ANTIBACTERIAL BENZOTHIAZOLE DERIVATIVES

Abstract

The invention relates to antibacterial compounds formula I

##STR00001##

wherein R.sup.1 is the group M, whereby M is one of the groups M.sup.A and M.sup.B represented below

##STR00002##

wherein A is a bond or C≡C; R.sup.1A is H or halogen; R.sup.2A is H or halogen; R.sup.3A is H, alkoxy, hydroxyalkoxy, hydroxyalkyl, dihydroxyalkyl, 2-hydroxyacetamido, substituted cycloprop-1-yl or substituted oxetan-3-yl; and R.sup.1B is hydroxyalkyl, dihydroxyalkyl, aminoalkyl, dialkylaminoalkyl, substituted cycloprop-1-yl, substituted cyclobutan-1-yl, substituted oxetan-3-yl, 3-hydroxythietan-3-yl, substituted azetidin-3-yl, trans-(cis-3,4-dihydroxy)-cyclopent-1-yl, 3-hydroxymethylbicyclo[1,1,1]pentan-1-yl, 4-hydroxytetrahydro-2H-pyran-4-yl, (3R,6S)-3-aminotetrahydro-2H-pyran-6-yl, piperidin-4-yl or 1-(2-hydroxyacetyppiperidin-4-yl;

and salts thereof.

Claims

1. A compound of formula I ##STR00035## wherein R.sup.1 is the group M, whereby M is one of the groups M.sup.A and M.sup.B represented below ##STR00036## wherein A represents a bond or C≡C; R.sup.1A is H or halogen; R.sup.2A is H or halogen; and R.sup.3A is H, (C.sub.1-C.sub.3)alkoxy, hydroxy(C.sub.2-C.sub.4)alkoxy, hydroxy(C.sub.1-C.sub.4)alkyl, dihydroxy(C.sub.2-C.sub.4)alkyl, 2-hydroxyacetamido, 1-hydroxymethyl-cycloprop-1-yl, trans-2-hydroxymethyl-cycloprop-1-yl, 3-hydroxyoxetan-3-yl, 3-(hydroxy(C.sub.1-C.sub.3)alkyl)oxetan-3-yl, 3-aminooxetan-3-yl or 1-aminocycloprop-1-yl; and wherein R.sup.1B is hydroxy(C.sub.1-C.sub.4)alkyl, dihydroxy(C.sub.2-C.sub.4)alkyl, amino(C.sub.1-C.sub.4)alkyl, di(C.sub.1-C.sub.4)alkylamino(C.sub.1-C.sub.3)alkyl, 1-amino-cycloprop-1-yl, 1-hydroxymethyl-cycloprop-1-yl, trans-2-hydroxymethyl-cycloprop-1-yl, trans-2-aminomethyl-cycloprop-1-yl, trans-2-hydroxymethyl-1-methyl-cycloprop-1-yl, trans-2-hydroxymethyl-2-methyl-cycloprop-1-yl, cis-1-fluoro-2-(hydroxymethyl)cycloprop-1yl, cis-2-fluoro-2-(hydroxymethyl)cycloprop-1-yl, 2-(1,2-dihydroxyethyl)-cycloprop-1yl, 1-(hydroxymethyl)-cyclobutan-1-yl, cis-3-(hydroxymethyl)-1-hydroxy-cyclobutan-1-yl, 3-hydroxyoxetan-3-yl, 3-hydroxyoxetan-3yl-(C.sub.1-C.sub.3)alkyl, 3-aminooxetan-3-yl, 3-hydroxymethyl-oxetan-3-yl, trans-(cis-3,4-dihydroxy)-cyclopent-1-yl, 3-hydroxymethylbicyclo[1,1,1]pentan-1yl, 4-hydroxytetrahydro-2H-pyran-4yl, or (3R,6S)-3-aminotetrahydro-2H-pyran-6-yl, piperidin-4-yl, 1-(2-hydroxyacetyl)piperidin-4-yl, 3-hydroxythietan-3yl, 1-(2-hydroxyacetyl)azetidin-3-yl or 1-glycylazetidin-3-yl; or a salt thereof.

2. The compound of formula I according to claim 1, wherein R.sup.1 is the group M.sup.A; or a salt thereof.

3. The compound of formula I according to claim 2, wherein A represents a bond or C≡C; R.sup.1A is H or halogen; R.sup.2A is H; and R.sup.3A is (C.sub.1-C.sub.3)alkoxy, hydroxy(C.sub.1-C.sub.4)alkyl, 1-hydroxymethyl-cycloprop-1-yl, 3-hydroxyoxetan-3-yl, or 3-aminooxetan-3-yl; or a salt thereof.

4. The compound of formula I according to claim 2, wherein A represents a bond; or a salt thereof.

5. The compound of formula I according to claim 4, wherein R.sup.1A is H or halogen; R.sup.2A is H; and R.sup.3A is (C.sub.1-C.sub.3)alkoxy; or a salt thereof.

6. The compound of formula I according to claim 2, wherein A represents C≡C; or a salt thereof.

7. The compound of formula I according to claim 6, wherein R.sup.1A and R.sup.2A are both H; and R.sup.3A is hydroxy(C.sub.1-C.sub.4)alkyl, 1-hydroxymethyl-cycloprop-1-yl, 3-hydroxyoxetan-3-yl, or 3-aminooxetan-3-yl; or a salt thereof.

8. The compound of formula I according to claim 1, wherein R.sup.1 is the group M.sup.B; or a salt thereof.

9. The compound of formula I according to claim 8, wherein R.sup.1B is hydroxy(C.sub.1-C.sub.4)alkyl, dihydroxy(C.sub.2-C.sub.4)alkyl, amino(C.sub.1-C.sub.4)alkyl, di(C.sub.1-C.sub.4)alkylamino(C.sub.1-C.sub.3)alkyl, 1-amino-cycloprop-1-yl, 1-hydroxymethyl-cycloprop-1-yl, trans-2-hydroxymethyl-cycloprop-1-yl, trans-2-hydroxymethyl-1-methyl-cycloprop-1-yl, cis-1-fluoro-2-(hydroxymethyl)cycloprop-1-yl, cis-2-fluoro-2-(hydroxymethyl)cycloprop-1-yl, 1-(hydroxymethyl)-cyclobutan-1-yl, cis-3-(hydroxymethyl)-1-hydroxy-cyclobutan-1-yl, 3-hydroxyoxetan-3-yl, 3-hydroxyoxetan-3-yl-(C.sub.1-C.sub.3)alkyl, 3-aminooxetan-3-yl, 3-hydroxymethyl-oxetan-3-yl, or trans-(cis-3,4-dihydroxy)-cyclopent-1-yl, 4-hydroxytetrahydro-2H-pyran-4-yl, (3R,6S)-3-aminotetrahydro-2H-pyran-6-yl, piperidin-4-yl, or 1-(2-hydroxyacetyl)piperidin-4-yl; or a salt thereof.

10. The compound of formula I according to claim 9, wherein R.sup.1B is hydroxy(C.sub.1-C.sub.4)alkyl, dihydroxy(C.sub.2-C.sub.4)alkyl, amino(C.sub.1-C.sub.4)alkyl, 1-amino-cycloprop-1-yl, 1-hydroxymethyl-cycloprop-1-yl, trans-2-hydroxymethyl-cycloprop-1-yl, trans-2-hydroxymethyl-1-methyl-cycloprop-1-yl, cis-1-fluoro-2-(hydroxymethyl)cycloprop-1-yl, cis-2-fluoro-2-(hydroxymethyl)cycloprop-1-yl, 3-hydroxyoxetan-3-yl, 3-hydroxyoxetan-3-yl-(C.sub.1-C.sub.3)alkyl, 3-hydroxymethyl-oxetan-3-yl, or trans-(cis-3,4-dihydroxy)-cyclopent-1-yl; or a salt thereof.

11. The compound of formula I according to claim 1, wherein R.sup.1 is the group M.sup.A, A represents a bond, R.sup.1A is halogen, R.sup.2A i.sub.s H, and R.sup.3A is (C.sub.1-C.sub.3)alkoxy; or R.sup.1 is the group M.sup.A, A represents C≡C, R.sup.1A and R.sup.2A are both H, and R.sup.3A is 1-hydroxymethyl-cycloprop-1-yl; or R.sup.1 is the group M.sup.B and R.sup.1B is di(C.sub.1-C.sub.4)alkylamino(C.sub.1-C.sub.3)alkyl, 1-(hydroxymethyl)-cyclobutan-1-yl, cis-3-(hydroxymethyl)-1-hydroxy-cyclobutan-1-yl, 3-aminooxetan-3-yl, 4-hydroxytetrahydro-2H-pyran-4-yl, (3R,6S)-3-aminotetrahydro-2H-pyran-6-yl, piperidin-4-yl, or 1-(2-hydroxyacetyl)piperidin-4-yl; or a salt thereof.

12. The compound of formula I according to claim 1, wherein A represents a bond or C≡C; R.sup.1A is H or halogen; R.sup.2A is H; and R.sup.3A is (C.sub.1-C.sub.3)alkoxy, hydroxy(C.sub.1-C.sub.4)alkyl, 1-hydroxymethyl-cycloprop-1-yl, 3-hydroxyoxetan-3-yl, or 3-aminooxetan-3-yl; and wherein R.sup.1B is hydroxy(C.sub.1-C.sub.4)alkyl, dihydroxy(C.sub.2-C.sub.4)alkyl, amino(C.sub.1-C.sub.4)alkyl, di(C.sub.1-C.sub.4)alkylamino(C.sub.1-C.sub.3)alkyl, 1-amino-cycloprop-1-yl, 1-hydroxymethyl-cycloprop-1-yl, trans-2-hydroxymethyl-cycloprop-1-yl, trans-2-hydroxymethyl-1-methyl-cycloprop-1-yl, cis-1-fluoro-2-(hydroxymethyl)cycloprop-1-yl, cis-2-fluoro-2-(hydroxymethyl)cycloprop-1-yl, 1-(hydroxymethyl)-cyclobutan-1-yl, cis-3-(hydroxymethyl)-1-hydroxy-cyclobutan-1-yl, 3-hydroxyoxetan-3-yl, 3-hydroxyoxetan-3-yl-(C.sub.1-C.sub.3)alkyl, 3-aminooxetan-3-yl, 3-hydroxymethyl-oxetan-3-yl, trans-(cis-3,4-dihydroxy)-cyclopent-1-yl, 4-hydroxytetrahydro-2H-pyran-4-yl, or (3R,6S)-3-aminotetrahydro-2H-pyran-6-yl, piperidin-4-yl, or 1-(2-hydroxyacetyl)piperidin-4-yl; or a salt thereof.

13. The compound of formula I according to claim 1, wherein the compound is: (R)-N-hydroxy-4-(6-((3-hydroxyoxetan-3-yl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide, (R)-4-(6-(2-fluoro-4-methoxyphenyl)benzo[d]thiazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide, (R)-N-hydroxy-4-(6-((4-(3-hydroxyoxetan-3-yl)phenyl)ethynyl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide, (R)-N-hydroxy-4-(6-(5-hydroxy-5-methylhexa-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide, (R)-4-(6-((S)-5,6-dihydroxyhexa-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide, (R)-4-(6-(5-amino-5-methylhexa-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide, (R)-N-hydroxy-4-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide, (R)-N-hydroxy-4-(6-((1-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide, (R)-4-(6-((3-aminooxetan-3-yl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide, (R)-4-(6-((1-aminocyclopropyl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide, (R)-N-hydroxy-4-(6-((4-(1-(hydroxymethyl)cyclopropyl)phenyl)ethynyl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide, (R)-N-hydroxy-4-(6-((1-(hydroxymethyl)cyclobutyl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide, (R)-4-(6-(((1s,3R,4S)-3,4-dihydroxycyclopentyl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide, (R)-N-hydroxy-4-(6-(5-(3-hydroxyoxetan-3-yl)penta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide, (R)-N-hydroxy-4-(6-(((1R,2R)-2-(hydroxymethyl)-1-methylcyclopropyl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide, (R)-4-(6-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide, (R)-4-(6-(5-(dimethylamino)penta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide, (R)-N-hydroxy-4-(6-((4-hydroxytetrahydro-2H-pyran-4-yl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide, (R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-4-(6-(piperidin-4-ylbuta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)butanamide, (R)-N-hydroxy-4-(6-((3-(hydroxymethyl)oxetan-3-yl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide, (R)-N-hydroxy-4-(6-((cis-1-hydroxy-3-(hydroxymethyl)cyclobutyl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide, (R)-N-hydroxy-4-(6-((1-(2-hydroxyacetyl)piperidin-4-yl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide, (R)-4-(6-(((1R*,2R1-1-fluoro-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide, or (R)-4-(6-(((1R*,2R*)-2-fluoro-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide, or a salt of such compound.

14. The compound of formula I according to claim 1, wherein the compound is: (R)-N-hydroxy-4-(6-(4-methoxyphenyl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide, (R)-N-hydroxy-4-(6-((4-(hydroxymethyl)phenyl)ethynyl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide, (R)-4-(6-((4-(3-aminooxetan-3-yl)phenyl)ethynyl)-benzo[d]thiazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide, or (R)-N-hydroxy-4-(6-(5-hydroxypenta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide, or a salt of such compound.

15. The compound of formula I according to claim 1, wherein the compound is: (R)-N-hydroxy-4-(6-((1-(2-hydroxyacetyl)azetidin-3-yl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide, (R)-N-hydroxy-4-(6-(((1R,2S)-2-(hydroxymethyl)-2-methylcyclopropyl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide, and or (R)-4-(6-(((1R,2R)-2-fluoro-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide, or a salt of such compound.

16. The compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, formulated as a medicament.

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

18. A method of preventing or treating a bacterial infection comprising administering to a subject an amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

19. The compound or pharmaceutically acceptable salt according to claim 18, which is for the prevention or treatment of a Gram-negative bacterial infection.

Description

EXAMPLES

[0298] All temperatures are stated in ° C. Unless otherwise indicated, the reactions take place at rt. CCs were performed using Brunschwig 60A silica gel (0.032-0.63 mm) or using an ISCO CombiFlash system and prepacked SiO.sub.2 cartridges, elution being carried out with either Hept-EA or DCM-MeOH mixtures with an appropriate gradient. When the compounds contained an acid function, 1% of AcOH was added to the eluent(s). When the compounds contained a basic function, 25% aq. NH.sub.4OH was added to the eluents.

[0299] The compounds were characterized by .sup.1H NMR. Chemical shifts δ are given in ppm relative to the solvent used; multiplicities: s=singlet, d=doublet, t=triplet, q=quartet, p=pentet, hex=hexet, hep=Heptet, m=multiplet, br.=broad; coupling constants J are given in Hz.

[0300] The analytical LC-MS data have been obtained using the following respective conditions: [0301] Column: Zorbax SB-Aq, 30.5 μm, 4.6×50 mm; [0302] Injection volume: 1 μL; [0303] Column oven temperature: 40° C.; [0304] Detection: UV 210 nm, ELSD and MS; [0305] MS ionization mode: ESI+; [0306] Eluents: A: H.sub.2O+0.04% TFA; and B: MeCN; [0307] Flow rate: 40.5 mL/min; [0308] Gradient: 5% B to 95% B (0.0 min-1.0 min), 95% B (1.0min-1.45 min).

[0309] The number of decimals given for the corresponding [M+H.sup.+] peak(s) of each tested compound depends upon the accuracy of the LC-MS device actually used.

[0310] The prep-HPLC purifications were performed on a Gilson HPLC system, equipped with a Gilson 215 autosampler, Gilson 333/334 pumps, Dionex MSQ Plus detector system, and a Dionex UVD340U (or Dionex DAD-3000) UV detector, using the following respective conditions: [0311] Method 1: [0312] Column: Waters Atlantis T3 OBD, 10 μm, 30×75 mm; [0313] Flow rate: 75 mL/min; [0314] Eluents: A: H.sub.2O+0.1% HCOOH; B: MeCN+0.1% HCOOH; [0315] Gradient: 90% A to 5% A (0.0 min-4.0 min), 5% A (4.0 min-6.0 min). [0316] Method 2: [0317] Column: Waters) (Bridge C18, 10 μm, 30×75 mm; [0318] Flow rate: 75 mL/min; [0319] Eluents: A: H.sub.2O+0.1% HCOOH; B: MeCN+0.1% HCOOH; [0320] Gradient: 70% A to 5% A (0.0 min-30.5 min), 5% A (30.5 min-6.0 min). [0321] Method 3: [0322] Column: Waters XBridge C18, 10 μm, 30×75 mm; [0323] Flow rate: 75 mL/min; [0324] Eluents: A: H.sub.2O+0.5% aq. NH.sub.4OH 25% solution; B: MeCN; [0325] Gradient: 90% A to 5% A (0.0 min-4.0 min), 5% A (4.0 min-6.0 min).

[0326] Besides, semi-preparative chiral HPLCs were performed using the conditions herafter.

[0327] Semi-Preparative Chiral HPLC Method A:

[0328] The semi-preparative chiral HPLC is performed on a Daicel ChiralPak IA column (20×250 mm, 5 μM) using the eluent mixture, flow rate and detection conditions indicated between brackets in the corresponding experimental protocol. The retention times are obtained by elution of analytical samples on a Daicel ChiralPak Lk column (4.6×250 mm, 5 μM) using the same eluent mixture with the flow rate indicated between brackets in the corresponding experimental protocol.

[0329] Semi-Preparative Chiral HPLC Method B:

[0330] The semi-preparative chiral HPLC is performed on a Daicel ChiralPak AY-H column (20×250 mm, 5 μM) using the eluent mixture, flow rate and detection conditions indicated between brackets in the corresponding experimental protocol. The retention times are obtained by elution of analytical samples on a Daicel ChiralPak AY-H column (4.6×250 mm, 5 μM) using the same eluent mixture with the flow rate indicated between brackets in the corresponding experimental protocol.

[0331] Preparations:

Preparation A: rac-4-(6-bromobenzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)-N-(((RS)-tetrahydro-2H-pyran-2-yl)oxy)butanamide

[0332] A.i. 2-(6-bromobenzo[d]thiazol-2-yl)ethyl methanesulfonate

[0333] To an ice-chilled solution of 2-(6-bromobenzo[d]thiazol-2-yl)ethanol (10.2 g, 39.5 mmol, prepared as described in US 2004/224953) in DCM (80 mL) was added dropwise TEA (11.7 mL, 84.2 mmol) and MsC1 (5.64 mL, 72.5 mmol). The mixture was stirred at 0° C. for 10 min. The mixture was diluted with a sat. NaHCO.sub.3 solution (100 mL), extracted with DCM (100 mL) and the org. layer was washed with brine (100 mL), dried over MgSO.sub.4 and concentrated to dryness to afford the title product as a yellow solid (12 g, 90% yield).

[0334] .sup.1H NMR (d6-DMSO) δ: 8.39 (d, J=1.8 Hz, 1H): 7.91 (d, J=8.7 Hz, 1H); 7.66 (dd, J=1.8, 8.7 Hz, 1H); 4.66 (t, J=6.1 Hz, 3H); 3.57 (t, J=6.1 Hz, 3H).

[0335] MS (ESI, m/z): 335.9 [M+H.sup.+] for C.sub.10H.sub.10NO.sub.3BrS.sub.2; t.sub.R=0.82 min.

A.ii. Rac-ethyl 4-(6-bromobenzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfanyl)butanoate

[0336] To a solution of ethyl 2-(methylsulfonyl)propanoate (4.3 g, 23.7 mmol, commercial) in DMF (26 mL) was added portionwise NaH (0.9 g, 22.5 mmol). The mixture was stirred at 0° C. for 15 min and was allowed to reach 10° C. Then, a solution of intermediate A.i (7.58 g, 22.5 mmol) in DMF (26 mL) was added dropwise. The mixture was stirred at 10° C. for 30 min. EA (100 mL) was added and the mixture was poured into 10% aq. NaHSO.sub.4 (100 mL). The org. layer was then washed with water (100 mL), brine (100 mL), dried over MgSO.sub.4 and concentrated to dryness. The residue was purified by CC (Hept-EA) to afford the title compound as a pale yellow solid (5.46 g, 58% yield).

[0337] .sup.1H NMR (d6-DMSO) δ: 8.38 (d, J=2.0 Hz, 1H); 7.89 (d, J=8.7 Hz, 1H); 7.65 (dd, J=2.0, 8.6 Hz, 1H); 4.18 (q, J=7.1 Hz, 2H); 3.28-3.33 (overlapped m, 1H); 3.15 (s, 3H); 3.07-3.11 (m, 1H); 2.66-2.75 (m, 1H); 2.31-2.40 (m, 1H); 1.60 (s, 3H); 1.21 (t, J=7.1 Hz, 3H).

[0338] MS (ESI, m/z): 422.0 [M+H.sup.+] for C.sub.15H.sub.18NO.sub.4BrS.sub.22; t.sub.R=0.89 min.

Rac4-(6-bromobenzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanoic acid lithium salt

[0339] To a solution of intermediate A.ii (6.93 g, 16.4 mmol) in MeOH (34 mL) and THF (34 mL) was added a solution of LiOH.H.sub.2O (1.461 g, 34.8 mmol) in water (17 mL). The mixture was stirred at 50° C. for 1 h. The mixture was concentrated to dryness and dried to a constant weight to afford the title product as a yellow foam (8.28 g, quant.).

[0340] .sup.1H NMR (d6-DMSO) δ: 8.34 (d, J=2 Hz, 1H); 7.87 (d, J=8.7 Hz, 1H); 7.62 (dd, J=2.0, 8.7 Hz, 1H); 3.13-3.20 (m, 2H); 3.08 (s, 3H); 2.50-2.58 (m, 1H); 2.06-2.18 (m, 1H); 1.40 (s, 3H).

[0341] MS (ESI, m/z): 391.9 [M+H.sup.+] for C.sub.13H.sub.15NO.sub.4BrS.sub.2; t.sub.R=0.76 min.

A.iv. Rac-4-(6-bromobenzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)-N-(((RS)-tetrahydro-2H-pyran-2-yl)oxy)butanamide

[0342] To a solution of intermediate A.iii (6.83 g, 17.4 mmol) in DMF (68 mL) was added O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (6.12 g, 52.2 mmol), EDC (10.02 g, 52.2 mmol), HOBT.H.sub.2O (7.05 g, 52.2 mmol) and TEA (7.39 mL, 53.1 mmol). It was stirred at 30° C. overnight. The mixture was concentrated to dryness and diluted in EA. The org. phase was washed with aq. sat. NaHCO.sub.3 and brine, dried over MgSO.sub.4 and concentrated to dryness. The residue was purified by CC (Hept-EA) to afford the title compound as a yellow foam (5.92 g, 69% yield).

[0343] .sup.1H NMR (d6-DMSO) δ: 11.39 (s, 1H); 8.37 (d, J=1.7 Hz, 1H); 7.89 (d, J=8.7 Hz, 1H); 7.65 (dd, J=2.0, 8.6 Hz, 1H); 4.96 (d, J=2.0 Hz, 1H); 3.98-4.11 (m, 2H); 3.45-3.54 (m, 1H); 3.07 (s, 1.5H); 3.05 (s, 1.5H); 2.91-3.04 (overlapped m, 1H); 2.68-2.84 (m, 1H); 2.19-2.33 (m, 1H); 1.47-1.65 (m, 9H).

[0344] MS (ESI, m/z): 491.4 [M+H.sup.+] for C.sub.18H.sub.23N.sub.2O.sub.5BrS.sub.2; t.sub.R=0.84 min.

Preparation B: rac-tert-butyl 2-(methylsulfonyl)propanoate

[0345] To a suspension of sodium methanesulfinate (6.20 g, 57.7 mmol) in tert-butanol (50 mL) was added at rt and in one portion tert-butyl 2-bromopropionate (8.6 mL, 52 mmol). The mixture was refluxed overnight. The mixture was cooled down at rt and the solvent was removed under reduced pressure. The residue was taken up in EA (200 mL), filtered through Celite and the pad was rinsed with EA (200 mL). The filtrate was concentrated to dryness to afford the title product as a white solid (9.91 g, 92% yield). .sup.1H NMR (d6-DMSO) δ: 4.24 (q, J=7.2 Hz, 1H); 3.11 (s, 3H); 1.45 (s, 9H); 1.40 (d, J=7.2 Hz, 3H).

Preparation C: rac-tert-butyl 4-(6-ethynylbenzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanoate

C.i. Tert-butyl 4-(6-bromobenzo[d]ithiazol-2-yl)-2-methyl-2-(methylsztlfonyl)butanoate

[0346] To a solution of the compound of Preparation B (2.07 g, 9.94 mmol) in DMF (11 mL) was added at 0° C. and portionwise NaH (0.320 g, 2.75 mmol). The mixture was stirred at 0° C. for 15 min and allowed to reach 10° C. A solution of intermediate A.i. (0.980 g, 2.91 mmol) in DMF (4 mL) was added dropwise. The mixture was stirred at rt for 10 min. The DMF was removed in vacuo and the residue was taken in water (20 mL) and EA (20 mL). The org. layer was dried over MgSO.sub.4 and concentrated to dryness. The residue was purified by CC (Hept-EA) to afford the title product as a yellow oil (2 g, quant.).

[0347] .sup.1H NMR (d6-DMSO) δ: 8.39 (d, J=1.9 Hz, 1H); 7.91 (d, J=8.7 Hz, 1H); 7.66 (dd, J=1.9, 8.7 Hz, 1H); 3.29-3.39 (overlapped m, 1H); 3.15 (s, 3H); 2.96-3.07 (m, 1H); 2.62-2.73 (m, 1H); 2.29-2.40 (m, 1H); 1.56 (s, 3H); 1.45 (s, 9H).

[0348] MS (ESI, m/z): 450.0 [M+H.sup.+] for C.sub.17H.sub.22NO.sub.4BrS.sub.2; t.sub.R0.96 min.

[0349] C.ii. Tert-butyl (RS)-4-(6-ethynylbenzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanoate

[0350] A mixture of intermediate C.i (0.860 g, 2.19 mmol), ethynyltributylstannane (0.960 g, 3.06 mmol) and Pd(PPh.sub.3).sub.4 (0.845 g, 0.0732 mmol) in degassed THF (14 mL) was stirred at rt for 8 h under a nitrogen atmosphere. The mixture was then concentrated to dryness and purified by CC (Hept-EA) to afford the title compound as an orange solid (0.205 g, 24% yield). .sup.1H NMR (d6-DMSO) δ: 8.26 (d, J=1.7 Hz, 1H); 7.94 (d, J=8.5 Hz, 1H); 7.57 (dd, J=1.7, 8.5 Hz, 1H); 4.26 (s, 1H); 3.30-3.40 (overlapped m, 1H); 3.13 (s, 3H); 2.92-3.07 (m, 1H); 2.56-2.73 (m, 1H); 2.24-2.40 (m, 1H); 1.56 (s, 3H); 1.45 (s, 9H).

[0351] MS (ESI, m/z): 394.1 [M+H.sup.+] for C.sub.19H.sub.23NO.sub.4S.sub.2; t.sub.R=0.93 min.

Preparation D: 3-(4-iodophenyl)oxetan-3-amine hydrochloride

D.i. N-(3-(4-iodophenyl)oxetan-3-yl)-2-methylpropane-2-sulfinamide

[0352] n-BuLi (1.1M in hexanes, 11.4 mL) was added dropwise to a solution of 1,4-iodobenzene (4.36 g) in THF (50 mL) at −78° C. After stirring for 1 h, a solution of 2-methyl-N-oxetan-3-ylidenepropane-2-sulfinamide (1.64 g; commercial) in THF (10 mL) was added dropwise over the course of 30 min at −78° C. The reaction mixture was gradually warmed to rt. After 1 h, sat. NH.sub.4Cl was added and the aq. layer was extracted with EA. The combined org. layer was washed with aq. sat. NaHCO.sub.3 and brine, dried over Na.sub.2SO.sub.4, filtered and concentrated to dryness. The residue was purified by CC (EA-Hept) to give the title compound as a colourless oil (0.751 g, 21% yield).

[0353] .sup.1H NMR (d6-DMSO) δ: 7.77 (d, J=8.4 Hz, 2H); 7.30 (d, J=8.4 Hz, 2H); 6.35 (s, 1H); 4.98 (d, J=6.3 Hz, 1H); 4.90-4.94 (m, 1H); 4.85-4.88 (m, 1H); 4.67 (d, J=6.3 Hz, 1H); 1.11 (s, 9H).

[0354] MS (ESI, m/z): 379.97 [M+H.sup.+] for C.sub.13H.sub.18NO.sub.2IS ; t.sub.R=0.78 min.

D.ii. 3-(4-iodophenyl)oxetan-3-amine hydrochloride

[0355] To a solution of intermediate D.i. (0.751 g, 1.98 mmol) in DCM (20 mL) was added a 4M solution of HCl in dioxane (1.06 mL). After stirring for 30 min at rt, the solids were filtered off and washed with Hex (3 mL) to afford the title compound as a white solid (0.624 g, 100% yield).

[0356] .sup.1H NMR (d6-DMSO) δ: 9.14-9.30 (m, 3H); 7.82-7.90 (m, 2H); 7.34-7.40 (d, J=8.5 Hz, 2H); 4.80-5.00 (m, 4H).

[0357] MS (ESI, m/z): 299.89 [M+Na.sup.+] for C.sub.9H.sub.10NOI; t.sub.R0.50 min.

Preparation E: rac-4-(6-ethynylbenzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)-N-(((RS)-tetrahydro-2H-pyran-2-yl)oxy)butanamide

[0358] To a mixture of the compound of Preparation A (2 g, 4.07 mmol), cesium fluoride (1.233 g, 8.14 mmol) and bis(tri-tert-butylphosphine)palladium (0.152 g, 0.297 mmol) in degassed dioxane (20 mL) was added ethynyltributylstannane (1.77 mL, 6.1 mmol). The mixture was stirred at 80° C. for 10 min under a nitrogen atmosphere. The mixture was diluted with DCM (100 mL) and aq. sat. NaHCO.sub.3 (100 mL). The org. layer was dried over MgSO.sub.4 and concentrated to dryness. The crude residue was purified by CC (Hept-EA) to afford the title compound as a yellow foam (1.33 g, 75% yield).

[0359] .sup.1H NMR (d6-DMSO) δ: 11.41-11.45 (m, 1H); 8.26-8.28 (m, 1H); 7.94 (d, J=8.4 Hz, 1H); 7.57 (dd, J=1.5, 8.4 Hz, 1H); 4.94-5.00 (m, 1H); 4.28 (s, 1H); 4.06-4.15 (m, 1H); 3.47-3.55 (m, 1H); 3.22-3.31 (overlapped m, 1H); 3.08 (s, 1.5H); 3.06 (s, 1.5H); 2.96-3.05 (m, 1H), 2.72-2.84 (m, 1H); 2.21-2.33 (m, 1H); 1.47-1.77 (m, 9H).

[0360] MS (ESI, m/z): 437.2 [M+H.sup.+] for C.sub.201.sup.-1.sub.24N.sub.2O.sub.5S.sub.2; t.sub.R=0.82 min.

Preparation F: 3-(iodoethynyl)oxetan-3-ol

[0361] To a solution of 3-ethynyloxetan-3-ol (1.097 g; 11.2 mmol; commercial) in MeOH (50 mL) and 1M aq. KOH (28 mL) was added iodine (3.549 g; 14 mmol). The reaction mixture was stirred for 2 h at rt. Water (150 mL) and DCM (500 mL) were added. The aq. layer was extracted with EA (500 mL). The org. layer were washed with brine, dried over MgSO.sub.4, filtered and concentrated down to afford the desired compound as a light yellow solid (2.21 g, 88% yield).

[0362] .sup.1H NMR (d6-DMSO) δ: 4.60 (d, J=6.5 Hz, 2H); 4.45 (d, J=6.5 Hz, 2H).

Preparation G: (2R)-4-(6-bromobenzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)-N-(((RS)-tetrahydro-2H-pyran-2-yl)oxy)butanamide

G.i. (R)-ethyl 4-(6-bromobenzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanoate

[0363] Intermediate Asii (8.42 g) was separated by semi-preparative chiral HPLC Method A (MeOH-DEA-DCM 74.92-0.08-25; flow rate: 16 mL/min; UV detection at 227 nM); the respective retention times (flow rate: 0.8 mL/min) were 5.45 and 6.17 min. The title (R)-enantiomer was identified as the second-eluting enantiomer and was obtained as a yellow solid (4 g).

[0364] .sup.1H NMR (d6-DMSO) δ: 8.38 (d, J=2.0 Hz, 1H); 7.89 (d, J=8.7 Hz, 1H); 7.65 (dd, J=2.0, 8.6 Hz, 1H); 4.18 (q, J=7.1 Hz, 2H); 3.28-3.33 (overlapped m, 1H); 3.15 (s, 3H); 3.07-3.11 (m, 1H); 2.66-2.75 (m, 1H); 2.31-2.40 (m, 1H); 1.60 (s, 3H); 1.21 (t, J=7.1 Hz, 3H).

[0365] MS (ESI, m/z): 419.8 [M+H.sup.+] for C.sub.15H.sub.18NO.sub.4BrS.sub.2; t.sub.R=0.90 min.

G.ii. (2R)-4-(6-bromobenzo[d]thiazol-2-yl)-2-methyl-2-(methylsztlfonyl)-N-(((RS)-tetrahydro-2H-pyran-2-yl)oxy)butanamide

[0366] Starting from the intermediate G.i (3.98 g, 9.45 mmol) and proceeding in analogy to Preparation A, steps A.iii-A.iv (yields: saponification 100%; amide coupling with THP—O—NH.sub.2 75%), the title product was obtained, after purification by CC (Hept-EA), as a pale yellow foam (3.69 g, 75% yield).

[0367] .sup.1H NMR (d6-DMSO) δ: 11.37 (s, 1H); 8.34 (s, 1H); 7.89 (d, J=8.7 Hz, 1H); 7.65 (dd, J=2.0, 8.6 Hz, 1H); 4.96 (d, J=2.0 Hz, 1H); 3.98-4.11 (m, 2H); 3.45-3.54 (m, 1H); 3.07 (s, 1.5H); 3.05 (s, 1.5H); 2.91-3.04 (overlapped m, 1H); 2.68-2.84 (m, 1H); 2.19-2.33 (m, 1H); 1.47-1.65 (m, 9H).

[0368] MS (ESI, m/z): 491.4 [M+H.sup.+] for C.sub.18H.sub.23N.sub.2O.sub.5BrS.sub.2; t.sub.R=0.84 min.

Preparation H: (2R)-4-(6-ethynylbenzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)-N-(((RS)-tetrahydro-2H-pyran-2-yl)oxy)butanamide

[0369] Starting from intermediate G.ii (1.5 g, 3.05 mmol) and proceeding in analogy to Preparation F, the title product was obtained, after purification by CC (Hept-EA), as an orange foam (1 g, 75% yield).

[0370] .sup.1H NMR (d6-DMSO) δ: 11.40 (s, 1H); 8.26 (s, 1H); 7.94 (d, J=8.4 Hz, 1H); 7.57 (dd, J=1.5, 8.4 Hz, 1H); 4.96 (s, 1H); 4.26 (s, 1H); 3.98-4.15 (m, 2H); 3.44-3.53 (m, 1H); 3.20-3.29 (overlapped m, 1H); 3.07 (s, 1.5H); 3.05 (s, 1.5H); 2.70-2.88 (m, 1H); 2.19-2.32 (m, 1H); 1.47-1.77 (m, 9H).

[0371] MS (ESI, m/z): 436.9 [M+H.sup.+] for C.sub.20H.sub.24N.sub.2O.sub.5S.sub.2; t.sub.R=0.82 min.

Preparation I: 3-(4-iodophenyl)oxetan-3-ol

[0372] A solution of 1,4-diiodobenzene (0.8 g, 2.43 mmol) in THF (8 mL) was treated at −78° C. with n-BuLi (1.68M in Hex; 2.23 mL). After stirring at this temperature for 30 min, the solution was treated with a suspension of 3-oxetanone (0.24 g, 3.34 mmol) in THF (3 mL). The reaction mixture was allowed to reach rt and was further stirred overnight. The reaction mixture was treated with 10% aq. NaHSO.sub.4 solution (4 mL) and diluted with water (10 mL) and EA (10 mL). The aq. layer was extracted with EA. The combined org. layers were washed with brine, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by CC (Hept-EA) to afford the title alcohol as a colourless solid (0.2 g; 55% yield).

[0373] .sup.11-1 NMR (d6-DMSO) δ: 7.73 (d, J=8.5 Hz, 2H); 7.39 (d, J=8.5 Hz, 2H); 6.39 (s, 1H); 4.73 (d, J=6.8 Hz, 2H); 4.60 (d, J=6.8 Hz, 2H).

Preparation J: 4-iodo-2-methylbut-3-yn-2-ol

[0374] To a solution of 2-methyl-3-butyl-2-ol (4 g, 19 mmol) in MeOH (144 mL) were added KI (3.48 g, 21 mmol) and tert-butylhydroperoxide (70% in water, 2.74 mL, 28.6 mmol). The mixture was stirred overnight at rt. The mixture was quenched with sat. aq. Na.sub.2S.sub.2O.sub.3 and extracted twice with EA (45 mL). The combined org. layers were washed with brine, dried over MgSO.sub.4 and concentrated to dryness. The crude residue was purified by CC (Hept-EA) to afford the title compound as a colourless oil (1.60 g, 40% yield).

[0375] .sup.1H NMR (d6-DMSO): 5.35 (s, 1H); 1.31 (s, 6H).

Preparation K: (S)-4-iodobut-3-yne-1,2-diol

Ki. (S)-4-(2,2-dibromovinyl)-2,2-dimethyl-1,3-dioxolane

[0376] To an ice-chilled solution of PPh.sub.3 (63.5 g, 242 mmol) in DCM (130 mL) was added dropwise a solution of CBr.sub.4 (40.3 g, 121 mmol) in DCM (50 mL) while maintaining the internal temperature below 15° C. The mixture was cooled to 0° C. and solution of (R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde (12.2 g, 93.4 mmol) and TEA (13 mL) in DCM (10 mL) was added dropwise. The mixture was stirred at 0° C. for 30 min. The mixture was then allowed to warm at rt and poured into PE (120 mL). The mixture was filtered through Celite and the solid was washed with Et.sub.2O (3×30 mL). The filtrate was concentrated to dryness and the residue was triturated in PE. The mixture was filtered, the filtrate was concentrated to dryness to afford the title compound as a pale yellow oil (18.02 g, 68% yield).

[0377] .sup.1H NMR (d6-DMSO) δ: 1.30 (s, 3H); 1.34 (s, 3H); 3.70 (t, J=7.1 Hz, 1H); 4.14 (t, J=7.1 Hz, 1H); 4.61 (dd, J=6.6, 13.3 Hz, 1H); 6.70 (d, J=7.9 Hz, 1H).

K.ii. (S)-4-(iodoethynyl)-2,2-dimethyl-1,3-dioxolane

[0378] To a solution of intermediate K.i (5 g, 17.5 mmol) in THF (75 mL) cooled to −78° C. was added dropwise n-BuLi (1.99 M in Hept; 17.5 mL, 35 mmol). The mixture was stirred 2 h at −78° C. and then warmed to 0° C. A solution of iodine (7.1 g, 28 mmol) in THF (50 mL) was added dropwise. The mixture was stirred at rt overnight. The reaction was quenched with sat. Na.sub.2S.sub.2O.sub.3 (75 mL) and the aq. layer was extracted twice with DCM (2×250 mL). The combined org. layers were dried over MgSO.sub.4 and concentrated to dryness. The crude residue was purified by CC (Hept-EA) to afford the title compound as a pale yellow oil (0.747 g, 17% yield).

[0379] .sup.1H NMR (CDCl.sub.3) δ: 4.82 (t, J=6.2 Hz, 1H); 4.13 (dd, J=6.4, 7.9 Hz, 1H); 3.94 (dd, J=6.4, 7.9 Hz, 1H); 1.48 (s, 3H); 1.36 (s, 3H).

K.iii. (S)-4-iodobut-3-yne-1,2-diol

[0380] To a solution of intermediate K.ii (747 mg, 2.96 mmol) in water (1.25 mL) was added TFA (2.5 mL, 32.7 mmol). The mixture was stirred at rt for 2 h. The mixture was concentrated to dryness and the residue was diluted in sat. NaHCO.sub.3 (20 mL). The aq. layer was extracted with DCM-MeOH (9-1, 3×20 mL) and the combined org. layers were dried over MgSO.sub.4 and concentrated to dryness to afford the title compound as a white solid (366 mg, 60% yield).

[0381] .sup.1H NMR (CDCl.sub.3) δ: 4.61 (dd, J=3.8, 6.2 Hz, 1H); 3.70-3.80 (m, 2H).

Preparation L: 4-iodo-2-methylbut-3-yn-2-amine

[0382] To a solution of 2-methylbut-3-yn-2-amine (0.633 mL, 6 mmol) in MeOH (30 mL) and KOH (1M; 15 mL, 15 mmol) was added iodine (1.9 g, 7.52 mmol). The mixture was stirred at rt for 2 h. Water (100 mL) and DCM (120 mL) were added. The aq. layer was extracted with DCM (120 mL). The combined org. layers were washed with brine, dried over MgSO.sub.4, filtered and concentrated down to afford the desired compound as a yellow solid (0.985 g, 78% yield).

[0383] .sup.1H NMR (d6-DMSO) δ: 2.01 (s, 2H); 1.24 (s, 6H).

[0384] MS (ESI, m/z): 210.01 [M+H.sup.+] for C.sub.5H.sub.8NI; t.sub.R=0.33 min.

Preparation M: ((1S,2S)-2-(bromoethynyl)cyclopropyl)methyl acetate and ((1R,2R)-2-(bromoethynyl)cyclopropyl)methyl acetate

M.i. ((1S*,2S*)-2-(2,2-dibromovinyl)cyclopropyl)methyl acetate

[0385] To a solution of CBr.sub.4 (36.56 g; 108 mmol) in DCM (76 mL) cooled to −20° C., was added dropwise over 1 h a solution of PPh.sub.3 (55.39 g, 211 mmol) in DCM (127 mL). The mixture was kept stirred at this temperature for 45 min and then cooled to −78° C. A solution of ((1S*,2S*)-2-formylcyclopropyl)methyl acetate (7.54 g, 53 mmol, prepared as described in WO 2012/154204) in DCM (100 mL) was added dropwise over 1.5 h, keeping the internal temperature below −70° C. The mixture was stirred at this temperature for 30 min and allowed to warm to rt over 30 min. The solvent was removed in vacuo and the residue was purified by CC (EA-Hept) to afford the title acetate as a colourless oil (7.98 g, 50% yield).

[0386] .sup.1H NMR (CDCl.sub.3) δ: 5.84 (d, J=9.0 Hz, 1H); 3.97 (m, 2H); 2.07 (s, 3H); 1.61 (m, 1H); 1.33 (m, 1H); 0.78-0.92 (m, 2H).

[0387] MS (ESI, m/z): 295.0 [M+H.sup.+] for C.sub.8H.sub.10O.sub.2Br.sub.2; t.sub.R=0.87 min.

M.ii. ((1S,2S)-2-(bromoethynyl)cyclopropyl)methyl acetate and ((1R,2R)-2-(bromoethynyl)cyclopropyl)methyl acetate

[0388] To a solution of intermediate M.i (7.98 g, 26.8 mmol) in THF (160 mL) was added TBAF trihydrate (48 g, 151 mmol). The reaction mixture was heated at 60° C. for 3 h. The reaction mixture was cooled to rt and diluted with diethyl ether (150 mL). The org. phase was washed with water (60 mL) and brine (60 mL), dried over MgSO.sub.4 and concentrated to dryness. The residue was purified by CC (EA-Hept) and by prep-HPLC (Method 1) to afford the title compound as a colourless oil (2.94 g, 51% yield). The racemic product was separated by semi-preparative chiral HPLC Method B (Hept-EtOH 9-1; flow rate: 16 mL/min, UV detection at 220 nm), the respective retention times (flow rate: 0.8 mL/min) were 5.9 and 8.7 min. The title enantiomers were obtained as colourless oils (1.4 g each).

[0389] First-Eluting Enantiomer, (1S,2S)-Configurated:

[0390] .sup.1H NMR (CDCl.sub.3) δ: 3.97 (dd, J=6.5, 11.7 Hz, 1H); 3.84 (dd, J=7.5, 11.7 Hz, 1H); 2.06 (s, 3H); 1.50 (m, 1H); 1.25 (m, 1H); 0.97 (m, 1H); 0.76 (m, 1H). [a].sub.D=+96° (c=1.03; MeOH).

[0391] Second-eluting enantiomer, (JR,2R)-configurated:

[0392] .sup.1H NMR (CDCl.sub.3) δ: 3.97 (dd, J=6.5, 11.7 Hz, 1H); 3.84 (dd, J=7.5, 11.7 Hz, 1H); 2.06 (s, 3H); 1.50 (m, 1H); 1.25 (m, 1H); 0.97 (m, 1H); 0.76 (m, 1H). [a].sub.D=−94° (c=1.01; MeOH).

[0393] The respective absolute configurations of these compounds have been determined though transformation of the second-eluting enantiomer into the corresponding (5) and (R) α-methoxy-α-trifluoromethylphenylacetyl esters and the subsequent analysis of their NMR spectra as described by Kobayashi et al. in Chem. Pharm. Bull. (2003), 51, 448.

Preparation N: ((1-(bromoethynyl)cyclopropyl)methoxy)(tert-butyl)diphenylsilane

[0394] To a mixture of (dibromomethyl)triphenylphosphonium bromide (8.527 g; 16.6 mmol; commercial) and THF (40 mL) was added a solution of tBuOK (1M in THF) (16.6 mL, 16.6 mmol) The resulting dark brown solution was stirred for 3 min at rt, then cooled to 0° C. A solution of 1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropanecarbaldehyde (2.2 g; 6.62 mmol; prepared as described in WO 2010/135536) in THF (23 mL) was added dropwise. The reaction was stirred at 0° C. for 40 min. The reaction mixture was cooled to −78° C. and tBuOK (1M in THF, 29.1 mL, 29.1 mmol) was added rapidly and stirred at −78° C. for 30 min. The reaction mixture was quenched with brine (150 mL). The aq. layer was separated and extracted with Et.sub.2O (3×150 mL). The combined org. phases were washed with brine, dried over MgSO.sub.4, filtered, and concentrated to dryness. The residue was purified by CC (Hept-EA) to afford the title compound as a colourless oil (2.052 g, 75% yield).

[0395] .sup.1H NMR (d6-DMSO) δ: 7.60-7.66 (m, 4H); 7.42-7.48 (m, 6H); 3.57 (s, 2H); 1.02 (s, 9H); 0.84-0.88 (m, 2H); 0.72-0.76 (m, 2H).

Preparation O: tert-butyl (3-(iodoethynyl)oxetan-3-yl)carbamate

O.i. Tert-butyl (3-((trimethylsilyl)ethynyl)oxetan-3-yl)carbamate

[0396] To a solution of 3-((trimethylsilyl)ethynyl)oxetan-3-amine hydrochloride (0.123 g; 0.6 mmol; commercial) in DCM (3 mL) were added TEA (0.18 mL; 1.29 mmol) and Boc.sub.2O (0.272 g; 1.25 mmol). The reaction mixture was stirred at rt for 6 h. Boc.sub.2O (0.272 g; 1.25 mmol) was added again and the reaction was stirred overnight. The reaction mixture was diluted with DCM (5 mL) and sat. aq. NaHCO.sub.3 (5 mL) was added. The phases were separated and the aq. layer was extracted twice with DCM (2×5 mL). The combined org. layers were washed with brine (5 mL), dried over MgSO.sub.4, filtered and the filtrate concentrated to dryness to afford the title compound, slightly contaminated by Boc.sub.2O, as a white gum (0.312 g).

[0397] .sup.1H NMR (CDCl.sub.3) δ: 4.72-4.81 (m, 4H); 3.05 (br. s, 1H); 1.47 (s, 9H); 0.18 (s, 9H).

O.ii. Tert-butyl (3-ethynyloxetan-3-yl)carbcunate

[0398] To a solution of intermediate O.i (0.211 g; 0.783 mmol) in MeOH (1.6 mL) was added K.sub.2CO.sub.3 (0.162 g; 1.17 mmol). The mixture was stirred at rt for 30 min. Water (5 mL) was added. The mixture was extracted twice with DCM (2×10 mL) and the org. layer was dried over MgSO.sub.4, filtered and the filtrate concentrated to dryness. The crude was purified by CC (PE-EA) to afford the title compound as a white solid (0.173 g).

[0399] .sup.1H NMR (CDCl.sub.3) δ: 5.02 (br. s, 1H); 4.84 (d, J=6.2 Hz, 2H); 4.73 (d, J=6.2 Hz, 2H); 2.57 (s, 1H); 1.47 (s, 9H).

O.iii. Tert-butyl (3-(iodoethynyl)oxetan-3-yl)carbamate

[0400] To a solution of intermediate O.ii (0.154 g; 0.783 mmol) in THF (2.4 mL) cooled to −78° C. was added, dropwise over 15 min, n-BuLi (2.11M in hexanes; 0.74 mL; 1.56 mmol), keeping the internal temperature below −70° C. After stirring for 1 h, a solution of iodine (0.201 g; 0.79 mmol) in THF (1.2 mL) was added dropwise over 5 min. The reaction mixture was stirred at −78° C. for 1.5 h, then was allowed to warm at rt for 30 min and stirred at rt for 30 min. The reaction mixture was quenched with a sat. Na.sub.2S.sub.2O.sub.3 solution (5 mL). The aq. layer was extracted with Et.sub.2O (2×10 mL). The combined org. layers were dried over MgSO.sub.4, filtered and concentrated to dryness to give the desired compound as a yellow oil (0.234 g, 92% yield).

[0401] .sup.1H NMR (CDCl.sub.3) δ: 5.02 (br. s, 1H); 4.81-4.85 (m, 2H); 4.70-4.75 (m, 2H); 1.47 (s, 9H).

Preparation P: 1-(iodoethynyl)cyclopropan-1-amine hydrochloride

P.i. Tert-butyl (1-(iodoethynyl)cyclopropyl)carbamate

[0402] Starting from tert-butyl (1-ethynylcyclopropyl)carbamate (0.885 g, 4.88 mmol; commercially available) and proceeding in analogy to Preparation L (iodination), the title compound was obtained as a crude light yellow solid (1.36 g, 91% yield).

[0403] .sup.1H NMR (CDCl.sub.3) δ: 5.00 (br. s, 1H); 1.49 (s, 9H); 1.23 (s, 2H); 1.11 (s, 2H).

P.ii. 1-(iodoethynyl)cyclopropan-1-amine hydrochloride

[0404] Starting from intermediate P.i (0.600 g, 1.95 mmol) and proceeding in analogy to Preparation D, step D.ii, the title compound was obtained, after trituration in Et.sub.2O, as a beige solid (0.358 g, 75% yield).

[0405] .sup.1H NMR (d6-DMSO)) δ: 8.78 (br. s, 3H); 1.23-1.29 (m, 2H); 1.16-1.22 (m, 2H).

Preparation Q: (1-(4-iodophenyl)cyclopropyl)methanol

[0406] A sealed tube was charged with NaI (0.83 g, 5.49 mmol), CuI (0.1 g, 0.55 mmol) and 1-(4-bromophenyl)cyclopropyl)methanol (0.62 g, 2.74 mmol). 1,4-Dioxane (3 mL) and trans-N-N′-dimethylcyclohexa-1,2-diamine (0.17 mL, 1.1 mmol) were added. The reaction mixture was heated at 180° C. for 40 min under microwave irradiation. The mixture was filtered over Celite. Solids were washed with EA and the filtrate was concentrated to dryness. The residue was purified by CC (Hept-EA) to obtain the title product as a white solid (0.654 g, 87% yield).

[0407] .sup.1H NMR (CDCl.sub.3) δ: 7.61 (d, J=8.5 Hz, 1H), 7.11 (d, J=8.5 Hz, 1H), 4.70 (t, J=5.7 Hz, 1H), 3.50 (d, J=5.7 Hz, 1H), 0.70-0.73 (m, 1H), 0.81-0.84 (m, 1H).

Preparation R: ((1-(bronmethynyl)cyclobutyl)methoxy)(tert-butyl)diphenylsilane

R.i. (1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)methanol

[0408] To a solution of cyclobutane-1,1-diyldimethanol (3.03 g, 24.8 mmol; commercial) in THF (190 mL) was added portionwise at 0° C. NaH (60% in dispersion, 0.99 g, 24.8 mmol). The resulting suspension was stirred at rt for 1 h and TBDPS-Cl (6.47 mL, 24.8 mmol) was added dropwise for 40 min. The reaction mixture was stirred at rt overnight. The mixture was diluted with sat. aq. NH.sub.4Cl (100 mL) and extracted with EA (3×80 mL). The combined org. layers were dried over Na.sub.2SO.sub.4 and the filtrate was concentrated to dryness. The residue was purified by CC (Hept-EA) to afford the title compound as a colourless oil (8.61 g, 98% yield)

[0409] .sup.1H NMR (CDCl.sub.3) δ: 7.69-7.72 (m, 4H), 7.41-7.49 (m, 6H), 3.76 (d, J=5.7 Hz, 2H), 3.74 (s, 2H), 2.51 (t, J=5.7 Hz, 1H), 1.89-1.95 (m, 1H), 1.80-1.87 (m, 3H), 1.73-1.77 (m, 2H), 1.08 (s, 9H).

[0410] MS (ESI, m/z): 355.0 [M+H.sup.+] for Ca.sub.8H.sub.10O.sub.2Br.sub.2; t.sub.R=−1.07 min.

R.ii. 1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobulane-1-carbaldehyde

[0411] To a suspension of intermediate R.i (5 g, 14.1 mmol) in DCM (34 mL) cooled to 0° C. was added dropwise DIPEA (7.24 mL, 42.3 mmol). A solution of sulfur trioxide pyridine complex (2.69 g, 7.61 mmol) in DMSO (17 mL) was added dropwise. The reaction mixture was stirred for 2 h with gradual warming to rt. Sat. aq. NaHCO.sub.3 (180 mL) and DCM (100 mL) were added. The two layers were separated and the aq. layer was extracted once with DCM (100 mL). The org. layer was washed with brine (80 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to dryness. The residue was purified by CC (Hept-EA gradient) to afford the title ketone as a colourless oil (4.28 g, 86% yield).

[0412] .sup.1H NMR (CDCl.sub.3) δ: 9.73 (s, 1H), 7.65-7.69 (m, 4H), 7.40-7.49 (m, 6H), 3.91 (s, 2H), 2.25-2.34 (m, 2H), 1.85-1.94 (m, 4H), 1.06 (s, 9H).

R.iii. Tert-butyl((1-(2,2-dibromovinyl)cyclobittyl)methoxy)diphenylsilane

[0413] Starting from intermediate R.ii (8.25 g, 24.6 mmol) and proceeding in analogy to Preparation M, step M.i the title compound was obtained as a colourless oil (5.73 g, 93% yield).

[0414] .sup.1H NMR (CDCl.sub.3) δ: 7.69-7.72 (m, 4H), 7.41-7.48 (m, 6H), 6.68 (s, 1H), 3.79 (s, 2H), 2.15-2.29 (m, 4H), 1.79-1.96 (m, 2H), 1.09 (s, 9H).

R.iv. ((1-(bromoethynyl)cyclobutyl)methoxy)(tert-butyl)diphenylsilane

[0415] A solution of intermediate R.iii (5.72 g, 11.3 mmol) in dry THF (26 mL) cooled to −78° C. was treated with a solution of tBuOK (1M in THF, 49.5 mL) over 45 min. The reaction mixture was stirred for 30 min at −78° C. then was diluted with brine (80 mL) and was allowed to reach rt. Et.sub.2O (150 mL) was added. The aq. layer was separated and extracted once again with Et.sub.2O (150 mL). The combined org. layers were washed with brine (80 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to afford the title compound as a colourless oil (4.79 g, quant.).

[0416] .sup.1H NMR (CDCl.sub.3) δ: 7.70-7.74 (m, 4H), 7.40-7.48 (m, 6H), 3.67 (s, 2H), 2.18-2.29 (m, 4H), 2.00-2.08 (m, 1H), 1.86-1.95 (m, 1H), 1.11 (s, 9H).

Preparation S: (1R,2S,4s)-4-(bromoethynyl)cyclopentane-1,2-diol

S.i. (3aR,5S,6aS)-5-(bromoethynyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxole

[0417] Starting from (3aR,5S,6aS)-5-(2,2-dibromovinyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxole (2.06 g; 6.32 mmol; prepared as described in WO 2013/170030) and proceeding in analogy to Preparation R, step R.iv, the title compound was obtained as a yellow oil (1.37 g, 88% yield).

[0418] .sup.1H NMR (CDCl.sub.3) δ: 4.60-4.63 (m, 2H); 2.85-2.93 (m, 1H); 2.12-2.17 (m, 2H); 1.51-1.60 (overlapped m, 2H); 1.41 (s, 3H); 1.26 (s, 3H).

S.ii. (1R,2S,4s)-4-(bromoethynyl)cyclopentane-1,2-diol

[0419] A solution of intermediate S.i (1 g, 0.204 mmol) in 1M HCl (20 mL, 20 mmol) and THF (20 mL) was stirred at rt overnight. EA (50 mL) was added and the phases were separated. The aq. layer was saturated with NaCl and extracted with EA (2×50 mL). The combined org. layers were dried over MgSO.sub.4, filtered and concentrated to dryness. The residue was purified by CC (Hept-EA) to afford the title compound as a white solid (0.652 g, 78% yield).

[0420] .sup.1H NMR (CDCl.sub.3) δ: 4.25 (quint, J=4.2 Hz, 2H), 3.10-3.18 (m, 1H), 2.05-2.13 (m, 2H), 1.98 (m, 2H).

Preparation T: 3-(3-iodoprop-2-yn-1-yl)oxetan-3-ol

[0421] A flask charged with ZnBr.sub.2 (1.08 g, 4.80 mmol) and Mg turnings (5.85 g) was heated with stirring under vacuum at 150° C. for 2 h and then cooled to rt. To this were added, Et.sub.2O (90 mL), a few drops of 1,2-dibromoethane, followed by dropwise addition of propargyl bromide (9 mL, 118.78 mmol) in Et.sub.2O (70 mL). The mixture was stirred at the same temperature for 1 h. In a separate flask, were introduced 3-oxetanone (3.15 g, 43.71 mmol) and THF (420 mL). The Grignard reagent solution (127 mL, 65.56 mmol), cannulated in a graduated addition funnel, was added dropwise. The solution was stirred at the same temperature for 1 h and diluted with sat. NH.sub.4Cl and Hex (100 mL). The two layers were separated and the aq. layer was extracted with Hex (100 mL). The combined org. layers were dried over MgSO.sub.4, filtered and concentrated under reduced pressure. Starting from the crude product (4.33 g, 38.63 mmol) and proceeding in analogy to Preparation L, the title compound was obtained as a yellow solid (3.01 g; 33% yield).

[0422] .sup.1H NMR (CDCl.sub.3) δ: 4.51 (d, J=7.4 Hz, 2H), 4.66 (d, J=7.1 Hz, 2H), 2.98 (s, 2H), 2.55 (s, 1H).

Preparation U: (((1R,2R)-2-(bromoethynyl)-2-methylcyclopropyl)methoxy)(tert-butyl)diphenylsilane

[0423] U.i. ((1R,2R)-2-(hydroxymethyl)-1-methylcyclopropyl)methyl acetate

[0424] To a solution of ((1R,2R)-2-formyl-1-methylcyclopropyl)methyl acetate (0.925 g; 5.92 mmol; prepared as described in WO 2012/154204) in MeOH (10 mL) was added NaBH.sub.4 (0.297 g; 7.7 mmol) portion-wise at 0° C. The reaction was stirred for 80 min at 0° C. then for 30 min at rt. Water (10 mL) and DCM (40 mL) were added and the phases were separated. The aq. layer was extracted with DCM-MeOH 9-1 (2×15 mL) and the combined org. layers were dried over Na.sub.2SO.sub.4 and filtered. The filtrate was evaporated under reduced pressure to give the title compound as a colourless oil (0.968 g; quant.).

[0425] .sup.1H NMR (CDCl.sub.3) δ: 3.89 (d, J=11.3 Hz, 1H); 3.82 (d, J=11.3 Hz, 1H); 3.74-3.80 (m, 1H); 3.49-3.56 (m, 1H); 2.08 (s, 3H); 1.19 (s, 3H); 1.09-1.15 (m, 1H); 0.70-0.76 (m, 1H); 0.27-0.31 (m, 1H).

U.ii. ((1R,2R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-1-methylcyclopropyl)methyl acetate

[0426] To a solution of intermediate U.i (0.94 g; 5.92 mmol) in DCM (12 mL) was added imidazole (0.819 g; 11.9 mmol). The solution was cooled to 0° C. and TBDPSCl (1.6 mL; 6.03 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 20 min then at rt for 2.5 h. Aq. NaHSO.sub.4 (15%, 20 mL) was added. The aq. phase was extracted with DCM (10 mL). The combined org. layers were dried over MgSO.sub.4, filtered and the filtrate concentrated to dryness. The residue was purified by CC (Hept-EA) to afford the title compound as a colourless oil (2.29 g; 97% yield).

[0427] .sup.1H NMR (CDCl.sub.3) δ: 7.66-7.70 (m, 4H); 7.35-7.45 (m, 6H); 3.84 (s, 2H); 3.82-3.88 (overlapped m, 1H); 3.46-3.55 (m, 1H); 2.07 (s, 3H); 1.14 (s, 3H); 1.05 (s, 9H), 1.03-1.11 (overlapped m, 1H); 0.59-0.65 (m, 1H); 0.14-0.19 (m, 1H).

[0428] MS (ESI, m/z): 397.01 [M+H.sup.+] for C.sub.24H.sub.32O.sub.3Si; t.sub.R=1.13 min.

U.iii. ((1R,2R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-1-methylcyclopropyl)methanol

[0429] To a solution of intermediate U.ii (2.29 g; 5.77 mmol) in MeOH (50 mL) was added K.sub.2CO.sub.3 (1.59 g; 11.5 mmol). The suspension was stirred at rt for 4 h. The reaction mixture was filtered and the solid was washed with DCM. The filtrate was evaporated under reduced pressure. The residue was partitioned between water (30 mL) and DCM (40 mL). The aq. layer was extracted with DCM-MeOH 9-1 (40 mL) and EA-MeOH 9-1 (40 mL). The combined org. layers were dried over MgSO.sub.4, filtered and evaporated under reduced pressure. The residue was purified by CC (Hept-EA) to afford the title compound as a colourless oil (1.59 g; 78% yield).

[0430] .sup.1H NMR (CDCl.sub.3) δ: 7.66-7.72 (m, 4H); 7.36-7.45 (m, 6H); 3.86 (dd, J=5.8, 11.1 Hz, 1H); 3.49 (dd, J=8.7, 11.1 Hz, 1H); 3.38 (d, J=11.0 Hz, 1H); 3.30 (d, J=11.0 Hz, 1H); 1.16 (s, 3H); 1.05 (s, 9H); 0.95-1.02 (m, 1H); 0.55 (dd, J=4.8, 9.0 Hz, 1H); 0.12-0.16 (m, 1H).

U.iv. (((1R,2R)-2-(bromoethynyl)-2-methylcyclopropyl)methoxy)(tert-butyl)diphenylsilane

[0431] Starting from intermediate U.iii (1.59 g; 4.5 mmol) and proceeding successively in analogy to Preparation R, step R.ii (92% yield), Preparation M, step M.i (85% yield) and Preparation R, step R.iv (98% yield), the title compound was obtained as a yellow oil (1.48 g).

[0432] .sup.1H NMR (CDCl.sub.3) δ: 7.65-7.72 (m, 4H); 7.36-7.46 (m, 6H); 3.79 (dd, J=5.6, 11.5 Hz, 1H); 3.49 (dd, J=8.4, 11.5 Hz, 1H); 1.43-1.51 (m, 1H); 1.25 (s, 3H); 1.05 (s, 9H); 1.02 (dd, J=4.7, 9.1 Hz, 1H); 0.37 (dd, J=4.7, 6.4 Hz, 1H).

Preparation V: (3R,6S)-6-(bromoethynyl)tetrahydro-2H-pyran-3-amine hydrochloride

V.i. Tert-butyl ((3R,6S)-6-(bromoethynyl)tetrahydro-2H-pyran-3-yl)carbamate

[0433] Starting from tert-butyl ((3R,6S)-6-formyltetrahydro-2H-pyran-3-yl)carbamate (3.1 g; 13.6 mmol, prepared as described by Surivet et al. in J. Med. Chem. (2013), 56, 7396-7415) and proceeding successively in analogy to Preparation M, step M.i (68% yield) and Preparation R, step R.iv (97% yield), the title compound was obtained, after purification by CC (Hept-EA), as a white solid (2.7 g).

[0434] .sup.1H NMR (d6-DMSO) δ: 6.84 (d, J=7.6 Hz, 1H); 4.13 (dd, J=2.7, 10.1 Hz, 1H); 3.76 (dd, J=3.0, 10.5 Hz, 1H); 3.59-3.63 (m, 1H); 3.00-3.05 (m, 1H); 1.87-1.93 (m, 1H); 1.80-1.86 (m, 1H); 1.75-1.79 (m, 1H); 1.52-1.61 (m, 1H); 1.38 (s, 9H).

V.ii. ((3R,6S)-6-(bromoethynyl)tetrahydro-2H-pyran-3-amine hydrochloride

[0435] A solution of intermediate V.i. (0.5 g, 1.64 mmol) in 4M HCl in dioxane (4 mL) was stirred for 3 h. The mixture was evaporated, taken in ether (2 mL) and filtered to afford a white solid (0.353 g, 89% yield).

[0436] .sup.1H NMR (d6-DMSO) δ: 8.21-8.38 (m, 3H), 4.41 (dd, J=3.2, 7.4 Hz, 1H), 3.97 (dd, J=3.2, 11.6 Hz, 1H), 3.45 (dd, J=7.4, 11.6 Hz, 1H), 3.12-3.21 (m, 1H), 1.98-2.08 (m, 2H), 1.55-1.72 (m, 2H).

Preparation W: 3-iodo-N,N-dimethylprop-2-yn-1-amine

[0437] Starting from N,N-dimethylprop-2-yn-1-amine (1 g; 12 mmol; commercial) and proceeding in analogy to Preparation L, the title compound was obtained as a yellow solid (0.746 g; 56% yield).

[0438] .sup.1H NMR (CDCl.sub.3) δ: 3.45 (s, 2H); 2.33 (s, 6H).

Preparation X: 4-(iodoethynyl)tetrahydro-2H-pyran-4-ol

[0439] Starting from 4-ethynyltetrahydro-2H-pyran-4-ol (1.17 g; 9.33 mmol; commercial) and proceeding in analogy to Preparation L, the title iodide was obtained, after purification by CC (Hept-EA), as a yellowish solid (1.57 g, 67% yield).

[0440] .sup.1H NMR (d6-DMSO) δ: 5.64 (s, 1H); 3.64-3.74 (m, 2H); 3.40-3.51 (m, 2H); 1.68-1.79 (m, 2H); 1.51-1.62 (m, 2H).

Preparation Y: 4-(iodoethynyl)piperidine hydrochloride

Y.i. Tert-butyl 4-(iodoethynyl)piperidine-1-carboxylate

[0441] Starting from tert-butyl 4-ethynylpiperidine-1-carboxylate (0.952 g; 4.55 mmol; commercial) and proceeding in analogy to Preparation L (99% yield), the title compound was obtained as a yellow solid (1.51 g).

[0442] .sup.1H NMR (CDCl.sub.3) δ: 3.62-3.74 (m, 2H); 3.14-3.23 (m, 2H); 2.70-2.78 (m, 1H); 1.72-1.80 (m, 2H); 1.55-1.63 (m, 2H); 1.45 (s, 9H).

[0443] MS (ESI, m/z): 335.85 [M+H+] for C.sub.12H.sub.18NO.sub.2I; t.sub.R=0.93 min.

Y.ii. 4-(iodoethynyl)piperidine hydrochloride

[0444] Starting from the intermediate Y.i (0.5 g, 1.5 mmol), and proceeding in analogy to Preparation V, step V.ii, the title compound (0.365 g, 90% yield) was obtained after drying as a yellow solid.

[0445] .sup.1H NMR (d6-DMSO) δ: 8.90-9.04 (m, 2H), 3.06-3.18 (m, 2H), 2.80-2.99 (m, 3H), 1.89-1.99 (m, 2H), 1.65-1.77 (m, 2H).

Preparation Z: tert-butyl((3-(iodoethynyl)oxetan-3-yl)methoxy)diphenylsilane

Z.i. 3-(((tert-butyldiphenylsilyl)oxy)methyl)oxetane-3-carbaldehyde

[0446] Starting from oxetane-3,3-diyldimethanol (5 g; 42.3 mmol; commercial) and proceeding successively in analogy to Preparation R, step R.i (95% yield) and step R.ii (90% yield), the title compound was obtained, after purification by CC (Hept-EA), as a colourless oil (12.87 g).

[0447] .sup.1H NMR (d6-DMSO) δ: 9.82 (s, 1H); 7.59-7.62 (m, 4H); 7.44-7.50 (m, 6H); 4.66 (d, J=6.3 Hz, 2H); 4.43 (d, J=6.3 Hz, 2H); 4.15 (s, 2H); 0.98 (s, 9H).

Z.ii. Tert-butyl((3-ethynyloretan-3-yl)methoxy)diphenylsilane

[0448] A suspension of intermediate Z.i (2 g, 5.64 mmol) and K.sub.2CO.sub.3 (1.56 g, 11.3 mmol) in methanol (50 mL) was treated dropwise with with dimethyl 1-diazo-2-oxopropylphosphonate (1.19 g, 6.21 mmol; commercial). The reaction mixture was stirred at rt overnight. The solvent was evaporated and the residue was dissolve in DCM (20 mL) and water (15 mL). The aq. layer was extracted once with DCM (15 mL). The combined org. layers were washed with brine, filtered and concentrated down. The crude product was purified by CC using a Hept-EA gradient to afford the desired product as a colourless oil (1.71 g).

[0449] .sup.1H NMR (d6-DMSO): 7.64-7.72 (m, 5H); 7.43-7.53 (m, 5H); 4.59 (d, J=5.6 Hz, 2H); 4.52 (d, J=5.6 Hz, 2H); 3.89 (s, 2H); 3.45 (s, 1H); 1.04 (s, 9H).

Z.iii. Tert-butyl((3-(iodoethynyl)oxetan-3-yl)methoxy)diphenylsilane

[0450] Starting from intermediate Z.ii (2 g; 5.64 mmol) and proceeding in analogy to Preparation L (41% yield), the title compound was obtained, after purification by prep-HPLC (Method 3), as a colourless oil (0.94 g).

[0451] .sup.1H NMR (d6-DMSO) δ: 7.64-7.72 (m, 4H); 7.42-7.54 (m, 6H); 4.58 (d, J=5.8 Hz, 2H); 4.48 (d, J=5.8 Hz, 2H); 3.90 (s, 2H); 1.03 (s, 9H).

Preparation AA: cis-3-(hydroxymethyl)-1-(3-iodoprop-2-yn-1-yl)cyclobutan-1-ol

AA.i. Cis-3-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(3-(trimethylsilyl)prop-2-yn-1-yl)cyclobutan-1-ol

[0452] To a solution of 3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutan-1-one (2 g; 3.54 mmol; prepared as described in WO 2006/063281) in dry THF (5.9 mL) at rt under nitrogen atmosphere, was added a solution of trimethyl(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-yn-1-yl)silane (1.27 g; 5.32 mmol; commercial) in dry THF (5.9 mL) followed by diethylzinc (15% in toluene; 0.73 mL; 1.06 mmol). The reaction was stirred at rt for 4 h. Water (10 mL) was added carefully followed by aq. HCl (6 M, 0.3 mL) and the reaction was stirred for 15 min. The mixture was extracted with EA (3×15 mL). The combined org. layers were washed with brine (15 mL), dried over Na.sub.2SO.sub.4, filtered and the filtrate concentrated under reduced pressure. The residue was purified by CC (Hept-EA) to afford the dirty desired product as a colourless oil (2 g, quant.).

[0453] .sup.1-H NMR (d6-DMSO) δ: 7.59-7.63 (m, 4H); 7.41-7.49 (m, 6H); 5.09 (s, 1H); 3.62 (d, J=6.8 Hz, 2H); 2.31 (s, 2H); 1.88-1.99 (m, 3H); 1.22-1.31 (m, 2H); 1.00 (s, 9H); 0.07 (s, 9H).

[0454] MS (ESI, m/z): 451.0 [M+H.sup.+] for C.sub.27H.sub.38O.sub.2Si.sub.2; t.sub.R=1.14 min.

AA.ii. Cis-3-(hydroxymethyl)-1-(3-iodoprop-2-yn-1-yl)cyclobutan-1-ol

[0455] Starting from intermediate AA.i (crude, 2 g; 1.77 mmol) and proceeding successively in analogy to Preparation M, step M.ii (72% yield) and Preparation G (48% yield), the title compound was obtained, after purification by CC (Hept-EA), as a yellow oil (0.4 g) which crystallized.

[0456] .sup.1H NMR (d6-DMSO) δ: 5.06 (s, 1H); 4.45 (t, J=5.4 Hz, 1H); 3.32-3.36 (overlapped m, 2H); 2.48-2.52 (overlapped m, 1H); 1.98-2.04 (m, 2H); 1.88 (m, 1H); 1.64-1.70 (m, 2H).

[0457] MS (ESI, m/z): 266.95 [M+H.sup.+] for C.sub.8H.sub.11O.sub.2I; t.sub.R=0.52 min.

Preparation AB: 2-hydroxy-1-(4-(iodoethynyl)piperidin-1-yl)ethan-1-one

AB.i. 1-(4-ethynylpiperidin-1-yl)-2-hydroxyethan-1-one

[0458] To a solution of 4-ethynylpiperidine hydrochloride (0.720 g, 4.94 mmol, commercial) in MeCN (9.5 mL) and DMF (4.5 mL) was added TEA (3 mL, 21.5 mmol), EDC (1.17 g, 5.97 mmol), HOBT (0.935 g, 6.71 mmol) and glycolic acid (0.425 g, 5.54 mmol. The reaction mixture was stirred at rt for 20 h. The solvent was removed under reduced pressure. The residue was diluted with water (15 mL) and EA (15 mL). The two phases were separated and the aq. layer was extracted with EA (3×15 mL). The combined org. layers were washed with NaHCO.sub.3 (30 mL) and brine (30 mL), dried over MgSO.sub.4 and concentrated to dryness. The residue was purified by CC (DCM-MeOH) to afford the title product as a white solid (0.569 g).

[0459] .sup.1H NMR (300 MHz, DMSO-d6) δ: 4.44 (t, J=5.4 Hz, 1H); 4.05 (d, J=5.3 Hz, 2H); 3.80 (m, 1H); 3.47 (m, 1H); 3.05-3.18 (m, 2H); 2.95 (d, J=2.4 Hz, 1H); 2.65 (m, 1H); 1.66-1.81 (m, 2H); 1.31-1.53 (m, 2H).

AB.ii. 2-hydroxy-1-(4-(iodoethynyl)piperidin-1-yl)ethan-1-one

[0460] Starting from intermediate AB.i (0.255 g; 1.52 mmol; commercial) and proceeding in analogy to Preparation L, the title compound was obtained as a yellow solid (0.400 g; 90% yield).

[0461] MS (ESI, m/z): 293.84 [M+H+] for C.sub.9H.sub.12NO2I; t.sub.R=0.63 min.

Preparation AC: (((1R*,2R*)-2-(bromoethynyl)-2-fluorocyclopropyl)methoxy)(tert-butyl)diphenylsilane

AC.i. ((1R*,2R*)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-1-fluorocyclopropyl)methanol

[0462] To a solution of ethyl (1R *,2R *)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-1-fluorocyclopropane-1-carboxylate (7.01 g; 17.5 mmol; prepared as described in Sakagami and al., Bioorg. & Med. Chem. (2008), 16(8), 4359-4366) in THF (125 mL), cooled to −78° C., was added LiBH.sub.4 (2M in THF; 31 mL; 62 mmol) dropwise over 10 min, keeping the IT below −70° C. The reaction mixture was allowed to reach rt and stirred for 1 day. The reaction mixture was cooled to −78° C. and LiBH.sub.4 (2M in THF; 10 mL; 20 mmol) was slowly added. The cooling bath was removed and the reaction mixture was stirred for 20 h. MeOH (34 mL) was slowly added (strong gas evolution) and the reaction mixture was stirred for 20 min before concentration. The solid residue was taken up in DCM (150 mL) and water (250 mL). The phases were separated and the aq. layer was extracted with DCM (3×50 mL). The combined org. layers were washed with brine (150 mL), dried over MgSO.sub.4 and evaporated under reduced pressure to afford the title compound as a colourless oil (6.89 g; quant.).

[0463] .sup.1H NMR (CDCl.sub.3) δ: 7.67-7.71 (m, 4H); 7.36-7.45 (m, 6H); 3.89 (ddd, J=1.7, 6.0, 11.0 Hz, 1H); 3.80-3.83 (m, 1H); 3.70-3.79 (m, 2H); 1.76 (t, J=6.4 Hz, 1H); 1.25-1.33 (m, 1H); 1.06 (s, 9H); 0.79-0.88 (m, 2H).

[0464] MS (ESI, m/z): 358.95 [M+H.sup.+] for C.sub.21H.sub.27O.sub.2FSi; t.sub.R=1.01 min.

AC.ii. (1R*,2R*)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-1-fluorocyclopropane-1-carhaldehyde

[0465] Starting from intermediate AC.i (2.043 g; 5.70 mmol) and proceeding in analogy to Preparation R, step R.ii, the title compound was obtained as a colourless oil (1.687 g; 83% yield).

[0466] .sup.1H NMR (CDCl.sub.3) δ: 9.73 (d, J=5.6 Hz, 1H); 7.65-7.69 (m, 4H); 7.37-7.46 (m, 6H); 3.96 (ddd, J=1.5, 5.3, 11.4 Hz, 1H); 3.73 (ddd, J=0.7, 8.2, 11.3 Hz, 1H); 1.86-1.95 (m, 1H); 1.50 (ddd, J=6.6, 8.7, 10.5 Hz, 1H); 1.26 (ddd, J=6.6, 8.5, 18.7 Hz, 1H); 1.04 (s, 9H).

[0467] MS (ESI, m/z): 357.12 [M+H.sup.+] for C.sub.21H.sub.25O.sub.2FSi; t.sub.R=1.06 min.

AC.iii. Tert-butyl(((1R*,2R *)-2-(2,2-dibromovinyl)-2-fluorocyclopropyl)methoxy)diphenylsilane

[0468] Starting from intermediate AC.ii (1.687 g; 4.73 mmol) and proceeding in analogy to Preparation M, step M.i, the title compound was obtained as a colourless oil (0.421 g; 17% yield).

[0469] .sup.1H NMR (CDCl.sub.3) δ: 7.67-7.72 (m, 4H); 7.36-7.46 (m, 6H); 6.72 (d, J=8.7 Hz, 1H); 3.79-3.89 (m, 2H); 1.42-1.51 (m, 1H); 1.24-1.33 (m, 1H); 0.96-1.12 (overlapped m, 1H); 1.06 (s, 9H).

[0470] t.sub.R=1.16 min.

AC.iv. (((1R*,2R*)-2-(bromoethynyl)-2-fluorocyclopropyl)methoxy)(tert-butyl)dipenylsilane

[0471] Starting from intermediate AC.iii (0.421 g; 0.82 mmol) and proceeding in analogy to Preparation R, step R.iv, the title compound was obtained as a brown oil (0.351 g; 99% yield).

[0472] .sup.1H NMR (CDCl.sub.3) δ: 7.66-7.70 (m, 4H); 7.36-7.45 (m, 6H); 3.84 (ddd, J=1.6, 5.8, 11.3 Hz, 1H); 3.71 (ddd, J=1.1, 8.0, 11.3 Hz, 1H); 1.56-1.64 (m, 1H); 1.14-1.20 (m, 1H); 1.06 (s, 9H); 0.98-1.04 (m, 1H).

[0473] t.sub.R=1.13 min.

Preparation AD: ((1R*,2R*)-2-(bromoethynyl)-1-fluorocyclopropyl)methyl acetate

AD.i. ((1R*,2R*)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-1-fluorocyclopropyl)methyl acetate

[0474] Starting from intermediate AC.i (2.12 g; 5.91 mmol) and proceeding in analogy to Preparation U, step U.i, the crude product was obtained as a yellow oil (2.3 g).

[0475] .sup.1H NMR (CDCl.sub.3) δ: 7.66-7.71 (m, 4H); 7.36-7.45 (m, 6H); 4.27-4.35 (m, 2H); 3.90 (ddd, J=1.6, 5.8, 11.0 Hz, 1H); 3.69 (ddd, J=1.2, 8.3, 11.0 Hz, 1H); 2.11 (s, 3H); 1.31-1.40 (m, 1H); 1.06 (s, 9H); 0.80-0.94 (m, 2H).

[0476] MS (ESI, m/z): 400.98 [M+H.sup.+] for C.sub.12H.sub.18NO.sub.2; t.sub.R=1.09 min.

AD.ii. ((1R*,2R*)-1-fluoro-2-(hydroxymethyl)cyclopropyl)methyl acetate

[0477] To a solution of intermediate AD.i (2.16 g; 5.39 mmol) in THF (10 mL) was added TBAF (1M in THF; 7 mL). The reaction mixture was stirred at rt for 1 h. The reaction mixture was concentrated in vacuo and purified by CC (DCM-MeOH) to afford the title alcohol as a yellow oil (0.726 g; 83% yield).

[0478] .sup.1H NMR (CDCl.sub.3) δ: 4.27-4.41 (m, 2H); 3.94 (m, 1H); 3.64 (m, 1H); 2.13 (s, 3H); 1.51 (m, 1H); 1.41 (m, 1H); 0.98-1.06 (m, 2H).

AD.iii. ((1R*,2R*)-2-(bromoethynyl)-1-fluorocyclopropyl)methyl acetate

[0479] Starting from intermediate AD.ii (0.725 g; 4.46 mmol) and proceeding successively in analogy to Preparation R, step R.ii (100% yield), Preparation M, step M.i (52% yield) and Preparation R, step R.iv (57% yield), the title compound was obtained as a colourless oil (0.351 g).

[0480] .sup.1H NMR (CDCl.sub.3) δ: 6.21 (dd, J=1.3, 8.8 Hz, 1H); 4.32-4.38 (m, 2H); 2.14 (s, 3H); 1.90-1.98 (m, 1H); 1.22-1.35 (m, 2H).

Preparation AE: 1-(3-(bromoethynyl)azetidin-1-yl)-2-hydroxyethan-1-one

AE.i. Tert-butyl3-(bromoethynyl)azetidine-1-carboxylate

[0481] To a solution of tert-butyl 3-ethynylazetidine-1-carboxylate (0.5 g; 2.76 mmol; prepared as described in WO 2014/165075) and NBS (0.591 g, 3.32 mmol) in acetone (11 mL) was added AgNO.sub.3 (0.05 g, 0.29 mmol). The mixture was stirred at rt for 90 min. The reaction mixture was filtered through Celite and the filtrate was concentrated to dryness. The residue was purified by CC (Hex-TBME) to give the title compound as a colourless oil (0.673 g, 94% yield).

[0482] .sup.1H NMR (CDCl.sub.3) δ: 4.14 (m, 2H); 3.96 (dd, J=6.3, 8.4 Hz, 2H); 3.34 (m, 1H); 1.46 (s, 9H).

AE.ii. 3-(bromoethynyl)azetidine hydrochloride

[0483] Starting from intermediate AE.i (0.670 g, 2.58 mmol) and proceeding in analogy to Preparation V, step V.ii, the title compound was obtained, after trituration in Et.sub.2O, as an off-white solid (0.49 g; 97% yield).

[0484] .sup.1H NMR (CDCl.sub.3) δ: 9.10-9.44 (m, 2H); 4.06-4.15 (m, 2H); 3.87-3.96 (m, 2H); 3.74 (m, 1H).

[0485] MS (ESI, m/z): 162.0 [M+H.sup.+] for C.sub.5H.sub.6NBr; t.sub.R=0.23 min.

AE.iii. 1-(3-(bromoethynyl)azetidin-1-yl)-2-hydroxyethan-1-one

[0486] To a solution of intermediate AE.ii (0.49 g; 2.48 mmol) in DMF (5 mL) were added successively HOBT (0.7 g; 5.05 mmol), TEA (1.21 mL; 8.69 mmol), glycolic acid (0.2 g; 2.63 mmol) and EDC (0.85 g; 4.38 mmol). The reaction mixture was diluted with DMF (4 mL) and the reaction mixture was stirred at 60° C. for 90 min. The solvent was removed in vacuo and the residue was partitioned between brine (20 mL) and EA-MeOH (9-1; 30 mL). The aq. layer was extracted with EA-MeOH (9-1; 4×20 mL). The org. layer was dried over Na.sub.2SO.sub.4, filtered and concentrated to dryness. The residue was purified by CC (Hept-EA) to afford the title compound as an off-white solid (0.32 g, 60% yield).

[0487] .sup.1H NMR (d6-DMSO) δ: 4.97 (t, J=6.1 Hz, 1H); 4.40 (t, J=8.7 Hz, 1H); 4.11 (m, 2H), 3.89 (d, J=6.0 Hz, 2H); 3.77 (dd, J=6.2, 9.0 Hz, 1H); 3.55 (m, 1H).

[0488] MS (ESI, m/z): 220.1 [M+H.sup.+] for C.sub.7H.sub.8NO.sub.2Br; t.sub.R=0.48 min.

Preparation AF: ((1S,2S)-2-(bromoethynyl)-1-methylcyclopropyl)methyl acetate

AF.i. (R,E)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-methylallyl acetate

[0489] To a solution of (R,E)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-methylprop-2-en-1-ol (1.4 g; 8.1 mmol; prepared as reported in Smith III et al., Tetrahedron (2009), 65(33), 6470-6488) in THF (48 mL) was added TEA (2.8 mL; 20.1 mmol). Then AcCl (1.2 mL; 16.5 mmol) was added dropwise over 10 min at 0° C. The reaction mixture was stirred at 0° C. for 2 h. The reaction mixture was poured into water (80 mL) and extracted with EA (3×50 mL). The combined org. layers were dried over MgSO.sub.4, filtered and the filtrate concentrated under reduced pressure. The crude product was purified by CC (PE-EA) to afford the title compound as a colourless oil (1.64 g; 94% yield).

[0490] .sup.1H NMR (CDCl.sub.3) δ: 5.48-5.51 (m, 1H); 4.79-4.84 (m, 1H); 4.44-4.52 (m, 2H); 4.07-4.11 (m, 1H); 3.55 (t, J=8.0 Hz, 1H); 2.09 (s, 3H); 1.75 (d, J=1.3 Hz, 3H); 1.43 (s, 3H); 1.40 (s, 3H).

AF.ii. ((1S,2S)-2-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-1-methylcyclopropyl)methyl acetate

[0491] To a mechanically stirred solution of intermediate AF.i (1.64 g; 7.65 mmol) in toluene (102 mL), cooled to −25° C., was added dropwise ZnEt.sub.2 (15% in toluene; 34.5 mL; 38.3 mmol) over 20 min, keeping IT below −20° C. Then diiodomethane (6.5 mL; 79.9 mmol) was added dropwise over 10 min, keeping IT below −20° C. The reaction mixture was stirred at −20° C. for 2 h, then allowed to slowly warm up to rt and stirred overnight. The reaction mixture was quenched with sat. aq. NH.sub.4Cl (33 mL) and extracted with Et.sub.2O (4×30 mL). The combined org. layers were washed with sat. aq. Na.sub.2S.sub.2O.sub.3 (30 mL), water (30 mL) and brine (30 mL), then dried over MgSO.sub.4 and filtered. After evaporation of the filtrate under reduced pressure, a yellow oil (22.4 g) was obtained. The crude product was purified by CC (PE-EA) to afford the title compound as a colourless oil (1.4 g; 80% yield).

[0492] .sup.1H NMR (CDCl.sub.3) δ: 4.09 (dd, J=5.9, 7.9 Hz, 1H); 3.89 (d, J=11.3 Hz, 1H); 3.77 (d, J=11.3 Hz, 1H); 3.70-3.76 (overlapped m, 1H); 3.61-3.66 (m, 1H); 2.07 (s, 3H); 1.45 (s, 3H); 1.36 (s, 3H); 1.13 (s, 3H); 0.85-0.95 (m, 2H); 0.56 (t, J=5.0 Hz, 1H).

AF.iii. ((1S,2S)-2-((R)-1,2-dihydroxyethyl)-1-methylcyclopropyl)methyl acetate

[0493] A mixture of intermediate AF.ii (1.4 g; 6.1 mmol) in AcOH (80%; 14 mL) was stirred at rt for 23 h. The mixture was added to sat. aq. NaHCO.sub.3 (100 mL; pH 6-7) and the aq. layer was extracted with DCM (3×60 mL). The combined org. layers were washed with water (10 mL) and brine (20 mL), dried over MgSO.sub.4, filtered and concentrated to dryness. The residue was co-evaporated with cyclohexane. The crude product was purified by CC (DCM-MeOH) to afford the title compound as a colourless oil (1 g; 87% yield).

[0494] .sup.1H NMR (CDCl.sub.3) δ: 3.89 (d, J=11.3 Hz, 1H); 3.74 (d, J=11.3 Hz, 1H); 3.68 (dd, J=3.4, 11.2 Hz, 1H); 3.57 (dd, J=7.4, 11.2 Hz, 1H); 3.33-3.39 (m, 1H); 2.07 (s, 3H); 1.16 (s, 3H); 0.89 (td, J=5.7, 9.0 Hz, 1H); 0.80 (dd, J=4.9, 8.8 Hz, 1H); 0.48 (t, J=5.3 Hz, 1H).

AF.iv. ((1S,2S)-2-formyl-1-methylcyclopropyl)methyl acetate

[0495] To a solution of intermediate AF.iii (1 g; 5.3 mmol) in THF (16.5 mL), water (3.4 mL) and sat. aq. NaHCO.sub.3 (1.6 mL), cooled to 0° C., was added NaIO.sub.4 (1.48 g; 6.9 mmol). The reaction mixture was stirred at 0° C. for 30 min, then filtered and the precipitate washed with Et.sub.2O. The layers were separated and the aq. layer was extracted with Et.sub.2O (3×40 mL). The combined org. layers were dried over MgSO.sub.4, filtered and concentrated to dryness. The title compound was obtained as a colourless oil (0.81 g; 98% yield).

[0496] .sup.1H NMR (CDCl.sub.3) δ: 9.47 (d, J=4.7 Hz, 1H); 4.00 (d, J=11.4 Hz, 1H); 3.85 (d, J=11.4 Hz, 1H); 2.09 (s, 3H); 1.92-1.97 (m, 1H); 1.39 (t, J=5.3 Hz, 1H); 1.32 (s, 3H); 1.21 (dd, J=5.0, 8.3 Hz, 1H).

AF.v. ((1S,2S)-2-(bromoethynyl)-1-methylcyclopropyl)methyl acetate

[0497] Starting from intermediate AF.iv (0.81 g; 5.19 mmol) and proceeding successively in analogy to Preparation M, steps M.i (81% yield) and M.ii (62% yield), the title compound was obtained, after purification by CC (PE/TBME), as a colourless oil (0.6 g).

[0498] .sup.1H NMR (CDCl.sub.3) δ: 3.89 (d, J=11.4 Hz, 1H); 3.80 (d, J=11.4 Hz, 1H); 2.07 (s, 3H); 1.39 (dd, J=5.5, 8.9 Hz, 1H); 1.27 (s, 3H); 0.94 (dd, J=4.8, 8.9 Hz, 1H); 0.65 (t, J=5 1 Hz, 1H).

Preparation AG: ((1R,2R)-2-(bromoethynyl)-1-fluorocyclopropyl)methyl benzoate

AG.i. ((1R*,2R*)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-1-fluorocyclopropyl)methanol

[0499] To a solution of ethyl (1R*,2R*)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-1-fluorocyclopropyl)methanol 1-fluorocyclopropane-1-carboxylate (0.5 g; 1.25 mmol; prepared as described in Sakagami et al., Bioorg. Med Chem. (2008), 16(8), 4359-4366) in TRF (9 mL), cooled to −78° C., was added dropwise LiBH.sub.4 (2M in THF; 2.2 mL; 4.4 mmol). The reaction mixture was allowed to reach rt and stirred at rt for 24 h. MeOH (2 mL) was carefully added, the reaction mixture was stirred for 20 min, concentrated to dryness and partitioned between water (10 mL) and DCM (15 mL). The aq. layer was extracted with DCM (2×10 mL). The combined org. layers were dried over Na.sub.2SO.sub.4 and filtered. After concentration of the filtrate to dryness, the title compound was obtained as a colourless oil (0.429 g; 96% yield).

[0500] .sup.1H NMR (CDCl.sub.3) δ: 7.66-7.72 (m, 4H); 7.36-7.45 (m, 6H); 3.89 (ddd, J=1.6, 6.0, 11.0 Hz, 1H); 3.80-3.83 (m, 1H); 3.70-3.78 (m, 2H); 1.74 (t, J=6.4 Hz, 1H); 1.24-1.33 (m, 1H); 1.05 (s, 9H); 0.79-0.88 (m, 2H).

[0501] MS (ESI, m/z): 358.95 [M+H.sup.+] for C.sub.21I.sup.H.sub.27O.sub.2FSi; t.sub.R=1.01 min.

AG.ii. ((1R*,2R*)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-1-fluorocyclopropyl)methyl benzoate

[0502] To a solution of intermediate AG.i (5.51 g, 15.4 mmol) in THF (93 mL) was added TEA (6 mL; 43.1 mmol). Benzoyl chloride (3.6 mL; 30.7 mmol) was added dropwise over 2 min at 0° C. The reaction mixture was stirred at 0° C. for 5 h before being poured onto water (75 mL). The aq. layer was extracted with EA (3×50 mL). The combined org. layers were dried over MgSO.sub.4 and concentrated to dryness. The residue was purified by CC (Hept-EA) to afford the title compound as a colourless oil (6.49 g; 91% yield).

[0503] .sup.1H NMR (CDCl.sub.3) δ: 8.09-8.12 (m, 2H); 7.67-7.70 (m, 4H); 7.56 (m, 1H); 7.40-7.44 (m, 4H); 7.35-7.38 (m, 4H); 4.62 (m, 1H); 4.51 (ddd, J=1.1, 13.0, 23.8 Hz, 1H); 3.93 (ddd, J=1.5, 5.6, 11.0 Hz, 1H); 3.70 (ddd, J=1.1, 8.4, 10.9 Hz, 1H); 1.46 (m, 1H); 1.30 (m, 1H); 1.02 (s, 7H); 0.97 (m, 1H); 0.84-0.91 (m, 2H).

[0504] MS (ESI, m/z): 463.07 [M+H.sup.+] for C.sub.28H.sub.31O.sub.3FSi; t.sub.R=1.14 min.

AG.iii. ((1R*,2R*)-1-fluoro-2-(hydroxymethyl)cyclopropyl)methyl benzoate

[0505] To a solution of intermediate AG.ii (6.49 g; 14 mmol) in THF (26 mL) was added TBAF (1M in THF, 17 mL). The reaction mixture was stirred at rt for 45 min. The reaction mixture was concentrated in vacuo and the residue was purified by CC (DCM-MeOH) to afford the title compound (2.81 g; 89% yield) as a yellow oil.

[0506] .sup.1H NMR (CDCl.sub.3) δ: 8.08-8.10 (m, 2H); 7.58 (m, 1H); 7.45-7.48 (m, 2H); 4.64 (m, 1H); 4.55 (m, 1H); 3.97 (ddd, J=1.5, 5.8, 11.8 Hz, 1H); 3.68 (ddd, J=1.4, 8.7, 11.8 Hz, 1H); 1.52 (m, 1H); 1.04-1.12 (m, 2H).

AG.iv. ((1R,2R)-2-(2,2-dibromovinyl)-1-fluorocyclopropyl)methyl benzoate

[0507] Starting from intermediate AG.iii (2.77 g; 12.4 mmol) and proceeding successively in analogy to Preparation R, step R.ii (84% yield) and Preparation M, step M.i (77% yield), a mixture of enantiomers (2.71 g) was obtained. After separation by semi-preparative chiral HPLC Method B (Hept-EtOH 3-7; flow rate: 16 mL/min, UV detection at 224 nM), the title enantiomer (first-eluting enantiomer) was obtained as a white solid (1 25 g). The retention time on analytical chiral HPLC (flow rate 0.80 mL/min) was 5.3 min.

[0508] .sup.1H NMR (d6-DMSO) δ: 7.99-8.01 (m, 2H); 7.69 (m, 1H); 7.54-7.58 (m, 2H); 6.38 (dd, J=1.4, 8.9 Hz, 1H); 4.57-4.75 (m, 2H); 2.09 (m, 1H); 1.48-1.55 (m, 2H).

AG.v. ((1R,2R)-2-(bromoethynyl)-1-fluorocyclopropyl)methyl benzoate

[0509] To a solution of intermediate AG.iv (2.05 g, 5.42 mmol) in THF (20 mL) was added TBAF (1M in THF, 22 mL; 21.7 mmol). The mixture was stirred overnight. The reaction mixture was diluted with EA (50 mL) and water (30 mL). The two layers were separated and the org. layer was extracted with EA (3×50 mL). The evaporation residue was purified by CC (Hept-EA) to afford the title compound as a yellowish oil (1.1 g; 68% yield).

[0510] .sup.1H NMR (d6-DMSO) δ: 7.99-8.03 (m, 2H); 7.70 (m, 1H); 7.55-7.60 (m, 2H); 4.51-4.67 (m, 2H); 2.04-2.09 (m, 1H); 1.37-1.49 (m, 2H).

Reference Example 1

(RS)-N-hydroxy-4-(6-(4-methoxyphenyl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide

[0511] A sealed tube was charged with the compound of Preparation A (0.194 g, 0.395 mmol), 4-methoxyphenylboronic acid (0.101 g, 0.592 mmol, commercial), bis(tri-tert-butylphosphine)palladium(0) (0.0127 g, 0.0249 mmol) and degassed TEA (0.0974 mL, 0.701 mmol). Dioxane (3 mL) was added and the mixture was refluxed under an Argon atmosphere for 2 h. The mixture was diluted with EA (50 mL) and water (50 mL). The org. phase was dried over MgSO.sub.4 and concentrated to dryness. The crude residue was purified by prep-HPLC (Method 2) to afford the title compound as a yellow solid (0.04 g, 23% yield).

[0512] .sup.1H NMR (d6-DMSO) δ: 8.27-8.34 (m, 1H); 7.92-8.00 (m, 1H); 7.70-7.79 (m, 1H); 7.65-7.70 (m, 2H); 7.00-7.08 (m, 2H); 3.79 (s, 3H); 3.17-3.25 (m, 1H); 3.06 (s, 3H); 2.88-3.02 (m, 1H); 2.70-2.83 (m, 1H); 2.17-2.31 (m, 1H); 1.55 (s, 3H).

[0513] MS (ESI, m/z): 435.1 [M+H.sup.+] for C.sub.20H.sub.22N.sub.2O.sub.5S.sub.2; t.sub.R=0.69 min.

Reference Example 2

(RS)-N-hydroxy-4-(6-((4-(hydroxymethyl)phenyl)ethynyl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide

RE2.i. (RS)-tert-butyl 4-(6-((4-(hydroxymethyl)phenyl)ethynyl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanoate

[0514] To a solution of the compound of Preparation C (0.198 g, 0.503 mmol) in degassed THF (5 mL) were added 4-iodobenzyl alcohol (0.118 g, 0.503 mmol, commercial), CuI (24.7 mg, 0.13 mmol), TEA (0.245 mL, 3.5 mmol) and PdCl.sub.2(PPh.sub.3).sub.2 (0.038 g, 0.0553 mmol). The mixture was stirred at rt for 3 h. The mixture was then concentrated to dryness and purified by CC (Hept-EA) to afford the title compound as a yellow solid (0.203 g, 81% yield).

[0515] .sup.1H NMR (d6-DMSO) δ: 8.32 (d, J=1.1 Hz, 1H); 7.98 (d, J=8.4 Hz, 1H); 7.64 (dd, J=1.5, 8.4 Hz, 1H); 7.50-7.56 (m, 2H); 7.34-7.42 (m, 2H); 5.28 (t, J=5.8 Hz, 1H); 4.54 (d, J=5.8 Hz, 2H); 3.30-3.42 (overlapped m, 1H); 3.14 (s, 3H); 2.95-3.11 (overlapped m, 1H); 2.53-2.75 (m, 1H); 2.24-2.43 (m, 1H); 1.57 (s, 3H); 1.45 (s, 9H).

[0516] MS (ESI, m/z): 500.1 [M+H.sup.+] for C.sub.26H.sub.29NO.sub.5S.sub.2; t.sub.R=0.95 min.

RE2.ii. (RS)-4-(6-((4-(hydroxymethyl)phenyl)ethynyl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanoic acid

[0517] To a solution of intermediate RE2.i (0.186 g, 0.372 mmol) in dioxane (4.8 mL) and water (0.34 mL) was added a HCl solution (4M in dioxane, 2.8 mL). The mixture was stirred at rt overnight. The mixture was then concentrated to dryness and the residue was triturated in water (5 mL) and filtered. The solid was triturated in EA (3 mL), filtered and dried to afford the title product as a yellow solid (0.08 g, 48% yield).

[0518] .sup.1H NMR (d6-DMSO) δ: 8.28-8.32 (m, 1H); 7.94-7.99 (m, 2H); 7.64 (dd, J=1.3, 8.6 Hz, 1H); 7.50-7.56 (m, 2H); 7.35-7.41 (m, 2H); 4.54 (br. s, 2H); 3.31-3.41 (overlapped m, 1H); 3.15 (s, 3H); 3.02-3.14 (overlapped m, 1H); 2.62-2.74 (m, 1H); 2.27-2.45 (m, 1H): 1.58 (m, 3H).

[0519] MS (ESI, m/z): 444.2 [M+H.sup.+] for C.sub.22H.sub.21NO.sub.5S.sub.2; t.sub.R=0.77 min.

RE2.iii. Rac-4-(6-((-4-(hydroxymethyl)phenyl)ethynyl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)-N-(((RS)-tetrahydro-2H-pyran-2-yl)oxy)butanamide

[0520] Starting from intermediate RE2.ii (0.08 g, 0.18 mmol), and proceeding in analogy to Preparation A, step A.iv, the title compound was obtained, after purification by CC (Hept-EA), as a colourless oil (0.03 g; 31% yield).

[0521] .sup.1H NMR (d6-DMSO) δ: 11.38 (s, 1H); 8.27-8.30 (m, 1H); 7.95 (d, J=8.4 Hz, 1H); 7.61-7.66 (m, 1H); 7.53 (d, J=8.0 Hz, 2H); 7.36 (d, J=8.0 Hz, 2H); 5.26 (t, J=5.7 Hz, 1H); 4.91-5.00 (m, 1H); 4.54 (d, J=5.7 Hz, 2H); 3.98-4.20 (m, 1H); 3.31-3.51 (m, 1H); 3.17-3.30 (overlapped m, 1H); 3.06 (s, 1.5H); 3.08 (s, 1.5H); 2.93-3.04 (overlapped m, 1H); 2.68-2.81 (m, 1H); 2.18-2.31 (m, 1H); 1.47-1.71 (m, 9H).

[0522] MS (ESI, m/z): 543.22 [M+H.sup.+] for C.sub.27H.sub.30N.sub.2O.sub.6S.sub.2; t.sub.R=0.84 min.

RE2.iv. (RS)-N-hydroxy-4-(6-((4-(hydroxymethyl)phenyl)ethynyl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide

[0523] To a solution of intermediate RE2.iii (0.027 g, 0.05 mmol) in EtOH (1 mL) was added pyridinium p-toluenesulfonate (0.07 g, 0.25 mmol). The mixture was stirred at 80° C. for 2 h. Water (1 mL) was added. The mixture was cooled to 0° C. and stirred for 30 min at this temperature. The precipitate was filtered, washed with EtOH (1 mL) and dried to afford the title compound as an off-white solid (0.018 g, 80% yield).

[0524] .sup.1H NMR (d6-DMSO) δ: 10.98 (m, 1H); 9.21 (m, 1H); 8.29 (d, J=0.9 Hz, 1H); 7.95 (d, J=8.4 Hz, 1H); 7.62 (m, 1H); 7.52 (d, J=8.1 Hz, 2H); 7.36 (d, J=8.1 Hz, 2H); 5.26 (t, J=6 Hz, 1H); 4.51 (d, J=6 Hz, 2H); 3.15-3.25 (overlapped m, 1H); 3.05 (m, 3H); 2.86-3.00 (overlapped m, 1H); 2.68-2.83 (m, 1H); 2.16-2.30 (m, 1H); 1.55 (s, 3H).

[0525] MS (ESI, m/z): 459.13 [M+H.sup.+] for C.sub.22H.sub.22N.sub.2O.sub.5S.sub.2; t.sub.R=0.71 min.

Reference Example 3

(RS)-4-(6-((4-(3-aminooxetan-3-yl)phenyl)ethynyl)-benzo[d]thiazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 4-methyl-benzenesulfonate

[0526] Starting from the compound of Preparation E (0.1 g, 0.229 mmol) and the compound of Preparation D (0.070 g, 0.228 mmol) and proceeding in analogy to Reference Example 2, steps RE2.i and RE2.iv (yields: Sonogashira coupling 71%; deprotection 46%), the title compound was obtained as a yellow solid (0.050 g).

[0527] .sup.1H NMR (d6-DMSO) δ: 11.01 (s, 1H); 9.24 (s, 1H); 8.35 (s, 1H); 8.00 (d, J=8.4 Hz, 1H); 7.56-7.76 (m, 5H); 7.47 (d, J=7.9 Hz, 2H); 7.11 (d, J=7.9 Hz, 2H); 4.87-4.99 (m, 4H); 3.21-3.30 (overlapped m, 1H); 3.07 (s, 3H); 2.91-3.03 (m, 1H); 2.71-2.84 (m, 1H); 2.18-2.28 (overlapped m, 1H); 2.30 (s, 3H); 1.57 (m, 3H).

[0528] MS (ESI, m/z): 541.1 [M+CH.sub.3CN.sup.+] for C.sub.24H.sub.25N.sub.3O.sub.5S.sub.2; t.sub.R=0.46 min.

Reference Example 4

(RS)-N-hydroxy-4-(6-(5-hydroxypenta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide

[0529] Starting from the compound of Preparation E (0.3 g, 0.687 mmol) and 3-iodoprop-2-yn-1-ol (0.175 g, 0.962 mmol) and proceeding in analogy to Reference Example 2, steps RE2.i and RE2.iv (yields: Sonogashira coupling 23%; deprotection 61%), the title compound was obtained as a beige solid (0.015 g).

[0530] .sup.1H NMR (d6-DMSO) δ: 11.03 (s, 1H), 9.26 (s, 1H), 8.37 (s, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 5.50 (t, J=5.8 Hz, 1H), 4.28 (d, J=5.8 Hz, 2H), 3.24-3.32 (m, 1H), 3.08 (s, 3H), 2.92-3.02 (m, 1H), 2.74-2.82 (m, 1H), 2.21-2.31 (m, 1H), 1.56 (s, 3H).

[0531] MS (ESI, m/z): 406.7 [M+H.sup.+] for C.sub.20H.sub.22N.sub.2O.sub.5S.sub.2; t.sub.R=0.66 min.

Examples of Compounds According to the Invention

Example 1

(R)-N-hydroxy-4-(6-((3-hydroxyoxetan-3-yl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide

1.i. (RS)-4-(6((3-hydroxyoxetan-3-yl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)butanamide

[0532] Starting from the compound of Preparation E (0.5 g, 1.15 mmol) and the compound of Preparation F (0.282 g, 1.26 mmol) and proceeding in analogy to Reference Example 2, steps RE2.i and RE2.iv (yields: Sonogashira coupling 51%; deprotection 78%), the title compound (0.197 g) was obtained as a grey solid.

[0533] .sup.1H NMR (d6-DMSO) δ: 11.01 (s, 1H); 9.14-9.29 (m, 1H); 8.37-8.40 (m, 1H); 7.98 (d, J=8.4 Hz, 1H); 7.67 (dd, J=1.5, 8.4 Hz, 1H); 6.66-6.85 (m, 1H); 4.70-4.75 (m, 2H); 4.53-4.59 (m, 2H); 3.20-3.31 (m, 1H); 3.07 (s, 3H); 2.91-3.02 (overlapped m, 1H); 2.70-2.83 (m, 1H); 2.19-2.32 (m, 1H); 1.56 (s, 3H).

[0534] MS (ESI, m/z): 449.1 [M+H.sup.+] for C.sub.20H.sub.20N.sub.2O.sub.6S.sub.2; t.sub.R=0.66 min.

1.ii. (R)-N-hydroxy-4-(6-((3-hydroxyoxetan-3-yl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide

[0535] Intermediate 1.i (0.197 g) was separated by semi-preparative chiral HPLC Method A (DCM-MeOH-TFA-DEA 10-90-0.09-0.036; flow rate: 20 mL/min; UV detection at 297 nM); the respective retention times (flow rate: 1 mL/min) were 4.98 and 7.27 min. The title (R)-enantiomer, identified as the first eluting compound, was obtained as a beige solid (0.053 g). .sup.1H NMR (d6-DMSO) δ: 11.01 (s, 1H); 9.14-9.29 (m, 1H); 8.37-8.40 (m, 1H); 7.98 (d, J=8.4 Hz, 1H); 7.67 (dd, J=1.5, 8.4 Hz, 1H); 6.66-6.85 (m, 1H); 4.73 (d, J=6.7 Hz, 2H); 4.56 (d, J=6.7 Hz, 2H); 3.20-3.31 (m, 1H); 3.07 (s, 3H); 2.91-3.02 (overlapped m, 1H); 2.70-2.83 (m, 1H); 2.19-2.32 (m, 1H); 1.56 (s, 3H).

[0536] MS (ESI, m/z): 449.1 [M+H.sup.+] for C.sub.20H.sub.20N.sub.2O.sub.6S.sub.2; t.sub.R=0.66 min.

Example 2

(R)-4-(6-(2-fluoro-4-methoxyphenyl)benzo[d]thiazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

[0537] Starting from the compound of Preparation G (0.15 g, 0.305 mmol) and 2-fluoro-4-methoxyphenylboronic acid (0.078 g, 0.458 mmol; commercial) and proceeding in analogy to Reference Example 1, the title compound was obtained, after purification by prep-HPLC (Method 2), as a white solid (0.104 g, 74% yield).

[0538] .sup.1H NMR (d6-DMSO) δ: 11.00 (s, 1H); 9.27 (s, 1H); 8.21 (s, 1H); 8.01 (d, J=8.5 Hz, 1H); 7.62 (dt, J=1.7, 8.5 Hz, 1H); 7.53 (t, J=9.0 Hz, 1H); 6.98 (dd, J=2.5, 13.0 Hz, 1H); 6.92 (dd, J=2.5, 8.6 Hz, 1H); 3.83 (s, 3H); 3.20-3.30 (m, 1H); 3.08 (s, 3H); 2.89-3.00 (m, 1H); 2.73-2.83 (m, 1H); 2.20-2.30 (m, 1H); 1.56 (s, 3H).

[0539] MS (ESI, m/z): 453.1 [M+H.sup.+] for C.sub.20H.sub.21N.sub.2O.sub.5FS.sub.2; t.sub.R=0.78 min.

Example 3

(R)-N-hydroxy-4-(6-((4-(3-hydroxyoxetan-3-yl)phenyl)ethynyl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide

[0540] Starting from the compound of Preparation I (0.060 g, 0.137 mmol) and the compound of Preparation J (0.053 g, 0.194 mmol) and proceeding in analogy to Reference Example 2, steps RE2.i and RE2.iv (yields: Sonogashira coupling 65%; deprotection 55%), the title product was obtained as an orange solid (0.024 g).

[0541] .sup.1H NMR (d6-DMSO) δ: 11.04 (s, 1H); 9.27 (s, 1H); 8.34 (s, 1H); 7.99 (d, J=8.4 Hz, 1H); 7.66 (m, 5H); 6.49 (s, 1H); 4.80 (d, J=6.4 Hz, 2H); 4.69 (d, J=6.4 Hz, 2H); 3.23-3.31 (m, 1H); 3.09 (s, 3H); 2.92-3.01 (m, 1H); 2.79 (td, J=4.3 12.5 Hz, 1H); 2.20-2.29 (m, 1H); 1.57 (s, 3H).

[0542] MS (ESI, m/z): 500.8 [M+H.sup.+] for C.sub.20H.sub.22N.sub.2O.sub.5S.sub.2; t.sub.R=0.70 min.

Example 4

(R)-N-hydroxy-4-(6-(5-hydroxy-5-methylhexa-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide

[0543] Starting from the compound of Preparation H (0.060 g, 0.137 mmol) and the compound of Preparation J (0.034 g, 0.165 mmol) and proceeding in analogy to Reference Example 2, steps RE2.i and RE2.iv (yields: Sonogashira coupling 56%; deprotection 42%), the title compound was obtained, after purification by prep-HPLC (Method 2), as a yellow solid (0.014 g).

[0544] .sup.1H NMR (d6-DMSO) δ: 10.85-11.29 (m, 1H); 9.20-9.32 (m, 1H); 8.33-8.38 (m, 1H); 7.97 (d, J=8.4 Hz, 1H); 7.65 (d, J=8.4 Hz, 1H); 5.69 (s, 1H); 3.23-3.31 (m, 1H); 3.08 (s, 3H); 2.91-3.01 (m, 1H); 2.73-2.82 (m, 1H); 2.21-2.30 (m, 1H); 1.56 (s, 3H); 1.44 (s, 6H).

[0545] MS (ESI, m/z): 434.9 [M+H.sup.+] for C.sub.20H.sub.22N.sub.2O.sub.5S.sub.2; t.sub.R=0.71 min.

Example 5

(R)-4-(6-((S)-5,6-dihydroxyhexa-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

[0546] Starting from the compound of Preparation H (0.060 g, 0.137 mmol) and the compound of Preparation K (0.040 g, 0.192 mmol) and proceeding in analogy to Reference Example 2, steps RE2.i and RE2.iv (yields: Sonogashira coupling 80%; deprotection 14%), the title compound was obtained, after purification by prep-HPLC (Method 2), as a yellowish foam (0.008 g).

[0547] .sup.1H NMR (d6-DMSO) δ: 10.5-11.3 (s, 1H); 9.09-9.45 (s, 1H); 8.37 (s, 1H); 7.97 (d, J=8.5 Hz, 1H); 7.65 (d, J=8.5 Hz, 1H); 5.73 (d, J=6 Hz, 1H); 5.08 (t, J=6 Hz, 1H); 4.36 (q, J=5.8 Hz, 1H); 3.48 (t, J=5.8 Hz, 2H); 3.24-3.30 (m, 1H); 3.06 (s, 3H); 2.92-3.01 (m, 1H); 2.73-2.81 (m, 1H); 2.25 (d, J=4.8 Hz, 1H); 1.56 (s, 3H).

[0548] MS (ESI, m/z): 436.9 [M+H.sup.+] for C.sub.19H.sub.20N.sub.2O.sub.6S.sub.2; t.sub.R=0.59 min.

Example 6

(R)-4-(6-(5-amino-5-methylhexa-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

[0549] Starting from the compound of Preparation H (0.100 g, 0.229 mmol) and the compound of Preparation L (0.060 g, 0.287 mmol) and proceeding in analogy to Reference Example 2, steps RE2.i and RE2.iv (yields: Sonogashira coupling 47%; deprotection 56%), the title compound was obtained after precipitation in water, as a beige solid (0.026 g).

[0550] .sup.1H NMR (d6-DMSO) δ: 9.33 (s, 1H); 8.32 (s, 1H); 7.96 (d, J=8.5 Hz, 1H); 7.62 (d, J=8.5 Hz, 1H); 3.22-3.32 (m, 1H); 3.07 (s, 3H); 2.92-3.0 (m, 1H); 2.71-2.80 (m, 1H); 2.20-2.29 (m, 1H); 1.56 (s, 3H); 1.34 (s, 6H).

[0551] MS (ESI, m/z): 416.9 [M+H.sup.+] for C.sub.20H.sub.23N.sub.3O.sub.4S.sub.2; t.sub.R=0.56 min.

Example 7

(R)-N-hydroxy-4-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide:

7.i. ((1S,2S)-2-((2-(3-methyl-3-(methylsulfonyl)-4-oxo-4-(((tetrahydro-2H-pyran-2-yl)oxy)amino)butyl)benzo[d]thiazol-6yl)buta-1,3-diyn-1-yl)cyclopropyl)methyl acetate

[0552] Starting from the compound of Preparation H (0.3 g, 0.687 mmol) and the compound of Preparation M ((S,S)-enantiomer, 156 mg, 0.719 mmol) and proceeding in analogy to Reference Example 2, step RE2.i, the title compound was obtained, after purification by CC (Hept-EA), as a white solid (0.126 g, 32% yield).

[0553] .sup.1H NMR (d6-DMSO) δ: 11.43 (m, 1H); 8.32 (s, 1H); 7.95 (d, J=8.5 Hz, 1H); 7.61 (dd, J=1.2, 8.4 Hz, 1H); 4.94-4.97 (m, 1H); 3.96-4.14 (m, 2H); 3.84 (dd, J=7.6, 11.7 Hz, 1H); 3.46-3.53 (m, 1H); 3.24-3.30 (m, 1H); 3.08 (s, 1.5H); 3.06 (s, 1.5H); 2.96-3.05 (m, 1H); 2.76-2.81 (m, 1H); 2.22-2.31 (m, 1H); 2.05 (s, 3H); 1.50-1.71 (m, 9H); 1.22-1.29 (m, 1H); 1.05-1.10 (m, 1H); 0.95-1.00 (m, 1H); 0.84-0.88 (t, J=6.7 Hz, 1H).

[0554] MS (ESI, m/z): 572.9 [M+H.sup.+] for C.sub.28H.sub.32N.sub.2O.sub.7S.sub.2; t.sub.R=0.94 min.

7.ii. 4-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylszdfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)butanamide

[0555] To a solution of intermediate 7.i (0.100 g, 0.175 mmol) in MeOH (1.1 mL) was added K.sub.2CO.sub.3 (0.048 g, 0.349 mmol). The suspension was stirred at rt for 40 min. The mixture was diluted with DCM (20 mL) and washed with 15% aq. NaHSO.sub.4 solution (10 mL). The aq. layer was extracted with DCM-MeOH (9:1, 2×20 mL). The combined org. layers were dried over MgSO.sub.4 and concentrated to dryness. The crude residue was purified by CC (DCM-MeOH) to afford the title compound as a yellow oil (0.089 g, 97% yield).

[0556] .sup.1H NMR (d6-DMSO) δ: 11.44 (s, 1H); 8.31 (s, 1H); 7.94 (d, J=8.5 Hz, 1H); 7.59-7.60 (m, 1H); 4.91-4.97 (s, 1H); 4.72 (t, J=5.7 Hz, 1H); 4.05-4.11 (m, 1H); 3.41-3.51 (m, 2H); 3.22-3.29 (m, 2H); 3.08 (s, 1.5H); 3.06 (s, 1.5H); 2.97-3.05 (m, 1H); 2.69-2.80 (m, 1H); 2.20-2.30 (m, 1H); 1.40-1.76 (m, 11H); 0.92-0.97 (m, 1H); 0.91 (m, 1H).

[0557] MS (ESI, m/z): 530.9 [M+H.sup.+] for C.sub.26H.sub.30N.sub.2O.sub.6S.sub.2; t.sub.R=0.85 min.

7.iii. (R)-N-hydroxy-4-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide

[0558] Starting from intermediate 7.ii (0.090 g, 0.169 mmol) and proceeding in analogy to Reference Example 2, step RE2.iv, the title compound was obtained, after precipitation in water, as a yellow solid (0.048 g, 64% yield).

[0559] .sup.1H NMR (d6-DMSO) δ: 11.03 (s, 1H); 9.26 (s, 1H); 8.31 (s, 1H); 7.94 (d, J=8.5 Hz, 1H); 7.61 (d, J=8.5 Hz, 1H); 4.72 (t, J=5.7 Hz, 1H); 3.40-3.46 (m, 1H); 3.23-3.30 (m, 2H); 3.08 (s, 3H); 2.90-2.99 (m, 1H); 2.72-2.80 (m,1H); 2.20-2.27 (m, 1H); 1.56 (s, 3H); 1.40-1.48 (m, 2H); 0.93-0.96 (m, 1H); 0.84-0.90 (m, 1H).

[0560] MS (ESI, m/z): 446.9 [M+H.sup.+] for C.sub.21H.sub.22N.sub.2O.sub.5S.sub.2; t.sub.R=0.71 min.

Example 8

(R)-N-hydroxy-4-(6-((1-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide

8.i. (R)-4-(6-((1-(((tert-butyldiphenylsdyl)oxy)methylkyclopropyl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)butanamide

[0561] To a solution of n-butylamine (0.116 mL, 2.61 mmol) in water (0.2 mL) was added CuCl (0.061 g, 0.062 mmol). Then, NH.sub.2OH.HCl (0.060 g, 0.852 mmol) was added, followed by the compound of Preparation H (0.100 g, 0.237 mmol). The resulting suspension was immediately cooled with an ice bath. n-Butylamine (0.116 mL, 2.37 mmol) was added. The compound of Preparation N (0.503 g, 1.24 mmol) was added at once and the ice bath was removed. The mixture was stirred at rt for 4 h. MgSO.sub.4 was added followed by EA (50 mL). MgSO.sub.4 was removed by filtration and the filtrate was concentrated to dryness. The residue was purified by CC (Hept-EA) to afford the title compound as a yellow foam (0.124 g, 69% yield).

[0562] .sup.1H NMR (d6-DMSO) δ: 11.43 (s, 1H); 8.34 (s, 1H); 7.94-7.99 (m, 1H); 7.67 (m, 4H); 7.60-7.62 (m, 1H); 7.42-7.51 (m, 6H); 4.95-4.98 (m, 1H); 3.96-4.00 (overlapped m, 1H); 3.65 (s, 2H); 3.47-3.52 (m, 1H); 3.24-3.32 (m, 1H); 3.07 (m, 1.5H); 3.06 (s, 1.5H); 2.97-3.06 (m, 1H); 2.73-2.82 (m, 1H); 2.24-2.30 (m, 1H); 1.50-1.76 (m, 9H); 0.97-1.06 (m, 11H); 0.84-0.90 (m, 2H).

[0563] MS (ESI, m/z): 768.9 [M+H.sup.+] for C.sub.42H.sub.48N.sub.2O.sub.6S.sub.2Si; t.sub.R=1.15 min.

8.ii. (2R)-4-(6-(1-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsuffonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)butanamide

[0564] To a solution of intermediate 8.i (56 mg, 0.073 mmol) in THF (1 mL) was added TBAF (1M in THF, 0.2 mL). The mixture was stirred at rt for 1 h. The mixture was impregnated on silica and concentrated to dryness. The residue was purified by CC (Hept-EA) to afford the title compound as a yellow oil (10 mg, 26% yield).

[0565] MS (ESI, m/z): 530.9 [M+H.sup.+] for C.sub.26H.sub.30N.sub.2O.sub.6S.sub.2; t.sub.R=0.84 min.

8.iii. (R)-N-hydroxy-4-(6-((1-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butancimide

[0566] Starting from intermediate 8.ii (10 mg, 0.0188 mmol) and proceeding in analogy to Reference Example 2, step RE2.iv, the title compound was obtained, after precipitation in water, as a beige solid (2.6 mg, 31% yield).

[0567] .sup.1H NMR (d6-DMSO) δ: 11.03 (s, 1H); 9.26 (s, 1H); 8.31 (s, 1H); 7.95 (d, J=8.4 Hz, 1H); 7.61 (d, J=8.4 Hz, 1H); 5.06 (t, J=6.0 Hz, 1H); 3.40 (overlapped m, 2H); 3.23-3.29 (m, 1H); 3.07 (s, 3H); 2.91-2.99 (m, 1H); 2.77 (td, J=4.5, 12.5 Hz, 1H); 2.25 (td, J=4.5, 12.5 Hz, 1H); 1.55 (s, 3H); 0.88-0.97 (m, 4H).

[0568] MS (ESI, m/z): 446.9 [M+H.sup.+] for C.sub.25H.sub.30N.sub.2O.sub.6S.sub.2; t.sub.R=0.72 min.

Example 9

(R)-4-(6-((3-aminooxetan-3-yl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

[0569] Starting from the compound of Preparation H (0.168 g, 0.385 mmol) and the compound of Preparation O (0.124 g, 0.385 mmol) and proceeding successively in analogy to Reference Example 2, step RE2.i (42% yield) and to Preparation K, step K.iii (2% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a white solid (0.0013 g, 2% yield).

[0570] .sup.1H NMR (d6-DMSO) δ: 11.02 (br. s, 1H); 8.87 (br. s, 1H); 8.37 (s, 1H); 7.97 (d, J=8.0 Hz, 1H); 7.66 (d, J=8.0 Hz, 1H); 4.68 (d, J=4.1 Hz, 2H); 4.46 (d, J=4.5 Hz, 2H); 3.20-3.48 (overlapped m, 2H); 3.07 (s, 3H); 2.67-2.81 (m, 2H); 1.50 (s, 3H).

[0571] MS (ESI, m/z): 488.9 [M+MeCN+H.sup.+] for C.sub.20H.sub.21N.sub.3O.sub.5 S.sub.2; t.sub.R=0.51 min.

Example 10

(R)-4-(6-((1-aminocyclopropyl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide hydrochloride

[0572] Starting from the compound of Preparation H (0.181 g, 0.415 mmol) and the compound of Preparation P (0.131 g, 0.539 mmol) and proceeding successively in analogy to Reference Example 2, step RE2.i (quant.) and to Preparation K, step K.iii (30% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a beige solid (0.042 g).

[0573] .sup.1H NMR (d6-DMSO) δ: 10.99-11.09 (m, 1H); 9.22-9.31 (m, 1H); 8.60-8.99 (m, 3H); 8.37-8.43 (m, 1H); 7.99 (d, J=8.4 Hz, 1H); 7.67 (d, J=8.4 Hz, 1H); 3.24-3.32 (m, 1H); 3.08 (s, 3H); 2.93-3.02 (m, 1H); 2.73-2.83 (m, 1H); 2.21-2.31 (m, 1H); 1.56 (s, 3H); 1.34-1.44 (m, 4H).

[0574] MS (ESI, m/z): 472.9 [M+MeCN+H.sup.+] for C.sub.20H.sub.22N.sub.3O.sub.4ClS.sub.2; t.sub.R=0.53 min.

Example 11

(R)-N-hydroxy-4-(6-((4-(1-(hydroxymethyl)cyclopropyl)phenyl)ethynyl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide

[0575] Starting from the compound of Preparation H (0.100 g, 0.229 mmol) and the compound of Preparation Q (0.063 g, 0.229 mmol) and proceeding successively in analogy to Reference Example 2, step RE2.i (53% yield) and step RE2.iv (66% yield), the title product was obtained, after purification by prep-HPLC (Method 2), as a yellow solid (0.040 g).

[0576] .sup.1H NMR (d6-DMSO) δ: 11.03 (br. s, 1H); 9.26 (br. s, 1H); 8.32 (d, J=1.3 Hz, 1H); 7.98 (d, J=8.5 Hz, 1H); 7.64 (dd, J=1.7, 8.4 Hz, 1H); 7.48 (d, J=8.4 Hz, 2H); 7.36 (d, J=8.4 Hz, 2H); 4.74 (t, J=5.6 Hz, 1H); 3.57 (d, J=5.6 Hz, 2H); 3.23-3.31 (m, 1H); 3.09 (s, 3H); 2.93-3.01 (m, 1H); 2.78 (td, J=4.4, 12.7 Hz, 1H); 2.26 (td, J=5.0, 12.5 Hz, 1H); 1.57 (m, 3H); 0.88-0.91 (m, 2H); 0.78-0.81 (m, 2H).

[0577] MS (ESI, m/z): 499.0 [M+H.sup.+] for C.sub.25H.sub.26N.sub.2O.sub.5S.sub.2; t.sub.R=0.77 min.

Example 12

(R)-N-hydroxy-4-(6-((1-(hydroxymethyl)cyclobutyl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide

12.i. (2R)-4-(6-((1-(hydroxymethyl)cyclobutyl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)butanamide

[0578] Starting from the compound of Preparation H (0.100 g, 0.229 mmol) and the compound of Preparation R (0.127 g, 0.3 mmol) and proceeding successively in analogy to Example 8, steps 8.i to 8.ii (yields: Cadiot coupling 79%; deprotection 83%), the title product was obtained, after purification by CC using (Hept-EA), as a yellowish foam (0.083 g). .sup.1H NMR (d6-DMSO)) δ: 11.43 (s, 1H); 8.33 (s, 1H); 7.96 (d, J=8.4 Hz, 1H); 7.63 (dd, J=1.6, 8.4 Hz, 1H); 5.20 (t, J=5.8 Hz, 1H); 4.94-4.99 (m, 1H); 4.04-4.15 (m, 1H); 3.47-3.56 (m, 3H); 3.24-3.32 (m, 1H); 3.09 (s, 1.5H); 3.07 (s, 1.5H); 2.97-3.05 (m, 1H); 2.72-2.83 (m, 1H); 2.23-2.32 (m, 1H); 2.12-2.20 (m, 4H); 1.86-2.01 (m, 2H); 1.63-1.76 (m, 3H); 1.50-1.62 (m, 6H).

[0579] MS (ESI, m/z): 544.90 [M+H.sup.+] for C.sub.27H.sub.32N.sub.2O.sub.6S.sub.2; t.sub.R=0.88 min.

12.ii. (R)-N-hydroxy-4-(6-((1-(hydroxymethyl)cyclobutyl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide

[0580] To a solution of intermediate 12.i (0.0345 g, 0.0633 mmol) in EtOH (1 mL) was added amberlyst 15 (0.044 g). The mixture was stirred 1 h at 80° C. The solvent was evaporated in vacuo and the residue was taken in DMF (2 mL). The amberlyst was filtered and the filtrate was evaporated. The residue was taken up in water (1 mL) and filtered to afford the title compound as a pale yellow solid (0.020 g, 70% yield).

[0581] .sup.1H NMR (d6-DMSO)) δ: 11.03 (br. s, 1H); 9.26 (br. s, 1H); 8.33 (d, J=1.5 Hz, 1H); 7.96 (d, J=8.4 Hz, 1H); 7.63 (dd, J=1.5, 8.4 Hz, 1H); 5.20 (s, 1H); 3.51 (d, J=5.8 Hz, 2H); 3.23-3.30 (m, 1H); 3.08 (s, 3H); 2.93-3.01 (m, 1H); 2.74-2.83 (m, 1H); 2.22-2.31 (m, 1H); 2.15 (t, J=7.9 Hz, 4H); 1.86-2.04 (m, 2H); 1.56 (s, 3H).

[0582] MS (ESI, m/z): 460.97 [M+H.sup.+] for C.sub.22H.sub.24N.sub.2O.sub.5S.sub.2; t.sub.R=0.76 min.

Example 13

(R)-4-(6-(((1s,3R,4S)-3,4-dihydroxycyclopentyl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

[0583] Starting from the compound of Preparation H (0.100 g, 0.229 mmol) and the compound of Preparation S (0.061 g, 0.3 mmol) and proceeding successively in analogy to Example 8, step 8.i and Example 12, step 12.ii (yields: Cadiot coupling 46%; deprotection 17%), the title product was obtained, after purification by prep-HPLC (Method 2), as a yellow solid (0.009 g).

[0584] .sup.1H NMR (d6-DMSO)) δ: 10.54-11.22 (m, 1H); 9.11-9.51 (m, 1H); 8.32 (d, J=1.6 Hz, 1H); 7.95 (d, J=8.5 Hz, 1H); 7.60-7.64 (m, 1H); 4.55-4.59 (m, 2H); 3.94-4.00 (m, 2H); 3.23-3.30 (m, 1H); 3.14-3.22 (m, 1H); 3.08 (s, 3H); 2.92-3.00 (m, 1H); 2.73-2.81 (m, 1H); 2.20-2.30 (m, 1H); 1.90-1.99 (m, 2H); 1.76-1.83 (m, 2H); 1.56 (s, 3H).

[0585] MS (ESI, m/z): 476.96 [M+H+] for C.sub.22H.sub.24N.sub.2O.sub.6S.sub.2; t.sub.R=0.65 min.

Example 14

(R)-N-hydroxy-4-(6-(5-(3-hydroxyoxetan-3-yl)penta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide

[0586] Starting from the compound of Preparation H (0.08 g, 0.18 mmol) and the compound of Preparation T (0.056 g, 0.23 mmol) and proceeding successively in analogy to Example 8, step 8.i and Example 12, step 12.ii (yields: Cadiot coupling 55%; deprotection 16%), the title product was obtained, after purification by prep-HPLC (Method 2), as a yellow solid (0.008 g).

[0587] .sup.1H NMR (d6-DMSO) δ: 11.02 (m, 1H); 9.25 (s, 1H); 8.35 (d, J=1.5 Hz, 1H); 7.96 (d, J=8.5 Hz, 1H); 7.64 (dd, J=1.6, 8.4 Hz, 1H); 6.10 (s, 1H); 4.47 (d, J=6.6 Hz, 2H); 4.43 (d, J=6.7 Hz, 2H); 3.22-3.31 (m, 1H); 3.08 (s, 3H); 2.92-3.02 (m, 1H); 2.89 (s, 2H), 2.71-2.83 (m, 1H); 2.20-2.30 (m, 1H); 1.56 (s, 3H).

[0588] MS (ESI, m/z): 462.92 [M+H+] for C.sub.21H.sub.22N.sub.2O.sub.6S.sub.2; t.sub.R=0.65 min.

Example 15

(R)-N-hydroxy-4-(6-(((1R,2R)-2-(hydroxymethyl)-1-methylcyclopropyl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide

[0589] Starting from the compound of Preparation H (0.100 g, 0.229 mmol) and the compound of Preparation U (0.057 g, 0.24 mmol) and proceeding successively in analogy to Example 8, steps 8.i to 8.iii (yields: Cadiot coupling 78%; deprotections 26%), the title product was obtained, after purification by prep-HPLC (Method 2), as a yellow solid (0.022 g).

[0590] .sup.1H NMR (d6-DMSO)) δ: 11.03 (d, J=0.7 Hz, 1H); 9.26 (d, J=1.2 Hz, 1H); 8.31 (d, J=1.5 Hz, 1H); 7.95 (d, J=8.6 Hz, 1H); 7.61 (dd, J=1.6, 8.4 Hz, 1H); 4.69 (t, J=5.4 Hz, 1H); 3.60-3.66 (m, 1H); 3.33 (s, 3H); 3.23-3.31 (m, 2H); 3.08 (s, 3H); 2.92-3.00 (m, 1H); 2.75-2.81 (m, 1H); 2.21-2.30 (m, 1H); 1.56 (s, 3H); 1.42-1.50 (m, 1H); 1.11-1.16 (m, 1H); 0.62-0.68 (m, 1H).

[0591] MS (ESI, m/z): 460.96 [M+H.sup.+] for C.sub.22H.sub.24N.sub.2O.sub.5S.sub.2; t.sub.R=0.74 min.

Example 16

(R)-4-(6-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)buta-1,3-diyn-1yl)benzo[d]thiazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

[0592] Starting from the compound of Preparation H (0.08 g, 0.183 mmol) and the compound of Preparation V (0.127 g, 0.3 mmol) and proceeding successively in analogy to Example 8, step 8.i and Example 12, step 12.ii (yields: Cadiot coupling 59%; deprotection 9%), the title product was obtained, after purification by CC (DCM-MeOH containing 1% aq. NH.sub.4OH), as a white solid (0.005 g).

[0593] .sup.1H NMR (d6-DMSO)) δ: 8.38 (d, J=1.3 Hz, 1H); 7.97 (d, J=8.5 Hz, 1H); 7.66 (dd, J=1.6, 8.5 Hz, 1H); 4.31 (dd, J=2.5, 10.0 Hz, 1H); 3.76-3.82 (m, 1H); 3.22-3.32 (m, 1H); 3.08 (s, 3H); 2.94-3.03 (m, 2H); 2.70-2.83 (m, 1H); 2.60-2.68 (m, 1H); 2.17-2.30 (m, 1H); 1.86-1.98 (m, 2H); 1.57-1.70 (m, 1H); 1.55 (s, 3H); 1.19-1.32 (m, 1H).

[0594] MS (ESI, m/z): 516.96 [M+H.sup.+] for C.sub.22H.sub.25N.sub.3O.sub.5S.sub.2; t.sub.R=0.56 min.

Example 17

(R)-4-(6-(5-(dimethylamino)penta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

[0595] Starting from the compound of Preparation H (0.1 g, 0.23 mmol) and the compound of Preparation W (0.06 g, 0.3 mmol) and proceeding successively in analogy to Example 8, step 8.i and Example 12, step 12.ii (yields: Cadiot coupling 67%; deprotection 11%), the title product was obtained, after purification by prep-HPLC (Method 2), as a yellow beige solid (0.007 g).

[0596] .sup.1H NMR (d6-DMSO) δ: 10.02 (br. s., 1H); 9.28 (br. s., 1H); 8.38 (d, J=1.5 Hz, 1H); 7.97 (d, J=8.5 Hz, 1H); 7.66 (dd, J=1.5, 8.5 Hz, 1H); 3.24-3.33 (m, 3H); 3.33 (s, 3H); 2.91-3.03 (m, 1H); 2.74-2.84 (m, 1H); 2.24-2.30 (m, 1H); 2.23 (s, 6H); 1.56 (s, 3H).

[0597] MS (EST, m/z): 433.95 [M+H.sup.+] for C.sub.20H.sub.23N.sub.3O.sub.4S.sub.2; t.sub.R=0.53 min.

Example 18

(R)-N-hydroxy-4-(6-((4-hydroxytetrahydro-2H-pyran-4-yl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide

[0598] Starting from the compound of Preparation H (0.08 g, 0.18 mmol) and the compound of Preparation X (0.06 g, 0.24 mmol) and proceeding successively in analogy to Example 8, step 8.i and Reference Example RE2, step RE2.iv (yields: Cadiot coupling 64%; deprotection 76%), the title product was obtained, after precipitation in water and filtration, as a white solid (0.049 g). .sup.1H NMR (d6-DMSO) δ: 11.03 (d, J=1.6 Hz, 1H); 9.26 (d, J=1.6 Hz, 1H); 8.38 (d, J=1.3 Hz, 1H); 7.98 (d, J=8.5 Hz, 1H); 7.67 (dd, J=1.6, 8.5 Hz, 1H); 5.96 (s, 1H); 3.72-3.84 (m, 2H); 3.48-3.57 (m, 2H); 3.24-3.31 (m, 1H); 3.08 (s, 3H); 2.92-3.01 (m, 1H); 2.78 (td, J=4.5, 12.5 Hz, 1H); 2.26 (td, J=5.0, 12.5 Hz, 1H); 1.82-1.90 (m, 2H); 1.65-1.74 (m, 2H); 1.56 (s, 3H).

[0599] MS (ESI, m/z): 476.95 [M+H.sup.+] for C.sub.22H.sub.24N.sub.2O.sub.6S.sub.2; t.sub.R=0.68 min.

Example 19

(R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-4-(6-(piperidin-4-ylbuta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)butanamide

[0600] Starting from the compound of Preparation H (0.08 g, 0.18 mmol) and the compound of Preparation Y (0.065 g, 0.24 mmol) and proceeding successively in analogy to Example 8, step 8.i and Reference Example RE2, step RE2.iv (yields: Cadiot coupling 56%; deprotection 32%), the title product was obtained, after precipitation in water and filtration, as a white solid (0.015 g).

[0601] .sup.1H NMR (d6-DMSO) δ: 8.33 (d, J=1.4 Hz, 1H); 7.95 (d, J=8.5 Hz, 1H); 7.63 (dd, J=1.6, 8.4 Hz, 1H); 3.20-3.29 (m, 1H); 3.07 (s, 3H); 2.94-3.03 (m, 1H); 2.82-2.92 (m, 2H); 2.70-2.78 (m, 2H); 2.50 (overlapped m, 2H); 2.18-2.26 (m, 1H); 1.72-1.80 (m, 2H); 1.52 (s, 3H); 1.42-1.51 (m, 2H).

[0602] MS (ESI, m/z): 500.9 [M+H.sup.+] for C.sub.22H.sub.25N.sub.3O.sub.4S.sub.2; t.sub.R=0.57 min.

Example 20

(R)-N-hydroxy-4-(6-((3-(hydroxymethyl)oxetan-3-yl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide

[0603] Starting from the compound of Preparation H (0.08 g, 0.18 mmol) and the compound of Preparation Z (0.088 g, 0.183 mmol) and proceeding successively in analogy to Example 8, steps 8.i to 8.iii (yields: Cadiot coupling 66%; deprotections 37%), the title product was obtained, after precipitation in water and filtration, as a yellow solid (0.021 g).

[0604] .sup.1H NMR (d6-DMSO) δ: 11.03 (br. s, 1H); 9.26 (br. s, 1H); 8.36-8.38 (m, 1H); 7.98 (d, J=8.5 Hz, 1H); 7.66 (dd, J=1.7, 8.4 Hz, 1H); 5.50 (t, J=5.9 Hz, 1H); 4.62 (d, J=5.7 Hz, 2H); 4.54 (d, J=5.8 Hz, 2H); 3.74 (d, J=5.9 Hz, 2H); 3.24-3.31 (m, 1H); 3.08 (s, 3H); 2.92-3.01 (m, 1H); 2.78 (td, J=4.5, 12.6 Hz, 1H); 2.26 (td, J=5.1, 12.4 Hz, 1H); 1.56 (s, 3H).

[0605] MS (ESI, m/z): 462.92 [M+H.sup.+] for C.sub.21H.sub.22N.sub.2O.sub.6S.sub.2; t.sub.R=0.66 min.

Example 21

(R)-N-hydroxy-4-(6-((cis-1-hydroxy-3-(hydroxymethyl)cyclobutyl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide

[0606] Starting from the compound of Preparation H (0.08 g, 0.18 mmol) and the compound of Preparation AA (0.088 g, 0.183 mmol) and proceeding successively in analogy to Example 8, step 8.i and Reference Example RE2, step RE2.iv (yields: Cadiot coupling 62%; deprotection 69%), the title product was obtained, after precipitation in water and filtration, as a yellow solid (0.033 g).

[0607] .sup.1H NMR (d6-DMSO) δ: 11.02 (m, 1H); 9.24 (m, 1H); 8.34 (d, J=1.3 Hz, 1H); 7.96 (d, J=8.5 Hz, 1H); 7.64 (dd, J=1.6, 8.4 Hz, 1H); 5.27 (s, 1H); 4.49 (t, J=5.3 Hz, 1H); 3.37 (t, J=5.8 Hz, 2H); 3.23-3.31 (m, 1H); 3.08 (s, 3H); 2.91-3.00 (m, 1H); 2.77 (td, J=4.5, 12.5 Hz, 1H); 2.65 (s, 2H); 2.25 (td, J=5.0, 12.4 Hz, 1H); 2.05-2.11 (m, 2H); 1.91-2.00 (m, 1H); 1.71-1.80 (m, 2H); 1.56 (s, 3H).

[0608] MS (ESI, m/z): 490.96 [M+H.sup.+] for C.sub.23H.sub.26N.sub.2O.sub.6S; t.sub.R=0.65 min.

Example 22

(R)-N-hydroxy-4-(6-((1-(2-hydroxyacetyl)piperidin-4-yl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide

[0609] Starting from the compound of Preparation H (0.08 g, 0.18 mmol) and the compound of Preparation AB (0.086 g, 0.29 mmol) and proceeding successively in analogy to Example 8, step 8.i and Reference Example RE2, step RE2.iv (yields: Cadiot coupling 54%; deprotection 63%), the title product was obtained, after precipitation in water and filtration, as a white foam (0.031 g).

[0610] .sup.1H NMR (d6-DMSO) δ: 11.02 (m, 1H); 9.24 (m, 1H); 8.34 (d, J=1.3 Hz, 1H); 7.96 (d, J=8.5 Hz, 1H); 7.64 (dd, J=1.6, 8.4 Hz, 1H); 5.27 (s, 1H); 4.49 (t, J=5.3 Hz, 1H); 3.37 (t, J=5.8 Hz, 2H); 3.23-3.31 (m, 1H); 3.08 (s, 3H); 2.91-3.00 (m, 1H); 2.77 (td, J=4.5, 12.5 Hz, 1H); 2.65 (s, 2H); 2.25 (td, J=5.0, 12.4 Hz, 1H); 2.05-2.11 (m, 2H); 1.91-2.00 (m, 1H); 1.71-1.80 (m, 2H); 1.56 (s, 3H).

[0611] MS (ESI, m/z): 517.83 [M+H+] for C.sub.21H.sub.22N.sub.2O.sub.6S.sub.2; t.sub.R=0.71 min.

Example 23

(R)-4-(6-(((1R*,2R*)-1-fluoro-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

[0612] Starting from the compound of Preparation H (0.1 g, 0.23 mmol) and the compound of Preparation AC (0.128 g, 0.3 mmol) and proceeding successively in analogy to Example 8, steps 8.i and 8.ii and Reference Example RE2, step RE2.iv (yields: Cadiot coupling 86%; TBAF 76%; THP deprotection 79%), the title product was obtained, after purification by prep-HPLC (Method 2), as a white foam (0.048 g).

[0613] .sup.1H NMR (d6-DMSO) δ: 10.78-11.24 (br. s, 1H); 9.12-9.46 (br. s, 1H); 8.41 (d, J=1.3 Hz, 1H); 7.99 (d, J=8.5 Hz, 1H); 7.69 (dd, J=1.7, 8.5 Hz, 1H); 4.91 (t, J=5.6 Hz, 1H); 3.66-3.74 (m, 1H); 3.34-3.42 (m, 1H); 3.24-3.32 (m, 1H); 3.08 (s, 3H); 2.93-3.02 (m, 1H); 2.77 (td, J=4.5, 12.5 Hz, 1H); 2.26 (td, J=5.0, 12.5 Hz, 1H); 1.66-1.75 (m, 1H); 1.56 (s, 3H); 1.40-1.47 (m, 1H); 1.26-1.34 (m, 1H).

[0614] MS (ESI, m/z): 464.92 [M+H.sup.+] for C.sub.21H.sub.21N.sub.2O.sub.5FS.sub.2; t.sub.R=0.73 min.

Example 24

(R)-4-(6-(((1R*,2R*)-2-fluoro-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

[0615] Starting from the compound of Preparation H (0.1 g, 0.23 mmol) and the compound of Preparation AD (0.128 g, 0.3 mmol) and proceeding successively in analogy to Example 8, steps 8.i and 8.ii and Reference Example RE2, step RE2.iv (yields: Cadiot coupling 79%; TBAF deprotection 59%; THP deprotection 65%), the title product was obtained, after purification by prep-HPLC (Method 2), as a white foam (0.030 g).

[0616] .sup.1H NMR (d6-DMSO) δ: 10.69-11.29 (br. s, 1H); 9.18-9.52 (br. s, 1H); 8.35 (d, J=1.5 Hz, 1H); 7.96 (d, J=8.5 Hz, 1H); 7.64 (dd, J=1.5, 8.5 Hz, 1H); 5.26 (t, J=6.1 Hz, 1H); 3.59-3.76 (m, 2H); 3.23-3.31 (m, 1H); 3.08 (s, 3H); 2.93-3.01 (m, 1H); 2.72-2.84 (m, 1H); 2.25 (td, J=5.0, 12.5 Hz, 1H); 1.96-2.03 (m, 1H); 1.56 (s, 3H); 1.35-1.46 (m, 2H).

[0617] MS (ESI, m/z): 464.92 [M+H.sup.+] for C.sub.21H.sub.21N.sub.2O.sub.5FS.sub.2; t.sub.R=0.71 min.

Example 25

(R)-N-hydroxy-4-(6-((1-(2-hydroxyacetyl)azetidin-3-yl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide

[0618] Starting from the compound of Preparation H (0.100 g, 0.229 mmol) and the compound of Preparation AE (0.065 g, 0.298 mmol) and proceeding successively in analogy to Example 8, step 8.i and Reference Example RE2, step RE2.iv (yields: Cadiot coupling 75%; deprotection 56%), the title product was obtained, after purification by prep-HPLC (Method 2), as a white solid (0.048 g).

[0619] .sup.1H NMR (d6-DMSO) δ: 9.10-10.20 (br. s, 2H); 8.37 (d, J=1.3 Hz, 1H); 7.97 (d, J=8.5 Hz, 1H); 7.65 (dd, J=1.6, 8.4 Hz, 1H); 5.03 (m, 1H); 4.48 (t, J=8.8 Hz, 1H); 4.18-4.22 (m, 2H); 3.92 (s, 2H); 3.87 (m, 1H); 3.78 (m, 1H); 3.27 (m, 1H); 3.08 (s, 3H); 2.97 (m, 1H); 2.77 (td, J=4.4, 12.6 Hz, 1H); 2.25 (td, J=5.0, 12.4 Hz, 1H); 1.56 (s, 3H). MS (ESI, m/z): 489.99 [M+H.sup.+] for C.sub.22H.sub.23N.sub.3O.sub.6 S.sub.2, t.sub.R=0.65 min.

Example 26

(R)-N-hydroxy-4-(6-(((1R,2S)-2-(hydroxymethyl)-2-methylcyclopropyl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide

[0620] Starting from the compound of Preparation H (0.150 g, 0.344 mmol) and the compound of Preparation AF (0.103 g, 0.447 mmol) and proceeding successively in analogy to Example 8, step 8.i, Example 7, step 7.ii and Reference Example RE2, step RE2.iv (yields: Cadiot coupling 69%; deprotection 92%; deprotection 68%), the title product was obtained, after purification by prep-HPLC (Method 2), as a beige solid (0.07 g).

[0621] .sup.1H NMR (d6-DMSO) δ: 10.64-11.27 (m, 1H); 9.21-9.31 (m, 1H); 8.32 (d, J=1.3 Hz, 1H); 7.94 (d, J=8.5 Hz, 1H); 7.62 (dd, J=1.6, 8.4 Hz, 1H); 4.76 (t, J=5.8 Hz, 1H); 3.20-3.32 (m, 3H); 3.08 (s, 3H); 2.96 (m, 1H); 2.77 (td, J=4.5, 12.6 Hz, 1H); 2.25 (td, J=5.0, 12.4 Hz, 1H); 1.59 (dd, J=5.3, 8.7 Hz, 1H); 1.56 (s, 3H); 1.21 (s, 3H); 1.07 (dd, J=4.0, 8.7 Hz, 1H); 0.67 (m, 1H).

[0622] MS (ESI, m/z): 460.98 [M+H.sup.+] for C.sub.22H.sub.24N.sub.2O.sub.5S.sub.2; t.sub.R=0.74 min.

Example 27

(R)-4-(6-(((1R,2R)-2-fluoro-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

[0623] Starting from the compound of Preparation H (0.146 g, 0.334 mmol) and the compound of Preparation AG ((R,R)-enantiomer, 0.167 g, 0.502 mmol) and proceeding successively in analogy to Example 8, step 8.i, Example 7, step 7.ii and Reference Example RE2, step RE2.iv (yields: Cadiot coupling and deprotection 69%; deprotection 73%), the title product was obtained, after purification by prep-HPLC (Method 2), as a white solid (0.076 g).

[0624] .sup.1H NMR (d6-DMSO) δ: 10.10-11.10 (br. s, 1H); 8.97-9.67 (br. s, 1H); 8.32 (m, 1H); 7.96 (m, 1H); 7.58-7.72 (m, 1H); 5.26 (m, 1H); 3.58-3.79 (m, 2H); 3.25 (m, 1H); 3.08 (s, 3H); 2.97 (m, 1H); 2.77 (m, 1H); 2.25 (m, 1H); 1.97 (m, 1H); 1.51-1.60 (s, 3H); 1.32-1.46 (m, 2H).

[0625] MS (ESI, m/z): 464.95 [M+H.sup.+] for C.sub.21H.sub.21N.sub.2O.sub.5FS.sub.2; t.sub.R=0.71 min.

[0626] The racemic mixtures of Reference Examples 1 to 4 can be separated into their enantiomers using, for example, chiral HPLC. Thus the following further invention compounds or salts thereof would be obtained:

[0627] (R)-N-hydroxy-4-(6-(4-methoxyphenyl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide,

[0628] (R)-N-hydroxy-4-(6((4-(hydroxymethyl)phenyl)ethynyl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide, [0629] (R)-4-(6-((4-(3-aminooxetan-3-yl)phenyl)ethynyl)-benzo[d]thiazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide, and

[0630] (R)-N-hydroxy-4-(6-(5-hydroxypenta-1,3-diyn-1-yl)benzo[d]thiazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide.

[0631] Pharmacological Properties of the Invention Compounds

[0632] In Vitro Assays

[0633] Bacterial Growth Minimal Inhibitory Concentrations:

[0634] Experimental Methods:

[0635] Minimal Inhibitory Concentrations (MICs; mg/L) were determined in cation-adjusted Mueller-Hinton Broth by a microdilution method following the description given in “Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically”, Approved standard, 7.sup.th ed., Clinical and Laboratory Standards Institute (CLSI) Document M7-A7, Wayne, Pa., USA (2006).

[0636] Results:

[0637] All Example compounds were tested against several Gram-positive and Gram-negative bacteria. Typical antibacterial test results are given in Table 1 hereafter (MICs in mg/L). K pneumoniae A-651 is a multiply-resistant (in particular quinolone-resistant) strain, while E. coli ATCC25922 and P. aeruginosa ATCC27853 are quinolone-sensitive strains.

TABLE-US-00001 TABLE 1 MIC for MIC for MIC for Example E. coli P. aeruginosa K. Pneumoniae No. ATCC25922 ATCC27853 A-651 RE1 0.25 16 2 RE2 0.125 16 0.5 RE3 4 8 1 RE4 0.5 1 8 1 0.25 1 0.25 2 ≦0.063 2 0.25 3 4 8 1 4 0.5 1 0.5 5 1 1 8 6 0.25 1 1 7 ≦0.063 0.5 0.125 8 0.25 0.5 0.5 9 1 2 2 10 0.125 1 0.25 11 0.125 4 0.5 12 0.125 2 0.5 13 0.25 1 0.5 14 0.5 1 1 15 0.125 1 0.5 16 4 4 8 17 0.125 2 0.25 18 1 2 2 19 8 4 16 20 0.5 1 0.5 21 1 2 2 22 0.5 2 1 23 ≦0.063 0.5 0.25 24 ≦0.063 0.25 0.25 25 0.5 1 1 26 0.063 0.5 0.125 27 0.063 0.25 0.125 Cipro ≦0.063 0.25 >32