NOVEL POTASSIUM CHANNEL INHIBITORS

Abstract

The present invention relates to novel compounds, pharmaceutical compositions comprising such compounds and their use for treating, alleviating or preventing diseases or disorders relating to the activity of potassium channels.

Claims

1. A compound of formula (XIX): ##STR00039## wherein: R.sup.14 is C(O)OC.sub.1-8 alkyl; R.sup.8 is H or C.sub.1-5 linear or branched alkyl; A is of formula (X): ##STR00040## R.sup.9 is C(H), R.sup.10 is H, R.sup.11 is F and R.sup.12 is CF.sub.3; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein the compound is ethyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate, or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, wherein the compound is ethyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate, or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1, wherein the compound is ethyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((1-methylpyrrolidin-2-yl)methyl) carbamate, or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1, wherein the compound is isopropyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate, or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1, wherein the compound is cyclopropyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate, or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1, wherein the compound is cyclopropylmethyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate, or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1, wherein the compound is methyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate, or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1, wherein the compound is methyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate, or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1, wherein the compound is methyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((1-methylpyrrolidin-2-yl)methyl)carbamate, or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 1, wherein the compound is methyl (S)-(1-(4-fluoro-3-(trifluoro methyl) phenyl)cyclopropyl) ((1-methylpyrrolidin-2-yl)methyl) carbamate, or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 1, wherein the compound is methyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((2-methyl pyrrolidin-2-yl)methyl)carbamate, or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 1, wherein the compound is methyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((2-methylpyrrolidin-2-yl)methyl)carbamate, or a pharmaceutically acceptable salt thereof.

14. A method for treating inflammatory bowel disease (IBD), hereditary xerocytosis, acute respiratory distress syndrome (ARDS), or a combination thereof, in a subject in need thereof, comprising administering to the subject a compound pf formula (XIX): ##STR00041## wherein: R.sup.14 is C(O)OC.sub.1-8 alkyl; R.sup.8 is H or C.sub.1-5 linear or branched alkyl; A is of formula (X): ##STR00042## R.sup.9 is C(H), R.sup.10 is H, R.sup.11 is F and R.sup.12 is CF.sub.3; or a pharmaceutically acceptable salt thereof.

15. The method according to claim 14, wherein the compound is ethyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate, or a pharmaceutically acceptable salt thereof.

16. The method according to claim 14, wherein the compound is ethyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate, or a pharmaceutically acceptable salt thereof.

17. The method according to claim 14, wherein the compound is ethyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((1-methylpyrrolidin-2-yl)methyl) carbamate, or a pharmaceutically acceptable salt thereof.

18. The method according to claim 14, wherein the compound is methyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate, or a pharmaceutically acceptable salt thereof.

19. The method according to claim 14, wherein the compound is methyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((1-methylpyrrolidin-2-yl)methyl)carbamate, or a pharmaceutically acceptable salt thereof.

20. The method according to claim 14, wherein the compound is methyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((2-methyl pyrrolidin-2-yl)methyl)carbamate, or a pharmaceutically acceptable salt thereof.

Description

EXAMPLES

Example [1]Methyl N-(2-(dimethylamino)ethyl)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl) carbamate

Step 1

[0567] To a solution of the 4-fluoro-3-(trifluoromethyl)benzonitrile (105.75 mmol) and titanium(IV)isopropoxide (116.33 mmol) in dry diethyl ether was added ethylmagnesium bromide 3M solution in Ether (222.09 mmol) at 78 C. The resulting yellow solution was stirred for 10 minutes and slowly warmed to rt over 4 h. Then boron trifluoride diethyl etherate (211.51 mmol) was added and the reaction mixture was stirred for 24 h at rt. The reaction mixture was quenched with 1.5 N HCl solution and extracted with ethyl acetate. The aqueous phase was basified with 10% sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulphate to obtain crude which was purified by flash chromatography using neutral silica gel in 10% TEA in ethyl acetate:Pet-ether as eluent to afford 1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-amine [1.1](LCMS: MH+: 220.1) as product.

Step 2

[0568] To a stirred solution of 1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropan-1-amine [1.1](0.2 g, 0.912 mmol) in dichloromethane (10 mL) was added N,N-diisopropylethylamine (0.35 mL, 2 mmol) followed by methyl chloroformate (0.122 g, 1.29 mmol) at 0 C. and the reaction mixture was stirred at rt for 2 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine solution and dried over sodium sulphate, filtered and concentrated under reduced pressure to afford the crude product which was purified by flash chromatography using ethyl acetate in hexanes as eluent to afford methyl (1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate [1.2] as an off white solid (0.19 g, 75%).

Step 3

[0569] To a solution of methyl (1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate [1.2](0.08 g, 0.29 mmol) in DMF (3 mL) was added sodium hydride (60%, 0.016 g, 0.32 mmol). The reaction was stirred at 0 C. for 10 minutes then, 2-chloro-N,N-dimethylethan-1-amine hydrochloride (0.037 g, 0.26 mmol) added and the reaction stirred at rt for 1 h. The reaction mixture was poured into ice and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over sodium sulphate, filtered and concentrated under reduced pressure to afford the crude product, which was purified by column chromatography using ethyl acetate in hexane to afford methyl (2-(dimethylamino)ethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl) carbamate [1] as yellow gum (0.012 g, 15%). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 7.55 (bs, 1H), 7.45-7.35 (m, 2H), 3.55 (bs, 3H), 3.40-3.30 (m, 2H), 1.70 (bs, 2H), 2.05 (s, 6H), 1.48-1.18 (m, 4H). HRMS calculated for: [C.sub.16H.sub.20F.sub.4N.sub.2O.sub.2+H].sup.+ 349.1534; found: 349.1526 (deviation 2.3).

Example [2]Methyl (2-amino-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate

Step 1

[0570] To a solution of tert-butyl (1-hydroxy-2-methylpropan-2-yl)carbamate (20 g, 105.7 mmol) in dichloromethane (100 mL) was added Dess-Martin periodinane (55.4 g, 126.8 mmol) at 0 C. and stirred at room temperature for 16 h. The reaction mixture was filtered and the filtrate was extracted with dichloromethane, washed with saturated sodium thiosulphate solution and 10% sodium bicarbonate solution. The organic layer was dried over sodium sulphate, filtered and dried under vacuum to afford crude product, which was purified by flash chromatography using ethyl acetate in pet-ether as solvent to afford tert-butyl (2-methyl-1-oxopropan-2-yl)carbamate [2.1] as a white solid (19.5 g, 99%).

Step 2

[0571] To a stirred solution of 1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropan-1-amine [1.1](0.05 g, 0.22 mmol) in IPA (5 mL) at 0 C. was added tert-butyl (2-methyl-1-oxopropan-2-yl)carbamate [2.1](0.029 g, 0.16 mmol) and acetic acid (0.05 mL). The reaction was stirred for 1 h at room temperature, then sodium cyanoborohydride (0.016 g, 0.26 mmol) was added at 0 C., then the reaction stirred at room temperature for 2h. Saturated aq. sodium bicarbonate solution was added and the reaction extracted with DCM. The combined organic layers were washed with brine solution, dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude product which was purified by column chromatography using EtOAc in hexane as eluent to afford tert-butyl (1-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)-2-methylpropan-2-yl)carbamate [2.2] as a colourless liquid (0.03 g, 34%, LCMS MH.sup.+=391.1).

Step 3

[0572] The procedure used in Example [1], Step 2 was adapted such that 16 g of tert-butyl (1-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)-2-methylpropan-2-yl)carbamate [2.2] was reacted to afford methyl (2-((tert-butoxycarbonyl)amino)-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate [2.3](14 g, 76%, LCMS MH.sup.+=449.2).

Step 4

[0573] To a stirred solution of methyl (2-((tert-butoxycarbonyl)amino)-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate [2.3](7.8 g, 17.4 mmol) in dioxane (10 mL) was added dioxane.Math.HCl (20 mL) at 0 C. and the reaction stirred at room temperature for 12 h. The reaction was concentrated under reduced pressure and the residue triturated in pentane to afford methyl (2-amino-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate [2]hydrochloride salt as an off-white solid (6.5 g, 97%). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 7.53 (s, 2H), 7.42 (t, J=10.40 Hz, 1H), 3.57 (s, 3H), 3.32 (d, J=16.80 Hz, 2H), 1.65 (bs, 4H), 1.31 (s, 2H), 0.93 (s, 6H). HRMS calculated for: [C.sub.16H.sub.20F.sub.4N.sub.2O.sub.2+H].sup.+ 349.1534; found: 349.1521 (deviation 3.7 ppm).

Example [3]Methyl ((1-aminocyclopropyl)methyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl) carbamate

Step 1

[0574] To a solution of 1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropan-1-amine [1.1](0.2 g, 0.91 mmol) and 0.16 g of tert-butyl N-(1-formylcyclopropyl)carbamate (0.16 g, 0.91 mmol) in dichloromethane/isopropyl alcohol (3:2, 10 mL) was added sodium triacetoxy borohydride (0.38 g, 1.82 mmol) at room temperature and the reaction stirred for 2 h. The reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with brine solution and dried over sodium sulphate, filtered and concentrated under reduced pressure to afford crude product, which was purified by flash chromatography using ethyl acetate in pet-ether as solvent system to afford tert-butyl (1-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)cyclopropyl)carbamate [3.1] as an off white solid (0.11 g, 31%, LCMS MH.sup.+=389.2).

Step 2

[0575] The procedure used in Example [1], Step 2 was adapted such that 0.11 g of tert-butyl (1-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)cyclopropyl)carbamate [3.1] and 0.073 g of methyl chloroformate was reacted to afford the product methyl ((1-((tert-butoxycarbonyl)amino)cyclopropyl)methyl)(1-(4-fluoro-3-(trifluoro methyl)phenyl)cyclopropyl)carbamate [3.2] as an off white solid (0.1 g, 80%, LCMS MH+=447.2).

Step 3

[0576] The procedure used in Example [2], Step 4 was adapted such that 0.1 g of methyl ((1-((tert-butoxycarbonyl)amino)cyclopropyl)methyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate [3.2] was reacted to afford methyl ((1-aminocyclopropyl)methyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl) carbamate [3] as a an brown solid (0.055 g, 55%). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 7.60-7.32 (m, 4H), 3.65 (s, 3H), 1.60-1.42 (m, 2H), 1.36-1.28 (m, 2H), 1.30-1.21 (m, 2H), 0.95-0.70 (m, 5H). HRMS calculated for: [C.sub.16H.sub.18F.sub.4N.sub.2O.sub.2+H].sup.+ 347.1377; found: 347.1369 (deviation 2.5 ppm).

Example [4]Methyl 3-((1-(4-fluoro-3-(trifluoromethyl) phenyl) cyclopropyl) (methoxycarbonyl)amino)azetidine-1-carboxylate

Step 1

[0577] The procedure used in Example [3], Step 1 was adapted such that 0.5 g of 1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropan-1-amine and 0.117 g of tert-butyl 3-oxoazetidine-1-carboxylate were reacted to afford the product tert-butyl 3-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)azetidine-1-carboxylate [4.1](0.39 g, crude, LCMS MH.sup.+=375.1).

Step 2

[0578] The procedure used in Example [2], Step 4 was adapted such that 0.3 g of tert-butyl 3-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)azetidine-1-carboxylate [4.1] was reacted to afford the product N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl) azetidin-3-amine [4.2](0.2 g, crude, LCMS MH.sup.+=275.1).

Step 3

[0579] The procedure used in Example [1], Step 2 was adapted such that 0.2 g of N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)azetidin-3-amine and 0.2 mL of methyl carbonochloridate were reacted to afford methyl 3-((1-(4-fluoro-3-(trifluoromethyl) phenyl) cyclopropyl) (methoxycarbonyl)amino)azetidine-1-carboxylate [4](0.045 g, 30%). MS (M+1).sup.+=391.1. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 7.45 (t, J=8.80 Hz, 2H), 7.30 (d, J=5.20 Hz, 1H), 4.40 (q, J=6.80 Hz, 1H), 4.20-3.98 (m, 4H), 3.61 (s, 3H), 3.52 (s, 3H), 1.40 (s, 4H). HRMS calculated for: [C.sub.1-7H.sub.18F.sub.4N.sub.2O.sub.4+H].sup.+ 391.1275; found: 391.1264 (deviation 2.8 ppm).

Example [5]Methyl azetidin-3-yl(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate

Step 1

[0580] The procedure used in Example [1], Step 2 was adapted such that 0.3 g of tert-butyl 3-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)azetidine-1-carboxylate [4.1] and 0.226 g of methyl carbonochloridate were reacted to afford the product tert-butyl 3-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl) (methoxycarbonyl)amino) azetidine-1-carboxylate [5.1](0.3 g, crude, LCMS MH.sup.+=433.1).

Step 2

[0581] The procedure used in Example [2], Step 4 was adapted such that 0.25 g of tert-butyl 3-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(methoxy carbonyl)amino)azetidine-1-carboxylate [5.1] was reacted to afford methyl azetidin-3-yl(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate [5](0.04 g, 40%). MS (M+1).sup.+=333.1. .sup.1H-NMR (400 MHz, CDCl.sub.3): 7.32-7.27 (m, 2H), 7.15 (t, J=8.80 Hz, 1H), 4.60-4.50 (m, 1H), 4.50-4.20 (m, 4H), 3.82 (s, 3H), 1.32-1.25 (m, 4H). HRMS calculated for: [C.sub.15H.sub.16F.sub.4N.sub.2O.sub.2+H].sup.+ 333.1221; found: 333.1215 (deviation 1.6 ppm).

Example [6]N-(cyclopropylmethyl)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)azetidin-3-amine

Step 1

[0582] The procedure used in Example [3], Step 1 was adapted such that 0.25 g of tert-butyl 3-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)azetidine-1-carboxylate [4.1] and 0.274 g of cyclopropanecarbaldehyde was reacted to afford the product tert-butyl 3-((cyclopropylmethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl) cyclopropyl) amino)azetidine-1-carboxylate as colourless gum (0.15 g, crude, LCMS MH.sup.+=429.1).

Step 2

[0583] The procedure used in Example [2], Step 4 was adapted such that 0.15 g of tert-butyl 3-((cyclopropylmethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)azetidine-1-carboxylate [6.1] was reacted to afford N-(cyclopropylmethyl)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)azetidin-3-amine [6] as colourless gum (0.1 g, 87%). MS (M+1).sup.+=329.1. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 8.53 (s, 1H), 8.38 (s, 1H), 7.67-7.62 (m, 2H), 7.47 (t, J=8.80 Hz, 1H), 3.95-3.82 (m, 3H), 3.79 (t, J=8.00 Hz, 1H), 2.38-2.32 (m, 2H), 1.17 (q, J=42.00 Hz, 2H), 0.96 (q, J=11.60 Hz, 2H), 1.40-1.30 (m, 1H), 0.47-0.42 (m, 2H), 0.13 (q, J=3.20 Hz, 2H). HRMS calculated for: [C.sub.17H.sub.20F.sub.4N.sub.2+H].sup.+ 329.1635; found: 329.1624 (deviation 3.3 ppm).

Example [7]Methyl (2-aminoethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate

Step 1

[0584] The procedure used in Example [3], Step 1 was adapted such that 0.4 g of 1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropan-1-amine [1.1] and 0.29 g of tert-butyl (2-oxoethyl)carbamate was reacted to afford the product tert-butyl (2-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)ethyl)carbamate [7.1] as an off white solid (0.4 g, 60%, LCMS MH.sup.+=363.2).

Step 2

[0585] The procedure used in Example [1], Step 2 was adapted such that 0.4 g of tert-butyl (2-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)ethyl)carbamate [7.1] and 0.32 g of methyl chloroformate was reacted to afford the product methyl (2-((tert-butoxycarbonyl)amino)ethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate [7.2] as an off white solid (0.4 g, crude, LCMS MH.sup.+=421.2).

Step 3

[0586] The procedure used in Example [2], Step 4 was adapted such that 0.4 g methyl (2-((tert-butoxycarbonyl)amino)ethyl)(1-(4-fluoro-3-(trifluoromethyl) phenyl)cyclopropyl)carbamate [7.2] was reacted to afford methyl (2-aminoethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate [7] as a yellow oil (0.011 g, 04%). .sup.1H-NMR (400 MHz, CDCl.sub.3): 7.4 (bs, 3H), 3.72 (s, 3H), 3.40 (s, 2H), 2.82 (s, 2H), 1.45 (s, 2H), 1.25 (s, 4H). HRMS calculated for: [C.sub.14H.sub.16F.sub.4N.sub.2O.sub.2+H].sup.+ 321.1221; found: 321.1217 (deviation 1.1 ppm).

Example [8]N1-(cyclopropyl methyl)-N1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-2-methyl propane-1,2-diamine

Step 1

[0587] The procedure used in Example [3], Step 1 was adapted such that 0.22 g of tert-butyl (1-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)-2-methyl propan-2-yl)carbamate and 0.047 g of cyclopropanecarbaldehyde was reacted to afford the product tert-butyl (1-((cyclopropylmethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)-2-methylpropan-2-yl)carbamate [8.1] as a colourless gum (0.2 g, 80%, LCMS MH.sup.+=459.2).

Step 2

[0588] The procedure used in Example [2], Step 4 was adapted such that 0.2 g of tert-butyl (1-((cyclopropylmethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)-2-methylpropan-2-yl)carbamate [8.1] was reacted to afford N.sub.1-(cyclopropyl methyl)-N1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-2-methyl propane-1,2-diamine [8] as a yellow oil (0.1 g, 66%). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 7.70-7.60 (m, 2H), 7.45 (t, J=40.00 Hz, 1H), 2.52-2.40 (m, 2H), 2.37 (d, J=6.80 Hz, 2H), 1.40-1.20 (m, 4H), 1.10-1.00 (m, 2H), 1.00-0.88 (m, 7H), 0.45 (q, J=1.20 Hz, 2H), 0.07 (t, J=3.60 Hz, 2H). HRMS calculated for: [C.sub.18H.sub.24F.sub.4N.sub.2+H].sup.+ 345.1948; found: 345.1937 (deviation 3.3 ppm).

Example [9]N-(2-amino-2-methylpropyl)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)cyclopropanecarboxamide

Step 1

[0589] To a stirred solution of tert-butyl (1-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)-2-methyl propan-2-yl)carbamate [2.2](0.1 g, 0.256 mmol) and DIPEA (0.09 mL, 0.512 mmol) in DCM (5 mL) was added cyclopropanecarbonyl chloride (0.054 g, 0.512 mmol) and the reaction stirred at room temperature for 18 h. The reaction was diluted with water and extracted with DCM. The combined organic layers were washed with brine solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford tert-butyl (1-(N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)cyclopropanecarboxamido)-2-methylpropan-2-yl)carbamate [9.1] as a colourless liquid (0.1 g, 80%, LCMS MH.sup.+=445.2).

Step 2

[0590] The procedure used in Example [2], Step 4 was adapted such that 0.1 g of tert-butyl (1-(N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)cyclopropanecarboxamido)-2-methylpropan-2-yl)carbamate [9.1] was reacted to afford the crude product, which was purified by Prep HPLC using 0.2% TFA in acetonitrile to afford N-(2-amino-2-methylpropyl)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)cyclopropanecarboxamide [9] as TFA salt as a pale brown solid (0.08 g, 80%). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 7.76 (s, 3H), 7.52 (t, J=11.60 Hz, 1H), 7.44-7.39 (m, 1H), 7.27 (dd, J=3.20, 8.40 Hz, 1H), 3.88 (d, J=60.00 Hz, 1H), 3.30 (s, 1H), 2.15-1.95 (m, 1H), 1.95-1.80 (m, 1H), 1.80-1.65 (m, 1H), 1.65-1.50 (m, 1H), 1.50-1.35 (m, 1H), 1.22 (s, 4H), (s, 3H), 0.90-0.80 (m, 2H), 0.80-0.65 (m, 1H), 0.65-0.55 (m, 1H). HRMS calculated for: [C.sub.18H.sub.22F.sub.4N.sub.2O+H].sup.+ 359.1741; found: 359.1733 (deviation 2.2 ppm).

Example [10]N1-cyclopropyl-2-methyl-N1-(1-(3-(trifluoromethyl)phenyl)cyclopropyl)propane-1,2-diamine

Step 1

[0591] The procedure used in Example [1], Step 1 was adapted such that 1.5 g of 3-(trifluoromethyl)benzonitrile was reacted to afford 1-(3-(trifluoromethyl)phenyl)cyclopropan-1-amine [10.1](0.5 g, 30%, LCMS MH.sup.+=202.1).

Step 2

[0592] The procedure used in Example [3], Step 1 was adapted such that 0.275 g of 1-(3-(trifluoromethyl)phenyl)cyclopropan-1-amine [10.1] was reacted to afford tert-butyl (2-methyl-1-((1-(3-(trifluoromethyl)phenyl)cyclopropyl)amino)propan-2-yl)carbamate [10.2] as an off-white solid (0.37 g, 73%, LCMS MH.sup.+=373.2).

Step 3

[0593] The procedure used in Example [2], Step 2 was adapted such that 0.270 g of tert-butyl (2-methyl-1-((1-(3-(trifluoromethyl)phenyl)cyclopropyl)amino)propan-2-yl)carbamate [2.2] was reacted with [(1-ethoxycyclopropyl)oxy]trimethylsilane to afford tert-butyl (1-(cyclopropyl(1-(3-(trifluoromethyl) phenyl) cyclopropyl)amino)-2-methylpropan-2-yl)carbamate [10.3] as an off-white gum (0.1 g, 36%, LCMS MH.sup.+=413.4).

Step 4

[0594] The procedure used in Example [2], Step 4 was adapted such that 0.06 g tert-butyl(1-(cyclopropyl(1-(3-(trifluoromethyl)phenyl)cyclopropyl) amino)-2-methylpropan-2-yl)carbamate [10.3] was reacted to afford N.sub.1-cyclopropyl-2-methyl-N1-(1-(3-(trifluoromethyl)phenyl)cyclopropyl)propane-1,2-diamine [10] as an off-white solid (0.025 g, 50%, LCMS MH.sup.+=313.2). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 7.88 (s, 2H), 7.71-7.59 (m, 4H), 2.91 (s, 2H), 1.57 (m, 1H), 1.25 (d, J=5.68 Hz, 6H), 1.20-1.00 (m, 2H), 1.00-0.85 (m, 2H), 0.85-0.70 (m, 2H), 0.60-0.40 (m, 2H). HRMS calculated for: [C.sub.17H.sub.23F.sub.3N.sub.2+H].sup.+ 313.1886; found: 313.1880 (deviation 2.1 ppm).

Example [11]Methyl (2-amino-2-methylpropyl)(1-(3,5-dichlorophenyl)cyclopropyl)carbamate

Step 1

[0595] The procedure used in Example [1], Step 1 was adapted such that 0.5 g of 3,5-dichlorobenzonitrile was reacted to afford 1-(3,5-dichlorophenyl)cyclopropan-1-amine [11.1](0.2 g, 34%, LCMS MH.sup.+=203.1).

Step 2

[0596] The procedure used in Example [3], Step 1 was adapted such that 0.2 g of 1-(3,5-dichlorophenyl)cyclopropan-1-amine [11.1] and 0.18 g of tert-butyl (2-methyl-1-oxopropan-2-yl)carbamate [2.1] was reacted to afford the product tert-butyl (1-((1-(3,5-dichlorophenyl) cyclopropyl)amino)-2-methylpropan-2-yl)carbamate [11.2] as a brown liquid (0.2 g, 54%, LCMS MH.sup.+=374.1).

Step 3

[0597] The procedure used in Example [1], Step 2 was adapted such that 0.2 g of tert-butyl (1-((1-(3,5-dichlorophenyl)cyclopropyl)amino)-2-methylpropan-2-yl)carbamate [11.2] was reacted to afford the product methyl (2-((tert-butoxycarbonyl)amino)-2-methylpropyl)(1-(3,5-dichlorophenyl)cyclopropyl)carbamate [11.3] as colourless liquid (0.14 g, 60%, LCMS MH.sup.+=432.2).

Step 4

[0598] The procedure used in Example [2], Step 4 was adapted such that 0.14 g of methyl (2-((tert-butoxycarbonyl)amino)-2-methylpropyl)(1-(3,5-dichlorophenyl)cyclopropyl)carbamate [11.3] was reacted to afford methyl (2-amino-2-methylpropyl)(1-(3,5-dichlorophenyl)cyclopropyl)carbamate [11] as an off-white solid (0.037 g, 31%). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 7.80 (bs, 3H), 7.48 (d, J=1.20 Hz, 1H), 7.14 (bs, 1H), 3.65 (s, 3H), 3.56 (d, J=2.40 Hz, 1H), 3.50 (s, 1H), 1.45 (s, 2H), 1.35 (s, 1H), 1.30-1.22 (m, 1H), 1.17 (bs, 6H). HRMS calculated for: [C.sub.18H.sub.20Cl.sub.2N.sub.2O.sub.2+H].sup.+ 331.0975; found: 331.0966 (deviation 2.7 ppm).

Example [12]Methyl (2-amino-2-methylpropyl)(1-(3-bromophenyl)cyclopropyl)carbamate

Step 1

[0599] The procedure used in Example [1], Step 1 was adapted such that 3 g of 3-bromobenzonitrile was reacted to afford 1-(3-bromophenyl)cyclopropan-1-amine [12.1](1.3 g, 56%, LCMS MH.sup.+=213.0).

Step 2

[0600] The procedure used in Example [3], Step 1 was adapted such that 1 g of 1-(3-bromophenyl)cyclopropan-1-amine [12.1] and 0.97 g of tert-butyl (2-methyl-1-oxopropan-2-yl)carbamate [2.1] were reacted to afford the product tert-butyl (1-((1-(3-bromophenyl)cyclopropyl) amino)-2-methylpropan-2-yl)carbamate [2.2] as a yellow solid (0.9 g, 67%, LCMS MH.sup.+=384.2).

Step 3

[0601] The procedure used in Example [1], Step 2 was adapted such that 0.5 g of tert-butyl (1-((1-(3-bromophenyl)cyclopropyl)amino)-2-methylpropan-2-yl)carbamate [2.2] was reacted to afford the product methyl (1-(3-bromophenyl)cyclopropyl)(2-((tert-butoxycarbonyl)amino)-2-methylpropyl)carbamate as a colourless liquid (0.4 g, 69%, LCMS MH.sup.+=442.1).

Step 4

[0602] The procedure used in Example [2], Step 4 was adapted such that 0.1 g of methyl (1-(3-bromophenyl)cyclopropyl)(2-((tert-butoxycarbonyl)amino)-2-methylpropyl)carbamate [12.3] was reacted to afford methyl (2-amino-2-methylpropyl)(1-(3-bromophenyl)cyclopropyl)carbamate [12] as TFA salt (compound was purified by prep HPLC using 0.1% TFA in ACN) as a white solid (0.02 g, 26%). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 7.67 (bs, 2H), 7.42-7.38 (m, 1H), 7.27 (t, J=10.40 Hz, 2H), 7.10 (bs, 1H), 3.62 (s, 3H), 3.52-3.37 (m, 2H), 1.50-1.20 (m, 4H), 1.15 (s, 6H). HRMS calculated for: [C.sub.15H.sub.21BrN.sub.2O.sub.2+H].sup.+ 341.0859; 343.0839; found: 341.0847; 343.0828 (deviation 3.5; 3.3 ppm).

Example [13]Methyl (2-amino-2-methylpropyl)(1-(3-chlorophenyl)cyclopropyl)carbamate

Step 1

[0603] The procedure used in Example [1], Step 1 was adapted such that 1 g of 3-bromobenzonitrile was reacted to afford 1-(3-chlorophenyl)cyclopropan-1-amine [13.1](0.4 g, 32%, LCMS MH.sup.+=168.5).

Step 2

[0604] The procedure used in Example [3], Step 1 was adapted such that 0.4 g of 1-(3-chlorophenyl)cyclopropan-1-amine [13.1] and 0.49 g of tert-butyl (2-methyl-1-oxopropan-2-yl)carbamate [2.1] were reacted to afford the product tert-butyl (1-((1-(3-chlorophenyl)cyclopropyl) amino)-2-methylpropan-2-yl)carbamate [13.2] as a brown liquid (0.25 g, 31%, LCMS MH.sup.+=339.2).

Step 3

[0605] The procedure used in Example [1], Step 2 was adapted such that 0.2 g of tert-butyl (1-((1-(3-chlorophenyl)cyclopropyl)amino)-2-methylpropan-2-yl)carbamate [13.2] was reacted to afford methyl (2-((tert-butoxycarbonyl)amino)-2-methylpropyl)(1-(3-chlorophenyl)cyclopropyl)carbamate [13.3] as a colourless liquid (0.17 g, 72%, LCMS MH.sup.+=397.1).

Step 4

[0606] The procedure used in Example [2], Step 4 was adapted such that 0.17 g of methyl (2-((tert-butoxycarbonyl)amino)-2-methylpropyl)(1-(3-chlorophenyl)cyclopropyl)carbamate [13.3] was reacted to afford methyl (2-amino-2-methylpropyl)(1-(3-chlorophenyl)cyclopropyl)carbamate [13] as TFA salt (compound was purified by Prep HPLC using 0.1% TFA in ACN) as a colourless gum (0.1 g, 78%). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 7.59 (s, 2H), 7.36-7.24 (m, 2H), 7.33 (bs, 2H), 3.62 (s, 3H), 3.50 (bs, 2H), 1.35 (s, 4H), 1.15 (s, 6H). HRMS calculated for: [C.sub.15H.sub.21ClN.sub.2O.sub.2+H].sup.+ 297.1364; found: 297.1257 (deviation 2.5 ppm).

Example [14]1-((azetidin-2-ylmethyl)(1-(4-fluoro-3-(trifluoromethyl) phenyl)cyclopropyl)amino)-2-methyl propan-2-ol

Step 1

[0607] To a stirred solution of 1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropan-1-amine [1.1](1.5 g, 6.84 mmol) and 1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (1.23 g, 6.15 mmol) in DMF was added Hatu (3.12 g, 8.21 mmol), followed by DIPEA (2.2 g, 17.10 mmol) at 0 C. and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine solution. The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to afford a crude product, which was purified by flash chromatography using ethyl acetate in pet-ether as eluent to afford tert-butyl 2-((1-(4-fluoro-3-(trifluoromethyl)phenyl) cyclopropyl) carbamoyl) azetidine-1-carboxylate [14.1] as a colourless gum (2.3 g, 85%, LCMS MH.sup.+=403.3).

Step 2

[0608] To a solution of tert-butyl 2-((1-(4-fluoro-3-(trifluoromethyl)phenyl) cyclopropyl)carbamoyl)azetidine-1-carboxylate [14.1](2.3 g, 5.72 mmol) in tetrahydrofuran was added borane dimethyl sulphide complex (1.8 g, 22.86 mmol) at 0 C. and the reaction refluxed at 70 C. for 2 h. The reaction mixture was quenched with methanol at 0 C. until the effervescence stopped. The reaction mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate washed with water and brine solution. The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to afford crude product, which was purified by flash chromatography using ethyl acetate in pet-ether as solvent to afford tert-butyl 2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)azetidine-1-carboxylate [14.2] as colourless liquid (1.45 g, 55%, LCMS M+=389.4).

Step 3

[0609] To a solution of tert-butyl 2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)azetidine-1-carboxylate [14.2](0.3 g, 0.77 mmol) and potassium carbonate (0.32 g, 2.31 mmol) in acetonitrile was added methyl bromoacetate (0.35 g, 2.31 mmol) and the reaction mixture was heated at 80 C. for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate, washed with water and brine solution. The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to afford crude product, which was purified by flash chromatography using ethyl acetate in pet-ether as solvent to afford tert-butyl 2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(2-methoxy-2-oxoethyl) amino)methyl)azetidine-1-carboxylate [14.3] as a colourless liquid. (0.25 g, 70%, LCMS MH.sup.+=461.2).

Step 4

[0610] To a stirred solution of tert-butyl 2-(((1-(4-fluoro-3-(trifluoromethyl) phenyl)cyclopropyl)(2-methoxy-2-oxoethyl) amino)methyl) azetidine-1-carboxylate [14.3](0.2 g, 0.43 mmol) in tetrahydrofuran (5 mL) at 0 C. was added methylmagnesium bromide (0.21 g, 1.74 mmol) at 0 C. and the reaction mixture was stirred at same temperature for 2 h, then stirred at rt for 1h. The reaction mixture was quenched with aqueous ammonium chloride solution and extracted with ethyl acetate, washed with water and brine solution. The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to afford the crude product which was purified by column chromatography using ethyl acetate/hexane as eluent to afford tert-butyl 2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl) cyclopropyl)(2-hydroxy-2-methylpropyl)amino) methyl)azetidine-1-carboxylate [14.4] as colourless gum (0.15 g, 75%, LCMS MH.sup.+=461.2).

Step 5

[0611] The procedure used in Example [1], Step 2 was adapted such that 0.12 g of tert-butyl 2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(2-hydroxy-2-methylpropyl)amino)methyl)azetidine-1-carboxylate [14.4] was reacted to afford 1-((azetidin-2-ylmethyl)(1-(4-fluoro-3-(trifluoromethyl) phenyl)cyclopropyl)amino)-2-methyl propan-2-ol [14] as an off-white solid (0.06 g, 66%, LCMS MH.sup.+=361.2). .sup.1H-NMR (400 MHz, CDCl.sub.3): 7.52-7.45 (m, 2H), 7.07 (q, J=62.80 Hz, 1H), 3.45 (q, J=32.80 Hz, 1H), 3.01 (s, 1H), 2.60 (s, 2H), 2.58-1.87 (m, 4H), 1.60-1.40 (m, 2H), 1.30-1.22 (m, 2H), 1.20 (s, 6H), 0.95-0.90 (m, 2H). HRMS calculated for: [C.sub.18H.sub.24F.sub.4N.sub.2O+H].sup.+ 361.1898; found: 361.1889 (deviation 2.4 ppm).

Example [15]Methyl (2-amino-2-methylpropyl)(1-(3-(trifluoromethyl)phenyl)cyclopropyl)carbamate

Step 1

[0612] The procedure used in Example [3], Step 1 was adapted such that 0.4 g of 1-(3-(trifluoromethyl)phenyl)cyclopropan-1-amine [10.1] and 0.52 g of tert-butyl (2-methyl-1-oxopropan-2-yl)carbamate were reacted to afford the product tert-butyl (2-methyl-1-((1-(3-(trifluoromethyl)phenyl)cyclopropyl)amino)propan-2-yl)carbamate [15.1](0.35 g, 69%, LCMS MH.sup.+=373.3).

Step 2

[0613] The procedure used in Example [1], Step 2 was adapted such that 0.3 g of tert-butyl (2-methyl-1-((1-(3-(trifluoromethyl)phenyl)cyclopropyl)amino)propan-2-yl)carbamate [15.1] was reacted to afford the product methyl (2-((tert-butoxycarbonyl)amino)-2-methylpropyl)(1-(3-(trifluoromethyl)phenyl)cyclopropyl)carbamate [15.2] as colourless liquid (0.2 g, 57%, LCMS MH.sup.+=431.4).

Step 3

[0614] The procedure used in Example [2], Step 4 was adapted such that 0.2 g of methyl (2-((tert-butoxycarbonyl)amino)-2-methylpropyl)(1-(3-(trifluoromethyl)phenyl)cyclopropyl)carbamate [15.2] was reacted to afford methyl (2-amino-2-methylpropyl)(1-(3-(trifluoromethyl)phenyl)cyclopropyl)carbamate [15] as an off-white solid (0.03 g, 20%). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 7.85 (bs, 2H), 7.57 (t, J=5.20 Hz, 2H), 7.40 (bs, 2H), 3.63 (s, 3H), 3.53 (s, 1H), 1.50 (bs, 2H), 1.37 (bs, 2H), 1.23 (bs, 1H), 1.18 (s, 6H). HRMS calculated for: [C.sub.16H.sub.21F.sub.3N.sub.2O.sub.2+H].sup.+ 331.1628; found: 331.1620 (deviation 2.5 ppm).

Example [16]1-((1-(4-fluoro-3-(trifluoromethyl) phenyl)cyclopropyl)((1-methylazetidin-2-yl)methyl)amino)-2-methylpropan-2-ol

[0615] The procedure used in Example [2], Step 2 was adapted such that 0.09 g of 1-((azetidin-2-ylmethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl) amino)-2-methylpropan-2-ol [14] was reacted to afford 1-((1-(4-fluoro-3-(trifluoromethyl) phenyl)cyclopropyl)((1-methylazetidin-2-yl)methyl)amino)-2-methylpropan-2-ol [16] as colourless gum (0.02 g, 21%, LCMS MH.sup.+=375.2). .sup.1H-NMR (400 MHz, CDCl.sub.3): 7.46-7.43 (m, 2H), 7.14 (t, J=9.20 Hz, 1H), 3.52-3.48 (m, 1H), 3.42-3.33 (m, 1H), 3.01-2.96 (m, 1H), 2.80-2.70 (m, 3H), 2.65 (d, J=13.20 Hz, 1H), 2.41 (s, 3H), 2.15-2.12 (m, 1H), 1.80-1.70 (m, 2H), 1.30-1.23 (m, 2H), 1.21-1.19 (m, 3H), 1.90-1.30 (m, 3H), 1.08-0.80 (m, 1H), 0.30-0.20 (m, 1H). HRMS calculated for: [C.sub.19H.sub.26F.sub.4N.sub.2O+H].sup.+ 375.2054; found: 375.2044 (deviation 2.6 ppm).

Example [17]Methyl (2-amino-2-methylpropyl)(1-(5-fluoro-4-(trifluoromethyl)pyridin-2-yl)cyclopropyl) carbamate

Step 1

[0616] The procedure used in Example [3], Step 1 was adapted such that 0.054 g of 1-(5-fluoro-4-(trifluoromethyl)pyridin-2-yl)cyclopropan-1-amine [36.6] was reacted to afford tert-butyl (1-((1-(5-fluoro-4-(trifluoromethyl)pyridin-2-yl)cyclopropyl)amino)-2-methyl propan-2-yl)carbamate [17.1] as an off-white solid (0.052 g, 54%, LCMS MH.sup.+=392.2).

Step 2

[0617] The procedure used in Example [1], Step 2 was adapted such that 0.05 g of tert-butyl (1-((1-(5-fluoro-4-(trifluoromethyl)pyridin-2-yl)cyclopropyl)amino)-2-methylpropan-2-yl)carbamate [17.1] was reacted to afford methyl (2-((tert-butoxycarbonyl)amino)-2-methylpropyl)(1-(5-fluoro-4-(trifluoromethyl)pyridin-2-yl)cyclopropyl) carbamate [17.2] as an off-white solid (0.042 g, 73%, LCMS MH.sup.+=450.2).

Step 3

[0618] The procedure used in Example [2], Step 4 was adapted such that 0.04 g of methyl (2-((tert-butoxycarbonyl)amino)-2-methylpropyl)(1-(5-fluoro-4-(trifluoromethyl)pyridin-2-yl)cyclopropyl)carbamate was reacted to afford methyl (2-amino-2-methylpropyl)(1-(5-fluoro-4-(trifluoromethyl)pyridin-2-yl)cyclopropyl) carbamate [17] as an off-white solid (0.021 g, 61%, LCMS MH.sup.+=350.2). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 8.81 (s, 1H), 7.80 (s, 2H), 7.33 (s, 1H), 3.58 (s, 3H), 3.26-3.25 (m, 2H), 1.58-1.54 (m, 4H), 1.24-1.21 (m, 6H). HRMS calculated for: [C.sub.15H.sub.19F.sub.4N.sub.3O.sub.2+H].sup.+ 350.1486; found: 350.1483 (deviation 0.9 ppm).

Example [18]N1-cyclobutyl-2-methyl-N1-(1-(3-(trifluoromethyl)phenyl)cyclopropyl)propane-1,2-diamine

[0619] To a stirred solution of 2-(cyclobutyl(1-(3-(trifluoromethyl)phenyl)cyclopropyl)amino)acetonitrile [82](0.25 g, 0.85 mmol) in toluene (3 mL) was added titanium(IV)isopropoxide (0.26 mL, 0.85 mmol) at 40 C. and the reaction stirred for 15 minutes. Methylmagnesium bromide solution (7.2 mmol) was added dropwise over a period of 10 minutes and the reaction subsequently stirred at room temperature for 18 h. The reaction was quenched with ammonium chloride solution and extracted with DCM (350 mL). The combined organics were concentrated in vacuo and purified by flash column chromatography using 15% EtOAc/pet ether as eluent to afford N.sub.1-cyclobutyl-2-methyl-N1-(1-(3-(trifluoromethyl)phenyl)cyclopropyl)propane-1,2-diamine [18] as a brownish gum (0.05 g, 18%, LCMS MH.sup.+=327.1) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 7.60-7.54 (m, 5H), 3.45-3.43 (m, 1H), 2.76 (s, 2H), 1.99-1.93 (m, 4H), 1.56-1.45 (m, 2H), 1.37-1.34 (m, 2H), 1.24-1.22 (m, 5H), 1.10-1.07 (m, 2H). HRMS calculated for: [C.sub.18H.sub.25F.sub.3N.sub.2+H].sup.+ 327.2042; found: 327.2036 (deviation 2.2 ppm).

Example [19]Ethyl (2-amino-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate

Step 1

[0620] The procedure used in Example [1], Step 2 was adapted such that 0.15 g of tert-butyl (1-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)-2-methylpropan-2-yl)carbamate [2.2] was reacted with ethyl chloroformate to afford ethyl (2-((tert-butoxycarbonyl)amino)-2-methylpropyl) (1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate [19.1] as a colourless liquid (0.14 g, 79% LCMS MH.sup.+=463.2).

Step 2

[0621] The procedure used in Example [2], Step 4 was adapted such that 0.1 g of ethyl (2-((tert-butoxycarbonyl)amino)-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate [19.1] was reacted to afford ethyl (2-amino-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate [19] as an off-white solid (0.062 g, 72%, LCMS MH.sup.+=363.2). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 7.77 (bs, 3H), 7.63-7.58 (m, 1H), 7.54-7.45 (m, 2H), 4.13-4.08 (m, 2H), 3.55 (bs, 2H), 1.44 (s, 2H), 1.35 (bs, 2H), 2.00-1.50 (m, 6H), 1.50-1.10 (m, 3H). HRMS calculated for: [C.sub.17H.sub.22F.sub.4N.sub.2O.sub.2+H].sup.+ 363.1690; found: 363.1686 (deviation 1.1 ppm).

Example [20]Methyl (2-amino-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)carbamate

Step 1

[0622] The procedure used in Example [3], Step 1 was adapted such that 0.25 g of 1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropan-1-amine [9.1] and 0.19 g of tert-butyl (2-methyl-1-oxopropan-2-yl)carbamate [2.1] were reacted to afford the product tert-butyl (1-((1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)amino)-2-methylpropan-2-yl)carbamate [20.1] as brown gum (0.26 g, 60%, LCMS MH.sup.+=407.2).

Step 2

[0623] The procedure used in Example [1], Step 2 was adapted such that 0.26 g of tert-butyl (1-((1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)amino)-2-methylpropan-2-yl)carbamate [20.1] was reacted to afford the product methyl (2-((tert-butoxycarbonyl)amino)-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)carbamate [20.2] as colourless liquid (0.18 g, 60%, LCMS MH.sup.+=465.2).

Step 3

[0624] The procedure used in Example [2], Step 4 was adapted such that 0.18 g of methyl (2-((tert-butoxycarbonyl)amino)-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)carbamate [20.2] was reacted to afford methyl (2-amino-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)carbamate [20] as an off-white solid (0.1 g, 71%). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 7.68 (bs, 2H), 7.46-7.42 (m, 1H), 7.28 (bs, 2H), 3.62 (s, 3H), 3.50 (bs, 2H), 1.41 (bs, 2H), 1.25 (bs, 2H), 1.12 (s, 6H). HRMS calculated for: [C.sub.16H.sub.20F.sub.4N.sub.2O.sub.3+H].sup.+ 365.1483; found: 365.1473 (deviation 2.6 ppm).

Example [21]N-(2-amino-2-methylpropyl)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)methanesulfonamide

Step 1

[0625] The procedure used in Example [2], Step 4 was adapted such that 0.3 g of tert-butyl (1-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)-2-methyl propan-2-yl)carbamate [2.2] was reacted with 0.26 g of sulfuryl dichloride to afford tert-butyl (1-(N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)methylsulfonamido)-2-methylpropan-2-yl)carbamate [21.1](0.12 g, 33%, LCMS MH.sup.+=469.2).

Step 2

[0626] The procedure used in Example [2], Step 4 was adapted such that 0.12 g of tert-butyl (1-(N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl) methyl sulfonamido)-2-methylpropan-2-yl)carbamate [21.1] was reacted to afford N-(2-amino-2-methylpropyl)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)methanesulfonamide [21] as an off-white solid (0.048 g, 50%). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 7.77 (dd, J=2.40, 6.40 Hz, 1H), 7.63-7.57 (m, 1H), 7.48-7.40 (m, 1H), 3.16 (s, 2H), 3.11 (s, 3H), 1.75-1.68 (m, 2H), 1.55 (s, 2H), 1.36 (d, J=1.20 Hz, 2H), 0.98 (s, 6H). HRMS calculated for: [C.sub.15H.sub.20F.sub.4N.sub.2O.sub.2S+H].sup.+ 369.1254; found: 369.1242 (deviation 3.2 ppm).

Example [22]Methyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate

Step 1

[0627] The procedure used in Example [2], Step 1 was adapted such that 2 g of tert-butyl (2R)-2-(hydroxymethyl)pyrrolidine-1-carboxylate was reacted to afford tert-butyl (2R)-2-formylpyrrolidine-1-carboxylate [22.1] as a pale yellow liquid (1.5 g (crude), 79%).

Step 2

[0628] The procedure used in Example [2], Step 2 was adapted such that 1.5 g of 1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropan-1-amine [1.1] was reacted with tert-butyl (2R)-2-formylpyrrolidine-1-carboxylate [22.1] to afford tert-butyl (R)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl) amino)methyl)pyrrolidine-1-carboxylate as colourless liquid (1.3 g, 48%, LCMS MH.sup.+=403.2).

Step 3

[0629] The procedure used in Example [1], Step 2 was adapted such that 0.25 g of tert-butyl (R)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)pyrrolidine-1-carboxylate [22.2] and 0.09 g of methyl chloroformate were reacted to afford tert-butyl (R)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(methoxycarbonyl) amino)methyl)pyrrolidine-1-carboxylate [22.3] as a colourless gum (0.13 g, 52%, LCMS MH.sup.+=361.4 (Boc-cleaved mass)).

Step 4

[0630] To a stirred solution of tert-butyl (R)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl) (methoxycarbonyl)amino)methyl)pyrrolidine-1-carboxylate [22.3](0.12 g, 0.26 mmol) in DCM was added HCl gas in diethyl ether at 0 C. and the reaction stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to afford crude product which was purified by trituration in diethyl ether to afford methyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate [22](HCl salt) as a white solid (0.1 g, 97%, LCMS MH.sup.+=361.2). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 9.30-9.00 (bs, 1H), 8.60-8.20 (bs, 1H), 7.54-7.38 (m, 3H), 3.76-0.75 (m, 1H), 3.62-3.50 (m, 4H), 3.30-3.18 (m, 1H), 3.12-3.00 (m, 1H), 2.04-1.94 (m, 1H), 1.90-1.82 (m, 2H), 1.57-1.50 (m, 2H), 1.40-1.30 (m, 2H). HRMS calculated for: [C.sub.17H.sub.20F.sub.4N.sub.2O.sub.2+H].sup.+ 361.1534; found: 361.1521 (deviation 3.6 ppm).

Example [23]Methyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate

Step 1

[0631] The procedure used in Example [2], Step 1 was adapted such that 3 g of tert-butyl (2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate was reacted to afford tert-butyl (2S)-2-formylpyrrolidine-1-carboxylate [23.1] as a pale yellow liquid (2 g (crude), 62%).

Step 2

[0632] The procedure used in Example [2], Step 2 was adapted such that 1 g of 1-[4-fluoro-3-(trifluoromethyl)phenyl]cyclopropan-1-amine [1.1] was reacted with tert-butyl (2S)-2-formylpyrrolidine-1-carboxylate [23.1] to afford tert-butyl (S)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)pyrrolidine-1-carboxylate [23.2](1.2 g, 66%, LCMS MH.sup.+=403.2).

Step 3

[0633] The procedure used in Example [1], Step 2 was adapted such that 1 g of tert-butyl (S)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)pyrrolidine-1-carboxylate [23.2] and 0.21 g of methyl chloroformate were reacted to afford tert-butyl (S)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(methoxycarbonyl) amino)methyl)pyrrolidine-1-carboxylate (0.25 g, 73%, LCMS MH.sup.+=461.2).

Step 4

[0634] The procedure used in Example [22], Step 4 was adapted such that 0.12 g of tert-butyl (S)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl) (methoxycarbonyl)amino)methyl)pyrrolidine-1-carboxylate [23.3] was reacted to afford methyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate [23](HCl salt) as an off-white solid (0.09 g, 90%, LCMS MH.sup.+=361.2). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 9.60-9.40 (bs, 1H), 9.00-8.20 (bs, 1H), 7.49-7.38 (m, 3H), 3.73-3.60 (m, 6H), 3.23-3.07 (m, 2H), 1.98-1.85 (m, 3H), 1.70-1.40 (m, 3H), 1.36-1.29 (m, 2H). HRMS calculated for: [C.sub.17H.sub.20F.sub.4N.sub.2O.sub.2+H].sup.+ 361.1534; found: 361.1524 (deviation 2.6 ppm).

Example [24]Methyl (2-acetamido-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate

[0635] The procedure used in Example [1], Step 2 was adapted such that 0.1 g of methyl (2-amino-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate [2] and 0.022 g of acetyl chloride were reacted to afford methyl (2-acetamido-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate [24] as a colourless gum (0.034 g, 30%). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 7.53-7.38 (m, 2H), 7.30 (bs, 3H), 3.73 (s, 2H), 3.61 (s, 3H), 1.52 (s, 3H), 1.43 (bs, 2H), 1.30 (bs, 2H), 1.14 (s, 6H). HRMS calculated for: [C.sub.18H.sub.22F.sub.4N.sub.2O.sub.3+H].sup.+ 391.1639; found: 391.1637 (deviation 0.7 ppm).

Example [25]N1-(1-(4-fluoro-3-(trifluoromethyl)phenyl) cyclopropyl)-2-methylpropane-1,2-diamine

[0636] The procedure used in Example [2], Step 4 was adapted such that 0.1 g of tert-butyl (1-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)-2-methylpropan-2-yl)carbamate [2.2] was reacted to afford N.sub.1-(1-(4-fluoro-3-(trifluoromethyl)phenyl) cyclopropyl)-2-methylpropane-1,2-diamine [25] as a colourless gum (0.05 g, 67%). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 7.74 (dd, J=2.00, 7.00 Hz, 1H), 7.62-7.56 (m, 1H), 7.43-7.36 (m, 1H), 2.59 (bs, 1H), 2.20 (s, 2H), 1.40 (bs, 2H), 1.00-0.98 (m, 2H), 0.93 (s, 6H). HRMS calculated for: [C.sub.14H.sub.18F.sub.4N.sub.2+H].sup.+ 290.1479; found: 291.1467 (deviation 4.1 ppm).

Example [26]Methyl (azetidin-2-ylmethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate

Step 1

[0637] The procedure used in Example [1], Step 2 was adapted such that 0.45 g of tert-butyl 2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)azetidine-1-carboxylate [14.2] was reacted to afford tert-butyl 2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl) cyclopropyl)(methoxycarbonyl)amino)methyl)azetidine-1-carboxylate [26.1] as a colourless gum (0.125 g, 25%, LCMS MH.sup.+=447.1).

Step 2

[0638] To a stirred solution of tert-butyl 2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl) cyclopropyl)(methoxycarbonyl)amino)methyl)azetidine-1-carboxylate [26.1](0.25 g, 0.56 mmol) in dichloromethane (6 mL) at 0 C. was added trifluoroacetic acid (4 mL, 52 mmol) and the reaction stirred at rt for 12 h. The reaction was diluted with sat. aq. sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were washed with brine solution and concentrated under reduced pressure to afford the crude product which was purified by Prep HPLC to afford methyl (azetidin-2-ylmethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate [26]trifluoroacetate salt as a white solid, (0.035 g, 19%, LCMS MH.sup.+=347.1). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 8.58 (bs, 1H), 7.60-7.45 (m, 2H), 7.38 (s, 1H), 4.43 (bs, 1H), 3.90 (bs, 1H), 3.85-3.75 (m, 2H), 3.66-3.63 (m, 3H), 3.63-3.60 (m, 1H), 2.35-2.10 (m, 2H), 1.50-1.25 (m, 4H). HRMS calculated for: [C.sub.16H.sub.18F.sub.4N.sub.2O.sub.2+H].sup.+ 347.1377; found: 347.1374 (deviation 0.9 ppm).

Example [27]Methyl (S)-(1-(4-fluoro-3-(trifluoro methyl) phenyl)cyclopropyl) ((1-methylpyrrolidin-2-yl)methyl) carbamate

[0639] The procedure used in Example [2], Step 2 was adapted such that 0.08 g of methyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate [23] was reacted to afford methyl (S)-(1-(4-fluoro-3-(trifluoro methyl) phenyl)cyclopropyl) ((1-methylpyrrolidin-2-yl)methyl) carbamate [27] as a colourless gum (0.055 g, 73%). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 7.49-7.42 (m, 3H), 3.65-3.60 (m, 3H), 3.33-3.26 (m, 2H), 2.89-2.86 (m, 1H), 2.50-2.30 (m, 1H), 2.20 (s, 3H), 2.08-2.06 (m, 1H), 1.23-1.61 (m, 8H). HRMS calculated for: [C.sub.18H.sub.22F.sub.4N.sub.2O.sub.2+H].sup.+ 375.1690; found: 375.1683 (deviation 1.8 ppm).

Example [28]Methyl (S)-(1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate

Step 1

[0640] The procedure used in Example [3], Step 1 was adapted such that 0.3 g of 1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropan-1-amine [9.1] was reacted to afford tert-butyl (S)-2-(((1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)amino)methyl)pyrrolidine-1-carboxylate [28.1] as a pale brown gum (0.3 g, 54%, LCMS MH.sup.+=419.2).

Step 2

[0641] The procedure used in Example [1], Step 2 was adapted such that 0.3 g of tert-butyl (S)-2-(((1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)amino)methyl)pyrrolidine-1-carboxylate [28.1] was reacted to afford tert-butyl (S)-2-(((1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)(methoxycarbonyl)amino)methyl)pyrrolidine-1-carboxylate [28.2] as colourless gum (0.3 g, 85%, LCMS MH.sup.+=477.1).

Step 3

[0642] The procedure used in Example [2], Step 4 was adapted such that 0.15 g of tert-butyl (S)-2-(((1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)(methoxycarbonyl)amino)methyl)pyrrolidine-1-carboxylate [28.2] was reacted to afford methyl (S)-(1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate [28] as a white solid (0.65 g, 60%, LCMS MH.sup.+=377.1). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 9.20 (bs, 1H), 8.45 (bs, 1H), 7.50-7.42 (m, 1H), 7.25 (bs, 2H), 3.69 (bs, 1H), 3.64 (s, 3H), 3.56 (s, 2H), 3.30-3.20 (m, 1H), 3.12-3.02 (m, 1H), 2.05-1.45 (m, 1H), 1.95-1.28 (m, 2H), 1.60-1.40 (m, 3H), 1.35 (bs, 1H), 1.25 (bs, 1H). HRMS calculated for: [C.sub.17H.sub.20F.sub.4N.sub.2O.sub.3+H].sup.+ 377.1483; found: 377.1476 (deviation 1.8 ppm).

Example [29]Methyl (R)-(1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate

Step 1

[0643] The procedure used in Example [3], Step 1 was adapted such that 0.4 g of 1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropan-1-amine [9.1] was reacted to afford tert-butyl (R)-2-(((1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)amino)methyl)pyrrolidine-1-carboxylate [29.1] as a colourless liquid (0.35 g, 49%, LCMS MH.sup.+=419.1).

Step 2

[0644] The procedure used in Example [1], Step 2 was adapted such that 0.35 g of tert-butyl (R)-2-(((1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)amino)methyl)pyrrolidine-1-carboxylate [29.1] was reacted to afford tert-butyl (R)-2-(((1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)(methoxycarbonyl)amino)methyl)pyrrolidine-1-carboxylate [29.2] as a pale brown gum (0.2 g, 50%, LCMS MH.sup.+=477.2).

Step 3

[0645] The procedure used in Example [2], Step 4 was adapted such that 0.1 g of tert-butyl (R)-2-(((1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)(methoxycarbonyl)amino)methyl)pyrrolidine-1-carboxylate [29.2] was reacted to afford methyl (R)-(1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate [29](HCl salt) as a white solid (0.05 g, 58%, LCMS MH.sup.+=377.2). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 9.15 (bs, 1H), 8.25 (bs, 1H), 7.27-7.22 (m, 1H), 7.13 (bs, 2H), 3.80-3.68 (m, 1H), 3.64 (s, 3H), 3.62-3.50 (m, 2H), 3.30-3.20 (m, 1H), 3.12-3.02 (m, 1H), 2.05-1.78 (m, 3H), 1.60-1.40 (m, 2H), 1.40-1.20 (m, 2H). HRMS calculated for: [C.sub.17H.sub.20F.sub.4N.sub.2O.sub.3+H].sup.+ 377.1483; found: 377.1472 (deviation 2.9 ppm).

Example [30]Methyl (1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((1-methylazetidin-2-yl)methyl)carbamate

[0646] The procedure used in Example [2], Step 2 was adapted such that 0.19 g of methyl (azetidin-2-ylmethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate [26] was reacted to afford methyl (1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((1-methylazetidin-2-yl)methyl)carbamate [30] as a colourless gum (0.02 g, 10%, LCMS MH.sup.+=361.1). .sup.1H-NMR (400 MHz, CDCl.sub.3): 7.28-7.20 (m, 1H), 7.15-7.10 (m, 1H), 7.06-7.03 (m, 1H), 3.69 (s, 3H), 3.45-3.25 (m, 3H), 2.64 (bs, 1H), 2.20 (bs, 3H), 1.95-1.73 (m, 2H), 1.63 (bs, 2H), 1.44 (bs, 1H), 1.30-1.18 (m, 2H). HRMS calculated for: [C.sub.17H.sub.20F.sub.4N.sub.2O.sub.2+H].sup.+ 361.1534; found: 361.1528 (deviation 1.7 ppm).

Example [31]Methyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((1-methylpyrrolidin-2-yl)methyl)carbamate

[0647] The procedure used in Example [2], Step 2 was adapted such that 0.02 g of methyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate [22] was reacted to afford methyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((1-methylpyrrolidin-2-yl)methyl)carbamate [31] as colourless gum (0.013 g, 62%). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 7.60-7.30 (m, 3H), 3.59 (s, 3H), 3.35-3.25 (m, 2H), 2.91-2.80 (m, 1H), 2.38 (s, 1H), 2.19 (s, 3H), 2.11-2.00 (m, 1H), 1.70-1.50 (m, 4H), 1.50-1.20 (m, 4H). HRMS calculated for: [C.sub.18H.sub.22F.sub.4N.sub.2O.sub.3+H].sup.+ 375.1690; found: 375.1679 (deviation 3.1 ppm).

Example [32]Methyl (azetidin-2-ylmethyl)(1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)carbamate

Step 1

[0648] The procedure used in Example [14], Step 1 was adapted such that 0.6 g of 1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropan-1-amine [9.1] was reacted to afford tert-butyl 2-((1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)carbamoyl)azetidine-1-carboxylate [32.1] as a colourless gum (0.6 g, 56%, LCMS MH.sup.+=419.2).

Step 2

[0649] To a stirred solution of tert-butyl 2-((1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)carbamoyl)azetidine-1-carboxylate [32.1](0.6 g, 1.43 mmol) in dry THF (3 mL) was added borane dimethyl sulphide complex (0.46 g, 5.74 mmol) dropwise under N.sub.2 atm. The resultant reaction mixture was slowly warmed to rt, then heated to 60 C. for 2 h. The reaction mixture was quenched sat. aq. ammonium chloride solution and extracted with ethyl acetate (230 mL). The combined organic layer was washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure to afford the crude product which was purified by flash column chromatography using ethyl acetate/hexane as eluent to afford tert-butyl 2-(((1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)amino)methyl)azetidine-1-carboxylate [32.2] as a colourless gum (0.2 g, 34%, LCMS MH.sup.+=405.1).

Step 3

[0650] The procedure used in Example [1], Step 2 was adapted such that 0.2 g of tert-butyl 2-(((1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)amino)methyl)azetidine-1-carboxylate [32.2] was reacted to afford tert-butyl 2-(((1-(4-fluoro-3-(trifluoromethoxy)phenyl) cyclopropyl)(methoxycarbonyl)amino)methyl)azetidine-1-carboxylate [32.3] as a colourless gum (0.2 g, 87%, LCMS MH.sup.+=463.2).

Step 4

[0651] The procedure used in Example [26], Step 2 was adapted such that 0.2 g of tert-butyl 2-(((1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)(methoxycarbonyl)amino)methyl)azetidine-1-carboxylate [32.3] was reacted to afford methyl (azetidin-2-ylmethyl)(1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)carbamate [32] as a colourless gum (0.055 g, 35%, LCMS MH.sup.+=463.2). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 7.42 (t, J=10.40 Hz, 1H), 7.30-7.05 (m, 2H), 3.91 (s, 1H), 3.57 (s, 3H), 3.50-3.40 (m, 2H), 3.05 (s, 1H), 2.08-1.80 (m, 3H), 1.50-1.28 (m, 2H), 1.23 (s, 2H). HRMS calculated for: [C.sub.16H.sub.18F.sub.4N.sub.2O.sub.3+H].sup.+ 363.1326; found: 363.1321 (deviation 1.4 ppm).

Example [33]Methyl (1-(4-fluoro-3-(trifluoromethyl) phenyl)cyclopropyl)(2-(hydroxyamino)-2-methylpropyl)carbamate

Step 1

[0652] To a stirred solution of methyl (2-amino-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate [2](0.25 g, 0.717 mmol) in DMF (5 mL) was added benzoyl peroxide (0.26 g, 1.076 mmol) and potassium phosphate (0.146 g, 1.076 mmol) at 0 C. The resultant reaction mixture was slowly warmed to rt and stirred at rt for 12 h. The reaction mixture was quenched with water and extracted with ethyl acetate (2*25 mL), the combined organic layer was dried over sodium sulphate and concentrated to afford crude product which was purified by column chromatography using 15% ethyl acetate in hexane as eluent to afford methyl (2-((benzoyloxy)amino)-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethyl) phenyl)cyclopropyl)carbamate [33.1] as an off white solid (0.18 g, 54%).

Step 2

[0653] To a stirred solution of methyl (2-((benzoyloxy)amino)-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate [33.1](0.16 g, 0.341 mmol) in methanol (5 mL) was added hydrazine monohydrate (3 mL g, 61.72 mmol) at 0 C. The resultant reaction mixture was slowly warmed to rt and stir at rt for 12 h. The reaction mixture was quenched with water and extracted with ethyl acetate (2*25 mL), the combined organic layer was dried over sodium sulphate and concentrated to afford crude product which was purified by Prep HPLC to afford methyl (1-(4-fluoro-3-(trifluoromethyl) phenyl)cyclopropyl)(2-(hydroxyamino)-2-methylpropyl)carbamate [33] as an off white solid (15.7 mg, 13%). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 7.50 (bs, 1H), 7.42 (t, J=8.80 Hz, 2H), 6.87 (s, 1H), 5.05 (bs, 1H), 3.56 (s, 3H), 3.40-3.35 (m, 2H), 1.28-1.26 (m, 2H), 1.22-1.24 (m, 2H), 0.85 (d, J=10.40 Hz, 6H). HRMS calculated for: [C.sub.16H.sub.20F.sub.4N.sub.2O.sub.3+H].sup.+ 365.1483; found: 365.1478 (deviation 1.3 ppm).

Example [34]Ethyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate

Step 1

[0654] The procedure used in Example [1], Step 2 was adapted such that 0.25 g of tert-butyl (S)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)pyrrolidine-1-carboxylate [23.2] was reacted to afford tert-butyl (S)-2-(((ethoxycarbonyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)pyrrolidine-1-carboxylate [34.1] as colourless gum (0.16 g, 55%, LCMS MH.sup.+=375.2 (boc-cleaved mass)).

Step 2

[0655] The procedure used in Example [2], Step 4 was adapted such that 0.14 g of tert-butyl (S)-2-(((ethoxycarbonyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl) cyclopropyl)amino)methyl)pyrrolidine-1-carboxylate was reacted to afford ethyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate [34] as white solid (0.1 g, 83%). MS (M+1).sup.+=375.2. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 9.40-9.05 (bs, 1H), 8.60-8.20 (bs, 1H), 7.65-7.52 (m, 1H), 7.49 (t, J=9.20 Hz, 2H), 4.11 (q, J=7.20 Hz, 2H), 3.70-3.65 (m, 1H), 3.65-3.52 (m, 2H), 3.30-3.18 (m, 1H), 3.15-3.00 (m, 1H), 2.05-1.60 (m, 3H), 1.65-1.40 (m, 3H), 1.40-1.10 (m, 5H). HRMS calculated for: [C.sub.18H.sub.22F.sub.4N.sub.2O.sub.2+H].sup.+ 375.1690; found: 375.1686 (deviation 1.2 ppm).

Example [35]Ethyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((1-methylpyrrolidin-2-yl)methyl) carbamate

[0656] The procedure used in Example [2], Step 2 was adapted such that 0.1 g of ethyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate [34] was reacted to afford ethyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((1-methylpyrrolidin-2-yl)methyl) carbamate [35] as colourless gum (0.075 g, 80%, LCMS MH.sup.+=389.1). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 7.52 (d, J=5.20 Hz, 2H), 7.38 (t, J=8.80 Hz, 1H), 4.08 (q, J=7.20 Hz, 2H), 3.30 (d, J=6.00 Hz, 2H), 2.90 (q, J=4.80 Hz, 1H), 2.22 (s, 3H), 2.12 (q, J=8.40 Hz, 2H), 1.70-1.50 (m, 4H), 1.50-1.20 (m, 4H), 1.16 (t, J=6.80 Hz, 3H). HRMS calculated for: [C.sub.19H.sub.24F.sub.4N.sub.2O.sub.2+H].sup.+ 389.1847; found: 389.1843 (deviation 1.0 ppm).

Example [36](S)N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-N-(pyrrolidin-2-ylmethyl) methanesulfonamide

Step 1

[0657] The procedure used in Example [1], Step 2 was adapted such that 0.8 g of tert-butyl (S)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)pyrrolidine-1-carboxylate [23.2] and 0.69 g of methanesulphonyl chloride were reacted to afford the product tert-butyl (S)-2-((N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)methylsulfonamido)methyl)pyrrolidine-1-carboxylate [36.1] as a colourless gum (0.4 g, 42%).

Step 2

[0658] The procedure used in Example [22], Step 4 was adapted such that 0.4 g of tert-butyl (S)-2-((N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)methylsulfonamido)methyl)pyrrolidine-1-carboxylate [36.1] was reacted to afford (S)N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-N-(pyrrolidin-2-ylmethyl) methanesulfonamide [36] as an off-white solid (0.28 g, 80%). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 9.50-9.25 (s, 1H), 8.95-8.65 (s, 1H), 7.84-7.78 (m, 2H), 7.46 (t, J=8.80 Hz, 1H), 3.80-3.55 (m, 3H), 3.35-3.00 (m, 2H), 2.92 (s, 3H), 2.10-1.65 (m, 3H), 1.65-1.50 (m, 3H), 1.35-1.26 (m, 2H). HRMS calculated for: [C.sub.16H.sub.20F.sub.4N.sub.2O.sub.2+H].sup.+ 381.1254; found: 381.1250 (deviation 1.3 ppm).

Example [37](S)N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-N-((1-methylpyrrolidin-2-yl)methyl)methanesulfonamide

[0659] The procedure used in Example [2], Step 2 was adapted such that 0.12 g of (S)N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-N-(pyrrolidin-2-ylmethyl)methanesulfonamide [36] was reacted to afford (S)N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-N-((1-methylpyrrolidin-2-yl)methyl)methanesulfonamide [37] as a colourless gum (0.08 g, 67%). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 7.69 (dd, J=2.12, 6.68 Hz, 1H), 7.61-7.60 (m, 1H), 7.47 (t, J=9.04 Hz, 1H), 3.25 (dd, J=40.00 Hz, 1H), 3.13-3.04 (m, 1H), 2.95-2.90 (m, 3H), 2.90-2.85 (m, 1H), 2.40-2.32 (m, 1H), 2.30-2.20 (m, 3H), 2.15-2.00 (m, 1H), 1.70-1.50 (m, 6H), 1.45-1.20 (m, 2H). HRMS calculated for: [C.sub.17H.sub.22F.sub.4N.sub.2O.sub.2+H].sup.+ 395.1411; found: 395.1406 (deviation 1.3 ppm).

Example [38]Ethyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate

Step 1

[0660] The procedure used in Example [1], Step 2 was adapted such that 0.25 g of tert-butyl (R)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl) pyrrolidine-1-carboxylate [22.2] and 0.07 g of ethylchloroformate were reacted to afford tert-butyl (R)-2-(((ethoxycarbonyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino) methyl)pyrrolidine-1-carboxylate [38.1] as a colourless gum (0.14 g, 48%, LCMS MH.sup.+=375.1 (Boc-cleaved mass)).

Step 2

[0661] The procedure used in Example [22], Step 4 was adapted such that 0.13 g of tert-butyl (R)-2-(((ethoxycarbonyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl) cyclopropyl)amino)methyl)pyrrolidine-1-carboxylate was reacted to afford ethyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate [38](HCl salt) as a white solid (0.115 g, 99%, LCMS MH.sup.+=375.1). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 9.30-9.10 (bs, 1H), 8.60-8.20 (bs, 1H), 7.58-7.46 (m, 3H), 4.13-4.08 (m, 2H), 3.80-3.50 (m, 3H), 3.30-3.18 (m, 1H), 3.15-3.00 (m, 1H), 2.10-1.70 (m, 3H), 1.59-1.49 (m, 3H), 1.35-1.07 (m, 5H). HRMS calculated for: [C.sub.18H.sub.22F.sub.4N.sub.2O.sub.2+H].sup.+ 375.1690; found: 375.1688 (deviation 0.5 ppm).

Example [39]Methyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(morpholin-3-ylmethyl) carbamate

Step 1

[0662] To an ice cooled solution of (S)-4-(tert-butoxy carbonyl)-morpholine-3-carboxylic acid (0.37 g, 1.642 mmol) in dichloromethane (10 mL) was added triethylamine (0.76 mL, 5.474 mmol) and followed by propylphosphonic anhydride (2.61 g, 4.106 mmol) solution under N.sub.2 atm. The resultant reaction mixture was stirred at 0 C. for 20 min, then 1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropan-1-amine [1.1](0.3 g, 1.368 mmol) was added and the reaction stirred at rt for 5 h. The reaction mixture was quenched with water and extracted with ethyl acetate (2*80 mL). The combined organic layer was washed with 10% sodium bicarbonate solution, brine, dried over sodium sulphate, filtered and concentrated under reduced pressure to afford tert-butyl (S)-3-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamoyl)morpholine-4-carboxylate [39.1] as a yellow liquid (0.55 g, 93%, LCMS MH.sup.+=433.1).

Step 2

[0663] To a cooled solution of tert-butyl (S)-3-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamoyl)morpholine-4-carboxylate [39.1](0.55 g, 1.271 mmol) in dry THF (5 mL) was added borane dimethyl sulphide complex (9.6 mL, 2.543 mmol) dropwise under N.sub.2 atm. The resultant reaction mixture was slowly warmed to rt and stirred at rt for 16 h. The reaction mixture was quenched with methanol and the refluxed for 1h and then concentrated under reduced pressure. The obtained residue was diluted with water and extracted with dichloromethane (2*100 mL), the combined organic layer was washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure to afford tert-butyl (3R)-3-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)morpholine-4-carboxylate [39.2] as a colourless gum (0.28 g, 52%, LCMS MH.sup.+=419.2).

Step 3

[0664] The procedure used in Example [1], Step 2 was adapted such that 0.25 g of tert-butyl (3R)-3-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)morpholine-4-carboxylate [39.2] was reacted to afford the product tert-butyl (R)-3-(((1-(4-fluoro-3-(trifluoro methyl)phenyl)cyclopropyl)(methoxycarbonyl)amino)methyl)morpholine-4-carboxylate as a Colourless gum (0.2 g, 71%, LCMS MH.sup.+=477.2).

Step 4

[0665] The procedure used in Example [1], Step 2 was adapted such that 0.2 g of tert-butyl (R)-3-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(methoxycarbonyl)amino)methyl)morpholine-4-carboxylate [39.3] was reacted to afford methyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(morpholin-3-ylmethyl) carbamate [39] as a white solid (0.15 g, 88%, LCMS MH.sup.+=377.2). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 9.11 (bs, 1H), 7.70-7.30 (m, 3H), 3.85 (d, J=11.20 Hz, 2H), 3.75-3.68 (m, 1H), 3.63 (bs, 3H), 3.60-3.40 (m, 4H), 3.24 (d, J=32.00 Hz, 1H), 3.10-3.00 (m, 1H), 1.53 (bs, 2H), 1.50-1.20 (m, 2H). HRMS calculated for: [C.sub.17H.sub.20F.sub.4N.sub.2O.sub.3+H].sup.+ 377.1483; found: 377.1475 (deviation 2.1 ppm).

Example [40]Methyl (R)-(1-(4-fluoro-3-(trifluoromethyl) phenyl)cyclopropyl)((4-methylmorpholin-3-yl)methyl)carbamate

[0666] The procedure used in Example [2], Step 2 was adapted such that 0.1 g of methyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(morpholin-3-ylmethyl)carbamate [39] was reacted to afford methyl (R)-(1-(4-fluoro-3-(trifluoromethyl) phenyl)cyclopropyl)((4-methylmorpholin-3-yl)methyl)carbamate [40] as a colourless gum (0.08 g, 85%, LCMS MH.sup.+=391.2). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 7.54-7.44 (m, 3H), 3.61-3.58 (m, 3H), 3.47-3.39 (m, 2H), 3.34-3.33 (m, 2H), 3.30-3.26 (m, 1H), 3.20-3.10 (m, 1H), 2.67-2.61 (m, 1H), 2.27-2.07 (m, 5H), 1.46-1.25 (m, 4H). HRMS calculated for: [C.sub.18H.sub.22F.sub.4N.sub.2O.sub.3+H].sup.+ 391.1639; found: 391.1633 (deviation 1.7 ppm).

Example [41](R)N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-N-(pyrrolidin-2-ylmethyl) methane sulfonamide

Step 1

[0667] The procedure used in Example [1], Step 2 was adapted such that 0.25 g of tert-butyl (R)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl) pyrrolidine-1-carboxylate and 0.11 g of methanesulphonyl chloride were reacted to afford tert-butyl (R)-2-((N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)methylsulfonamido)methyl)pyrrolidine-1-carboxylate [41.1] as a colourless gum (0.16 g, 34%, LCMS MH.sup.+=381.1 (Boc-cleaved mass)).

Step 2

[0668] The procedure used in Example [22], Step 4 was adapted such that 0.15 g of tert-butyl (R)-2-((N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)methylsulfonamido)methyl)pyrrolidine-1-carboxylate [41.1] was reacted to afford (R)N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-N-(pyrrolidin-2-ylmethyl) methane sulfonamide [41](HCl salt) as an off white solid (0.11 g, 84%, LCMS MH.sup.+=381.1). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 9.27 (bs, 1H), 8.67 (bs, 1H), 7.80-7.75 (m, 2H), 7.52 (t, J=9.60 Hz, 2H), 3.65-3.56 (m, 3H), 3.22-3.12 (m, 2H), 2.90 (s, 3H), 2.00-1.75 (m, 3H), 1.70-1.50 (m, 3H), 1.30 (bs, 2H). HRMS calculated for: [C.sub.16H.sub.20F.sub.4N.sub.2O.sub.2S+H].sup.+ 381.1254; found: 381.1251 (deviation 0.7 ppm).

Example [42]Methyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(morpholin-3-ylmethyl) carbamate

Step 1

[0669] The procedure used in Example [2], Step 2 was adapted such that 0.8 g of 1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropan-1-amine [1.1] was reacted with tert-butyl (3R)-3-formylmorpholine-4-carboxylate to afford tert-butyl (S)-3-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)morpholine-4-carboxylate [42.1] as a colourless gum (0.9 g, 59%, LCMS MH.sup.+=419.2).

Step 2

[0670] The procedure used in Example [1], Step 2 was adapted such that 0.3 g of tert-butyl (S)-3-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)morpholine-4-carboxylate [42.1] was reacted to afford tert-butyl(S)-3-(((1-(4-fluoro-3-(trifluoromethyl) phenyl)cyclopropyl)(methoxycarbonyl)amino)methyl)morpholine-4-carboxylate [42.2] as a colourless gum (0.17 g, 50%, LCMS MH.sup.+=377.2).

Step 3

[0671] The procedure used in Example [2], Step 4 was adapted such that 0.17 g of tert-butyl (S)-3-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl) (methoxycarbonyl)amino)methyl)morpholine-4-carboxylate [42.2] was reacted to afford methyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(morpholin-3-ylmethyl) carbamate [42] as a white solid (0.135 g, 92%; LCMS MH.sup.+=377.2). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 9.15 (bs, 2H), 7.50-7.37 (m, 3H), 3.86 (d, J=11.60 Hz, 2H), 3.75-3.40 (m, 8H), 3.25 (d, J=40.00 Hz, 1H), 3.12-2.95 (m, 1H), 1.57 (bs, 2H), 1.31-1.23 (m, 2H). HRMS calculated for: [C.sub.17H.sub.20F.sub.4N.sub.2O.sub.3+H].sup.+ 377.1483; found: 377.1476 (deviation 1.9 ppm).

Example [43]Methyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((4-methylmorpholin-3-yl)methyl)carbamate

[0672] The procedure used in Example [2], Step 2 was adapted such that 0.1 g of methyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(morpholin-3-ylmethyl)carbamate [42] was reacted to afford methyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((4-methylmorpholin-3-yl)methyl)carbamate [43] as a white solid (0.075 g, 80%, LCMS MH.sup.+=391.2). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 7.52-7.42 (m, 3H), 3.70-3.55 (m, 5H), 3.53-3.37 (m, 2H), 3.35-3.22 (m, 1H), 3.00-3.02 (m, 1H), 2.68-2.58 (m, 1H), 2.35-2.18 (m, 4H), 2.15-2.05 (m, 1H), 1.55-1.33 (m, 4H). HRMS calculated for: [C.sub.18H.sub.22F.sub.4N.sub.2O.sub.3+H].sup.+ 391.1639; found: 391.1633 (deviation 1.7 ppm).

Example [44]Isopropyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate

Step 1

[0673] The procedure used in Example [45], Step 1 was adapted such that 0.1 g of tert-butyl (S)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)pyrrolidine-1-carboxylate [23.2] and 0.67 g of isopropyl chloroformate were reacted to afford tert-butyl (S)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(isopropoxycarbonyl)amino)methyl)pyrrolidine-1-carboxylate [44.1] as colourless liquid (0.1 g, 83%).

Step 2

[0674] The procedure used in Example [26], Step 2 was adapted such that 0.1 g of tert-butyl (S)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(isopropoxycarbonyl)amino)methyl)pyrrolidine-1-carboxylate [44.1] was reacted to afford isopropyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate [44] as a pale yellow liquid (0.07 g, 88%). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 8.45 (bs, 1H), 7.57 (d, J=2.64 Hz, 1H), 7.48 (t, J=8.24 Hz, 2H), 4.83 (t, J=6.24 Hz, 1H), 3.70-3.48 (m, 3H), 3.28-3.18 (m, 1H), 3.12-3.02 (m, 1H), 1.99 (bs, 1H), 1.92-1.74 (m, 2H), 1.60-1.38 (m, 3H), 1.38-1.24 (m, 2H), 1.22-1.05 (m, 6H). HRMS calculated for: [C.sub.19H.sub.24F.sub.4N.sub.2O.sub.2+H].sup.+ 389.1847; found: 389.1838 (deviation 2.3 ppm).

Example [45]Cyclopropyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate

Step 1

[0675] To a stirred solution of tert-butyl (S)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)pyrrolidine-1-carboxylate [23.2](0.15 g, 0.37 mmol) in acetonitrile (4 mL) was added cesium carbonate (0.36 g, 1.12 mmol) and cyclopropane chloroformate (0.09 g, 0.75 mmol). The reaction was stirred at room temperature for 3h, filtered and concentrated to afford the crude product, which was purified by flash column chromatography using ethyl acetate in pet ether as eluent to afford tert-butyl (S)-2-(((cyclopropoxycarbonyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl) cyclopropyl)amino)methyl)pyrrolidine-1-carboxylate [45.1] as a colourless liquid (0.16 g, 89%, LCMS MH.sup.+=387.1 (boc cleaved mass)).

Step 2

[0676] The procedure used in Example [26], Step 2 was adapted such that 0.16 g of tert-butyl (S)-2-(((cyclopropoxycarbonyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)pyrrolidine-1-carboxylate [45.1] was reacted to afford cyclopropyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate [45] as a yellow liquid (0.1 g, 83%). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 7.43-7.41 (m, 3H), 3.50-3.00 (m, 3H), 2.90-2.70 (m, 2H), 1.80-1.50 (m, 4H), 1.40-1.10 (m, 5H), 0.80-0.30 (m, 4H). HRMS calculated for: [C.sub.19H.sub.22F.sub.4N.sub.2O.sub.2+H].sup.+ 387.1690; found: 387.1688 (deviation 0.5 ppm).

Example [46]Methyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((2-methyl pyrrolidin-2-yl)methyl)carbamate

Step 1

[0677] The procedure used in Example [2], Step 2 was adapted such that 0.7 g of 1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropan-1-amine [1.1] and tert-butyl (2R)-2-formyl-2-methylpyrrolidine-1-carboxylate were reacted to afford tert-butyl (R)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)-2-methyl pyrrolidine-1-carboxylate [46.1] as a colourless liquid (0.68 g, 51%, LCMS MH.sup.+=417.2).

Step 2

[0678] The procedure used in Example [1], Step 2 was adapted such that 0.5 g of tert-butyl (R)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)-2-methylpyrrolidine-1-carboxylate [46.1] was reacted to afford tert-butyl (R)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(methoxycarbonyl)amino)methyl)-2-methylpyrrolidine-1-carboxylate [46.2] as a brown liquid (0.13 g, 22%, LCMS MH.sup.+=375.1 (boc-cleaved mass)).

Step 3

[0679] The procedure used in Example [22], Step 4 was adapted such that 0.15 g of tert-butyl (R)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(methoxycarbonyl)amino)methyl)-2-methylpyrrolidine-1-carboxylate [46.2] was reacted to afford methyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((2-methyl pyrrolidin-2-yl)methyl)carbamate [46] as colourless gum (0.125 g, 96%, LCMS MH.sup.+=375.4). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 8.64 (bs, 1H), 8.40 (bs, 1H), 7.59-7.48 (m, 3H), 3.84 (bs, 1H), 3.68 (bs, 3H), 3.60 (bs, 1H), 3.24-3.22 (m, 3H), 2.00-1.85 (m, 2H), 1.77 (bs, 2H), 1.95 (bs, 3H), 1.32-1.20 (m, 1H), 1.10 (bs, 2H). HRMS calculated for: [C.sub.18H.sub.22F.sub.4N.sub.2O.sub.2+H].sup.+ 375.1690; found: 375.1684 (deviation 1.8 ppm).

Example [47]N-((1-amino cyclopropyl)methyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropan-1-amine

[0680] The procedure used in Example [2], Step 4 was adapted such that 0.1 g of tert-butyl (1-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)cyclopropyl)carbamate [3.1] was reacted to afford N-((1-amino cyclopropyl)methyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropan-1-amine [47] as a white solid (0.08 g, 96%, LCMS MH.sup.+=288.1). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 10.60-10.20 (m, 2H), 8.90-8.65 (m, 2H), 8.20-7.90 (m, 2H), 7.65-7.55 (m, 1H), 3.30-3.10 (m, 2H), 1.75-1.55 (m, 2H), 1.35-1.15 (m, 2H), 1.14-0.80 (m, 4H). HRMS calculated for: [C.sub.14H.sub.16F.sub.4N.sub.2+H].sup.+ 289.1322; found: 289.1310 (deviation 4.2 ppm).

Example [48]Cyclopropylmethyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate

Step 1

[0681] The procedure used in Example [45], Step 1 was adapted such that 0.15 g of tert-butyl (S)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)pyrrolidine-1-carboxylate [23.2] and 0.125 g of cyclopropylmethyl chloroformate were reacted to afford tert-butyl (S)-2-((((cyclopropylmethoxy)carbonyl) (1-(4-fluoro-3-(trifluoro methyl)phenyl)cyclopropyl)amino)methyl)pyrrolidine-1-carboxylate [48.1](0.25 g, 80%).

Step 2

[0682] The procedure used in Example [26], Step 2 was adapted such that 0.12 g of tert-butyl (S)-2-((((cyclopropylmethoxy)carbonyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)pyrrolidine-1-carboxylate [48.1] was reacted to afford cyclopropylmethyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate [48] as a yellow liquid (0.085 g, 88%). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 7.52-7.43 (m, 3H), 3.87 (d, J=7.00 Hz, 2H), 3.55-3.45 (m, 3H), 3.00-2.53 (m, 2H), 4.80-1.55 (m, 4H), 1.45-1.20 (m, 4H), 1.00 (s, 1H), 0.45 (s, 2H), 0.20 (s, 2H). HRMS calculated for: [C.sub.20H.sub.24F.sub.4N.sub.2O.sub.2+H].sup.+ 401.1847; found: 401.1845 (deviation 0.3 ppm).

Example [49]N-((1-aminocyclopropyl)methyl)-N-(1-(4-fluoro-3-(trifluoromethyl)-phenyl)cyclopropyl)methanesulfonamide

Step 1

[0683] The procedure used in Example [1], Step 2 was adapted such that 0.3 g of tert-butyl (1-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)cyclopropyl)carbamate [3.1] and 0.13 g of methanesulfonyl chloride were reacted to afford tert-butyl (1-((N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)methylsulfonamido)methyl)cyclopropyl)carbamate [49.1] as a white solid (0.3 g, 83%, LCMS MH.sup.+=367.2).

Step 2

[0684] The procedure used in Example [2], Step 4 was adapted such that 0.1 g of tert-butyl (1-((N-(1-(4-fluoro-3-(trifluoromethyl) phenyl)cyclopropyl)methylsulfonamido)methyl)cyclopropyl)carbamate [49.1] was reacted to afford N-((1-aminocyclopropyl)methyl)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)methanesulfonamide [49] as a white solid (0.08 g, 93%, LCMS MH.sup.+=367.2). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 8.41 (bs, 3H), 7.76 (s, 1H), 7.66 (d, J=4.96 Hz, 1H), 7.49 (t, J=8.80 Hz, 1H), 3.53 (s, 2H), 3.01 (s, 3H), 1.67 (bs, 2H), 1.33 (s, 2H), 0.92 (d, J=44.32 Hz, 4H). HRMS calculated for: [C.sub.15H.sub.18F.sub.4N.sub.2O.sub.2S+H].sup.+ 367.1098; found: 367.1089 (deviation 2.5 ppm).

Example [50]Methyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((2-methylpyrrolidin-2-yl)methyl)carbamate

Step 1

[0685] The procedure used in Example [2], Step 2 was adapted such that 0.5 g of 1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropan-1-amine [1.1] and tert-butyl (2S)-2-formyl-2-methylpyrrolidine-1-carboxylate were reacted to afford tert-butyl (S)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)-2-methylpyrrolidine-1-carboxylate [50.1] as a colourless liquid (0.65 g, 68%, LCMS MH.sup.+=417.2).

Step 2

[0686] The procedure used in Example [1], Step 2 was adapted such that 0.4 g of tert-butyl (S)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)-2-methylpyrrolidine-1-carboxylate [50.1] was reacted to afford tert-butyl (S)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(methoxycarbonyl)amino)methyl)-2-methylpyrrolidine-1-carboxylate [50.2] as a brown liquid (0.32 g, 70%, LCMS MH.sup.+=375.1 (boc-cleaved mass)).

Step 3

[0687] The procedure used in Example [22], Step 4 was adapted such that 0.3 g of tert-butyl (S)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(methoxycarbonyl)amino)methyl)-2-methylpyrrolidine-1-carboxylate [50.2] was reacted to afford methyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((2-methylpyrrolidin-2-yl)methyl)carbamate [50] as a white solid (0.25 g, 96%, LCMS MH.sup.+=375.0). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 8.70 (bs, 1H), 8.46 (bs, 1H), 7.52 (q, J=9.68 Hz, 3H), 3.81 (t, J=45.48 Hz, 4H), 3.22 (d, J=6.84 Hz, 2H), 1.95 (d, J=8.36 Hz, 2H), 1.92 (d, J=5.52 Hz, 2H), 1.44 (s, 3H), 1.27 (bs, 2H), 1.10 (s, 3H). HRMS calculated for: [C.sub.18H.sub.20F.sub.4N.sub.2O.sub.2+H].sup.+ 375.1690; found: 375.1688 (deviation 0.6 ppm).

Example [51](1S, 2S)N1-(1-(4-fluoro-3-(trifluoromethyl) phenyl)cyclopropyl)-cyclopentane-1,2-diamine

Step 1

[0688] The procedure used in Example [2], Step 2 was adapted such that 0.8 g of 1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropan-1-amine [1.1] and tert-butyl N-[(1S)-2-oxocyclopentyl]carbamate were reacted to afford the diastereomers tert-butyl ((1S,2S)-2-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)cyclopentyl)carbamate [51.1] as yellow gum (0.43 g, 58%, LCMS MH.sup.+=403.2) and tert-butyl ((1S,2R)-2-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)cyclopentyl)carbamate [51.2] as a white solid (0.31 g, 42%, LCMS MH.sup.+=403.2).

Step 2

[0689] The procedure used in Example [22], Step 4 was adapted such that 0.04 g of tert-butyl ((1S,2S)-2-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)cyclopentyl)carbamate [51.1] was reacted to afford (1S, 2S)N1-(1-(4-fluoro-3-(trifluoromethyl) phenyl)cyclopropyl)cyclopentane-1,2-diamine [51] as a brown gum (0.012 g, 35%, LCMS MH.sup.+=303.2). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 7.93 (t, J=22.80 Hz, 2H), 7.51 (t, J=9.20 Hz, 1H), 3.54 (d, J=1.60 Hz, 2H), 3.40 (d, J=6.80 Hz, 2H), 3.15 (t, J=1.20 Hz, 1H), 2.00-1.88 (m, 2H), 1.63-1.55 (m, 3H), 1.63-1.55 (m, 5H). HRMS calculated for: [C.sub.15H.sub.18F.sub.4N.sub.2+H].sup.+ 303.1479; found: 303.1472 (deviation 2.3 ppm).

Example [52](1R,2S)N1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-cyclopentane-1,2-diamine

Step 1

[0690] The procedure used in Example [22], Step 4 was adapted such that 0.15 g of tert-butyl ((1S,2R)-2-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)cyclopentyl)carbamate [51.2] was reacted to afford (1R,2S)N1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)cyclopentane-1,2-diamine [52] as an off-white solid (0.112 g, 88%, LCMS MH.sup.+=303.2). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 10.66 (bs, 1H), 8.80-8.30 (m, 1H), 8.30-7.60 (m, 3H), 7.70-7.45 (m, 1H), 7.39-7.14 (m, 1H), 4.50-3.80 (m, 2H), 3.80-3.55 (m, 1H), 2.00-1.50 (m, 6H), 1.50-1.05 (m, 5H). HRMS calculated for: [C.sub.15H.sub.18F.sub.4N.sub.2+H].sup.+ 303.1479; found: 303.1474 (deviation 1.6 ppm).

Example [53]Methyl (S)-(azetidin-2-ylmethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)-cyclopropyl)carbamate

Step 1

[0691] The procedure used in Example [39], Step 1 was adapted such that 1.3 g of 1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropan-1-amine [1.1] was reacted to afford tert-butyl (S)-2-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamoyl)azetidine-1-carboxylate [53.1] as a brown liquid (2.2 g, 92%, LCMS MH.sup.+=303.1 (boc-cleaved mass)).

Step 2

[0692] The procedure used in Example [32], Step 2 was adapted such that 2.2 g of tert-butyl (S)-2-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamoyl)azetidine-1-carboxylate [53.1] was reacted to afford tert-butyl (S)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)azetidine-1-carboxylate [53.2] as colourless liquid (1.2 g, 57%, LCMS MH.sup.+=389.2).

Step 3

[0693] The procedure used in Example [1], Step 2 was adapted such that 0.25 g of tert-butyl (S)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)azetidine-1-carboxylate [53.2] was reacted to afford tert-butyl (S)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(methoxycarbonyl)amino)methyl)azetidine-1-carboxylate [53.3] as a brown gum (0.26 g, 92%, LCMS MH.sup.+=447.2).

Step 4

[0694] The procedure used in Example [26], Step 2 was adapted such that 0.5 g of tert-butyl (S)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(methoxycarbonyl)amino)methyl)azetidine [53.3] was reacted to afford methyl (S)-(azetidin-2-ylmethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate [53] as a brown liquid (0.04 g, 11%, LCMS MH.sup.+=347.0). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 7.44-7.28 (m, 3H), 3.91 (s, 1H), 3.58-3.33 (m, 5H), 3.05 (s, 2H), 2.00 (t, J=43.60 Hz, 1H), 1.76 (s, 2H), 1.39 (s, 2H), 1.24 (s, 2H). HRMS calculated for: [C.sub.16H.sub.18F.sub.4N.sub.2O.sub.2+H].sup.+ 347.1377; found: 347.1369 (deviation 2.4 ppm).

Example [54]Solubility of Compounds

[0695] The aim of this experiment was to determine solubility of test compounds in 50 mM Phosphate buffer by using HPLC.

Method

TABLE-US-00001 Incubation time 16 hr at ~25 C. Buffer pH 50 mM potassium phosphate buffer, pH 7.40 Test compound 1600 M Incubation concentration Replicates n = 2 Analysis HPLC Standard Caffeine [Solubility (1400-1900 M)], Diethylstilbestrol compounds [Solubility (0 M)] and Tamoxifen [Solubility (<20 M)] Deliverables Solubility of test compound mg/mL

Preparation of Phosphate Buffer (pH 7.4):

[0696] 2.79 g of K.sub.2HPO.sub.4 and 0.54 g of KH.sub.2PO.sub.4 was dissolved in 390 mL of milliQ water. pH was adjusted to 7.4 using 1N HCl/1N NaOH and final volume was made up to 400 mL with milliQ water.

Preparation and Dilution of Test Compound:

[0697] 80 mM master stock of test compounds was prepared in 100% DMSO. In case of compounds not soluble/less quantity submission, 40/20/10Mm stocks were prepared and used for experiment.

Assay Procedure:

[0698] 245 L of 50 mM phosphate buffer then 5 L each of test compound/standards (80 mM) in their respective positions was added to the 1.1 mL 96 well plate. [0699] DMSO Controls was prepared by taking 245 L of 100% DMSO then 5 L each of test compound in their respective positions and added to the 1.1 mL 96 well plate. [0700] Plate was incubated with mixing at 1600 RPM for 16 hours at room temperature (23 C.). [0701] After incubation, samples were filtered using Millipore plates. [0702] Filtrates were analysed by HPLC-UV.

Solubility Calculation:

[0703] Solubility is calculated using the following formula:

[00001]$\mathrm{Solubility}\left(M\right)=\frac{\left(\mathrm{Sample}\mathrm{area}\mathrm{in}\mathrm{Buffer}\right)}{\left(\mathrm{Sample}\mathrm{area}\mathrm{in}\mathrm{DMSO}\right)}1600$

Results

TABLE-US-00002 Measured Solubility in pH 7.4 phosphate buffer (M) Compound (mg/ml) (rounded) [1] 0.5409 1600 [2] 0.5555 1600 [3] 0.5599 1600 [4] 0.0279 100 [6] 0.6792 1500 [8] 0.5109 1500 [9] 0.582 1200 [10] 0.4809 1400 [11] 0.5778 1600 [12] 0.3755 800 [13] 0.6337 1500 [14] 0.7554 1600 [15] 0.526 1400 [16] 0.5974 1600 [17] 0.5636 1500 [19] 0.607 1500 [20] 0.5836 1500 [21] 0.5646 1500 [22] 0.6666 1700 [23] 0.653 1600 [24] 0.5958 1500 [25] 0.4824 1700 [26] 0.6868 1500 [27] 0.5918 1600 [28] 0.6738 1600 [29] 0.6773 1600 [30] 0.5984 1700 [31] 0.5575 1500 [32] 0.5578 1500 [33] 0.1375 400 [34] 0.594 1400 [35] 0.5679 1500 [36] 0.3218 800 [37] 0.621 1600 [38] 0.6157 1500 [42] 0.6118 1500 [43] 0.5996 1500 [44] 0.6148 1600 [45] 0.6009 1600 [46] 0.585 1400 [47] 0.4635 1400 [50] 0.5747 1400 [51] 0.2392 700 [52] 0.4797 1400 [53] 0.5907 1700 NS6180 0.0009 2.8

Conclusion

[0704] It is demonstrated that the tested compounds have solubility in pH 7.4 phosphate buffer of 400 to 1700 M, whereas NS6180 has a solubility of 2.8 M.

Example [55]Inhibition of K.SUB.Ca.3.1

Erythrocyte K.SUB.Ca.3.1 Assay

[0705] Human blood was drawn from healthy human volunteers in a standard heparinized blood sampling vial (Vacutainer, Li/heparin, BD Bioscience, Plymouth, UK). The erythrocytes were packed by centrifugation, and the plasma and buffy coat were removed by aspiration. Erythrocytes were washed three times in the experimental salt solution and then stored at 0 C. until use. Blood samples from NMRI mice or from Wistar rats were treated similarly. The methodological principle is outlined in Macey et al. (1978) and further described in Strbk et al. (2013). Activation of the erythrocyte K.sub.Ca3.1 channels were obtained by addition of the Ca.sup.2+ ionophore A23187, which causes synchronized hyperpolarization, which is reported as a CCCP-mediated shift in the unbuffered extracellular pH of the erythrocyte suspension. Standard procedure: 3 mL unbuffered experimental salt solution (in mM: 2 KCl, 154 NaCl, 0.05 CaCl.sub.2) was heated to 37 C. with stirring. Packed erythrocytes were added (50 L, final cytocrit 1.5%), and the extracellular pH (pH.sub.o) followed with a glass/calomel (pHG200-8/REF200, Radiometer, Denmark) electrode pair. CCCP (3 L, final concentration 20 PM) was added followed by varying concentrations of test compounds (DMSO concentration constant). After pH stabilization at 7.2, A23187 (3 L, final concentration 0.3 M) was added to initiate the experiment. After the peak hyperpolarization was attained, the intracellular pH (pH.sub.i constant during the experiment) was found by haemolysing the erythrocytes via addition of 100 L of Triton-X100.

[0706] The erythrocyte membrane potential, V.sub.m, was calculated according to:

[00002]$V_m=-61.5\mathrm{mV}\left({\mathrm{pH}}_0-{\mathrm{pH}}_1\right)$

and the fractional remaining Ca.sup.2+-activated K.sup.+-conductance at the concentration C of blocker, fG.sub.K(C), was calculated from

[00003]${\mathrm{fG}}_K\left(C\right)=\frac{\left(V_m\left(0\right)-E_K\right)*\left(E_{\mathrm{Cl}}-V_m\left(C\right)\right)}{\left(E_{\mathrm{Cl}}-V_m\left(0\right)\right)*\left(V_m\left(C\right)-E_K\right)}$

where the K.sup.+ equilibrium potential E.sub.K=107 mV, the Cl.sup. equilibrium potential E.sub.Cl=12 mV and the V.sub.m(0) and V.sub.m(C) are the peak hyperpolarizations in the control and in the presence of a concentration of C of blocker respectively.

[0707] IC.sub.50 values for compounds were calculated from a plot of fG.sub.K(C) versus C by a fit to the Hill equation, using a custom program written in the IGOR-Pro software (WaveMetrics, Lake Oswego, OR, USA). All IC.sub.50-values are reported in M.

Results

TABLE-US-00003 RBC K (in vitro) Compound Human IC.sub.50 (M) [1] 0.33 [2] 0.086 [3] 0.16 [4] 0.071 [5] 0.31 [6] 0.19 [7] 0.48 [8] 0.014 [9] 0.35 [10] 0.024 [11] 0.3 [12] 0.4 [13] 0.44 [14] 0.25 [15] 0.14 [16] 0.4 [17] 0.4 [18] 0.018 [19] 0.047 [20] 0.092 [21] 0.075 [22] 0.21 [23] 0.12 [24] 0.31 [25] 0.18 [26] 0.21 [27] 0.3 [28] 0.087 [29] 0.33 [30] 0.17 [31] 0.081 [32] 0.27 [33] 0.12 [34] 0.052 [35] 0.11 [36] 0.32 [37] 0.14 [38] 0.12 [39] 0.42 [40] 0.27 [41] 0.38 [42] 0.34 [43] 0.29 [44] 0.2 [45] 0.18 [46] 0.1 [47] 0.22 [48] 0.23 [49] 0.39 [50] 0.15 [51] 0.41 [52] 0.093 [53] 0.36

CONCLUSION

[0708] It is demonstrated that all the compounds inhibit K.sub.Ca3.1.

REFERENCES

[0709] Macey et al., Biochim. Biophys. Acta 1978, 22, 512(2), 284-95 [0710] Strbk et al., Br. J. Pharmacol. 2013, 168(2), 432-444 [0711] WO 2014/001363 [Clevexel Pharma; Aniona ApS; Saniona ApS] [0712] WO 2013/191984 [Boehringer Ingelheim] [0713] WO 2014/067861 [Hoffmann La Roche]