(R)-2-Methyl-piperazine Derivatives as CXCR3 Receptor Modulators

Abstract

The invention relates to compounds of Formula (I)

##STR00001##

wherein R.sup.1 and R.sup.2 are as described in the description; to pharmaceutically acceptable salts thereof, and to the use of such compounds as medicaments, especially as modulators of the CXCR3 receptor.

Claims

1. A compound of Formula (I) ##STR00006## wherein R.sup.1 represents (C.sub.1-4)alkyl, (C.sub.1-2)alkoxy-(C.sub.1-2)alkyl, hydroxy-(C.sub.1-4)alkyl or —C(O)NH.sub.2; and R.sup.2 represents (C.sub.3-6)cycloalkyl, (C.sub.1-4)alkoxy, (C.sub.3-6)cycloalkoxy or (C.sub.1-2)fluoroalkyl; or a salt thereof.

2. The compound according to claim 1, wherein R.sup.1 represents (C.sub.1-4)alkyl, (C.sub.1-2)alkoxy-(C.sub.1-2)alkyl or hydroxy-(C.sub.1-4)alkyl; and R.sup.2 represents (C.sub.3-6)cycloalkyl, (C.sub.1-4)alkoxy or (C.sub.1-2)fluoroalkyl; or a salt thereof.

3. The compound according to claim 1, wherein R.sup.1 represents ethyl, n-propyl, iso-propyl, tert.-butyl, methoxy-methyl or 1-hydroxy-ethyl; and R.sup.2 represents cyclopropyl, ethoxy or trifluoromethyl; or a salt thereof.

4. The compound according to claim 1, wherein R.sup.1 represents (C.sub.1-4)alkyl, (C.sub.1-2)alkoxy-(C.sub.1-2)alkyl, hydroxy-(C.sub.1-4)alkyl or —C(O)NH.sub.2; and R.sup.2 represents (C.sub.1-2)fluoroalkyl; or a salt thereof.

5. The compound according to claim 1, wherein R.sup.1 represents (C.sub.1-4)alkyl; or a salt thereof.

6. The compound according to claim 1, wherein R.sup.1 represents ethyl, n-propyl, iso-propyl or tert.-butyl; or a salt thereof.

7. The compound according to claim 1, wherein R.sup.2 represents (C.sub.3-6)cycloalkyl; or a salt thereof.

8. The compound according to claim 1, wherein R.sup.2 represents (C.sub.1-4)alkoxy; or a salt thereof.

9. The compound according to claim 1, wherein R.sup.2 represents (C.sub.1-2)fluoroalkyl; or a salt thereof.

10. The compound according to claim 1, wherein the compound is: 1-{(R)-4-[4-(2-Ethoxy-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-methyl-piperazin-1-yl}-2-(3-isopropyl-[1,2,4]triazol-1-yl)-ethanone; 1-{(R)-4-[4-(2-Ethoxy-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-methyl-piperazin-1-yl}-2-(3-ethyl-[1,2,4]triazol-1-yl)-ethanone; 2-(3-tert-Butyl-[1,2,4]triazol-1-yl)-1-{(R)-4-[4-(2-ethoxy-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-methyl-piperazin-1-yl}-ethanone, 1-{(R)-4-[4-(2-Ethoxy-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-methyl-piperazin-1-yl}-2-(3-methoxymethyl-[1,2,4]triazol-1-yl)-ethanone; 1-(2-{(R)-2-Methyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-oxo-ethyl)-1H-[1,2,4]triazole-3-carboxylic acid amide; 2-(3-Ethyl-[1,2,4]triazol-1-yl)-1-{(R)-2-methyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-ethanone; 2-(3-Isopropyl-[1,2,4]triazol-1-yl)-1-{(R)-2-methyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-ethanone; 2-(3-tert-Butyl-[1,2,4]triazol-1-yl)-1-{(R)-2-methyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-ethanone; 2-(3-Methoxymethyl-[1,2,4]triazol-1-yl)-1-{(R)-2-methyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)thiazol-5-yl]piperazin-1-yl}-ethanone; 2-(3-Hydroxymethyl-[1,2,4]triazol-1-yl)-1-{(R)-2-methyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-ethanone; 1-{(R)-2-Methyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-propyl-[1,2,4]triazol-1-yl)-ethanone; 2-[3-(1-Hydroxy-ethyl)-[1,2,4]triazol-1-yl]-1-{(R)-2-methyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-ethanone; 2-[3-(1-Hydroxy-1-methyl-ethyl)-[1,2,4]triazol-1-yl]-1-{(R)-2-methyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)thiazol-5-yl]-piperazin-1-yl}ethanone; 1-{(R)-4-[4-(2-Cyclobutoxy-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-methyl-piperazin-1-yl}-2-(3-isopropyl-[1,2,4]triazol-1-yl)-ethanone; 1-{(R)-4-[4-(2-Cyclopropyl-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-methyl-piperazin-1-yl}-2-(3-ethyl-[1,2,4]triazol-1-yl)-ethanone; 1-{(R)-4-[4-(2-Cyclopropyl-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-methyl-piperazin-1-yl}-2-(3-isopropyl-[1,2,4]triazol-1-yl)-ethanone; 2-(3-tert-Butyl-[1,2,4]triazol-1-yl)-1-{(R)-4-[4-(2-cyclopropyl-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-methyl-piperazin-1-yl}-ethanone; 1-{(R)-4-[4-(2-Cyclopropyl-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-methyl-piperazin-1-yl}-2-(3-methoxymethyl-[1,2,4]triazol-1-yl)-ethanone; 1-{(R)-4-[4-(2-Ethoxy-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-methyl-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone; 2-(3-Methyl-[1,2,4]triazol-1-yl)-1-{(R)-2-methyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-ethanone, or 1-{(R)-4-[4-(2-Cyclopropyl-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-methyl-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone; or a salt thereof.

11. A pharmaceutical composition comprising, as active principle, the compound according to claim 1, or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.

12. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, formulated as a medicament.

13. A method of preventing or treating a disease comprising administering to a patient in need thereof an effective amount of a compound according to claim 1, wherein the disease is an autoimmune disorder, an inflammatory disease, an infectious disease, a transplant rejection, fibrosis, a neurodegenerative disorder or a cancer.

14. A method of preventing or treating a disease comprising administering to a patient in need thereof an effective amount of a compound according to claim 11, wherein the disease is an autoimmune disorder, an inflammatory disease, an infectious disease, a transplant rejection, fibrosis, a neurodegenerative disorder or a cancer.

Description

EXPERIMENTAL SECTION

Abbrevations (as Used Herein and in the Description Above)

[0164] aq. aqueous [0165] Boc tert.-butyloxycarbonyl [0166] BSA Bovine serum albumine [0167] Bu butyl [0168] CC column chromatography on silica gel [0169] CHO Chinese hamster ovary [0170] CV column volume [0171] DCM dichloromethane [0172] DEA diethylamine [0173] DIPEA N-ethyldiisopropylamine [0174] DMF dimethylformamide [0175] DMSO dimethylsulfoxide [0176] EA ethyl acetate [0177] EDTA ethylenediaminetetraacetic acid [0178] EGTA ethylene glycol tetraacetic acid [0179] Et ethyl [0180] FBS fetal bovine serum [0181] FLIPR Fluorescent imaging plate reader [0182] Fluo-4-AM 2-{[2-(2-{5-[bis(carboxymethyl)amino]-2-methylphenoxy}ethoxy)-4-(2,7-difluoro-6-hydroxy-3-oxo-3H-xanthen-9-yl)phenyl](carboxymethyl)amino}acetic acid [0183] G418 (2R,3S,4R,5R,6S)-5-amino-6-[(1R,2S,3S,4R,6S)-4,6-diamino-3-[(2R,3R,4R,5R)-3,5-dihydroxy-5-methyl-4-methylaminooxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-2-(1-hydroxyethyl)oxane-3,4-diol [0184] h hour(s) [0185] HATU 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium [0186] Hep heptanes [0187] HEPES 4-(2-hydroxyethyl)-piperazine-1-ethanesulfonic acid [0188] HV High vacuum [0189] HPLC high performance liquid chromatography [0190] iPr iso-propyl [0191] LC liquid chromatography [0192] m multiplet [0193] M molarity [mol L.sup.−1] [0194] Me methyl [0195] MS mass spectrometry [0196] min minute(s) [0197] NMR nuclear magnetic resonance spectroscopy [0198] org. organic [0199] PBS Phosphate buffered saline [0200] Pd/C palladium on carbon [0201] PG protecting group [0202] Ph phenyl [0203] Prep preparative [0204] rpm rotations per minute [0205] RT room temperature [0206] s singulet [0207] sat. Saturated [0208] TFA trifluoroacetic acid [0209] THF tetrahydrofuran [0210] TLC Thin layer chromatography [0211] t.sub.R retention time [0212] UPLC Ultra performance liquid chromatography

I. Chemistry

[0213] The following examples illustrate the preparation of biologically active compounds of the invention but do not at all limit the scope thereof.

[0214] General: All temperatures are stated in degrees Celsius (° C.). Unless otherwise indicated, the reactions take place at RT under an argon atmosphere and are run in a flame dried round-bottomed flask equipped with a magnetic stir bar.

Characterization Methods Used:

[0215] The LC-MS retention times have been obtained using the following elution conditions:

I) LC-MS (A):

[0216] Zorbax SB-Aq, 3.5 μm, 4.6×50 mm column thermostated at 40° C. The two elution solvents were as follows: solvent A=water+0.04% TFA; solvent B=MeCN. The eluent flow rate was 4.5 mL/min and the characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the table below (a linear gradient being used between two consecutive time points):

TABLE-US-00001 t (min) 0 1.0 1.45 1.55 Solvent A (%) 95 5 5 95 Solvent B (%) 5 95 95 5

II) LC-MS (B):

[0217] Acquity UPLC CSH C18 1.7 μM 2.1×50 mm ID column from Waters, thermostated in the Acquity UPLC Column Manager (60° C.) was used. The two elution solvents were as follows: solvent A=water+0.05% formic acid; solvent B=MeCN+0.045% formic acid. The eluent flow rate was 1 mL/min and the characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the table below (a linear gradient being used between two consecutive time points):

TABLE-US-00002 t (min) 0 1.4 1.8 1.9 2.0 Solvent A (%) 98 5 2 2 98 Solvent B (%) 2 95 98 98 2

[0218] Compound purity and identity was further confirmed by NMR spectroscopy (Bruker Avance II 400 MHz Ultrashield™ or Bruker Ascend™ 500 equipped with a 5 mm DCH cryoprobe), 1H (400 MHz or 500 MHz), 19F (376 MHz). The chemical shifts are reported in parts per million (ppm) relative to tetramethylsilane (TMS) or trichlorofluoromethane, and multiplicities are given as s (singlet) or m (multiplet).

[0219] The purifications by preparative LC-MS have been performed using the conditions described hereafter.

I) Preparative LC-MS (I):

[0220] A X-Bridge column (Waters C18, 10 μm OBD, 30×75 mm) was used. The two elution solvents were as follows: solvent A=water+0.5% NH.sub.4OH (25%); solvent B=MeCN. The eluent flow rate was 75 mL/min and the characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the tables below (a linear gradient being used between two consecutive time points):

TABLE-US-00003 t (min) 0 0.01 4.0 6.0 6.2 6.6 Solvent A (%) 80 80 5 5 80 80 Solvent B (%) 20 20 95 95 20 20

II) Preparative LC-MS (II):

[0221] X-Bridge column (Waters C18, 10 μm OBD, 30×75 mm) was used. The two elution solvents were as follows: solvent A=water+0.5% NH.sub.4OH (25%); solvent B=MeCN. The eluent flow rate was 75 mL/min and the characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the tables below (a linear gradient being used between two consecutive time points):

TABLE-US-00004 t (min) 0 0.01 3.5 6.0 6.2 6.6 Solvent A (%) 70 70 5 5 70 70 Solvent B (%) 30 30 95 95 30 30

III) Preparative LC-MS (III):

[0222] A X-Bridge column (Waters C18, 10 μm OBD, 30×75 mm) was used. The two elution solvents were as follows: solvent A=water+0.5% formic acid; solvent B=MeCN. The eluent flow rate was 75 mL/min and the characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the tables below (a linear gradient being used between two consecutive time points):

TABLE-US-00005 t (min) 0 0.01 4.0 6.0 6.2 6.6 Solvent A (%) 80 80 5 5 80 80 Solvent B (%) 20 20 95 95 20 20

IV) Preparative LC-MS (IV):

[0223] An Atlantis column (Waters T3, 10 μm OBD, 30×75 mm) was used. The two elution solvents were as follows: solvent A=water+0.5% formic acid; solvent B=MeCN. The eluent flow rate was 75 mL/min and the characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the tables below (a linear gradient being used between two consecutive time points):

TABLE-US-00006 t (min) 0 0.01 4.0 6.0 6.2 6.6 Solvent A (%) 80 80 5 5 80 80 Solvent B (%) 20 20 95 95 20 20

V) Preparative LC-MS (V):

[0224] A X-Bridge column (Waters C18, 10 μm OBD, 30×75 mm) was used. The two elution solvents were as follows: solvent A=water+0.5% NH.sub.4OH (25%); solvent B=MeCN. The eluent flow rate was 75 mL/min and the characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the tables below (a linear gradient being used between two consecutive time points):

TABLE-US-00007 t (min) 0 0.01 4.0 6.0 6.2 6.6 Solvent A (%) 90 90 5 5 90 90 Solvent B (%) 10 10 95 95 10 10

Preparative Chiral HPLC Methods Used:

[0225] The purifications by preparative chiral HPLC have been performed using the conditions described hereafter.

I) Preparative Chiral HPLC (I):

[0226] A ChiralPak IB column (5 μm, 30×250 mm) was used. The elution solvent was Hep/EtOH 60/40, run for 9 min and at a flow rate of 40 mL/min.

II) Preparative Chiral HPLC (II):

[0227] A (R,R) Whelk-01 column (10 μm, 50×250 mm) was used. The elution solvent was Hep/EtOH 70/30, run for 16.3 min and at a flow rate of 100 mL/min.

III) Preparative Chiral HPLC (III):

[0228] A ChiralPak IB column (5 μm, 30×250 mm) was used. The elution solvent was Hep/EtOH 50/50, run for 8 min and at a flow rate of 34 mL/min.

IV) Preparative Chiral HPLC (IV):

[0229] A ChiralPak IB column (5 μm, 20×250 mm) was used. The elution solvent was Hep/EtOH 50/50, 0.1% DEA, run for 18.7 min and at a flow rate of 16 mL/min.

V) Preparative Chiral HPLC (V):

[0230] A ChiralPak IB column (5 μm, 30×250 mm) was used. The elution solvent was Hep/EtOH 70/30, run for 11.8 min and at a flow rate of 34 mL/min.

VI) Preparative Chiral HPLC (VI):

[0231] A ChiralPak OZ-H column (5 μm, 20×250 mm) was used. The elution solvent was Hep/EtOH 50/50, 0.1% DEA, run for 11 min and at a flow rate of 19 mL/min.

Example 1: 1-{(R)-4-[4-(2-Ethoxy-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-methyl-piperazin-1-yl}-2-(3-isopropyl-[1,2,4]triazol-1-yl)-ethanone

1.1. 5-Bromo-2-trifluoromethyl-thiazole-4-carboxylic acid

[0232] To a solution of 2-(trifluoromethyl)thiazole-4-carboxylic acid (3.2 g) in anhydrous THF (60 mL) under argon cooled down to −78° C. was added n-BuLi (1.6M in hexane, 21.3 mL) dropwise over 15 min so that the internal temperature did not rise above −60° C. A solution of Br.sub.2 (0.92 mL) in cyclohexane (8 mL) was then added dropwise to keep the internal temperature below −60° C. The resulting mixture was stirred at −78° C. for 2 h and carefully quenched by addition of water (50 mL). Citric acid (10%) was added until pH=2 and the mixture was extracted with EA. The org. layers were washed with brine, dried (MgSO.sub.4), filtered off and evaporated to dryness to afford 4.15 g of brown solid, used without further purification. LC-MS (A): t.sub.R=0.67 min. F-NMR (CD.sub.3OD): −63.57 ppm (s).

1.2. 5-Bromo-2-trifluoromethyl-thiazole-4-carboxylic acid methyl ester

[0233] To a solution of intermediate 1.1 (12 g), MeOH (130 mL) was added H.sub.2SO.sub.4 (96%, 6.5 mL) and the mixture was stirred at 70° C. for 3 h. After cooling down, the reaction mixture was quenched with sat. aq. Na.sub.2CO.sub.3 and the solvent partially evaporated off. The residue was diluted with DCM and washed with aq. sat. Na.sub.2CO.sub.3 (1×), water (1×) and brine (1×), and the aq. phases were extracted with DCM (2×). The combined org. layers were dried over MgSO.sub.4, filtrated off, evaporated and dried under HV to afford 12 g of brown resin. LC-MS (A): t.sub.R=0.83 min. F-NMR (CD.sub.3OD): −63.59 ppm (s).

1.3. (R)-4-(4-Methoxycarbonyl-2-trifluoromethyl-thiazol-5-yl)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester

[0234] To a solution of intermediate 1.2 (10 g) in MeCN (250 mL) were added (R)-1-N-Boc-2-methylpiperazine (7.19 g) and DIPEA (8.85 mL) at RT. The reaction mixture was stirred at 80° C. for 43 h. After cooling down, the reaction mixture was diluted with EA and washed with water and brine. The aq. layers were extracted with EA. The combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated to dryness. The crude was purified by CC (Biotage, SNAP 340 g, solvent A: Hep; solvent B: EA; gradient in % B: 10 over 5CV, 10 to 30 over 5CV, 30 over 5CV) to afford 9.14 g of yellow resin. LC-MS (A): t.sub.R=0.97 min; [M+H].sup.+: 410.0.

1.4. (R)-4-(4-Carboxy-2-trifluoromethyl-thiazol-5-yl)-2-methyl-piperazine-1-carboxylic Acid tert-butyl ester

[0235] To a solution of intermediate 1.3 (4.25 g) in EtOH (40 mL) was added 1M NaOH (40 mL) at RT and the reaction mixture was stirred for 1 h 20. The solvent was evaporated off and the residue acidified to pH 2 by the addition of aq. citric acid (10%). The aq. layer was extracted with DCM (3×) and the combined org. layers were dried over Na.sub.2SO.sub.4 and concentrated to dryness to afford 4.1 g as orange solid. LC-MS (A): t.sub.R=0.88 min; [M+H].sup.+: 395.9.

1.5. (R)-4-(4-Bromo-2-trifluoromethyl-thiazol-5-yl)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester

[0236] To a solution of intermediate 1.4 (10.17 g) in THF (210 mL) were added LiBr (2.26 g) and (diacetoxyiodo)benzene (8.45 g) at RT. The resulting suspension was stirred at RT for 1 h 30. The reaction mixture was diluted with H.sub.2O and extracted with DCM (3×). The combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated to dryness. The crude was purified by CC (Biotage, SNAP 340 g cartridge, solvent A: Hep; solvent B: EA; gradient in % B: 5 for 5CV, 5 to 10 over 3CV) to afford 9.63 g as yellow solid. LC-MS (A): t.sub.R=1.04 min; [M+H].sup.+: 429.2.

1.6. (R)-4-[4-(2-Ethoxy-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-methyl-piperazine-1-carboxylic acid tert-butyl ester

[0237] A mixture of intermediate 1.5 (1.63 g), 2-ethoxypyrimidine-5-boronic acid (778 mg), Pd(PPh.sub.3).sub.2Cl.sub.2 (152 mg), 1M Na.sub.2CO.sub.3 (12 mL) in MeCN (12 mL) was vigorously stirred at 80° C. under argon overnight. The reaction mixture was allowed to cool down to RT, diluted with H.sub.2O and extracted with DCM (3×). The combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated to dryness. The crude was purified by CC (Biotage, SNAP 50 g cartridge, solvent A: Hep; solvent B: EA; gradient in % B: 10 for 5CV, 10 to 30 over 5CV, 30 for 3CV) to afford 1.35 g as pale yellow resin. LC-MS (A): t.sub.R=1.04 min; [M+H].sup.+: 473.9.

1.7. 2-Ethoxy-5-[5-((R)-3-methyl-piperazin-1-yl)-2-trifluoromethyl-thiazol-4-yl]-pyrimidine

[0238] To solution of intermediate 1.6 (1.32 g) in DCM (45 mL) was added TFA (4.28 mL) at RT. The resulting mixture was stirred at RT overnight. The reaction mixture was treated with 1M NaOH to pH=14 and extracted with DCM (3×). The combined org. layers were dried over MgSO.sub.4, filtrated off, evaporated and dried at HV to afford 1.01 g as beige solid. LC-MS (A): t.sub.R=0.64 min; [M+H].sup.+: 374.0.

1.8. (3-Bromo-[1,2,4]triazol-1-yl)-acetate, lithium salt

[0239] To a solution of ethyl (3-bromo-1H-1,2,4-triazole-1-yl)acetate (200 mg) in THF (0.75 mL) and EtOH (0.75 mL) was added H.sub.2O (0.5 mL) followed by 2M LiOH (0.47 mL). The reaction mixture was stirred at RT overnight, was evaporated off and the residue dried at HV to afford 201 mg as white solid. LC-MS (A): t.sub.R=0.29 min; [M+H].sup.+: 205.9.

1.9. 2-(3-Bromo-[1,2,4]triazol-1-yl)-1-{(R)-4-[4-(2-ethoxy-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-methyl-piperazin-1-yl}-ethanone

[0240] A mixture of intermediate 1.7 (120 mg), intermediate 1.8 (76 mg), HATU (159 mg), and DIPEA (82 μL) in DCM (4 mL) and DMF (1 mL) was stirred at RT overnight. DCM was removed by evaporation and the crude purified by Prep LC-MS (IV) to afford 102 mg as white solid. LC-MS (A): t.sub.R=0.9 min; [M+H].sup.+: 561.0.

1.10. 1-{(R)-4-[4-(2-Ethoxy-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-methyl-piperazin-1-yl}-2-(3-isopropenyl-[1,2,4]triazol-1-yl)-ethanone

[0241] A mixture of intermediate 1.9 (40 mg), isopropenylboronic acid pinacol ester (15.1 mg), Pd(PPh.sub.3).sub.2Cl.sub.2 (2.8 mg), 1M Na.sub.2CO.sub.3 (1 mL) in MeCN (1 mL) was vigorously stirred at 80° C. under argon for 2 h. The reaction mixture was allowed to cool down to RT and evaporated to dryness. The crude was purified by Prep LC-MS (I). LC-MS (A): t.sub.R=0.9 min; [M+H].sup.+: 523.2.

1.11. 1-{(R)-4-[4-(2-Ethoxy-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-methyl-piperazin-1-yl}-2-(3-isopropyl-[1,2,4]triazol-1-yl)-ethanone

[0242] A flask containing intermediate 1.10 (g), Pd/C (1.5 mg) in MeOH (1 mL) was evacuated and backfilled with argon (3×), afterwards evacuated and backfilled with H.sub.2 (3×) and the reaction mixture was stirred at RT overnight. The reaction mixture was filtered over a syringe filter and the filtrate was evaporated to dryness. The crude was purified by Prep LC-MS (IV) to afford 7 mg as white solid. LC-MS (B): t.sub.R=1.11 min; [M+H].sup.+: 525.2.

Example 2: 1-{(R)-4-[4-(2-Ethoxy-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-methyl-piperazin-1-yl}-2-(3-ethyl-[1,2,4]triazol-1-yl)-ethanone

2.1. (3-Ethyl-[1,2,4]triazol-1-yl)-acetic acid benzyl ester

[0243] To a solution of 3-ethyl-1H-1,2,4-triazole (2 g) in MeCN (125 mL) was added Cs.sub.2CO.sub.3 (6.37 g) followed by benzyl bromoacetate (3.23 mL). The reaction mixture was stirred at RT overnight and evaporated to dryness. The residue was taken up in EA and washed with water. The aq. layers were extracted with EA (2×) and the combined org. layers were dried over Na.sub.2SO.sub.4, filtered off and evaporated to dryness. The residue was purified by CC (Biotage, SNAP 100 g cartridge, solvent A: DCM; solvent B: DCM/MeOH 8:2; gradient in % B: 15 for 4CV, 15 to 100 over 4CV, 100 for 1CV) to afford 3.89 g as first eluting fraction (mixture of two triazole regioisomers) and 309 mg as second eluting fraction ((3-ethyl-[1,2,4]triazol-4-yl)-acetic acid benzyl ester). The mixture of regioisomers was purified by preparative chiral HPLC (I). First eluting fraction: (5-ethyl-[1,2,4]triazol-1-yl)-acetic acid benzyl ester: 1.39 g yellow oil. LC-MS (A): t.sub.R=0.72 min; [M+H].sup.+: 246.2. Roesy signal seen between CH.sub.2CH.sub.3 at 2.72 ppm and CH.sub.2CO.sub.2 at 4.93 ppm.

[0244] Second eluting fraction: (3-ethyl-[1,2,4]triazol-1-yl)-acetic acid benzyl ester: 2.08 g yellow solid. LC-MS (A): t.sub.R=0.71 min; [M+H].sup.+: 246.2. Roesy signal seen between CH at 8.08 ppm (triazole) and CH.sub.2CO.sub.2 at 4.96 ppm.

2.2. (3-Ethyl-[1,2,4]triazol-1-yl)-acetic acid

[0245] A flask containing (3-ethyl-[1,2,4]triazol-1-yl)-acetic acid benzyl ester from step 2.1 (2.06 g), Pd/C (445 mg) in EtOH (20 mL) was evacuated and backfilled with argon (3×), afterwards evacuated and backfilled with H.sub.2 (3×) and the reaction mixture was stirred at RT for 9 h. The reaction mixture was filtered over a celite plug and the filtrate was evaporated to dryness to afford 1.27 g as white solid. LC-MS (A): t.sub.R=0.25 min; [M+H].sup.+: 156.2.

2.3. 1-{(R)-4-[4-(2-Ethoxy-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-methyl-piperazin-1-yl}-2-(3-ethyl-[1,2,4]triazol-1-yl)-ethanone

[0246] A mixture of intermediate 1.7 (50 mg), intermediate 2.2 (21 mg), HATU (66 mg), and NEt.sub.3 (284) in DCM (1.5 mL) was stirred at RT overnight. The reaction mixture was evaporated to dryness and the crude purified by Prep LC-MS (I) to afford 15 mg as white solid. LC-MS (B): t.sub.R=1.05 min; [M+H].sup.+: 511.2.

Example 3: 2-(3-tert-Butyl-[1,2,4]triazol-1-yl)-1-{(R)-4-[4-(2-ethoxy-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-methyl-piperazin-1-yl}-ethanone

3.1. (3-tert-Butyl-[1,2,4]triazol-1-yl)-acetic acid benzyl ester

[0247] This compound was prepared using a method analogous to that of Example 2, step 2.1, 3-tert-butyl-1H-1,2,4-triazole replacing 3-ethyl-1H-1,2,4-triazole. The desired compound was obtained after CC as single regioisomer. LC-MS (A): t.sub.R=0.73 min; [M+H].sup.+: 274.1.

3.2. (3-tert-Butyl-[1,2,4]triazol-1-yl)-acetic acid

[0248] This compound was prepared using a method analogous to that of Example 2, step 2.2, intermediate 3.1 replacing (3-ethyl-[1,2,4]triazol-1-yl)-acetic acid benzyl ester. LC-MS (A): t.sub.R=0.36 min; [M+H].sup.+: 184.3.

3.3. 2-(3-tert-Butyl-[1,2,4]triazol-1-yl)-1-{(R)-4-[4-(2-ethoxy-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-methyl-piperazin-1-yl}-ethanone

[0249] This compound was prepared using a method analogous to that of Example 2 step 2.3, intermediate 3.2 replacing intermediates 2.2. The desired compound was purified by Prep LC-MS (IV). LC-MS (A): t.sub.R=0.84 min; [M+H].sup.+: 539.1.

Example 4: 1-{(R)-4-[4-(2-Ethoxy-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-methyl-piperazin-1-yl}-2-(3-methoxymethyl-[1,2,4]triazol-1-yl)-ethanone

4.1. (3-Methoxymethyl-[1,2,4]triazol-1-yl)-acetic acid benzyl ester

[0250] This compound was prepared using a method analogous to that of Example 2, step 2.1, 3-(methoxymethyl)-1H-1,2,4-triazol replacing 3-ethyl-1H-1,2,4-triazole. The crude was purified by two CC (1. Biotage, SNAP 10 g cartridge, solvent A: DCM; solvent B: DCM/MeOH 8:2; gradient in % B: 5 for 7CV, 5 to 15 over 3CV, 15 for 3CV. 2. Biotage, SNAP 10 g cartridge, solvent A: DCM; solvent B: DCM/MeOH 8:2; gradient in % B: 5 for 5CV, 5 to 10 over 3CV, 10 for 3CV, 10 to 15 for 3 CV) to yield two regiosiomers:

[0251] First eluting fraction: (5-methoxymethyl-[1,2,4]triazol-1-yl)-acetic acid benzyl ester: colourless oil. LC-MS (A): t.sub.R=0.71 min; [M+H].sup.+: 262.2.

[0252] Second eluting fraction: (3-methoxymethyl-[1,2,4]triazol-1-yl)-acetic acid benzyl ester: colourless oil. LC-MS (A): t.sub.R=0.67 min; [M+H].sup.+: 262.1. Roesy signal seen between CH (triazole) at 8.17 ppm and NCH.sub.2CO.sub.2 at 5.01 ppm.

4.2. (3-Methoxymethyl-[1,2,4]triazol-1-yl)-acetic acid

[0253] This compound was prepared using a method analogous to that of Example 2, step 2.2, (3-methoxymethyl-[1,2,4]triazol-1-yl)-acetic acid benzyl ester from step 4.1 replacing (3-ethyl-[1,2,4]triazol-1-yl)-acetic acid benzyl ester. LC-MS (A): t.sub.R=0.24 min; [M+H].sup.+: 172.0.

4.3. 1-{(R)-4-[4-(2-Ethoxy-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-methyl-piperazin-1-yl}-2-(3-methoxymethyl-[1,2,4]triazol-1-yl)-ethanone

[0254] This compound was prepared using a method analogous to that of Example 2, step 2.3, intermediate 4.2 replacing intermediate 2.2. The desired compound was purified by Prep LC-MS (IV). LC-MS (B): t.sub.R=1.02 min; [M+H].sup.+: 527.2.

Example 5: 1-(2-{(R)-2-Methyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-oxo-ethyl)-1H-[1,2,4]triazole-3-carboxylic acid amide

5.1. (R)-2-Methyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazine-1-carboxylic acid tert-butyl ester

[0255] This compound was prepared using a method analogous to that of Example 1, step 1.6, 2-(trifluoromethyl)pyrimidine-5-yl-boronic acid replacing 2-ethoxypyrimidine-5-boronic acid. LC-MS (A): t.sub.R=1.06 min; [M+H].sup.+: 497.9.

5.2. 5-[5-((R)-3-Methyl-piperazin-1-yl)-2-trifluoromethyl-thiazol-4-yl]-2-trifluoromethyl-pyrimidine, as hydrochloride Salt

[0256] A mixture of intermediate 5.1 (2.3 g) in HCl (10.2 mL, 4M in dioxane) was stirred at RT for 3 h. The white suspension was filtrated, the filtrate washed with Et.sub.2O and dried under HV to give 1.6 g as white solid. LC-MS (A): t.sub.R=0.72 min; [M+H++CH.sub.3CN].sup.+: 438.9.

5.3. 1-(2-{(R)-2-Methyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-oxo-ethyl)-1H-[1, 2, 4]triazole-3-carbonitrile

[0257] This compound was prepared using a method analogous to that of Example 2, step 2.3, 2-(3-cyano-1H-1,2,4-triazol-1-yl)acetic acid replacing intermediate 2.2 and intermediate 5.2 replacing intermediate 1.7. The desired compound was purified by Prep LC-MS (IV). LC-MS (B): t.sub.R=1.19 min; [M+H].sup.+: 532.1.

5.4. 1-(2-{(R)-2-Methyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-oxo-ethyl)-1H-[1,2,4]triazole-3-carboxylic Acid amide

[0258] To a solution of intermediate 5.3 (18 mg) in DCM (0.1 mL) was added conc. H.sub.2SO.sub.4 (0.1 mL), and the resulting emulsion was vigorously stirred for 4 h 15. The reaction mixture was added portionwise to a mixture of NH.sub.4OH (25%) and ice, and the aq. layer was extracted with DCM (5×). The combined org. layers were washed with brine, dried over MgSO.sub.4, evaporated and dried at HV. Purification by Prep. TLC (DCM/MeOH 95:5) afforded 9 mg as white solid. LC-MS (A): t.sub.R=0.82 min; [M+H].sup.+: 550.0.

Example 6: 2-(3-Ethyl-[1,2,4]triazol-1-yl)-1-{(R)-2-methyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-ethanone

[0259] This compound was prepared using a method analogous to that of Example 2, step 2.3, intermediate 5.2 replacing intermediate 1.7. The desired compound was purified by Prep LC-MS (IV). LC-MS (A): t.sub.R=0.89 min; [M+H].sup.+: 535.0.

Example 7: 2-(3-Isopropyl-[1,2,4]triazol-1-yl)-1-{(R)-2-methyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-ethanone

7.1. (3-Isopropyl-[1,2,4]triazol-1-yl)-acetic Acid benzyl ester and (5-Isopropyl-[1,2,4]triazol-1-yl)-acetic Acid benzyl ester

[0260] These compounds were prepared using a method analogous to that of Example 3, step 3.1, 3-isopropyl-1H-1,2,4-triazole replacing 3-ethyl-1H-1,2,4-triazole. The mixture of regioisomers was purified by preparative chiral HPLC (II). First eluting fraction: (3-isopropyl-[1,2,4]triazol-1-yl)-acetic acid benzyl ester. LC-MS (A): t.sub.R=0.76 min; [M+H].sup.+: 260.2. Roesy signal seen between CH.sub.2 at 4.96 ppm and CH (triazole) at 8.08 ppm.

[0261] Second eluting fraction: (5-isopropyl-[1,2,4]triazol-1-yl)-acetic acid benzyl ester. LC-MS (A): t.sub.R=0.76 min; [M+H].sup.+: 260.2. Roesy signal seen between CH.sub.2 at 4.96 ppm and CH (isopropyl) at 2.97 ppm.

7.2. (3-Isopropyl-[1,2,4]triazol-1-yl)-acetic Acid and (5-Isopropyl-[1,2,4]triazol-1-yl)-acetic Acid

[0262] (3-Isopropyl-[1,2,4]triazol-1-yl)-acetic acid was prepared using a method analogous to that of Example 2, step 2.2, (3-isopropyl-[1,2,4]triazol-1-yl)-acetic acid benzyl ester of step 7.1 replacing intermediate 2.1. LC-MS (A): t.sub.R=0.30 min; [M+H].sup.+: 170.2.

[0263] Alternatively, the mixture of regioisomers from step 7.1 was used to give a mixture of (3-isopropyl-[1,2,4]triazol-1-yl)-acetic acid and (5-isopropyl-[1,2,4]triazol-1-yl)-acetic acid.

7.3. 2-(3-Isopropyl-[1,2,4]triazol-1-yl)-1-{(R)-2-methyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-ethanone

[0264] This compound was prepared using a method analogous to that of Example 2, step 2.3, intermediate 5.2 replacing intermediate 1.7 and the mixture of regioisomers in step 7.2 replacing intermediate 2.2. The desired compound was purified by Prep LC-MS (IV) followed by preparative chiral HPLC (VI). First eluting fraction of preparative chiral HPLC: 2-(3-isopropyl-[1,2,4]triazol-1-yl)-1-{(R)-2-methyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-ethanone. LC-MS (B): t.sub.R=1.17 min; [M+H].sup.+: 549.2.

Example 8: 2-(3-tert-Butyl-[1,2,4]triazol-1-yl)-1-{(R)-2-methyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-ethanone

[0265] This compound was prepared using a method analogous to that of Example 2, step 2.3, intermediate 5.2 replacing intermediate 1.7 and intermediate 3.2 replacing intermediate 2.2. The desired compound was purified by Prep LC-MS (II). LC-MS (B): t.sub.R=1.23 min; [M+H].sup.+: 563.2.

Example 9: 2-(3-Methoxymethyl-[1,2,4]triazol-1-yl)-1-{(R)-2-methyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-ethanone

[0266] This compound was prepared using a method analogous to that of Example 2, step 2.3, intermediate 5.2 replacing intermediate 1.7 and intermediate 4.2 replacing intermediate 2.2. The desired compound was purified by Prep LC-MS (I). LC-MS (B): t.sub.R=1.09 min; [M+H].sup.+: 551.2.

Example 10: 2-(3-Hydroxymethyl-[1,2,4]triazol-1-yl)-1-{(R)-2-methyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-ethanone

[0267] To solution of Example 9 (25 mg) in DCM (1 mL) was added at −30° C. BBr.sub.3 (58 μL; 1M in DCM) under argon and the resulting suspension was stirred at 0° C. for 3 h. The reaction mixture was quenched with H.sub.2O, diluted with aq. sat. NaHCO.sub.3 and extracted with EA (3×). The combined org. layers were washed with brine, dried over MgSO.sub.4, filtrated off and evaporated to dryness. Prep LC-MS (IV) gave 5 mg as white powder. LC-MS (A): t.sub.R=0.81 min; [M+H].sup.+: 537.1.

Example 11: 1-{(R)-2-Methyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-propyl-[1,2,4]triazol-1-yl)-ethanone

11.1. (3-propyl-[1,2,4]triazol-1-yl)-acetic Acid benzyl ester

[0268] These compounds were prepared using a method analogous to that of Example 2, step 2.1, 3-propyl-1H-1,2,4-triazole replacing 3-ethyl-1H-1,2,4-triazole. The mixture of regioisomers was purified by preparative chiral HPLC (III). First eluting fraction: (5-propyl-[1,2,4]triazol-1-yl)-acetic acid benzyl ester. LC-MS (A): t.sub.R=0.77 min; [M+H].sup.+: 260.1. Roesy signal seen between CH.sub.2CO.sub.2 at 4.95 ppm and CH.sub.2CH.sub.2CH.sub.3 at 2.65 ppm.

[0269] Second eluting fraction: (3-propyl-[1,2,4]triazol-1-yl)-acetic acid benzyl ester. LC-MS (A): t.sub.R=0.76 min; [M+H].sup.+: 260.1. Roesy signal seen between CH.sub.2CO.sub.2 at 4.96 ppm and CH (triazole) at 8.08 ppm.

11.2. (3-Propyl-[1,2,4]triazol-1-yl)-acetic Acid

[0270] These compounds were prepared using a method analogous to that of Example 2, step 2.2, (3-propyl-[1,2,4]triazol-1-yl)-acetic acid benzyl ester of step 11.1 replacing intermediate 2.1. LC-MS (A): t.sub.R=0.35 min; [M+H].sup.+: 170.4.

11.3. 1-{(R)-2-Methyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-propyl-[1,2,4]triazol-1-yl)-ethanone

[0271] This compound was prepared using a method analogous to that of Example 2, step 2.3, intermediate 5.2 replacing intermediate 1.7 and intermediate 11.2 replacing intermediate 2.2. The desired compound was purified by Prep LC-MS (I). LC-MS (B): t.sub.R=1.17 min; [M+H].sup.+: 548.9.

Example 12: 2-[3-(1-Hydroxy-ethyl)-[1,2,4]triazol-1-yl]-1-{(R)-2-methyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-ethanone

12.1. (3-Acetyl-[1,2,4]triazol-1-yl)-acetic Acid benzyl ester

[0272] This compound was prepared using a method analogous to that of Example 2, step 2.1, 1-(1H-1,2,4-triazol-5-yl)ethanone replacing 3-ethyl-1H-1,2,4-triazole. The crude was purified by CC (Biotage, SNAP 10 g cartridge, solvent A: Hep; solvent B: EA; gradient in % B: 30 for 4CV, 30 to 70 over 4CV, 70 for 2CV, 70 to 100 over 2CV, 100 for 2CV) to give the desired triazole regioisomer as second fraction. LC-MS (A): t.sub.R=0.7 min; [M+H].sup.+: 260.1. Roesy signal seen between CH (triazole) at 8.28 ppm and CH.sub.2 at 5.1 ppm.

12.2. (3-Acetyl-[1,2,4]triazol-1-yl)-acetic Acid

[0273] This compound was prepared using a method analogous to that of Example 2, step 2.2, intermediate 12.1 replacing intermediate 2.1. LC-MS (A): t.sub.R=0.25 min; [M+H].sup.+: 170.0.

12.3. 2-(3-Acetyl-[1,2,4]triazol-1-yl)-1-{(R)-2-methyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-ethanone

[0274] This compound was prepared using a method analogous to that of Example 2, step 2.3, intermediate 5.2 replacing intermediate 1.7 and intermediate 12.2 replacing intermediate 2.2. The desired compound was purified by Prep LC-MS (I). LC-MS (A): t.sub.R=0.89 min; [M+H].sup.+: 549.0.

12.4. 2-[3-(1-Hydroxy-ethyl)-[1,2,4]triazol-1-yl]-1-{(R)-2-methyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-ethanone

[0275] To pale yellow solution of intermediate 12.3 (40 mg) in THF (0.75 mL) and EtOH (0.25 mL) was added NaBH.sub.4 (1.4 mg) at 0° C. under argon and the reaction mixture was stirred at 0° C. for 1 h 30. Then a second batch of NaBH.sub.4 (0.7 mg) was added and the mixture further stirred for 2 h 20. The reaction mixture was evaporated to dryness, the residue was suspended in EA and aq. sat. NH.sub.4Cl was added and stirring was allowed for 30 min at RT. The layers were separated and the org. layer was washed with 1× brine. The aq. layers were re-extracted with EA (2×). The combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated to dryness. Purification by Prep TLC (DCM/MeOH 95/5) gave 10 mg as white solid. LC-MS (A): t.sub.R=0.82 min; [M+H].sup.+: 551.1.

Example 13: 2-[3-(1-Hydroxy-1-methyl-ethyl)-[1,2,4]triazol-1-yl]-1-{(R)-2-methyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-ethanone

[0276] To a suspension of intermediate 12.3 (40 mg) in Et.sub.2O (0.75 mL) was added MeMgBr (48 μL; 3M in Et.sub.2O) at −20° C. and the resulting suspension was stirred at RT for 1 h 30. The reaction mixture was quenched by addition of aq. sat. NH.sub.4Cl and the aq. layer was extracted with EA (3×). The combined org. layers were dried over MgSO.sub.4, filtrated and evaporated to dryness. Purification by Prep LC-MS (IV) gave 7 mg as white powder. LC-MS (A): t.sub.R=0.84 min; [M+H].sup.+: 565.1.

Example 14: 1-{(R)-4-[4-(2-Cyclobutoxy-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-methyl-piperazin-1-yl}-2-(3-isopropyl-[1,2,4]triazol-1-yl)-ethanone

14.1. (R)-4-[4-(2-Cyclobutoxy-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-methyl-piperazine-1-carboxylic Acid tert-butyl ester

[0277] This compound was prepared using a method analogous to that of Example 1, step 1.6, 2-(cyclobutoxy)pyrimidine-5-boronic replacing 2-ethoxypyrimidine-5-boronic acid. The crude was purified by Prep LC-MS (II) instead of CC. LC-MS (A): t.sub.R=1.08 min; [M+H].sup.+: 500.1.

14.2. 2-Cyclobutoxy-5-[5-((R)-3-methyl-piperazin-1-yl)-2-trifluoromethyl-thiazol-4-yl]-pyrimidine, as hydrochloride Salt

[0278] This compound was prepared using a method analogous to that of Example 5, step 5.2, intermediate 14.1 replacing intermediate 5.1. LC-MS (A): t.sub.R=0.71 min; [M+H].sup.+: 400.1.

14.3. 1-{(R)-4-[4-(2-Cyclobutoxy-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-methyl-piperazin-1-yl}-2-(3-isopropyl-[1,2,4]triazol-1-yl)-ethanone

[0279] This compound was prepared using a method analogous to that of Example 2, step 2.3, intermediate 14.2 replacing intermediate 1.7 and the regioisomeric mixture in step 7.2 replacing intermediate 2.2. The crude was purified by CC (DCM/MeOH 97:3) followed by Prep LC-MS (I) and Preparative chiral HPLC (IV).

[0280] Second eluting fraction (preparative chiral HPLC): 1-{(R)-4-[4-(2-cyclobutoxy-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-methyl-piperazin-1-yl}-2-(3-isopropyl-[1,2,4]triazol-1-yl)-ethanone: LC-MS (B): t.sub.R=1.21 min; [M+H].sup.+: 551.3. Roesy signal seen between CH.sub.2 at 5.14-5.37 ppm and CH (triazole) at 8.36 ppm.

Example 15: 1-{(R)-4-[4-(2-Cyclopropyl-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-methyl-piperazin-1-yl}-2-(3-ethyl-[1,2,4]triazol-1-yl)-ethanone

15.1. (R)-4-[4-(2-Cyclopropyl-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-methyl-piperazine-1-carboxylic acid tert-butyl ester

[0281] This compound was prepared using a method analogous to that of Example 1, step 1.6, 2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine replacing 2-ethoxypyrimidine-5-boronic acid. LC-MS (A): t.sub.R=1.06 min; [M+H].sup.+: 470.3.

15.2. 2-Cyclopropyl-5-[5-((R)-3-methyl-piperazin-1-yl)-2-trifluoromethyl-thiazol-4-yl]-pyrimidine, as hydrochloride Salt

[0282] This compound was prepared using a method analogous to that of Example 5, step 5.2, intermediate 15.1 replacing intermediate 5.1. LC-MS (A): t.sub.R=0.6 min; [M+H].sup.+: 370.1.

15.3. 1-{(R)-4-[4-(2-Cyclopropyl-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-methyl-piperazin-1-yl}-2-(3-ethyl-[1,2,4]triazol-1-yl)-ethanone

[0283] This compound was prepared using a method analogous to that of Example 2, step 2.3, intermediate 15.2 replacing intermediate 1.7. The crude was purified by Prep LC-MS (IV). LC-MS (B): t.sub.R=1.07 min; [M+H].sup.+: 507.2.

Example 16: 1-{(R)-4-[4-(2-Cyclopropyl-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-methyl-piperazin-1-yl}-2-(3-isopropyl-[1,2,4]triazol-1-yl)-ethanone

[0284] This compound was prepared using a method analogous to that of Example 2, step 2.3, intermediate 15.2 replacing intermediate 1.7 and (3-isopropyl-[1,2,4]triazol-1-yl)-acetic acid from step 7.2 replacing intermediate 2.2. The crude was purified by Prep LC-MS (IV). LC-MS (A): t.sub.R=0.8 min; [M+H].sup.+: 521.2.

Example 17: 2-(3-tert-Butyl-[1,2,4]triazol-1-yl)-1-{(R)-4-[4-(2-cyclopropyl-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-methyl-piperazin-1-yl}-ethanone

[0285] This compound was prepared using a method analogous to that of Example 2, step 2.3, intermediate 15.2 replacing intermediate 1.7 and intermediate 3.2 replacing intermediate 2.2. The crude was purified by Prep LC-MS (IV). LC-MS (B): t.sub.R=1.18 min; [M+H].sup.+: 535.2.

Example 18: 1-{(R)-4-[4-(2-Cyclopropyl-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-methyl-piperazin-1-yl}-2-(3-methoxymethyl-[1,2,4]triazol-1-yl)-ethanone

[0286] This compound was prepared using a method analogous to that of Example 2, step 2.3, intermediate 15.2 replacing intermediate 1.7 and intermediate 4.2 replacing intermediate 2.2. The crude was purified by Prep LC-MS (IV). LC-MS (A): t.sub.R=0.75 min; [M+H].sup.+: 523.2.

Example 19: 1-{(R)-4-[4-(2-Ethoxy-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-methyl-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone

19.1. (3-Methyl-[1,2,4]triazol-1-yl)-acetic acid benzyl ester

[0287] This compound was prepared using a method analogous to that of Example 2, step 2.1, 3-methyl-1H-1,2,4-triazole replacing 3-ethyl-1H-1,2,4-triazole. The mixture of regioisomers was purified by preparative chiral HPLC (V). First eluting fraction: (5-methyl-[1,2,4]triazol-1-yl)-acetic acid benzyl ester. LC-MS (A): t.sub.R=0.68 min; [M+H].sup.+: 232.16. .sup.1H-NMR (CDCl.sub.3): 7.83 (s, 1H); 7.40-7.33 (m, 5H); 5.23 (s, 2H); 4.93 (s, 2H); 2.43 (s, 3H). Roesy signal seen between CH.sub.2CO.sub.2 at 4.93 ppm and CH.sub.3 at 2.43 ppm.

[0288] Second eluting fraction: (3-methyl-[1,2,4]triazol-1-yl)-acetic acid benzyl ester. LC-MS (A): t.sub.R=0.67 min; [M+H].sup.+: 232.16. .sup.1H-NMR (CDCl.sub.3): 8.05 (s, 1H); 7.40-7.30 (m, 5H); 5.23 (s, 0.95H, CH.sub.2); 4.93-4.88 (3s, 2H); 2.42 (s, 3H). Roesy signal seen between CH (triazole) at 8.05 ppm and CH.sub.2CO.sub.2 at 4.93-4.88 ppm.

19.2. (3-Methyl-[1,2,4]triazol-1-yl)-acetic Acid

[0289] This compound was prepared using a method analogous to that of Example 2, step 2.2, (3-methyl-[1,2,4]triazol-1-yl)-acetic acid benzyl ester from step 19.1 replacing intermediate 2.1. LC-MS (A): t.sub.R=0.18 min; [M+H].sup.+: 142.22.

19.3. 1-{(R)-4-[4-(2-Ethoxy-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-methyl-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone

[0290] This compound was prepared using a method analogous to that of Example 2, step 2.3, intermediate 19.2 replacing intermediate 2.2. The crude was purified by Prep LC-MS (V). LC-MS (A): t.sub.R=0.81 min; [M+H].sup.+: 497.1.

Example 20: 2-(3-Methyl-[1,2,4]triazol-1-yl)-1-{(R)-2-methyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-ethanone

[0291] This compound was prepared using a method analogous to that of Example 2, step 2.3, intermediate 5.2 replacing intermediate 1.7 and intermediate 19.2 replacing intermediate 2.2. DIPEA was used instead of NEt.sub.3. The crude was purified by Prep LC-MS (III). LC-MS (A): t.sub.R=0.87 min; [M+H].sup.+: 521.0.

Example 21: 1-{(R)-4-[4-(2-Cyclopropyl-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-methyl-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone

[0292] This compound was prepared using a method analogous to that of Example 2, step 2.3, intermediate 15.2 replacing intermediate 1.7 and intermediate 19.2 replacing intermediate 2.2. The crude was purified by Prep LC-MS (V). LC-MS (A): t.sub.R=0.81 min; [M+H].sup.+: 493.1.

II. Biological Assays

A) FLIPR Assay:

[0293] The bioactivity of compounds is tested in a fluorometric imaging plate reader (FLIPR: Molecular Devices) using engineered CHO-K1 cells expressing the human CXCR3A (GenBank: AY242128) coupled to a G protein (Galpha(16)). Cells are plated the day prior to bioassay in F12 medium supplemented with 10% FBS and G418 and hygromycin antibiotics to maintain recombinant selection. At the day of bioassay, cells are washed and dye loaded for one hour with Fluo-4-AM (Invitrogen) in Hanks Balanced Salt Solution (Invitrogen), buffered with 20 mM Hepes at pH 7.4 and sodium bicarbonate (0.038%), containing 5 mM probenecid. This buffer, but lacking the dye and containing probenecid at a concentration of 2.5 mM, is also used for washing steps (wash buffer); or lacking both dye and probenecid but supplemented with 0.1% BSA for compound dilution steps (dilution buffer). Cells are washed free of excess dye and 60 microliter of wash buffer is added. Stock solutions of test compounds are made up at a concentration of 10 mM in DMSO, and serially diluted in dilution buffer to concentrations required for inhibition dose response curves. After a 10 minute incubation period at 37° C., 10 microliters of each compound dilution are transferred from a compound plate to the plate containing the recombinant cells in the FLIPR instrument according to the manufacturer's instructions. Following basal readings, 10 microliter CXCL10 agonist at a concentration of 20 nM (from Peprotech) is added, again using the FLIPR instrument. Changes in fluorescence are monitored before and after addition of the test compounds. Emission peak values above base level after CXCL10 addition are exported after base line subtraction.

B) Receptor Internalization Assay (RIA):

[0294] Stock solutions of test compounds are made up at a concentration of 10 mM in DMSO, and serially diluted in PBS containing 0.5% BSA to concentrations required for inhibition dose response curves. Diluted compounds are then mixed with an equal volume of CXCL10 (Peprotech) diluted in PBS. Anticoagulated venous human whole blood is added to the mixture, which is then incubated in a CO.sub.2 incubator at 37° C. to allow for ligand mediated receptor internalization (final CXCL10 concentration is 9 nM). After 30 min, the blood is mixed with fluorescently labeled CXCR3 and CD4 specific antibodies (Becton Dickinson) and incubated on ice for 10 minutes. Samples are then mixed with BD FACS Lysing Solution (Becton Dickinson) in order to eliminate red blood cells. After washing the cells with PBS containing 0.5% BSA, the samples are then analyzed in a flow cytometer (FACS Canto II, Becton Dickinson). For data analysis using FACSDiva software (Becton Dickinson), the mean fluorescence corresponding to CXCR3 cell surface expression was determined on CD4 positive cells.

[0295] The calculated IC.sub.50 values may fluctuate depending on the daily assay performance. Fluctuations of this kind are known to those skilled in the art. In the case where IC.sub.50 values have been determined several times for the same compound, mean values are given. Data for the FLIPR assay are shown in Table 1 and for the receptor internalization assay (RIA) in Table 2.

TABLE-US-00008 TABLE 1 Example No FLIPR: IC.sub.50 (nM) 1 2.3 2 1.6 3 1.0 4 13 5 12 6 2.0 7 1.3 8 1.6 9 2.7 10 5.2 11 4.4 12 0.9 13 3.2 14 1.2 15 2.5 16 0.7 17 4.6 18 3.1 19 1.8 20 1.6 21 5.2

TABLE-US-00009 TABLE 2 Example No RIA: IC.sub.50 (nM) 1 299 2 235 3 552 4 950 5 1710 6 148 7 174 8 349 9 606 10 809 11 221 12 564 13 830 14 459 15 190 16 524 17 679 18 1390 19 211 20 189 21 462
C) hERG Q-Patch Assay:

[0296] Compounds are evaluated for block of the hERG K channel using CHO cells stably expressing the hERG gene (accession number U04270, bSys, Witterswil, Switzerland) and the QPatch robotic platform (Sophion, Ballerup, Denmark) in single-cell mode at room temperature. Cells are grown in culture flasks at 37° C. in 5% CO.sub.2, in culture medium (Ham's F-12 Nutrient Mixture, Invitrogen 21765-029) supplemented with 9% (v/v) fetal calf serum, 0.9% Penicillin/Streptomycin (10,000 U/mL, Invitrogen 15140148), 100 μg/mL Hygromycin B (Invitrogen 10687010). When the cells are ˜80% confluent (every 2-3 days), they are either split for further culture or used for electrophysiology. For further culture, cells are detached with 0.25% Trypsin EDTA solution (Invitrogen 25200-056) and a fraction of the cells (10-30%) is reseeded in culture medium. For electrophysiology, on the experimental day, cells are detached with 0.25% Trypsin EDTA solution and all cells are suspended in suspension medium (293 SFM II, Invitrogen 11686-029) supplemented with 20 mM HEPES and 0.04 mg/mL Trypsin inhibitor. Cells are kept in suspension medium at 32-35° C. in the QPatch robot until use, at which time aliquots are transferred to the extracellular solution (in mM: NaCl 150; KCl 4; CaCl.sub.2 1.2; MgCl.sub.2 1; HEPES 10; pH 7.4 with NaOH) containing 0.3% v/v DMSO and applied to the test plates. K+ currents are measured with the patch-voltage-clamp technique in the whole-cell configuration with the internal solution (in mM: KCl, 140; NaCl, 10; MgCl.sub.2, 1; HEPES, 10; EGTA, 5; pH=7.2 with KOH). Currents are low-pass filtered using the internal Bessel filter of the QPatch robot with a cut-off frequency of 2 kHz and are digitized at 10 kHz. K.sup.+ tail currents are produced from a holding voltage of −80 mV by a 500-ms depolarization to +20 mV followed by a 500-ms repolarization to −40 mV; tail current amplitudes are measured at the end of the repolarization to −40 mV. The pulse pattern is repeated every 10 sec during the experiment, baseline K.sup.+ current is measured after 3 min in extracellular solution, test-solution containing compound is then applied, and K.sup.+ current in presence of compound is measured 3 minutes after application to the cells. The respective test-solution is prepared by (1) dissolving the test-compound in pure DMSO, (2) diluting this DMSO solution in extracellular solution, and (3) adding further DMSO, such that the final test-solution has a concentration of either 300 nM or 3000 nM of the test-compound and contains 0.3% v/v DMSO. Compound effects are quantified as % block by dividing the current in presence of compound by the baseline current; two or three experiments are performed for each compound and the final value represents the mean of the results of each experiment.

TABLE-US-00010 concentration concentration Example No [nM] % block [nM] % block 1 300 6 3000 20 2 300 −2 3000 4 3 300 10 3000 20 4 300 5 3000 10 5 300 1 3000 5 6 300 5 3000 22 7 300 5 3000 24 8 300 4 3000 23 9 300 2 3000 11 10 300 6 3000 17 11 300 5 3000 30 12 300 0 3000 4 13 300 10 3000 21 14 300 4 3000 27 15 300 3 3000 27 16 300 1 3000 25 17 300 0 3000 23 18 300 10 3000 22 19 300 9 3000 14 20 300 2 3000 18 21 300 3 3000 17