m, 1 H), 7.23-7.13 (m, 3 H), 4.52 (br. s., 1 H), 4.11 (t, J=5.1 Hz, 2 H), 3.61 (br. s., 1 H), 3.18 (d, J=5.1 Hz, 2 H), 3.05 (t, J=5.1 Hz, 2 H), 2.90-2.79 (m, 2 H), 2.08-1.95 (m, 2 H), 1.79 (br. s., 3 H)

[0332] .sup.13C NMR (75 MHz, CDCl.sub.3) : 168.1, 160.5, 157.1, 154.9, 142.3, 137.9, 132.9, 129.7, 127.1, 123.8, 121.1, 116.8, 95.5, 93.3, 93.2, 67.8, 57.5, 57.2, 49.1

[0333] MS: 410 [M+H.sup.+]

Compound 20

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-(pyridin-4-yloxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0334] The title compound was prepared starting from the compound (IIa-1) and amine (IIb-13)

[0335] MS: 410 [M+H.sup.+]

Compound 21

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-((5-methylpyridin-2-yl)oxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0336] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-14)

[0337] .sup.1H-NMR (300 MHz, CDCl.sub.3) : 7.94-7.9 3 (m., 1H), 7.49-7.47 (m., 1H), 7.41-7.28 (m., 2H), 7.20-7.16 (m., 1H), 6.67-6.65 (d., 1H), 4.51 (m., 1H), 4.38-4.35 (t., J=5.1 Hz, 2H), 3.64-3.18 (m., 3H), 3.04-3.01 (t., J=5.3 Hz, 2H), 2.87-2.82 (d., J=19.9 Hz, 2H), 2.24 (s., 3H), 2.00 (br s., 2H) 1,83-1.51 (m., 3H).

[0338] MS: 424 [M+H.sup.+]

Compound 22

(3-chloro-4-fluorophenyl)(4-(((2-((5-chloropyridin-2-yl)oxy)ethyl)amino)methyl)-4-fluoropiperidin-1-yl)methanone

[0339] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-15)

[0340] .sup.1H NMR (300 MHz, CDCl.sub.3) : 8.08 (d, J=2.1 Hz, 1 H), 7.56-7.45 (m, 2 H), 7.33-7.26 (m, 1 H), 7.22-7.13 (m, 1 H), 6.70 (dd, J=0.6, 8.8 Hz, 1 H), 4.51 (br. s., 1 H), 4.41-4.31 (m, 2 H), 3.64 (d, J=19.5 Hz, 1 H), 3.43-3.13 (m, 2 H), 3.02 (t, J=5.3 Hz, 1 H), 2.89-2.77 (m, 2 H), 2.00 (br. s., 2 H), 1.62 (br. s., 3 H)

[0341] .sup.13C NMR (75 MHz, CDCl.sub.3) : 168.1, 162.1, 160.5, 157.1, 145.1, 138.6, 132.9, 129.7, 127.1, 124.2, 116.8, 112.0, 95.5, 93.2, 65.7, 57.4, 57.1, 49.1

[0342] MS: 444 [M+H.sup.+]

Compound 23

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-((3-methoxypyridin-2-yl)oxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0343] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-16)

[0344] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.70 (dd, J=1.4, 5.0 Hz, 1 H), 7.47 (dd, J=2.1, 6.9 Hz, 1 H), 7.32-7.26 (m, 1 H), 7.22-7.13 (m, 1 H), 7.05 (dd, J=1.4, 7.8 Hz, 1 H), 6.84 (dd, J=5.1, 7.7 Hz, 1 H), 4.48 (t, J=5.5 Hz, 3 H), 3.85 (s, 3 H), 3.60 (br. s., 1 H), 3.44-3.15 (m, 2 H), 3.08 (t, J=5.4 Hz, 2 H), 2.92-2.77 (m, 2 H), 1.98 (br. s., 2 H), 1.66 (br. s., 3 H)

[0345] MS: 440 [M+H.sup.+]

Compound 24

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-((4-(trifluoromethyl)pyridin-2-yl)oxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0346] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-17)

[0347] .sup.1H NMR (300 MHz, CDCl.sub.3) : 8.28 (d, J=5.4 Hz, 1 H), 7.47 (dd, J=2.1, 6.9 Hz, 1 H), 7.32-7.26 (m, 1 H), 7.21-7.13 (m, 1 H), 7.07 (dd, J=0.9, 5.3 Hz, 1 H), 6.99-6.94 (m, 1 H), 4.50 (br. s., 1 H), 4.46-4.40 (m, 2 H), 3.60 (br. s., 1 H), 3.34 (br. s., 2 H), 3.03 (t, J=5.3 Hz, 2 H), 2.90-2.76 (m, 2 H), 2.00 (br. s., 2 H), 1.69 (br. s., 3 H)

[0348] .sup.13C NMR (75 MHz, CDCl.sub.3) : 168.1, 164.0, 160.4, 157.1, 148.3, 140.7, 132.9, 129.7, 127.1, 121.5, 116.8, 112.4, 107.7, 95.5, 93.2, 66.0, 57.4, 57.1, 49.0

[0349] MS: 478 [M+H.sup.+]

Compound 25

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-((6-fluoropyridin-2-yl)oxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0350] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-B-1)

[0351] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.64 (q, J=8.0 Hz, 1 H), 7.47 (dd, J=2.1, 6.9 Hz, 1 H), 7.33-7.27 (m, 1 H), 7.22-7.11 (m, 1 H), 6.59 (dd, J=1.7, 8.1 Hz, 1 H), 6.46 (dd, J=2.4, 7.8 Hz, 1 H), 4.50 (br. s., 1 H), 4.40-4.31 (m, 2 H), 3.58 (br. s., 1 H), 3.44-3.10 (m, 2 H), 3.01 (t, J=5.4 Hz, 2 H), 2.89-2.75 (m, 2 H), 2.00 (br. s., 2 H), 1.64 (br. s., 3 H)

[0352] .sup.13C NMR (75 MHz, CDCl.sub.3) : 168.1, 163.7, 162.8, 160.4, 157.1, 142.6, 132.9, 129.7, 127.1, 121.5, 116.8, 107.1, 100.2, 95.5, 93.2, 65.9, 57.3, 57.0, 48.9

[0353] MS: 428 [M+H.sup.+]

Compound 26

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-((6-(methylamino)pyridin-2-yl)oxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0354] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-F-1) and also was prepared from compound 49 (pre-compound 26)

[0355] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.47 (dd, J=2.3, 7.0 Hz, 1 H), 7.35 (t, J=1.0 Hz, 1 H), 7.31-7.26 (m, 1 H), 7.21-7.11 (m, 1 H), 6.00 (d, J=8.2 Hz, 1 H), 5.93 (d, J=8.2 Hz, 1 H), 4.50 (br. s., 1 H), 4.39 (d, J=4.7 Hz, 1 H), 4.33-4.25 (m, 2 H), 3.57 (br. s., 1 H), 3.45-3.03 (m, 2 H), 2.99 (t, J=5.3 Hz, 2 H), 2.89-2.74 (m, 5 H), 1.99 (br. s., 2 H), 1.66 (br. s., 3 H)

[0356] .sup.19F NMR (282 MHz, CDCl.sub.3) : 112.71 (s, 1F), 166.27 (s, 1F)

[0357] .sup.13C NMR (75 MHz, CDCl.sub.3) : 168.0, 163.1, 160.4, 158.6, 157.1, 140.1, 132.9, 129.7, 127.1, 121.5, 116.8, 97.3, 95.5, 93.2, 64.8, 57.4, 57.1, 49.4, 29.1

[0358] MS: 439 [M+H.sup.+]

Compound 27

(3-chloro-4-fluorophenyl)(4-(((2-((6-(dimethylamino)pyridin-2-yl)oxy)ethyl)amino)methyl)-4-fluoropiperidin-1-yl)methanone

[0359] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-F-2)

[0360] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.47 (dd, J=1.8, 7.0 Hz, 1 H), 7.40-7.32 (m, 1 H), 7.31-7.26 (m, 1 H), 7.20-7.11 (m, 1 H), 5.99 (dd, J=7.6, 15.2 Hz, 2 H), 4.49 (br. s., 1 H), 4.40-4.32 (m, 2 H), 3.58 (br. s., 1 H), 3.46-3.06 (m, 2 H), 3.05-2.94 (m, 8 H), 2.83 (d, J=19.9 Hz, 2 H), 2.00 (br. s., 2 H), 1.72 (br. s., 3 H)

[0361] .sup.19F NMR (282 MHz, CDCl.sub.3) : 112.70 (s, 1F), 166.30 (s, 1F)

[0362] .sup.13C NMR (75 MHz, CDCl.sub.3) : 168.0, 162.5, 160.4, 158.3, 157.1, 139.8, 132.9, 129.7, 127.1, 121.5, 116.8, 97.2, 96.1, 95.5, 93.2, 64.6, 57.4, 57.1, 49.4, 37.9

[0363] MS: 453 [M+H.sup.+]

Compound 28

(3-chloro-4-fluorophenyl)(4-(((2-((6-(diethylamino)pyridin-2-yl)oxy)ethyl)amino)methyl)-4-fluoropiperidin-1-yl)methanone

[0364] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-C-4)

[0365] MS: 481 [M+H.sup.+]

Compound 29

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-((6-(pyrrolidin-1-yl)pyridin-2-yl)oxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0366] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-C-1)

[0367] .sup.1H NMR (300 MHz, CDCl.sub.3) 5: 7.48 (dd, J=1.9, 7.1 Hz, 1 H), 7.38-7.31 (m, 1 H), 7.31-7.26 (m, 1 H), 7.21-7.14 (m, 1 H), 5.94 (d, J=7.7 Hz, 1 H), 5.88 (d, J=8.2 Hz, 1 H), 4.51 (br. s., 1 H), 4.39-4.33 (m, 2 H), 3.64 (d, J=19.5 Hz, 1 H), 3.41 (t, J=6.8 Hz, 4 H), 3.17 (br. s., 2 H), 3.01 (t, J=5.3 Hz, 2 H), 2.88-2.77 (m, 2 H), 2.08-1.92 (m, 6 H), 1.63 (br. s., 3 H)

[0368] .sup.13C NMR (75 MHz, CDCl.sub.3) : 168.0, 162.9, 160.4, 156.7, 139.6, 133.0, 129.7, 127.1, 121.5, 116.7, 95.4, 93.2, 64.6, 57.4, 57.1, 49.5, 46.6

[0369] MS: 479 [M+H.sup.+]

Compound 30

(4-(((2-((6-(1H-pyrazol-1-yl)pyridin-2-yl)oxy)ethyl)amino)methyl)-4-fluoropiperidin-1-yl)(3-chloro-4-fluorophenyl)methanone

[0370] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-C-2)

[0371] .sup.1H NMR (300 MHz, CDCl.sub.3) : 8.45 (d, J=2.6 Hz, 1 H), 7.73-7.65 (m, 2 H), 7.51 (d, J=7.7 Hz, 1 H), 7.47 (dd, J=2.1, 6.9 Hz, 1 H), 7.32-7.26 (m, 1 H), 7.21-7.12 (m, 1 H), 6.62 (d, J=7.4 Hz, 1 H), 6.43 (dd, J=1.8, 2.6 Hz, 1 H), 4.61-4.37 (m, 3 H), 3.59 (br. s., 1 H), 3.44-3.15 (m, 2 H), 3.14-3.07 (m, 2 H), 2.97-2.85 (m, 2 H), 1.99-1.90 (m, 2 H), 1.85-1.43 (m, 3 H)

[0372] .sup.13C NMR (75 MHz, CDCl.sub.3) : 175.6, 168.2, 162.4, 160.5, 157.1, 149.3, 142.0, 141.2, 132.7, 129.7, 127.0, 121.5, 116.8, 107.7, 104.2, 95.2, 92.9, 65.0, 57.0, 56.5, 48.8

[0373] MS: 476 [M+H.sup.+]

Compound 31

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-((5-methyl-6-(methylamino)pyridin-2-yl)oxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0374] The title compound was prepared starting from the compound 50 (pre-compound-31).

[0375] MS: 453 [M+H.sup.+]

Compound 32

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-(pyrimidin-2-yloxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0376] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-18)

[0377] .sup.1H-NMR (300 MHz, CDCl.sub.3) : 8.52-8.51 (m., 2H), 7.49-7.47 (m., 1H), 7.29-7.28 (m., 1H), 7.20-7.16 (m., 1H), 6.97-6.94 (m., 1H), 4.51 (br. s., 1H), 4.48-4.45 (t., J=5.0 Hz, 2H), 3.73-3.15 (m., 3H), 3.08-3.05 (t., J=5.3 Hz, 2H), 2.85 (m., 2H), 2.01 (br. s. 2H) 1.77-1.50 (m., 3H).

[0378] MS: 411 [M+H.sup.+]

Compound 33

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-(pyrimidin-5-yloxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0379] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-A-2)

[0380] .sup.1H NMR (300 MHz, CDCl.sub.3) : 8.85 (s, 1 H), 8.41 (s, 2 H), 7.47 (dd, J=2.1, 6.9 Hz, 1 H), 7.32-7.26 (m, 1 H), 7.21-7.12 (m, 1 H), 4.50 (br. s., 1 H), 4.16 (t, J=5.0 Hz, 2 H), 3.60 (br. s., 1 H), 3.46-3.12 (m, 2 H), 3.07 (t, J=5.0 Hz, 2 H), 2.91-2.78 (m, 2 H), 2.00 (br. s., 2 H), 1.79-1.55 (m, 3 H)

[0381] .sup.13C NMR (75 MHz, CDCl.sub.3) : 168.1, 160.5, 157.1, 152.8, 151.7, 143.6, 132.8, 129.7, 127.1, 116.8, 95.5, 93.2, 68.3, 57.5, 57.2, 48.9

[0382] MS: 411 [M+H.sup.+]

Compound 34

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-(pyrimidin-4-yloxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0383] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-19)

[0384] MS: 411 [M+H.sup.+]

Compound 35

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-((5-methylpyrimidin-2-yl)oxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0385] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-20)

[0386] .sup.1H-NMR (CDCl.sub.3) : 8.32 (s, 2H), 7.49-7.47 (m, 1H), 7.32-7.28 (m, 1H), 7.20-7.16 (m, 1H), 4.54 (br s, 1H), 4.44-4.41 (t, J=5.0 Hz, 2H), 3.60-3.16 (m, 3H), 3.06-3.02 (t, J=5.3 Hz, 2H), 2.86 (m, 2H), 2.25 (s, 3H), 2.04 (br s, 2H) 1.81-1.52 (m, 3H).

[0387] MS: 425 [M+H.sup.+]

Compound 36

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-(pyrazin-2-yloxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0388] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-B-2)

[0389] .sup.1H NMR (300 MHz, CDCl.sub.3) : 8.22 (d, J=1.3 Hz, 1 H), 8.11 (d, J=2.8 Hz, 1 H), 8.06 (dd, J=1.4, 2.7 Hz, 1 H), 7.47 (dd, J=2.1, 6.9 Hz, 1 H), 7.32-7.26 (m, 1 H), 7.21-7.12 (m, 1 H), 4.63-4.36 (m, 3 H), 3.59 (br. s., 1 H), 3.27 (br. s., 2 H), 3.04 (t, J=5.3 Hz, 2 H), 2.90-2.77 (m, 2 H), 2.00 (br. s., 2 H), 1.64 (br. s., 3 H)

[0390] .sup.13C NMR (75 MHz, CDCl.sub.3) : 168.1, 160.3, 157.1, 140.5, 136.7, 135.9, 132.9, 129.7, 127.1, 121.5, 116.8, 95.5, 93.2, 65.7, 57.4, 57.1, 48.9

[0391] MS: 411 [M+H.sup.+]

Compound 37

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-(pyridazin-4-yloxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0392] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-A-1)

[0393] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.88 (d, J=3.1 Hz, 1 H), 7.76 (d, J=7.7 Hz, 1 H), 7.46 (dd, J=2.1, 6.9 Hz, 1 H), 7.31-7.24 (m, 1 H), 7.22-7.14 (m, 1 H), 6.42 (dd, J=3.2, 7.8 Hz, 1 H), 4.48 (br. s., 1 H), 4.08-4.00 (m, 2 H), 3.59 (br. s., 1 H), 3.42-3.14 (m, 2 H), 3.13-3.05 (m, 2 H), 2.81-2.67 (m, 2 H), 1.94 (br. s., 2 H), 1.70 (br. s., 3 H)

[0394] .sup.13C NMR (75 MHz, CDCl.sub.3) : 168.1, 160.5, 157.1, 150.1, 142.1, 132.7, 129.7, 127.1, 121.6, 117.0, 116.6, 95.4, 93.1, 59.5, 57.3, 57.0, 48.9

[0395] MS: 411 [M+H.sup.+]

Compound 38

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-(pyridazin-3-yloxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0396] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-21)

[0397] MS: 411 [M+H.sup.+]

Compound 39

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-((3-methoxyphenyl)thio)ethyl)amino)methyl)piperidin-1-yl)methanone

[0398] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-23)

[0399] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.48 (dd, J=1.9, 7.1 Hz, 1 H), 7.32-7.26 (m, 1 H), 7.18 (dt, J=6.4, 8.3 Hz, 2 H), 6.95-6.90 (m, 1 H), 6.90-6.88 (m, 1 H), 6.73 (ddd, J=1.0, 2.5, 8.3 Hz, 1 H), 4.62-4.37 (m, 1 H), 3.79 (s, 3 H), 3.54 (br. s., 1 H), 3.44-3.11 (m, 2 H), 3.09-3.02 (m, 2 H), 2.91-2.84 (m, 2 H), 2.80-2.69 (m, 2 H), 2.07-1.89 (m, 2 H), 1.60 (br. s., 3 H)

[0400] .sup.13C NMR (75 MHz, CDCl.sub.3) : 168.1, 160.4, 159.8, 157.1, 137.0, 132.9, 129.8, 127.0, 121.6, 121.4, 116.8, 115.0, 111.8, 95.4, 93.1, 57.1, 56.8, 55.3, 48.7, 34.0

[0401] MS: 455 [M+H.sup.+]

Compound 40

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-(pyridin-2-ylthio)ethyl)amino)methyl)piperidin-1-yl)methanone

[0402] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-22)

[0403] .sup.1H NMR (300 MHz, CDCl.sub.3) : 8.39 (td, J=1.2, 5.5 Hz, 1 H), 7.52-7.40 (m, 2 H), 7.32-7.26 (m, 1 H), 7.21-7.13 (m, 2 H), 6.97 (ddd, J=1.0, 5.0, 7.3 Hz, 1 H), 4.50 (br. s., 1 H), 3.59 (br. s., 1 H), 3.41-3.07 (m, 5 H), 2.96 (t, J=6.4 Hz, 2 H), 2.86-2.72 (m, 2 H), 1.97 (br. s., 2 H), 1.63 (br. s., 3 H)

[0404] .sup.13C NMR (75 MHz, CDCl.sub.3) : 168.0, 160.4, 158.4, 157.1, 149.4, 135.9, 132.9, 129.7, 127.1, 122.5, 121.5, 119.5, 116.8, 95.5, 93.2, 57.0, 56.7, 49.4, 30.0

[0405] MS: 426 [M+H.sup.+]

Compound 41

(3,4-dichlorophenyl)(4-fluoro-4-(((2-phenoxyethyl)amino)methyl)piperidin-1-yl)methanone

[0406] The title compound was prepared starting from the compound (IIa-1) and amine (IIb-1)

[0407] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.54-7.45 (m, 2 H), 7.33-7.26 (m, 2 H), 7.23 (dd, J=2.1, 8.2 Hz, 1 H), 7.00-6.86 (m, 3 H), 4.52 (br. s., 1 H), 4.07 (t, J=5.1 Hz, 2 H), 3.58 (br. s., 1 H), 3.44-3.10 (m, 2 H), 3.03 (t, J=5.1 Hz, 2 H), 2.91-2.78 (m, 2 H), 2.02 (br. s., 2 H), 1.61 (s, 3 H)

[0408] MS: 426 [M+H.sup.+]

Compound 42

(3,4-dichlorophenyl)(4-fluoro-4-(((2-(3-fluorophenoxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0409] The title compound was prepared starting from the compound (IIa-1) and amine (IIb-4)

[0410] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.57-7.42 (m, 2 H), 7.26-7.17 (m, 2 H), 6.73-6.55 (m, 3 H), 4.52 (br. s., 1 H), 4.04 (t, J=5.1 Hz, 2 H), 3.59 (br. s., 1 H), 3.44-3.10 (m, 2 H), 3.03 (t, J=5.0 Hz, 2 H), 2.91-2.75 (m, 2 H), 2.01 (br. s., 2 H), 1.62 (br. s., 3 H)

[0411] MS: 444 [M+H.sup.+]

Compound 43

(4-(((2-(3-chlorophenoxy)ethyl)amino)methyl)-4-fluoropiperidin-1-yl)(3,4-dichlorophenyl)methanone

[0412] The title compound was prepared starting from the compound (IIa-1) and amine (IIb-3)

[0413] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.53-7.46 (m, 2 H), 7.25-7.15 (m, 2 H), 6.97-6.87 (m, 2 H), 6.78 (ddd, J=1.0, 2.4, 8.3 Hz, 1 H), 4.52 (br. s., 1 H), 4.04 (t, J=5.1 Hz, 2 H), 3.59 (br. s., 1 H), 3.46-3.12 (m, 2 H), 3.02 (t, J=5.1 Hz, 2 H), 2.91-2.76 (m, 2 H), 2.00 (d, J=12.3 Hz, 2 H), 1.61 (br. s., 3 H)

[0414] MS: 460 [M+H.sup.+]

Compound 44

(4-(((2-((1H-indo1-4-yl)oxy)ethyl)amino)methyl)-4-fluoropiperidin-1-yl)(3-chloro-4-fluorophenyl)methanone

[0415] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-24)

[0416] .sup.1H NMR (300 MHz, CD.sub.3OD) : 7.57 (dd, J=1.8, 7.0 Hz, 1 H), 7.40-7.27 (m, 2 H), 7.13-7.06 (m, 1 H), 7.03-6.96 (m, 2 H), 6.53-6.47 (m, 2 H), 4.41 (br. s., 1 H), 4.22 (t, J=5.3 Hz, 2 H), 3.67-3.33 (m, 2 H), 3.27-3.14 (m, 1 H), 3.09 (t, J=5.3 Hz, 2 H), 2.97-2.85 (m, 2 H), 2.04 -1.69 (m, 4 H) NH protons not detected

[0417] .sup.19F NMR (282 MHz, CDCl.sub.3) : 112.58 (s, 1F), 166.43 (s, 1F)

[0418] .sup.13C NMR (75 MHz, CD.sub.3OD) : 168.5, 152.1, 137.8, 135.9, 135.5, 133.0, 129.3, 127.2, 122.6, 121.6, 121.0, 118.8, 116.5, 104.7, 99.9, 98.1, 66.9, 56.7, 56.2, 48.9

[0419] MS: 448 [M+H.sup.+]

Compound 45

(3-chloro-4-fluorophenyl)(4-(((2-(3-(dimethylamino)phenoxy)ethyl)amino)methyl)-4-fluoropiperidin-1-yl)methanone

[0420] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-25)

[0421] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.48 (dd, J=2.1, 6.7 Hz, 1 H), 7.34-7.25 (m, 1 H), 7.22-7.07 (m, 2 H), 6.40-6.32 (m, 1 H), 6.31-6.22 (m, 2 H), 4.50 (br. s., 1 H), 4.06 (t, J=5.0 Hz, 2 H), 3.60 (br. s., 1 H), 3.47-3.08 (m, 2 H), 3.02 (t, J=5.0 Hz, 2 H), 2.93 (s, 6 H), 2.84 (d, J=19.9 Hz, 2 H), 2.00 (br. s., 2 H), 1.87-1.47 (m, 3 H)

[0422] .sup.13C NMR (75 MHz, CDCl.sub.3) : 168.1, 160.4, 159.8, 157.1, 152.0, 132.9, 129.7, 127.1, 121.5, 116.8, 105.9, 101.9, 99.6, 95.5, 93.2, 67.0, 57.4, 57.1, 49.4, 40.6

[0423] MS: 452 [M+H.sup.+]

Compound 46

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-(3-(trifluoromethyl)phenoxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0424] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-26)

[0425] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.48 (dd, J=2.1, 6.7 Hz, 1 H), 7.42-7.34 (m, 1 H), 7.33-7.26 (m, 1 H), 7.24-7.16 (m, 2 H), 7.13 (d, J=3.5 Hz, 1 H), 7.06 (dd, J=2.9, 8.2 Hz, 1 H), 4.48 (br. s., 1 H), 4.09 (t, J=5.0 Hz, 2 H), 3.75-3.48 (m, 1 H), 3.47-3.10 (m, 2 H), 3.05 (t, J=5.0 Hz, 2 H), 2.91-2.76 (m, 2 H), 2.07-1.95 (m, 2 H), 1.83-1.44 (m, 3 H)

[0426] .sup.13C NMR (75 MHz, CDCl.sub.3) : 168.1, 160.5, 158.9, 157.1, 132.9, 130.0, 129.7, 127.1, 121.5, 117.9, 117.6, 116.9, 116.6, 111.3, 95.5, 93.2, 67.7, 57.5, 57.2, 49.1

[0427] MS: 477 [M+H.sup.+]

Compound 47

3-(2-(((1-(3-chloro-4-fluorobenzoyl)-4-fluoropiperidin-4-yl)methyl)amino)ethoxy)benzamide

[0428] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-27)

[0429] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.46 (dd, J=1.8, 7.0 Hz, 1 H), 7.42-7.37 (m, 1 H), 7.35-7.23 (m, 3 H), 7.20-7.11 (m, 1 H), 7.04 (td, J=2.9, 5.9 Hz, 1 H), 6.43-6.04 (m, 2 H), 4.49 (br. s., 1 H), 4.09 (t, J=5.3 Hz, 2 H), 3.58 (br. s., 1 H), 3.45-3.08 (m, 2 H), 3.02 (t, J=5.3 Hz, 2 H), 2.83 (d, J=19.9 Hz, 2 H), 1.98 (br. s., 3 H), 1.81-1.48 (m, 2 H)

[0430] .sup.19F NMR (282 MHz, CDCl.sub.3) : 112.58 (s, 1F), 166.41 (s, 1F)

[0431] MS: 452 [M+H.sup.+]

Compound 48

2-(2-(((1-(3-chloro-4-fluorobenzoyl)-4-fluoropiperidin-4-yl)methyl)amino)ethoxy)benzamide

[0432] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-28)

[0433] .sup.1H NMR (300 MHz, DMSO-d.sub.6) : 7.95 (s, 1 H), 7.81 (dd, J=1.8, 7.6 Hz, 1 H), 7.65 (dd, J=1.8, 7.0 Hz, 1 H), 7.54 (br. s., 1 H), 7.50-7.37 (m, 3 H), 7.12 (d, J=8.2 Hz, 1 H), 7.00 (t, J=7.9 Hz, 1 H), 4.33-4.07 (m, 3 H), 3.38 (br. s., 1 H), 3.27-2.97 (m, 2 H), 2.93 (t, J=5.3 Hz, 2 H), 2.81-2.66 (m, 2 H), 2.13 (br. s., 1 H), 1.96-1.64 (m, 4 H)

[0434] .sup.13C NMR (75 MHz, DMSO-d.sub.6) : 167.2, 166.8, 159.7, 157.2, 134.4, 132.9, 131.3, 129.7, 128.2, 123.1, 121.0, 120.2, 117.4, 113.8, 96.7, 94.4, 68.5, 56.9, 56.6, 49.0

[0435] MS: 452 [M+H.sup.+]

Compound 49 (Pre-Compound 26)

(4-(((2-((6-(benzyl(methyl)amino)pyridin-2-yl)oxy)ethyl)amino)methyl)-4-fluoropiperidin-1-yl)(3-chloro-4-fluorophenyl)methanone

[0436] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-C-6).

[0437] 1H-NMR (300 MHz, CDCl.sub.3) : 7.15-7.49 (4 m, 9 H), 6.00-6.05 (dd, 2 H), 4.79 (s, 2 H), 4.48 (bs, 1 H), 4.32 (t, 2 H), 3.02-3.62 (m, 4 H), 3.00 (s, 3 H), 2.95 (t, 2 H), 1.52-2.02 (m, 4 H).

[0438] MS: 530 [M+H.sup.+]

Compound 50 (Pre-Compound 31)

(4-(((2-((6-(benzyl(methyl)amino)-5-methylpyridin-2-yl)oxy)ethyl)amino)methyl)-4-fluoropiperidin-1-yl)(3-chloro-4-fluorophenyl)methanone

[0439] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-C-5)

[0440] MS: 544 [M+H.sup.+]

Compound 51

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-(2-(methylamino)phenoxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0441] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-D-1)

[0442] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.52-7.44 (m, 1 H), 7.34-7.26 (m, 1 H), 7.23-7.12 (m, 1 H), 6.96-6.87 (m, 1 H), 6.78 (dd, J=1.5, 7.9 Hz, 1 H), 6.64 (dq, J=1.8, 7.8 Hz, 2 H), 4.50 (br. s., 1 H), 4.09 (t, J=5.3 Hz, 2 H), 3.60 (br. s., 1 H), 3.45-3.13 (m, 2 H), 3.05 (t, J=5.0 Hz, 2 H), 2.90-2.75 (m, 5 H), 2.00 (br. s., 3 H), 1.64 (m., J=15.8 Hz, 3 H)

[0443] .sup.19F NMR (282 MHz, CDCl.sub.3) : 112.58 (s, 1F), 166.62 (s, 1F)

[0444] MS: 438 [M+H.sup.+]

Compound 52

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-(3-(methylamino)phenoxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0445] The title compound was prepared from the compound 75.

[0446] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.48 (dd, J=1.8, 7.0 Hz, 1 H), 7.33-7.25 (m, 1 H), 7.19 (td, J=8.3, 11.6 Hz, 2 H), 6.86-6.77 (m, 2 H), 6.74-6.65 (m, 1 H), 4.51 (br. s., 1 H), 4.04 (t, J=5.3 Hz, 2 H), 3.58 (br. s., 1 H), 3.35 (br. s., 1 H), 3.23 (s, 3 H), 3.02 (t, J=5.0 Hz, 2 H), 2.91-2.75 (m, 2 H), 2.00 (br. s., 2 H), 1.64 (br. s., 3 H)

[0447] .sup.19F NMR (282 MHz, CDCl.sub.3) : 114.75 (s, 1F), 166.64 (s, 1F)

[0448] .sup.13C NMR (75 MHz, CDCl.sub.3) : 169.0, 160.0, 156.1, 150.7, 129.7, 129.3, 128.8, 127.1, 122.5, 111.6, 105.9, 102.8, 98.9, 95.6, 93.3, 67.0, 57.5, 57.2, 56.2, 49.4

[0449] MS: 438 [M+H.sup.+]

Compound 53

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-(phenylamino)ethyl)amino)methyl)piperidin-1-yl)methanone

[0450] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-29)

[0451] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.48 (dd, J=1.8, 7.0 Hz, 1 H), 7.33-7.24 (m, 1 H), 7.22-7.13 (m, 3 H), 6.76-6.67 (m, 1 H), 6.66-6.58 (m, 2 H), 4.51 (br. s., 1 H), 3.60 (br. s., 1 H), 3.35 (d, J=15.8 Hz, 1 H), 3.24-3.17 (m, 2 H), 3.17-3.02 (m, 1 H), 2.91 (t, J=5.6 Hz, 2 H), 2.85-2.71 (m, 2 H), 2.02 (br. s., 3 H), 1.84-1.41 (m, 3 H)

[0452] .sup.13C NMR (75 MHz, CDCl.sub.3) : 168.1, 160.5, 157.1, 148.3, 129.7, 129.3, 127.1, 127.1, 117.6, 116.8, 113.0, 95.4, 93.2, 57.1, 56.9, 48.9, 43.3

[0453] MS: 408 [M+H.sup.+]

Compound 54

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-(pyridin-2-ylamino)ethyl)amino)methyl)piperidin-1-yl)methanone

[0454] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-30)

[0455] .sup.1H NMR (300 MHz, CDCl.sub.3) : 8.08-8.00 (m, 1 H), 7.47 (dd, J=2.1, 6.7 Hz, 1 H), 7.44-7.35 (m, 1 H), 7.32-7.26 (m, 1 H), 7.20-7.11 (m, 1 H), 6.55 (dd, J=5.3, 6.4 Hz, 1 H), 6.39 (d, J=8.2 Hz, 1 H), 5.10 (br. s., 1 H), 4.48 (br. s., 1 H), 3.57 (br. s., 1 H), 3.40-3.08 (m, 4 H), 3.00 (br. s., 1 H), 2.89 (t, J=5.9 Hz, 2 H), 2.78 (d, J=1.0 Hz, 2 H), 2.67 (br. s., 1 H), 2.01 (s, 2 H), 1.59 (d, J=17.0 Hz, 2 H)

[0456] .sup.19F NMR (282 MHz, CDCl.sub.3) : 112.61 (s, 1F); 166.72 (s, 1F)

[0457] MS: 409 [M+H.sup.+]

Compound 55

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((3-(pyridin-2-yl)propyl)amino)methyl)piperidin-1-yl)methanone

[0458] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-31)

[0459] .sup.1H NMR (300 MHz, CDCl.sub.3) : 8.53-8.43 (m, 1 H), 7.57 (dt, J=1.8, 7.6 Hz, 1 H), 7.46 (dd, J=1.8, 7.0 Hz, 1 H), 7.32-7.24 (m, 1 H), 7.21-7.04 (m, 3 H), 4.47 (br. s., 1 H), 3.57 (br. s., 1 H), 3.44-3.05 (m, 2 H), 2.80 (dd, J=7.9, 15.5 Hz, 3 H), 2.73-2.60 (m, 3 H), 2.07-1.84 (m, 4 H), 1.69 (br. s., 3 H)

[0460] .sup.19F NMR (282 MHz, CDCl.sub.3) : 112.68 (s, 1F), 166.56 (s, 1F)

[0461] .sup.13C NMR (75 MHz, CDCl.sub.3) : 168.0, 161.7, 160.4, 157.1, 149.2, 136.3, 132.9, 129.7, 127.1, 122.8, 121.0, 116.8, 95.5, 93.2, 57.5, 57.2, 49.8, 35.9, 29.9

[0462] MS: 408 [M+H.sup.+]

Compound 56

4-(2-(((1-(3-chloro-4-fluorobenzoyl)-4-fluoropiperidin-4-yl)methyl)amino)ethoxy)indolin-2-one

[0463] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-32)

[0464] MS: 464 [M+H.sup.+]

Compound 57

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-(indolin-4-yloxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0465] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-33)

[0466] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.48 (dd, J=2.3, 7.0 Hz, 1 H), 7.35-7.26 (m, 1 H), 7.23-7.11 (m, 1 H), 6.97 (t, J=7.9 Hz, 1 H), 6.29 (dd, J=7.9, 14.4 Hz, 2 H), 4.51 (br. s., 1 H), 4.08 (t, J=5.0 Hz, 2 H), 3.56 (t, J=8.5 Hz, 3 H), 3.47-3.08 (m, 2 H), 3.06-2.93 (m, 4 H), 2.91-2.76 (m, 2 H), 2.02 (br. s., 2 H), 1.85-1.44 (m, 2 H) NH protons not detected

[0467] .sup.19F NMR (282 MHz, CDCl.sub.3) : 112.63 (s, 1F), 166.68 (s, 1F)

[0468] MS: 450 [M+H.sup.+]

Compound 58

N-(6-(2-(((1-(3-chloro-4-fluorobenzoyl)-4-fluoropiperidin-4-yl)methyl)amino)ethoxy)pyridin-2-yl)acetamide

[0469] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-F-3)

[0470] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.78 (br. s., 1 H), 7.71 (d, J=7.6 Hz, 1 H), 7.56 (t, J=7.9 Hz, 1 H), 7.46 (dd, J=1.8, 7.0 Hz, 1 H), 7.33-7.26 (m, 1 H), 7.21-7.08 (m, 1 H), 6.45 (d, J=8.8 Hz, 1 H), 4.50 (br. s., 1 H), 4.27 (t, J=5.0 Hz, 2 H), 3.58 (br. s., 1 H), 3.47-3.03 (m, 2 H), 2.98 (t, J=5.3 Hz, 2 H), 2.88-2.71 (m, 2 H), 2.17 (s, 3 H), 1.95 (br. s., 3 H), 1.79-1.45 (m, 2 H)

[0471] .sup.19F NMR (282 MHz, CDCl.sub.3) : 112.57 (s, 1F), 166.35 (s, 1F)

[0472] .sup.13C NMR (75 MHz, CDCl.sub.3) : 168.4, 168.0, 162.3, 160.4, 157.1, 148.9, 141.0, 132.9, 129.7, 127.1, 121.5, 116.8, 105.7, 95.5, 93.3, 65.4, 57.4, 57.1, 49.2, 24.7

[0473] MS: 467 [M+H.sup.+]

Compound 59

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((3-phenylpropyl)amino)methyl)piperidin-1-yl)methanone

[0474] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-34)

[0475] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.48 (dd, J=2.3, 7.0 Hz, 1 H), 7.34-7.23 (m, 3 H), 7.22-7.10 (m, 4 H), 4.50 (br. s., 1 H), 3.60 (d, J=19.9 Hz, 1 H), 3.46-3.08 (m, 2 H), 2.80-2.60 (m, 6 H), 2.09-1.90 (m, 2 H), 1.87-1.45 (m, 5 H)

[0476] .sup.13C NMR (75 MHz, CDCl.sub.3) : 168.0, 160.4, 157.1, 142.0, 132.9, 129.7, 128.3, 127.1, 125.8, 121.5, 116.8, 95.5, 93.2, 57.6, 57.3, 49.8, 33.5, 31.5

[0477] MS: 407 [M+H.sup.+]

Compound 60

(3-chloro-4-fluorophenyl)(4-(((2-((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)oxy)ethyl)amino)methyl)-4-fluoropiperidin-1-yl)methanone

[0478] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-35)

[0479] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.48 (dd, J=1.8, 7.0 Hz, 1 H), 7.32-7.25 (m, 1 H), 7.22-7.13 (m, 1 H), 6.81-6.70 (m, 3 H), 4.50 (br. s., 1 H), 4.15 (t, J=5.0 Hz, 2 H), 3.71-3.50 (m, 1 H), 3.48-3.08 (m, 2 H), 3.06-2.96 (m, 4 H), 2.83 (d, J=19.9 Hz, 2 H), 1.99 (br. s., 2 H), 1.83 (br. s., 3 H), 1.49 (s, 6 H)

[0480] .sup.13C NMR (75 MHz, CDCl.sub.3) : 168.0, 160.4, 157.1, 147.9, 143.5, 132.9, 129.7, 128.6, 127.1, 120.3, 118.1, 116.8, 113.7, 95.5, 93.2, 87.3, 69.0, 57.4, 57.1, 49.2, 43.2, 28.3

[0481] MS: 479 [M+H.sup.+]

Compound 61

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-(2-fluorophenoxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0482] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-36)

[0483] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.51-7.45 (m, 1 H), 7.33-7.25 (m, 1 H), 7.21-7.13 (m, 1 H), 7.11-7.01 (m, 2 H), 7.01-6.86 (m, 2 H), 4.50 (br. s., 1 H), 3.58 (br. s., 1 H), 3.47-3.14 (m, 2 H), 3.05 (t, J=5.0 Hz, 2 H), 2.86 (d, J=19.9 Hz, 2 H), 2.00 (s, 2 H), 1.83-1.51 (m, 3 H)

[0484] .sup.13C NMR (75 MHz, CDCl.sub.3) : 160.4, 157.1, 154.5, 151.2, 146.8, 132.9, 129.7, 127.1, 124.3, 121.5, 116.9, 116.6, 116.4, 116.1, 115.3, 95.5, 93.2, 69.2, 57.4, 57.1, 49.2

[0485] MS: 427 [M+H.sup.+]

Compound 62

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-(2-chlorophenoxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0486] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-37)

[0487] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.47 (dd, J=1.8, 7.0 Hz, 1 H), 7.35 (dd, J=1.8, 7.6 Hz, 1 H), 7.32-7.26 (m, 1 H), 7.24-7.12 (m, 2 H), 6.96-6.84 (m, 2 H), 4.49 (br. s., 1 H), 4.12 (t, J=5.0 Hz, 2 H), 3.59 (d, J=5.9 Hz, 1 H), 3.45-3.12 (m, 2 H), 3.07 (t, J=5.0 Hz, 2 H), 2.95-2.80 (m, 2 H), 2.00 (br. s., 2 H), 1.84 (s, 1 H), 1.77-1.53 (m, 2 H)

[0488] .sup.13C NMR (75 MHz, CDCl.sub.3) : 168.0, 160.4, 157.1, 154.2, 133.0, 130.3, 129.7, 127.8, 127.0, 121.7, 116.9, 116.6, 113.7, 95.5, 93.2, 68.9, 57.4, 57.1, 49.0

[0489] MS: 443 [M+H.sup.+]

Compound 63

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-(m-tolyloxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0490] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-38)

[0491] .sup.1H NMR (300 MHz, CD.sub.3OD) : 7.59 (dd, J=1.8, 7.0 Hz, 1 H), 7.45-7.37 (m, 1 H), 7.36-7.28 (m, 1 H), 7.17-7.06 (m, 1 H), 6.78-6.66 (m, 3 H), 4.43 (br. s., 1 H), 4.05 (t, J=5.3 Hz, 2 H), 3.68-3.49 (m, 1 H), 3.39 (br. s., 1 H), 3.28-3.09 (m, J=5.3 Hz, 1 H), 3.00 (t, J=5.6 Hz, 2 H), 2.91-2.79 (m, 2 H), 2.29 (s, 3 H), 2.06-1.62 (m, 4 H) NH proton not detected

[0492] .sup.13C NMR (75 MHz, CD.sub.3OD) : 168.6, 160.4, 158.8, 157.0, 139.2, 133.0, 129.1, 127.3, 121.3, 121.0, 116.6, 114.9, 111.1, 95.0, 92.7, 66.5, 56.7, 56.4, 48.8, 20.2

[0493] MS: 423 [M+H.sup.+]

Compound 64

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-(4-fluorophenoxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0494] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-39)

[0495] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.48 (dd, J=2.3, 7.0 Hz, 1 H), 7.33-7.24 (m, 1 H), 7.22-7.11 (m, 1 H), 7.01-6.90 (m, 2 H), 6.88-6.78 (m, 2 H), 4.51 (br. s., 1 H), 4.02 (t, J=5.3 Hz, 2 H), 3.62 (d, J=19.3 Hz, 1 H), 3.48-3.10 (m, 2 H), 3.01 (t, J=5.0 Hz, 2 H), 2.83 (d, J=19.9 Hz, 2 H), 2.06-1.94 (m, 2 H), 1.83-1.45 (m, 3 H)

[0496] .sup.13C NMR (75 MHz, CDCl.sub.3) : 168.1, 160.5, 158.9, 157.1, 155.7, 154.9, 132.9, 129.7, 127.1, 121.5, 116.8, 115.8, 115.5, 95.5, 93.2, 68.0, 57.5, 57.2, 49.3

[0497] MS: 427 [M+H.sup.+]

Compound 65

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-(4-chlorophenoxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0498] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-40)

[0499] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.48 (dd, J=2.1, 6.7 Hz, 1 H), 7.34-7.12 (m, 4 H), 6.87-6.77 (m, 2 H), 4.50 (br. s., 1 H), 4.02 (t, J=5.0 Hz, 2 H), 3.74-3.49 (m, 1 H), 3.24 (br. s., 2 H), 3.02 (t, J=5.0 Hz, 2 H), 2.91-2.74 (m, 2 H), 2.00 (br. s., 2 H), 1.88-1.44 (m, 3 H)

[0500] .sup.13C NMR (75 MHz, CDCl.sub.3) : 168.1, 160.5, 157.4, 157.1, 132.9, 129.7, 129.3, 127.1, 125.8, 121.5, 116.9, 116.6, 115.7, 95.5, 93.2, 67.7, 57.5, 57.2, 49.2

[0501] MS: 443 [M+H.sup.+]

Compound 66

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-((6-methoxypyridin-2-yl)oxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0502] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-41)

[0503] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.52-7.43 (m, 2 H), 7.33-7.23 (m, 1 H), 7.22-7.12 (m, 1 H), 6.29 (dd, J=1.5, 7.9 Hz, 2 H), 4.49 (br. s., 1 H), 4.41-4.32 (m, 2 H), 3.88 (s, 3 H), 3.67-3.53 (m, 1 H), 3.46-3.10 (m, 2 H), 3.02 (t, J=5.3 Hz, 2 H), 2.90-2.76 (m, 2 H), 1.99 (br. s., 2 H), 1.83-1.56 (m, 3 H)

[0504] .sup.13C NMR (75 MHz, CDCl.sub.3) : 168.1, 163.0, 162.6, 160.4, 157.1, 141.0, 132.9, 129.7, 127.1, 121.5, 116.8, 101.2, 95.4, 93.1, 65.2, 57.4, 57.1, 53.4, 49.2

[0505] MS: 440 [M+H.sup.+]

Compound 67

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-((5-methoxypyridin-2-yl)oxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0506] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-42)

[0507] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.77 (d, J=2.9 Hz, 1 H), 7.47 (dd, J=1.8, 7.0 Hz, 1 H), 7.33-7.26 (m, 1 H), 7.23-7.12 (m, 2 H), 6.67 (d, J=9.4 Hz, 1 H), 4.51 (br. s., 1 H), 4.33 (t, J=5.3 Hz, 2 H), 3.80 (s, 3 H), 3.70-3.48 (m, 1 H), 3.45-3.06 (m, 2 H), 3.00 (t, J=5.3 Hz, 2 H), 2.83 (d, J=1.0 Hz, 2 H), 2.01 (br. s., 2 H), 1.62 (br. s., 3 H)

[0508] .sup.19F NMR (282 MHz, CDCl.sub.3) : 112.66 (s, 1F), 166.47 (s, 1F)

[0509] .sup.13C NMR (75 MHz, DMSO-d.sub.6) : 163.3, 155.7, 153.4, 146.4, 128.2, 126.3, 125.0, 122.3, 121.9, 116.8, 112.0, 106.3, 90.8, 88.5, 60.5, 52.7, 52.4, 51.5, 44.6

[0510] MS: 440 [M+H.sup.+]

Compound 68

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-((4-methoxypyridin-2-yl)oxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0511] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-B-3)

[0512] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.88 (d, J=6.4 Hz, 1 H), 7.44 (dd, J=2.1, 6.7 Hz, 1 H), 7.29-7.20 (m, 1 H), 7.19-7.08 (m, 1 H), 6.44 (dd, J=2.3, 5.9 Hz, 1 H), 6.17 (d, J=1.8 Hz, 1 H), 4.45 (br. s., 1 H), 4.37-4.28 (m, 2 H), 3.77 (s, 3 H), 3.67-3.45 (m, 1 H), 3.44-3.02 (m, 2 H), 2.97 (t, J=5.3 Hz, 2 H), 2.79 (d, J=19.9 Hz, 2 H), 2.38 (br. s., 1 H), 1.97 (br. s., 2 H), 1.60 (d, J=17.0 Hz, 2 H)

[0513] .sup.13C NMR (75 MHz, CDCl.sub.3) : 168.1, 165.5, 160.4, 157.1, 147.2, 132.7, 129.6, 127.1, 121.5, 116.8, 106.3, 95.3, 94.1, 93.0, 65.1, 57.2, 56.9, 55.2, 49.1

[0514] MS: 440 [M+H.sup.+]

Compound 69

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-((5-fluoropyridin-2-yl)oxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0515] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-43)

[0516] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.96 (d, J=2.9 Hz, 1 H), 7.47 (dd, J=2.1, 6.7 Hz, 1 H), 7.38-7.26 (m, 2 H), 7.22-7.11 (m, 1 H), 6.70 (dd, J=3.2, 9.1 Hz, 1 H), 4.50 (br. s., 1 H), 4.39-4.28 (m, 2 H), 3.74-3.48 (m, 1 H), 3.46-3.06 (m, 2 H), 3.00 (t, J=5.3 Hz, 2 H), 2.90-2.74 (m, 2 H), 2.01 (br. s., 2 H), 1.62 (br. s., 3 H)

[0517] .sup.19F NMR (282 MHz, CDCl.sub.3) : 112.63 (s, 1F), 139.15 (s, 1F), 166,59 (s, 1F)

[0518] .sup.13C NMR (75 MHz, CDCl.sub.3) : 168.1, 160.1, 157.1, 153.8, 133.3, 132.9, 129.7, 127.1, 126.6, 121.5, 116.8, 111.5, 95.5, 93.2, 65.7, 57.4, 57.1, 49.1

[0519] MS: 428 [M+H.sup.+]

Compound 70

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-((4-fluoropyridin-2-yl)oxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0520] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-44)

[0521] .sup.1H NMR (300 MHz, CDCl.sub.3) : 8.08 (dd, J=5.9, 8.8 Hz, 1 H), 7.47 (dd, J=1.8, 7.0 Hz, 1 H), 7.33-7.27 (m, 1 H), 7.23-7.11 (m, 1 H), 6.65 (ddd, J=2.3, 5.7, 7.8 Hz, 1 H), 6.43 (dd, J=2.3, 10.0 Hz, 1 H), 4.51 (br. s., 1 H), 4.44-4.34 (m, 2 H), 3.58 (br. s., 1 H), 3.47-3.07 (m, 2 H), 3.01 (t, J=5.3 Hz, 2 H), 2.83 (d, J=19.9 Hz, 2 H), 2.01 (br. s., 2 H), 1.58 (br. s., 3 H)

[0522] .sup.19F NMR (282 MHz, CDCl.sub.3) : 101.70 (s, 1F), 112.61 (s, 1F), 166.62 (s, 1F)

[0523] .sup.13C NMR (75 MHz, CDCl.sub.3) : 171.9, 168.3, 165.7, 160.4, 148.8, 132.9, 129.7, 127.1, 121.5, 116.8, 106.2, 97.8, 95.5, 93.2, 65.9, 57.4, 57.1, 49.1

[0524] MS: 428 [M+H.sup.+]

Compound 71

(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-((6-(trifluoromethyl)pyridin-2-yl)oxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0525] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-45)

[0526] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.70 (t, J=7.6 Hz, 1 H), 7.47 (dd, J=1.8, 7.0 Hz, 1 H), 7.33-7.26 (m, 1 H), 7.25-7.12 (m, 2 H), 6.91 (d, J=8.2 Hz, 1 H), 4.64-4.35 (m, 3 H), 3.59 (br. s., 1 H), 3.47-3.09 (m, 2 H), 3.04 (t, J=5.6 Hz, 2 H), 2.84 (d, J=19.9 Hz, 2 H), 2.00 (br. s., 2 H), 1.87-1.53 (m, 3 H)

[0527] .sup.13C NMR (75 MHz, CDCl.sub.3) : 168.1, 163.6, 160.4, 157.1, 139.5, 132.9, 129.7, 127.1, 121.5, 116.8, 114.6, 113.3, 95.5, 93.2, 65.7, 57.3, 57.0, 48.9

[0528] MS:478 [M+H.sup.+]

Compound 72

(3-chloro-4-fluorophenyl)(4-(((2-((6-chloropyridin-2-yl)oxy)ethyl)amino)methyl)-4-fluoropiperidin-1-yl)methanone

[0529] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-46)

[0530] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.55-7.41 (m, 2 H), 7.33-7.25 (m, 1 H), 7.21-7.12 (m, 1 H), 6.88 (d, J=7.6 Hz, 1 H), 6.64 (d, J=8.2 Hz, 1 H), 4.50 (br. s., 1 H), 4.41-4.34 (m, 2 H), 3.60 (d, J=19.9 Hz, 1 H), 3.46-3.09 (m, 2 H), 3.04-2.95 (m, 2 H), 2.89-2.73 (m, 2 H), 1.99 (br. s., 2 H), 1.82-1.49 (m, 3 H)

[0531] .sup.13C NMR (75 MHz, CDCl.sub.3) : 168.0, 163.3, 160.4, 157.1, 148.3, 140.7, 132.9, 129.7, 127.1, 121.5, 116.8, 116.5, 109.1, 95.5, 93.2, 65.8, 57.3, 57.0, 49.0

[0532] MS: 444 [M+H.sup.+]

Compound 73

(3-chloro-4-fluorophenyl)(4-(((2-((6-methylpyridin-2-yl)oxy)ethyl)amino)methyl)-4-fluoropiperidin-1-yl)methanone

[0533] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-47)

[0534] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.51-7.40 (m, 2 H), 7.32-7.26 (m, 1 H), 7.17 (t, J=8.5 Hz, 1 H), 6.71 (d, J=7.0 Hz, 1 H), 6.51 (d, J=8.2 Hz, 1 H), 4.48 (br. s., 1 H), 4.41-4.33 (m, 2 H), 3.58 (br. s., 1 H), 3.47-3.06 (m, 2 H), 3.01 (t, J=5.3 Hz, 2 H), 2.90-2.76 (m, 2 H), 2.42 (s, 3 H), 2.00 (br. s., 2 H), 1.85-1.52 (m, 3 H)

[0535] .sup.13C NMR (75 MHz, CDCl.sub.3) : 168.0, 163.2, 160.4, 156.7, 138.9, 132.9, 129.7, 127.1, 121.5, 116.8, 115.9, 107.0, 95.5, 93.2, 65.0, 57.4, 57.1, 49.4, 24.1

[0536] MS: 424 [M+H.sup.+]

Compound 74

(3,4-dichlorophenyl)(4-fluoro-4-(((2-(pyridin-2-yloxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0537] The title compound was prepared starting from the compound (IIa-1) and amine (IIb-11)

[0538] .sup.1H NMR (300 MHz, CDCl.sub.3) : 8.17-8.08 (m, 1 H), 7.61-7.53 (m, 1 H), 7.52-7.44 (m, 2 H), 7.23 (dd, J=1.8, 8.2 Hz, 1 H), 6.91-6.82 (m, 1 H), 6.77-6.69 (m, 1 H), 4.50 (br. s., 1 H), 4.43-4.34 (m, 2 H), 3.71-3.47 (m, 1 H), 3.47-3.07 (m, 2 H), 3.03 (t, J=5.3 Hz, 2 H), 2.84 (d, J=1.0 Hz, 2 H), 2.00 (br. s., 2 H), 1.61 (br. s., 3 H)

[0539] .sup.19F NMR (282 MHz, CDCl.sub.3) : 166.55 (s, 1F)

[0540] .sup.13C NMR (75 MHz, CDCl.sub.3) : 167.9, 163.6, 146.8, 138.7, 135.6, 134.1, 133.0, 130.6, 129.1, 126.2, 116.9, 111.0, 95.5, 93.2, 64.9, 57.3, 57.1, 49.2

[0541] MS: 426 [M+H.sup.+]

Compound 75 (Pre-Compound 52)

(3,4-dichlorophenyl)(4-fluoro-4-(((2-(pyridin-2-yloxy)ethyl)amino)methyl)piperidin-1-yl)methanone

[0542] The title compound was prepared starting from the compound (IIa-2) and amine (IIb-E-1)

[0543] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.48 (dd, J=1.8, 7.0 Hz, 1 H), 7.33-7.25 (m, 1 H), 7.19 (td, J=8.3, 11.6 Hz, 2 H), 6.86-6.77 (m, 2 H), 6.74-6.65 (m, 1 H), 4.51 (br. s., 1 H), 4.04 (t, J=5.3 Hz, 2 H), 3.58 (br. s., 1 H), 3.35 (br. s., 1 H), 3.23 (s, 3 H), 3.20-3.08 (m, 1 H), 3.02 (t, J=5.0 Hz, 2 H), 2.91-2.75 (m, 2 H), 2.00 (br. s., 2 H), 1.64 (br. s., 3 H), 1.45 (s, 9 H)

[0544] MS: 538 [M+H.sup.+]

[0545] In one embodiment, the present invention also concerns compounds 49 and 50 as intermediates for the preparation of compounds of general formula I. [0546] 49. (4-(((2-((6-(benzyl(methyl)amino)pyridin-2-yl)oxy)ethyl)amino)methyl)-4-fluoropiperidin-1-yl)(3-chloro-4-fluorophenyl)methanone [0547] 50.(4-(((2-((6-(benzyl(methyl)amino)-5-methylpyridin-2-yl)oxy)ethyl)amino)methyl)-4-fluoropiperidin-1-yl)(3-chloro-4-fluorophenyl)methanone

[0548] Within the context of the present invention, the preferred compounds of formula (I) are: [0549] 1. (3-chloro-4-fluorophenyl)-4-fluoro-4-(((2-phenoxyethyl)amino)methyl)piperidin-1-yl)methanone [0550] 2. N-(3-(2-(((1-(3-chloro-4-fluorobenzoyl)-4-fluoropiperidin-4-yl)methyl)amino)ethoxy)phenyl)acetamide [0551] 3. N-(3-(2-(((1-(3,4-dichlorobenzoyl)-4-fluoropiperidin-4-yl)methyl)amino)ethoxy)phenyl)acetamide [0552] 5. (3-chloro-4-fluorophenyl)-4-fluoro-4-(((2-(3-fluorophenoxy)ethyl)amino)methyl)piperidin-1-yl)methanone [0553] 8. (3-chloro-4-fluorophenyl)-4-fluoro-4-(((2-(3-methoxyphenoxy)ethyl)amino)methyl)piperidin-1- yl)methanone [0554] 18. (3-chloro-4-fluorophenyl)-4-fluoro-4-(((2-(pyridin-2-yloxy)ethyl)amino)methyl)piperidin-1-yl)methanone [0555] 29. (3-chloro-4-fluorophenyl)-4-fluoro-4-(((2-((6-(pyrrolidin-1-yl)pyridin-2-yl)oxy)ethyl)amino)methyl)piperidin-1-yl)methanone [0556] 36. (3-chloro-4-fluorophenyl)-4-fluoro-4-(((2-(pyrazin-2-yloxy)ethyl)amino)methyl)piperidin-1-yl)methanone as well as their salts with pharmaceutically acceptable mineral or organic acids or hydrates.

[0557] The subject of the invention is also the pharmaceutical compositions containing, as active ingredient, at least one of the compounds of general formula (I) or one of its salts or hydrates of its salts in combination with one or more inert carriers or other pharmaceutically acceptable vehicles.

[0558] More particularly, the purpose of the invention is the use of a compound with formula (I) or one of its pharmaceutically acceptable salts according to this invention, for use as a drug that can be administrated orally, intravenously, or by an intraperitoneal or intramuscular route, or by any other route which permits to obtain an antidepressant effect according to this invention, or making patients suffering from major depression who were resistant to classical antidepressant treatments, sensitive to these treatments, or to obtain the required prevention or treatment in the previous uses.

[0559] Active substances of drugs or pharmaceutical compositions according to the invention may be in any of the oral galenic forms normally used including tablets, capsules and liquid preparations such as elixirs and suspensions containing various colour, taste and stabilisation masking substances.

[0560] To produce oral galenic forms according to the invention, the active substance may be mixed with various conventional materials such as starch, calcium carbonate, lactose, sucrose and dibasic calcium phosphate to facilitate the encapsulation process. Magnesium stearate as an additive, provides a useful lubrication function if necessary.

[0561] Active substances of pharmaceutical compositions according to the invention may be dissolved or present in suspension in a pharmaceutically acceptable sterile liquid such as sterile water, a sterile organic solvent or a mixture of these two liquids. Preferably, such a liquid is appropriate for parenteral injection.

[0562] When the active substance is sufficiently soluble, it can be dissolved in a normal saline solution such as a pharmaceutically acceptable sterile liquid; if it is not sufficiently soluble, it can be dissolved in aqueous solutions of an appropriate organic solvent, for example propylene glycol or polyethylene glycol. Aqueous propylene glycol containing 10 to 75% by weight of glycol is usually appropriate. In other examples, other compositions can be obtained by dispersing the active substance as a very fine concentrate in an aqueous carboxymethylic solution of starch cellulose or sodium, or in an appropriate oil, for example peanut oil.

[0563] Liquid pharmaceutical compositions such as sterile solutions or suspensions can be used for intramuscular, intraperitoneal or subcutaneous injections.

[0564] Preferably, the pharmaceutical composition is in the form of unit doses, for example such as tablets or capsules. In this form, the composition is subdivided into unit doses containing appropriate quantities of active substance; unit doses may be packaged compositions, for example powders, flasks or phials. The quantity of active substance in a unit dose of the composition may be modified or adjusted by 2 mg or less, or by 50 mg or more, depending on the particular need and the activity of the active substance.

[0565] The recommended oral dose of compounds with formula (I) for man may be from 0.01 to 100 mg/day and this dose may be administered in two to four separate doses.

[0566] Those skilled in the art also are aware that methods of administrating compounds according to this invention can change significantly. Apart from other oral administrations, slow release compositions may be preferred. Other administration methods may include but are not limited to intravenous injections, intramuscular and intraperitoneal injections, subcutaneous implants, and mouth, sublingual, transdermal, topic, rectal and intranasal administration.

[0567] The pharmaceutical compositions according to the invention may be, by way of example, compounds which can be administered orally, nasally, sublingually, rectally or parenterally. By way of example of compositions which can be administered orally, there may be mentioned tablets, gelatin capsules, granules, powders and oral solutions or suspensions. The formulations appropriate for the chosen form for administration are known and described for example in: Remington, The Science and Practice of Pharmacy, 19th edition, 1995, Mack Publishing Company.

[0568] The term pharmaceutically acceptable refers to molecular entities and compositions which have no adverse or allergic effect or any unwanted reaction when administered to humans. When used here, the term pharmaceutically acceptable excipient includes any diluents, adjuvants or excipients, such as preservatives, fillers, disintegrating agents, wetting agents, emulsifiers, dispersing agents, antibacterial or antifungal agents, or even agents which help delay intestinal and digestive absorption and resorption. The use of these media or carriers is well known to the person skilled in the art. The term pharmaceutically acceptable salts of a compound refers to the salts defined here and which possess the pharmacological activity of the parent compound.

[0569] Such salts include: acid addition salts formed with mineral acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid and similar, or formed with organic salts, such as acetic acid, benzensulphonic acid, benzoic acid, camphorsulphonic acid, citric acid, ethanesulphonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphtoic acid, 2-hydroxyethanesulphonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulphonic acid, muconic acid, 2-napthalenesulphonic acid, proprionic acid, salicylic acid, succinic acid, dibenzoyl-L-tartic acid, tartric acid, p-toluenesulphonic acid, trimethylacetic acid, trifluoroacetic acid and similar.

[0570] The pharmaceutically acceptable salts also include solvent (solvates) addition forms or crystalline forms (polymorphs), such as defined here, of the same acid addition salt.

[0571] The effective dose of a compound of the invention varies according to numerous parameters such as for example the chosen route of administration, the weight, age, gender, state of progression of the pathology to be treated and the sensitivity of the individual to be treated. Consequently, the optimum dosage will have to be determined according to the parameters which are judged to be relevant by the specialist in the field.

[0572] Although the effective doses of a compound of the invention can vary in large proportions, the daily doses could be between 0.001 mg and 10 mg per kg of bodyweight of the individual to be treated.

[0573] A daily dose of a compound of the invention of between 0.01 mg and 1 mg per kg of bodyweight of the individual to be treated is however preferred.

[0574] The examples and the Figures described below are intended to illustrate the invention without in any way limiting its scope.

Binding Affinity and In Vivo Tests

[0575] The binding affinity of the compounds of the invention for 5-HT.sub.1A serotonin receptor, alpha1 adrenergic receptor and D.sub.2 dopamine receptor were evaluated according to the testing procedure as depicted below:

Radioligand Binding AssayPreparation of Test Compounds

[0576] 10 mM stock solutions of tested compounds were prepared in DMSO. Serial dilutions of compounds were prepared in 96-well microplate in assay buffers using automated pipetting system epMotion 5070 (Eppendorf) or CyBio Felix (CyBio AG). Each compound was tested in 10 concentrations from 10.sup.6 to10.sup.10 M (final concentration). In case of very high affinity, the test was repeated with the concentration range shifted to 10.sup.8 to10.sup.13 M (final concentration).

5-HT.SUB.1A .Serotonin Receptor Binding Assay

[0577] Radioligand binding was performed using membranes from CHO-K1 cells stably transfected with the human 5-HT.sub.1A receptor. All assays were carried out in duplicates. 50 L working solution of the tested compounds, 50 L [3H]-8-OH-DPAT (final concentration 1 nM, Kd 0.8 nM) and 150 L diluted membranes (10 g protein per well) prepared in assay buffer (50 mM Tris-HCl, pH 7.4, 10 mM MgCl.sub.2, 0.1 mM EDTA, 0.1% ascorbic acid) were transferred to polypropylene 96-well microplate using 96-wells pipetting station Rainin Liquidator (MettlerToledo). Serotonin (10 M) was used to define nonspecific binding. Microplate was covered with a sealing tape, mixed and incubated for 60 minutes at 27 C. The reaction was terminated by rapid filtration through GF/C filter mate presoaked with 0.3% polyethyleneimine for 30 minutes. Ten rapid washes with 200 L 50 mM Tris-HCl buffer (4 C., pH 7.4) were performed using automated harvester system Harvester-96 MACH III FM (Tomtec). The filter mates were dried at 37 C. in forced air fan incubator and then solid scintillator MeltiLex was melted on filter mates at 90 C. for 5 minutes. Radioactivity was counted in MicroBeta2 scintillation counter (PerkinElmer) at approximately 30% efficiency. Data were fitted to a one-site curve-fitting equation with Prism 6 (GraphPad Software) and Ki values were estimated from the Cheng-Prusoff equation.

Alpha1-Adrenergic Receptor Binding Assay

[0578] Radioligand binding was performed using tissue (rat cortex). All assays were carried out in duplicates. 50 L working solution of the tested compounds, 50 L [3H]-prazosin (final concentration 0.2 nM, Kd 0.2 nM) and 150 L tissue suspension prepared in assay buffer (50 mM Tris-HCl, pH 7.6) were transferred to polypropylene 96well microplate using 96wells pipetting station Rainin Liquidator (MettlerToledo). Phentolamine (10 M) was used to define nonspecific binding. Microplate was covered with a sealing tape, mixed and incubated for 30 minutes at 30 C. The reaction was terminated by rapid filtration through GF/B filter mate. Ten rapid washes with 200 L 50 mM Tris-HCl buffer (4 C., pH 7.6) were performed using automated harvester system Harvester-96 MACH III FM (Tomtec). The filter mates were dried at 37 C. in forced air fan incubator and soaked in 10 mL of liquid scintillation cocktail Ultima Gold MV (PerkinElmer, USA). After even distribution of scintillation cocktail filter bag was sealed. Radioactivity was counted in MicroBeta2 scintillation counter (PerkinElmer) at approximately 30% efficiency. Data were fitted to a one-site curve-fitting equation with Prism 6 (Graph Pad Software) and Ki values were estimated from the Cheng-Prusoff equation.

D.SUB.2 .Dopamine Receptor Binding Assay

[0579] Radioligand binding was performed using membranes from CHO-K1 cells stably transfected with the human D2 receptor. All assays were carried out in duplicates. 50 L working solution of the tested compounds, 50 L [3H]-methylspiperon (final concentration 0.4 nM, Kd 0.4 nM) and 150 L diluted membranes (10 g protein per well) prepared in assay buffer (50 mM HEPES, pH 7.4, 50 mM NaCl, 5 mM MgCl.sub.2, 0.5 mM EDTA) were transferred to polypropylene 96well microplate using 96wells pipetting station Rainin Liquidator (MettlerToledo). (+)-butaclamol (10 M) was used to define nonspecific binding. Microplate was covered with a sealing tape, mixed and incubated for 60 minutes at 37 C. The reaction was terminated by rapid filtration through GF/C filter mate presoaked with 0.3% polyethyleneimine for 30 minutes. Ten rapid washes with 200 L 50 mM Tris buffer (4 C., pH 7.4) were performed using automated harvester system Harvester-96 MACH III FM (Tomtec). The filter mates were dried at 37 C. in forced air fan incubator and then solid scintillator MeltiLex was melted on filter mates at 90 C. for 5 minutes. Radioactivity was counted in MicroBeta2 scintillation counter (PerkinElmer) at approximately 30% efficiency. Data were fitted to a one-site curve-fitting equation with Prism 6 (GraphPad Software) and Ki values were estimated from the Cheng-Prusoff equation.

5-HT.SUB.1A .Serotonin Receptor Agonist Efficacy Assay

[0580] A cellular aequorin-based functional assay was performed with recombinant CHO-K1 cells expressing mitochondrially targeted aequorin, human GPCR and the promiscuous G protein 16 for 5-HT1A. Assay was executed according to previously described protocol (Kolaczkowski et al., 2014). After thawing, cells were transferred to assay buffer (DMEM/HAM's F12 with 0.1% protease free BSA) and centrifuged. The cell pellet was resuspended in assay buffer and coelenterazine h was added at final concentrations of 5 M. The cells suspension was incubated at 16 C., protected from light with constant agitation for 16 h and then diluted with assay buffer to the concentration of 100,000 cells/ml. After 1 h of incubation, 50 l of the cells suspension was dispensed using automatic injectors built into the radiometric and luminescence plate counter MicroBeta2 LumiJET (PerkinElmer, USA) into white opaque 96-well microplates preloaded with test compounds. Immediate light emission generated following calcium mobilization was recorded for 30 s. In antagonist mode, after 25 min of incubation the reference agonist was added to the above assay mix and light emission was recorded again. Final concentration of the reference agonist was equal to EC80 (100 nM serotonin).

Forced Swim Test (FST) in Rats

[0581] The experiment was carried out according to a well-characterized method (Porsolt et al., 1978). On the first day of an experiment, the animals (n=7-8 per group) were gently individually placed in Plexiglas cylinders (40 cm high, 18 cm in diameter) containing water (15 cm deep) maintained at 23-25 C. for 15 min. On removal from water, the rats were placed for 30 min in a Plexiglas box under a 60 W incandescent filament bulb to dry. On the following day (24 h later), test compound was administered to rats by oral administration (p.o.) route 60 minutes before the rats were re-placed in the cylinder and the total duration of their immobility was recorded during the 5-min test period. The swimming behaviour entailed active swimming motions, e.g., moving horizontally around in the cylinder, and immobility was assigned when no additional activity was observed other than that necessary to keep the rat's head above the water. Fresh water was used for each animal. Data were analysed by One-way ANOVA, followed by Dunnet's post-hoc test for comparison with control (vehicle-treatment) group.

[0582] Developed formulas of compounds 1-75 are detailed below.

##STR00003## ##STR00004## ##STR00005## ##STR00006## ##STR00007## ##STR00008## ##STR00009## ##STR00010## ##STR00011## ##STR00012##

TABLE-US-00001 TABLE 1 Binding affinities of the compounds of the invention 5-HT.sub.1A 5-HT.sub.1A Alpha1 receptor Ki 5-HT.sub.1A receptor Ki D2 receptor Compound (nM) E.sub.max (%) (nM) Ki (nM) 1 0.061 58% 380 >1000 2 0.083 96% >1000 >1000 3 0.073 86% >1000 >1000 4 0.043 69% >1000 >1000 5 0.023 57% >1000 >1000 6 0.035 70 570 7 0.38 46 450 8 0.052 67% >1000 >1000 9 0.057 57% >1000 >1000 10 8.6 >1000 >1000 11 1.2 >1000 >1000 12 0.029 140 >1000 13 0.50 75 670 14 0.18 190 >1000 15 0.20 190 >1000 16 0.15 50% 170 >1000 17 0.45 230 640 18 0.065 40% 170 >1000 19 1.7 91% >1000 >1000 21 5,2 >1000 >1000 22 8.2 >1000 >1000 23 0.40 59 680 24 0.55 32% >1000 >1000 25 0.28 40% 270 >1000 26 0.08 107% 320 850 27 0.08 94% 300 >1000 29 1.7 95% 630 >1000 30 2.7 39% 290 >1000 32 32 >1000 >1000 35 12 23% >1000 >1000 36 0.57 47% >1000 >1000 39 0.7 31% 33 >1000 40 1.8 >1000 >1000 44 0.1 73% 110 >1000 45 0.2 84% >1000 >1000 46 0.3 81% >1000 >1000 47 0.1 98% >1000 >1000 48 0.2 92% >1000 >1000 51 0.4 47% 900 >1000 52 0.2 88% >1000 >1000 53 1.3 62% >1000 >1000 54 2.7 72% 40 >1000 55 2.5 45% 200 >1000 58 0.5 77% >1000 >1000 59 2.0 45% >1000 >1000 60 0.01 89% 25 25 61 0.3 81% >1000 >1000 62 0.2 >1000 >1000 63 0.5 51% >1000 >1000 64 .8 77% >1000 >1000 65 5.5 71% >1000 >1000 66 0.5 77% >1000 >1000 67 1.1 54% 400 >1000 68 0.09 67% 770 >1000 69 0.25 84% >1000 >1000 70 0.05 76% 900 >1000 71 3.7 45% >1000 >1000 72 0.2 62% 180 >1000 73 0.9 78% 110 >1000 74 0.2 74% 130 >1000 Buspirone 5.0 9% >5000 240 Befiradol 0.4 92% >1000 >1000 8-OH-DPAT 0.9 31% >1000 >1000

[0583] The results highlighted in Table 1 demonstrate the high affinity of the compounds of the invention for 5-HT.sub.1A receptors while exhibiting low affinity for alpha1 and D2 receptors. They also show that the efficacy of the compounds of the present invention are equivalent to or greater than those of the best known agonists (WO 98/22459) and far superior to that of the reference agonists (Buspirone and 8-OH-DPAT).

[0584] FIG. 1 shows the effects of Compound 18 in the rat Forced Swim Test

[0585] Compound 18 was tested in the rat Forced Swim Test, an in vivo behavioural model of potential antidepressant activity (Porsolt et al. 1978). In this test, control rats (i.e. that received only vehicle) exhibited immobility times of over 200 seconds (see Table 2). In contrast, rats that were treated with 18 showed decreased immobility. Statistical analysis (One-way ANOVA) indicated a highly significant effect of the treatment (F(4.33)=43.736; p<0,0001) with a lowest significant dose of 0.16 mg/kg p.o. Immobility behaviour was further dose-dependently reduced and almost abolished at the dose of 2.5 mg/kg p.o. Such activity is much greater in terms of effect size than that of commonly-used antidepressants such as imipramine or paroxetine(Koek et al., 1998).These data show that 18 has potent in vivo antidepressant-like effects that are exhibited by oral administration route, as is desirable for a pharmacotherapeutic agent to be used in a clinical environment. *p<0.01; **p<0.0001

[0586] These results suggest that compounds (I) are therefore potentially useful for treating disorders sensitive to a serotoninergic regulation controlled by the 5-HT.sub.1A receptors such as, for instance, the treatment and/or prevention of depression, the treatment and/or prevention of major depressive disorders, the treatment and/or prevention of anxiety, and the treatment and/or prevention of bipolar depression.

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