Pyridine derivatives

Abstract

The invention relates to a compound of formula (I) ##STR00001##
wherein A and R.sup.1 to R.sup.4 are defined as in the description and in the claims. The compound of formula (I) can be used as a medicament.

Claims

1. A compound selected from the group consisting of: 5-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-3-methyl-1,2,4-oxadiazole; 5[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-3-phenyl-1,2,4-oxadiazole; 3-cyclopropyl-5-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole; 3-cyclopentyl-5-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole; 3-benzyl-5-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]1,2,4-oxadiazole; 3-tert-butyl-5-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole; 3-cyclopropyl-5-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole; 5-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-3-(trifluoromethyl)-1,2,4-oxadiazole; 5-cyclopropyl-3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole; 3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-5-(methoxymethyl)-1,2,4-oxadiazole; 3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-5-ethyl-1,2,4-oxadiazole; 3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-5-propan-2-yl-1,2,4-oxadiazole; [3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazol-5-yl]methanol; 3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-5-(trifluoromethyl)-1,2,4-oxadiazole; 1-[3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazol-5-yl]cyclopropan-1-ol; 3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-5-(1-methylcyclopropyl)-1,2,4-oxadiazole; 1-[3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboxamide; 2-[3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazol-5-yl]propan-2-ol; 5-tert-butyl-3-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole; 3-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-5-(1-methylcyclopropyl)-1,2,4-oxadiazole; 3-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-5-propan-2-yl-1,2,4-oxadiazole; 1-[3-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazol-5-yl]cyclopropan-1-ol; 3-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole; 3-tert-butyl-5-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole; 5-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-3 -propan-2-yl-1,2,4-oxadiazole; 5-tert-butyl-3-[4-(cyclopropylmethoxy)-5-methylsulfonylpyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-[5-cyclopropyl-4-[(2S)-1,1,1-trifluoropropan-2-yl]oxypyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-[5-cyclopropyl-4-[(2R)-1,1,1-trifluoropropan-2-yl]oxypyridin-2-yl]-1,2,4-oxadiazole; 3-tert-butyl-5-[5-cyclopropyl-4-[(2R)-1,1,1-trifluoropropan-2-yl]oxypyridin-2-yl]-1,2,4-oxadiazole; 3-tert-butyl-5-[5-cyclopropyl-4-[(2S)-1,1,1-trifluoropropan-2-yl]oxypyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3[5-cyclopropyl-4-[(4-fluorophenyl)methoxy]pyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-[5-cyclopropyl-4-[(3-methyloxetan-3-yl)methoxy]pyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-[5-cyclopropyl-4-(oxolan-2-ylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-[5-cyclopropyl-4-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]pyridin -2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-[5-cyclopropyl-4-(oxetan-2-ylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-[5-cyclopropyl-4-(4-fluorophenoxy)pyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-[5-methylsulfonyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-[5-chloro-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole; 3-[5-chloro-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-5-cyclopropyl-1,2,4-oxadiazole; 5-cyclopropyl-3-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-[5-cyclopropyl-4-(4-methylsulfonylphenoxy)pyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-(5-cyclopropyl-4-cyclopropylsulfonylpyridin-2-yl)-1,2,4-oxadiazole; 5-tert-butyl-3-[5-cyclopropyl-4-(2-ethoxyethoxy)pyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-[5-cyclopropyl-4-(1-methoxybutan-2-yloxy)pyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3[5-cyclopropyl-4-[2-[(2-methylpropan-2-yl)oxy]ethoxy]pyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-[5-cyclopropyl-4-[1-[(2-methylpropan-2-yl)oxy]propan-2-yloxy]pyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-[5cyclopropyl-4-(1-methoxypropan-2-yloxy)pyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-[5-cyclopropyl-4-(3-methoxybutoxy)pyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-[5-cyclopropyl-4-(oxetan-3-ylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole; 5-cyclopropyl-3-[5-cyclopropyl-4-[(2S)-1,1,1-trifluoropropan-2-yl]oxypyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-[5-cyclopropyl-4-(2-pyrrolidin-l-ylethoxy)pyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-[5-cyclopropyl-4-(2-piperidin-l-ylethoxy)pyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-[5-cyclopropyl-4-(1-piperidin-1-ylpropan-2-yloxy)pyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-[5-cyclopropyl-4-[(1-methylpiperidin-2-yl)methoxy]pyridin-2-yl]-1,2,4-oxadiazole; 2-[2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-cyclopropylpyridin-4-yl]oxy-N,N-diethylpropan-1-amine; 3-[[2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-cyclopropylpyridin-4-yl]oxyethyl]morpholine; 4-[2-[2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-cyclopropylpyridin-4-yl]oxyethyl]morpholine; 5-tert-butyl-3-[5-cyclopropyl-4-[(3-fluorooxetan-3-yl)methoxy]pyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-[5-cyclopropyl-4-[(2,5-dimethyl-1,3-oxazol-4-yl)methoxy]pyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-[5-cyclopropyl-4-[(5-methyl-1,2-oxazol-3-yl)methoxy]pyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-[5-cyclopropyl-4-(3-methylsulfonylphenoxy)pyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-(6-chloro-5-cyclopropyl-4-(4-fluorobenzyloxy)pyridin-2-yl)-1,2,4-oxadiazole; 2-tert-butyl-5-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,3,4-oxadiazole; 5-tert-butyl-3-[5-cyclopropyl-4-(2,2-difluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-[5-cyclopropyl-4-(2-fluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-[5-cyclopropyl-4-(pyridin-2-ylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-[5-cyclopropyl-4-[(5-fluoropyridin-2-yl)methoxy]pyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-[5-cyclopropyl-4-(pyridin-3-ylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole; 2-tert-butyl-5-[5-cyclopropyl-4-[(2S)-1,1,1-trifluoropropan-2-yl]oxypyridin-2-yl]-1,3,4-oxadiazole; 3-tert-butyl-5-[5-cyclopropyl-4-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]pyridin-2-yl]-1,2,4-oxadiazole; and 3-tert-butyl-5-(5-cyclopropyl-4-(2,2-difluoroethoxy)pyridin-2-yl)-1,2,4-oxadiazole; or a pharmaceutically acceptable salt thereof.

2. A compound selected from the group consisting of: 5-tert-butyl-3-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole; 3 -tert-butyl-5-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-[5-cyclopropyl-4-[(3-methyloxetan-3-yl)methoxy]pyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-[5-cyclopropyl-4-(oxolan-2-ylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-[5-cyclopropyl-4-(4-fluorophenoxy)pyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-[5-cyclopropyl-4-(2-ethoxyethoxy)pyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-[5-cyclopropyl-4-(3-methoxybutoxy)pyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-[5-cyclopropyl-4-(oxetan-3-ylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-[5-cyclopropyl-4-[(5-fluoropyridin-2-yl)methoxy]pyridin-2-yl]-1,2,4-oxadiazole; 3-tert-butyl-5-(5-cyclopropyl-4-(2,2-difluoroethoxy)pyridin-2-yl)-1,2,4-oxadiazole; or a pharmaceutically acceptable salt thereof.

3. A compound of claim 2 selected from the group consisting of: 5-tert-butyl-3-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-[5-cyclopropyl-4-[(3-methyloxetan-3-yl)methoxy]pyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-[5-cyclopropyl-4-(oxolan-2-ylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-[5-cyclopropyl-4-(4-fluorophenoxy)pyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-[5-cyclopropyl-4-(2-ethoxyethoxy)pyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-[5-cyclopropyl-4-(3-methoxybutoxy)pyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-[5-cyclopropyl-4-(oxetan-3-ylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole; 5-tert-butyl-3-[5-cyclopropyl-4-[(5-fluoropyridin-2-yl)methoxy]pyridin-2-yl]-1,2,4-oxadiazole; or a pharmaceutically acceptable salt thereof.

4. A compound of claim 2 selected from the group consisting of: 3-tert-butyl-5-(5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)-1,2,4-oxadiazole; 3-tert-butyl-5-(5-cyclopropyl-4-(2,2-difluoroethoxy)pyridin-2-yl)-1,2,4-oxadiazole; or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

6. A pharmaceutical composition comprising a compound of claim 2, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

7. A pharmaceutical composition comprising a compound of claim 3, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

8. A pharmaceutical composition comprising a compound of claim 4, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

9. A compound, which is 3-tert-butyl-5-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole, or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a compound of claim 9, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

Description

EXAMPLES

(1) Abbreviations

(2) MPLC=medium pressure liquid chromatography, model Combiflash Companion from TELEDYNE ISCO; MS=mass spectrometry; ESI=electrospray; BINAP=2,2-bis(diphenylphosphino)-1,1-binaphthyl; CDI=1,1-carbonyldiimidazole; Cs.sub.2CO.sub.3=cesium carbonate; DCM=dichloromethane; DIPEA=N-ethyl-N-isopropylpropan-2-amine; DBU=1,8-Diazabicyclo[5.4.0]undec-7-ene; DMF=dimethylformamide; DMSO=dimethyl-sulfoxide; dppf=1,1-bis(diphenylphosphino)ferrocene; EtOH=ethanol; HATU=2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V); HBTU=O-benzotriazole-N,N,N,N-tetramethyl-uronium-hexafluoro-phosphate; HPLC=LC=high performance liquid chromatography; m-CPBA=meta-chloroperoxybenzoic acid; MeOH=methanol; NaHCO.sub.3=sodium hydrogenocarbonate; Na.sub.2SO.sub.4=sodium sulfate; Pd(OAc).sub.2=palladium(II) acetate; RT=room temperature; TBTU=O-(benzotriazol-1-yl)-N,N,N,N-tetramethyl-uronium-tetrafluoroborate; TBME=methyl tert-butylether, THF=tetrahydrofuran; TFA=trifluoroacetic acid; TLC=thin layer chromatography; TMS-CN=Trimethylsilyl cyanide.

Example 1

5-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-3-methyl-1,2,4-oxadiazole

a) 3-bromo-4-(cyclopropylmethoxy)pyridine

(3) ##STR00033##

(4) To a solution of 3-bromo-4-chloropyridine (CAS 36953-42-1) (8 g, 41.6 mmol, Eq: 1.00) in dry DMF (100 mL) under argon atmosphere at RT was added cyclopropylmethanol (CAS 2516-33-8) (3.15 g, 3.45 mL, 43.6 mmol, Eq: 1.05) and by portions NaH (1.75 g, 43.6 mmol, Eq: 1.05). The resulting reaction was stirred at RT until gas evolution stopped. The reaction mixture was then stirred at 100 C. for 3 h and controlled by TLC. The reaction was cooled down to RT, quenched by addition of water and the mixture concentrated in vacuo. The residue was redissolved in ethyl acetate, extracted with aqueous NaHCO.sub.3 1M, the organic phase dried over Na.sub.2SO.sub.4, filtered and evaporated down to dryness. Flash chromatography with a 120 g SiO.sub.2 column, with an eluent mixture of heptane and ethyl acetate to give 8.25 g of light yellow oil (Yield: 87%). MS (ESI, m/z): 228.2 (M).

b) 3-cyclopropyl-4-(cyclopropylmethoxy)pyridine

(5) ##STR00034##

(6) To a solution of 3-bromo-4-(cyclopropylmethoxy)pyridine (8.1 g, 35.5 mmol, Eq: 1.00) in a mixture of toluene (150 mL) and water (18 mL) was added potassium cyclopropyltrifluoroborate (CAS 1065010-87-8) (5.52 g, 37.3 mmol, Eq: 1.05), Cs.sub.2CO.sub.3 (23.1 g, 71.0 mmol, Eq: 2.0), butyldi-1-adamantylphosphine (382 mg, 1.07 mmol, Eq: 0.03) and Pd(OAc).sub.2 (159 mg, 710 mol, Eq: 0.02). The reaction mixture was stirred at 125 C. for 7 h. Reaction mixture was cooled down and poured into a separatory funnel, ethyl acetate and water were added. After extraction of the mixture, the organic phase was collected, dried over Na.sub.2SO.sub.4 and evaporated down to dryness. Flash chromatography with a 120 g SiO.sub.2 column, and an eluent mixture of heptane and ethyl acetate gave 4.6 g of the desired product (Yield 68%). MS (ESI, m/z): 190.3 (MH.sup.+).

c) 2-bromo-5-cyclopropyl-4-(cyclopropylmethoxy)pyridine

(7) ##STR00035##

(8) To a solution of N,N-dimethylethanolamine (1.13 g, 1.28 mL, 12.7 mmol, Eq: 3.0) in hexane (9 mL) under an argon atmosphere at 15 C. was slowly added BuLi 1.6M in hexane (15.9 mL, 25.4 mmol, Eq: 6.0) and the reaction mixture was stirred at 15 C. for 15 min. Addition of 3-cyclopropyl-4-(cyclopropylmethoxy)pyridine (0.8 g, 4.23 mmol, Eq: 1.00) in dry toluene (5 mL) to the reaction at 15 C. was followed by stirring at 15 C. for 1 h. Reaction was then cooled down to 78 C. and a solution of 1,2-dibromotetrachloroethane (4.13 g, 12.7 mmol, Eq: 3.0) in dry toluene (6 mL) was added. The resulting white suspension was then stirred for 1 h at 78 C. and controlled by LC-MS. The reaction was then quenched with water, allowed to warm up to RT and diluted with ethyl acetate. The mixture was poured into a separatory funnel, extracted with aqueous NaHCO.sub.3 1M. The organic phase was dried over Na.sub.2SO.sub.4 and evaporated down to dryness. Flash chromatography with a 70 g SiO.sub.2 column, and an eluent mixture of heptane and ethyl acetate gave 980 mg of colorless oil (Yield 77%). MS (ESI, m/z): 268.1 (M).

d) 5-cyclopropyl-4-(cyclopropylmethoxy)picolinonitrile

(9) ##STR00036##

(10) To a solution of 2-bromo-5-cyclopropyl-4-(cyclopropylmethoxy)pyridine (1.15 g, 3.65 mmol, Eq: 1.00) in Dioxane (25 mL) under an argon atmosphere was added copper (I) cyanide (1.31 g, 14.6 mmol, Eq: 4.0), tetraethylammonium cyanide (570 mg, 3.65 mmol, Eq: 1.00), dppf (323 mg, 583 mol, Eq: 0.16) and Pd.sub.2(dba).sub.3 (134 mg, 146 mol, Eq: 0.04). The resulting reaction mixture was stirred at 110 C. for 4 h. Reaction mixture was filtered over a pad of Celite, and the filtrate was poured into a separatory funnel. After dilution with ethyl acetate, extraction with aqueous NaHCO.sub.3 1M, the organic phase was collected, dried and evaporated down to dryness. Flash chromatography with a 50 g SiO.sub.2 column, and an eluent mixture of heptane and ethyl acetate gave 392 mg of the desired product (Yield 50%). MS (ESI, m/z): 215.3 (MH.sup.+).

e) 5-cyclopropyl-4-(cyclopropylmethoxy)picolinic acid

(11) ##STR00037##

(12) To a solution of 5-cyclopropyl-4-(cyclopropylmethoxy)picolinonitrile (200 mg, 933 mol, Eq: 1.00) in water (4 mL) was added potassium hydroxide (786 mg, 14.0 mmol, Eq: 15.0). The reaction was stirred at 110 C. overnight and monitored by TLC. KOH was neutralized using HCl aqueous solution and the pH was adjusted to 1-2. Afterwards an extraction with DCM/MeOH (4:1) was made and the organic phase was collected, dried and the solvent evaporated. The crude material was purified by MPLC ISCO on SiO.sub.2 column giving 200 mg of compound as a white powder (Yield 92%). MS (ESI, m/z): 234.6 (MH.sup.+).

f) 5-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-3-methyl-1,2,4-oxadiazole

(13) ##STR00038##

(14) In a micro-wave vial with DMF (1.5 mL), 5-cyclopropyl-4-(cyclopropylmethoxy)picolinic acid (46.7 mg, 200 mol, Eq: 1.00) was combined with CDI (32.4 mg, 200 mol, Eq: 1.0). The reaction mixture was stirred for 30 min at room temperature under Argon. N-hydroxyacetimidamide (CAS 22059-22-9) (14.8 mg, 200 mol, Eq: 1.0) was added. The reaction mixture was stirred for 1 h, and then heated to 130 C. with microwave for another 1 h. The reaction was controlled by LC-MS which showed complete conversion. The reaction mixture was directly purified by preparative HPLC without any work-up. MS (ESI, m/z): 272.5 (MH+).

Example 2

5-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-3-phenyl-1,2,4-oxadiazole

(15) ##STR00039##

(16) The title compound was synthesized in analogy to Example 1f, using 5-cyclopropyl-4-(cyclopropylmethoxy)picolinic acid and N-hydroxybenzimidamide (CAS 613-92-3) as starting materials, and directly purified by preparative HPLC without any work-up. MS (ESI, m/z): 334.5 (MH+).

Example 3

3-cyclopropyl-5-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole

(17) ##STR00040##

(18) The title compound was synthesized in analogy to Example 1f, using 5-cyclopropyl-4-(cyclopropylmethoxy)picolinic acid and N-hydroxycyclopropanecarboximidamide (CAS 51285-13-3) as starting materials, and directly purified by preparative HPLC without any work-up. MS (ESI, m/z): 298.5 (MH+).

Example 4

3-cyclopentyl-5-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole

(19) ##STR00041##

(20) The title compound was synthesized in analogy to Example 1f, using 5-cyclopropyl-4-(cyclopropylmethoxy)picolinic acid and N-hydroxycyclopentanecarboximidamide (CAS 99623-12-8) as starting materials, and directly purified by preparative HPLC without any work-up. MS (ESI, m/z): 326.3 (MH+).

Example 5

3-benzyl-5-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole

(21) ##STR00042##

(22) The title compound was synthesized in analogy to Example 1f, using 5-cyclopropyl-4-(cyclopropylmethoxy)picolinic acid and N-hydroxy-2-phenylacetimidamide (CAS 19227-11-3) as starting materials, and directly purified by preparative HPLC without any work-up. MS (ESI, m/z): 348.2 (MH+).

Example 6

3-tert-butyl-5-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole

(23) ##STR00043##

(24) The title compound was synthesized in analogy to Example 1f, using 5-cyclopropyl-4-(cyclopropylmethoxy)picolinic acid and N-hydroxypivalimidamide (CAS 42956-75-2) as starting materials, and directly purified by preparative HPLC without any work-up. MS (ESI, m/z): 314.2 (MH+).

Example 7

3-cyclopropyl-5-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole

a) 3-bromo-4-(2,2,2-trifluoroethoxy)pyridine

(25) ##STR00044##

(26) To a solution of 3-bromo-4-chloropyridine (CAS 36953-42-1) (25 g, 130 mmol, Eq: 1.00) in DMF (333 mL) was added 2,2,2-trifluoroethanol (CAS 75-89-8) (19.5 g, 195 mmol, Eq: 1.5) and potassium tert-butoxide (21.9 g, 195 mmol, Eq: 1.5). The reaction was stirred overnight at 110 C. The solvent was partially evaporated and partitioned between NaHCO.sub.3 aqueous saturated solution and ethyl acetate. The organic layer was dried over Na.sub.2SO.sub.4 and evaporated. Product used as a crude (85% yield). MS (ESI, m/z): 257.3 (MH+).

b) 3-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine

(27) ##STR00045##

(28) To a solution of 3-bromo-4-(2,2,2-trifluoroethoxy)pyridine (28.44 g, 88.9 mmol, Eq: 1.00) in a mixture of toluene (275 mL) and water (32.5 mL) was added potassium cyclopropyltrifluoroborate (CAS 1065010-87-8) (14.5 g, 97.8 mmol, Eq: 1.1), palladium (II) acetate (798 mg, 3.55 mmol, Eq: 0.04), butyldi-1-Adamantylphosphine (1.27 g, 3.55 mmol, Eq: 0.04) and Cs.sub.2CO.sub.3 (72.4 g, 222 mmol, Eq: 2.5) under an argon atmosphere. The reaction mixture was stirred over night at 115 C. and controlled by TLC. The reaction mixture was extracted with ethyl acetate and water. The organic phase was dried over Na.sub.2SO.sub.4 and evaporated down to dryness. The crude material was purified by MPLC ISCO on SiO.sub.2 column with a gradient heptane in ethyl acetate giving yellow viscous oil (Yield 72%). MS (ESI, m/z): 218.5 (MH+).

c) 3-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine 1-oxide

(29) ##STR00046##

(30) To a solution of 3-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine (13.89 g, 64 mmol, Eq: 1.00) in DCM (355 mL) was added m-CPBA (16.6 g, 95.9 mmol, Eq: 1.5). Reaction was stirred overnight at RT. Extraction with NaHCO.sub.3 saturated aqueous solution and DCM. Organic layer was dried on Na.sub.2SO.sub.4 and evaporated. Column on SiO.sub.2 using MPLC ISCO with a gradient DCM/MeOH (Yield 68%). MS (ESI, m/z): 234.5 (MH+).

d) 5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinonitrile

(31) ##STR00047##

(32) 3-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine 1-oxide (10.20 g, 43.7 mmol, Eq: 1.00) was dissolved in DCM (163 mL). Trimethylsilanecarbonitrile (CAS 7677-24-9) (5.64 g, 7.11 mL, 56.9 mmol, Eq: 1.3) was then added dropwise followed by dimethylcarbamic chloride (7.06 g, 6.03 mL, 65.6 mmol, Eq: 1.5). The reaction mixture was stirred at room temperature over night. Saturated aqueous NaHCO.sub.3 (20 mL) was added with stirring. The reaction mixture was poured into DCM and extracted with H.sub.2O. The organic layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude material was purified by flash chromatography on SiO.sub.2 using MPLC ISCO with a gradient heptane in ethyl acetate (Yield 64%). MS (ESI, m/z): 243.5 (MH+).

e) 5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinic acid

(33) ##STR00048##

(34) 5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinonitrile (6.87 g, 28.4 mmol, Eq: 1.00) was dissolved in HCl 25% aqueous sol (170 mL, 1.4 mol, Eq: 50.0). Reaction was heated at 110 C. After 3 h reaction was complete. Reaction was cooled down to RT. HCl was neutralized using 6M NaOH aqueous solution followed by NaOH pellets. Then the pH was adjusted to 1-2 with HCl 2M. The precipitate formed was filtered off to give title compound (Yield 99%). MS (ESI, m/z): 262.5 (MH+).

f) 3-cyclopropyl-5-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole

(35) ##STR00049##

(36) To a solution of 5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinic acid (50 mg, 191 mol, Eq: 1.00) in dry DMF (1.5 mL) was added CDI (34.1 mg, 211 mol, Eq: 1.1) and reaction stirred for 30 min at RT N-hydroxycyclopropanecarboximidamide (CAS 51285-13-3) (211 mol, Eq: 1.1) was added, stirred for 1 h at RT and after that overnight at 120 C. The reaction mixture was controlled by LC-MS. The reaction was directly purified by preparative HPLC without any further work-up. MS (ESI, m/z): 326 (MH+).

Example 8

5-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-3-(trifluoromethyl)-1,2,4-oxadiazole

(37) ##STR00050##

(38) The title compound was synthesized in analogy to Example 7f, using 5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinic acid and 2,2,2-trifluoro-N-hydroxyacetimidamide (CAS 4314-35-6) as starting materials, and directly purified by preparative HPLC without any further work-up. MS (ESI, m/z): 354 (MH+).

Example 9

5-cyclopropyl-3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole

a) 5-cyclopropyl-4-(cyclopropylmethoxy)-N-hydroxypicolinimidamide

(39) ##STR00051##

(40) To a solution of 5-cyclopropyl-4-(cyclopropylmethoxy)picolinonitrile (synthesis described previously as Example 1d) (390 mg, 1.82 mmol, Eq: 1.00) in EtOH (4 mL) was added hydroxylamine hydrochloride (126 mg, 1.82 mmol, Eq: 1.00) and triethylamine (184 mg, 254 L, 1.82 mmol, Eq: 1.00). The reaction mixture was stirred at 70 C. for 4 h and controlled by LC-MS which showed complete conversion to the desired product. The reaction mixture was diluted with ethyl acetate, poured into a separatory funnel, washed with water, and the organic phase dried over Na.sub.2SO.sub.4 and evaporated down to dryness. Flash chromatography with a 20 g SiO.sub.2 column, eluent mixture of DCM and MeOH gave 418 mg of the desired product (Yield 88%). MS (ESI, m/z): 248.2 (MH+).

b) 5-cyclopropyl-3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole

(41) ##STR00052##

(42) To a solution of cyclopropanecarboxylic acid (CAS 1759-53-1) (179 mol, Eq: 1.05) in dry DMF (1.0 mL) was added CDI (28.9 mg, 179 mol, Eq: 1.05) and the resulting reaction mixture was stirred at RT for 45 min, followed by addition of 5-cyclopropyl-4-(cyclopropylmethoxy)-N-hydroxypicolinimidamide (42.0 mg, 170 mol, Eq: 1.00). The reaction was then stirred at RT for 2 h and controlled by LC-MS which showed complete consumption of the starting material to produce the intermediate. The reaction was then heated at 130 C. in a micro-wave for 45 min, controlled by LC-MS. The reaction was directly purified by preparative HPLC without any work-up. MS (ESI, m/z): 298.4 (MH+).

Example 10

5-tert-butyl-3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole

(43) ##STR00053##

(44) The title compound was synthesized in analogy to Example 9b, using pivalic acid (CAS 75-98-9) and 5-cyclopropyl-4-(cyclopropylmethoxy)-N-hydroxypicolinimidamide as starting materials, and directly purified by preparative HPLC without any work-up. MS (ESI, m/z): 354 (MH+).

Example 11

2-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-4,4-diethyl-5H-1,3-oxazole

a) 5-cyclopropyl-4-(cyclopropylmethoxy)-N-(3-(hydroxymethyl)pentan-3-yl)picolinamide

(45) ##STR00054##

(46) To a solution of 5-cyclopropyl-4-(cyclopropylmethoxy)picolinic acid (previously described as Example 1e) (50 mg, 0.214 mmol, Eq: 1.00) in DCM (2 mL) was added 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (CAS 3945-69-5) (69.5 mg, 0.236 mmol, Eq: 1.1). The reaction was stirred 30 min at RT. Then 2-amino-2-ethylbutan-1-ol (27.6 mg, 0.236 mmol, Eq: 1.1) (CAS 39884-49-6) was added and the reaction stirred at RT overnight. LC-MS showed reaction was complete. Extraction with NaHCO.sub.3 saturated aqueous solution and columning on SiO.sub.2 with a gradient heptane/ethyl acetate gave 30 mg of the title compound (Yield 42%). MS (ESI, m/z): 333.3 (MH+).

b) 2-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-4,4-diethyl-5H-1,3-oxazole

(47) ##STR00055##

(48) To a solution of 5-cyclopropyl-4-(cyclopropylmethoxy)-N-(3-(hydroxymethyl)pentan-3-yl)picolinamide (34 mg, 102 mol, Eq: 1.00) (carefully dried) in dry THF was added Burgess reagent (25.6 mg, 107 mol, Eq: 1.05). Reaction was stirred at RT under argon overnight. LC-MS showed reaction was complete. Evaporation of the solvent and extraction with NaHCO.sub.3 saturated aqueous solution and ethyl acetate. Organic layer was dried on Na.sub.2SO.sub.4 and evaporated. Column on SiO.sub.2 with a gradient heptane/ethyl acetate (Yield 62%). MS (ESI, m/z): 315.2 (MH+).

Example 12

3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-5-(methoxymethyl)-1,2,4-oxadiazole

(49) ##STR00056##

(50) The title compound was synthesized in a similar manner as Example 9b, using 5-cyclopropyl-4-(cyclopropylmethoxy)-N-hydroxypicolinimidamide with potassium carbonate (Eq: 1.0) and 2-methoxyacetyl chloride (CAS 38870-89-2) as starting materials and, directly purified by preparative HPLC without any work-up. MS (ESI, m/z): 302.3 (MH+).

Example 13

3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-5-ethyl-1,2,4-oxadiazole

(51) ##STR00057##

(52) The title compound was synthesized in a similar manner as Example 9b, using 5-cyclopropyl-4-(cyclopropylmethoxy)-N-hydroxypicolinimidamide with potassium carbonate (Eq: 1.0) and propionyl chloride (CAS 79-03-8) as starting materials, and directly purified by preparative HPLC without any work-up. MS (ESI, m/z): 286.2 (MH+).

Example 14

3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-5-propan-2-yl-1,2,4-oxadiazole

(53) ##STR00058##

(54) The title compound was synthesized in a similar manner as Example 9b, using 5-cyclopropyl-4-(cyclopropylmethoxy)-N-hydroxypicolinimidamide with potassium carbonate (Eq: 1.0) and isobutyryl chloride (CAS 79-30-1) as starting materials, and directly purified by preparative HPLC without any work-up. MS (ESI, m/z): 300.3 (MH+).

Example 15

3-cyclopropyl-5-[5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole

a) 3-bromo-4-(2,2,2-trifluoroethoxy)pyridine 1-oxide

(55) ##STR00059##

(56) To a solution of 3-bromo-4-(2,2,2-trifluoroethoxy)pyridine (previously described as Example 7a) (21 g, 67.3 mmol, Eq: 1.00) in DCM (400 mL) was added by portions m-CPBA (19.6 g, 87.4 mmol, Eq: 1.3). The reaction mixture was then stirred over the week-end at RT and monitored by LC-MS. Reaction mixture was poured into a separatory funnel and extracted with aqueous NaHCO.sub.3 1M. Aqueous phase was back-extracted with a mixture of ethyl acetate and organic phases were combined, dried over Na.sub.2SO.sub.4 and evaporated down to dryness. Flash chromatography with a 330 g SiO.sub.2 column, eluent mixture of DCM and MeOH giving 16.2 g of the desired product (Yield 88%). MS (ESI, m/z): 272.3 (M).

b) 5-bromo-4-(2,2,2-trifluoroethoxy)picolinonitrile

(57) ##STR00060##

(58) 3-bromo-4-(2,2,2-trifluoroethoxy)pyridine 1-oxide (21.5 g, 79 mmol, Eq: 1.00) was combined with DCM (344 mL). Trimethylsilanecarbonitrile (11.8 g, 14.8 mL, 119 mmol, Eq: 1.5) was then added dropwise followed by dimethylcarbamic chloride (12.7 g, 10.9 mL, 119 mmol, Eq: 1.5). The reaction mixture was stirred at room temperature over night. Saturated aqueous NaHCO.sub.3 (20 mL) was added with stirring. The reaction mixture was poured into DCM and extracted with H.sub.2O. The organic layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude material was purified by flash chromatography on SiO.sub.2 using MPLC ISCO with a eluent gradient of heptane/ethyl acetate (Yield 27%). MS (ESI, m/z): 281.3 (M).

c) 5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)picolinonitrile

(59) ##STR00061##

(60) To a solution of 5-bromo-4-(2,2,2-trifluoroethoxy)picolinonitrile (587 mg, 2.09 mmol, Eq: 1.00) in dry toluene (10.4 mL) in a schlenk tube was added 3,3-difluoroazetidine hydrochloride (CAS 288315-03-7) (298 mg, 2.3 mmol, Eq: 1.1), Cs2CO3 (1.36 g, 4.18 mmol, Eq: 2.0), Pd(OAc).sub.2 (46.9 mg, 209 mol, Eq: 0.1) and BINAP (130 mg, 209 mol, Eq: 0.1). The reaction mixture was heated to 120 C. and stirred for 1 h. Reaction mixture filtered over a pad of Celite, diluted with ethyl acetate, organic phase extracted with aqueous saturated NaHCO.sub.3, dried over Na.sub.2SO.sub.4 and evaporated down to dryness. The crude material was purified by flash chromatography (SiO.sub.2, 50 g, gradient ethyl acetate in heptane) giving 480 mg (Yield 78%) of the desired compound. MS (ESI, m/z): 294.2 (MH+).

d) 5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)picolinic acid

(61) ##STR00062##

(62) To a solution of 5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)picolinonitrile (680 mg, 2.32 mmol, Eq: 1.00) in EtOH (7.73 mL) in a schlenk tube was added KOH 4M aqueous solution (651 mg, 11.6 mmol, Eq: 5.0). The reaction mixture was heated to 105 C. and stirred for 2 h. The reaction mixture was poured in a separatory funnel with a mixture of ethyl acetate and HCl 6.9M (2.69 mL, 18.6 mmol, Eq: 8.0) and water, extraction, the organic phase were collected, dried over Na.sub.2SO.sub.4 and evaporated down to give 397 mg of the desired product as an off-white solid (Yield 54%). MS (ESI, m/z): 311.2 (MH).

e) 3-cyclopropyl-5-[5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole

(63) ##STR00063##

(64) In a 5 mL sealed vial, 5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)picolinic acid (100 mg, 320 mol, Eq: 1.00) and CDI (54.5 mg, 336 mol, Eq: 1.05) were combined with DMF (1.5 mL). The reaction mixture was stirred at room temp for 30 min. N-hydroxycyclopropanecarboximidamide (CAS 51285-13-3) (336 mol, Eq: 1.05) was added and the mixture was stirred at room temp for 1 h. The reaction mixture was then heated to 120 C. for 4 h. The reaction mixture was poured into EtOAc and extracted with saturated NaHCO.sub.3 aqueous solution. The organic layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude material was purified by flash chromatography (SiO.sub.2, 10 g, with a gradient ethyl acetate in heptane) to give 33.6 mg of the title compound (Yield 27%). MS (ESI, m/z): 377.4 (MH+).

Example 16

5-[5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-3-methyl-1,2,4-oxadiazole

(65) ##STR00064##

(66) The title compound was synthesized in analogy to Example 15e, using 5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)picolinic acid and N-hydroxyacetimidamide (CAS 22059-22-9) as starting materials, and directly purified by flash chromatography (SiO.sub.2, 10 g, gradient ethyl acetate in heptane) giving 26 mg of desired compound (Yield 23%). MS (ESI, m/z): 351.2 (MH+).

Example 17

3-tert-butyl-5-[5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole

(67) ##STR00065##

(68) The title compound was synthesized in analogy to Example 15e, using 5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)picolinic acid and N-hydroxypivalimidamide (CAS 42956-75-2) as starting materials, and directly purified by flash chromatography (SiO.sub.2, 10 g, gradient ethyl acetate in heptane giving 55 mg of desired compound (Yield 44%). MS (ESI, m/z): 393.3 (MH+).

Example 18

[3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazol-5-yl]methanol

(69) ##STR00066##

(70) The title compound was synthesized in a similar manner as Example 9b, using 5-cyclopropyl-4-(cyclopropylmethoxy)-N-hydroxypicolinimidamide with potassium carbonate (Eq: 1.00) and 2-methoxyacetyl chloride (CAS 38870-89-2) as starting materials and after microwave heating was followed by addition of NaOH 4M aqueous solution (Eq: 1.5) Reaction was stirred overnight at 80 C. and directly purified by preparative HPLC without any work-up. MS (ESI, m/z): 288.1 (MH+).

Example 19

3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-5-(trifluoromethyl)-1,2,4-oxadiazole

(71) ##STR00067##

(72) The title compound was synthesized in a similar manner as Example 9b, using 5-cyclopropyl-4-(cyclopropylmethoxy)-N-hydroxypicolinimidamide with triethylamine (Eq: 1.1) and 2,2,2-trifluoroacetic anhydride (CAS 407-25-0) as starting materials in DCM and heated at 70 C. with microwave. Solvent was removed in vacuo, residue redissolved in DMF and directly purified by preparative HPLC to give the desired compound. MS (ESI, m/z): 326.2 (MH+).

Example 20

(4S)-4-tert-butyl-2-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-4,5-dihydro-1,3-oxazole

(73) ##STR00068##

(74) The title compound was synthesized in analogy to Example 11, using 5-cyclopropyl-4-(cyclopropylmethoxy)picolinic acid (previously described as Example 1e) and (S)-2-amino-3,3-dimethylbutan-1-ol (CAS 112245-13-3) as starting materials for the first step. MS (ESI, m/z): 315.2 (MH+).

Example 21

2-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-4-ethyl-4,5-dihydro-1,3-oxazole

(75) ##STR00069##

(76) The title compound was synthesized in analogy to Example 11, using 5-cyclopropyl-4-(cyclopropylmethoxy)picolinic acid (previously described as Example 1e) and 2-aminobutan-1-ol (CAS 96-20-8) as starting materials for the first step. MS (ESI, m/z): 287.2 (MH+).

Example 22

2-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-3-oxa-1-azaspiro[4.5]dec-1-ene

(77) ##STR00070##

(78) The title compound was synthesized in analogy to Example 11, using 5-cyclopropyl-4-(cyclopropylmethoxy)picolinic acid (previously described as Example 1e) and (1-aminocyclohexyl)methanol (CAS 4313-56-8) as starting materials for the first step. MS (ESI, m/z): 327.3 (MH+).

Example 23

1-[3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazol-5-yl]cyclopropan-1-ol

(79) ##STR00071##

(80) The title compound was synthesized in analogy to Example 9b, using 1-hydroxycyclopropanecarboxylic acid (CAS 17994-25-1) and 5-cyclopropyl-4-(cyclopropylmethoxy)-N-hydroxypicolinimidamide as starting materials, and directly purified by preparative HPLC without any work-up. MS (ESI, m/z): 314.0 (MH+).

Example 24

3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-5-(1-methylcyclopropyl)-1,2,4-oxadiazole

(81) ##STR00072##

(82) The title compound was synthesized in analogy to Example 9b, using 1-methylcyclopropanecarboxylic acid (CAS 6914-76-7) and 5-cyclopropyl-4-(cyclopropylmethoxy)-N-hydroxypicolinimidamide as starting materials, and directly purified by preparative HPLC without any work-up. MS (ESI, m/z): 312.1 (MH+).

Example 25

1-[3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboxamide

(83) ##STR00073##

(84) The title compound was synthesized in analogy to Example 9b, using 1-carbamoylcyclopropanecarboxylic acid (CAS 6914-74-5) and 5-cyclopropyl-4-(cyclopropylmethoxy)-N-hydroxypicolinimidamide as starting materials, and directly purified by preparative HPLC without any work-up. MS (ESI, m/z): 341.1 (MH+).

Example 26

2-[3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazol-5-yl]propan-2-ol

(85) ##STR00074##

(86) The title compound was synthesized in analogy to Example 9b, using 2-hydroxy-2-methylpropanoic acid (CAS 594-61-6) and 5-cyclopropyl-4-(cyclopropylmethoxy)-N-hydroxypicolinimidamide as starting materials, and directly purified by preparative HPLC without any work-up. MS (ESI, m/z): 316.2 (MH+).

Example 27

2-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-4,4-diethyl-5H-1,3-oxazole

(87) ##STR00075##

(88) The title compound was synthesized in analogy to Example 11, using 5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinic acid (previously described as Example 7e) and 2-amino-2-ethylbutan-1-ol (CAS 39884-49-6) as starting materials for the first step. MS (ESI, m/z): 343.2 (MH+).

Example 28

3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-5-(3-methyloxetan-3-yl)-1,2,4-oxadiazole

(89) ##STR00076##

(90) The title compound was synthesized in analogy to Example 9b, using 3-methyloxetane-3-carboxylic acid (CAS 28562-68-7) and 5-cyclopropyl-4-(cyclopropylmethoxy)-N-hydroxypicolinimidamide as starting materials, and directly purified by preparative HPLC without any work-up. MS (ESI, m/z): 328.3 (MH+).

Example 29

5-(azetidin-3-yl)-3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole

(91) ##STR00077##

(92) The title compound was synthesized in analogy to Example 9b, using 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (CAS 142253-55-2) and 5-cyclopropyl-4-(cyclopropylmethoxy)-N-hydroxypicolinimidamide as starting materials followed by deprotection of the Boc group by evaporation of the DMF, crude redissolved in TFA. The reaction was stirred at RT for 30 min, volatiles were removed in vacuo and residue was redissolved in ethyl acetate. Organic phase was extracted with aqueous NaOH 1M, dried over Na.sub.2SO.sub.4 and evaporated down to dryness. Crude was purified by preparative HPLC. MS (ESI, m/z): 313.1 (MH+).

Example 30

2-[5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-4,4-diethyl-5H-1,3-oxazole

(93) ##STR00078##

(94) The title compound was synthesized in a similar manner as Example 11, using 5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)picolinic acid (previously described as Example 15d) and 2-amino-2-ethylbutan-1-ol (CAS 39884-49-6) as starting materials for the first step. MS (ESI, m/z): 394.0 (MH+).

Example 31

2-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-3-oxa-1-azaspiro[4.5]dec-1-ene

(95) ##STR00079##

(96) The title compound was synthesized in analogy to Example 11, using 5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinic acid (previously described as Example 7e) and (1-aminocyclohexyl)methanol (CAS 4313-56-8) as starting materials for the first step. MS (ESI, m/z): 355.5 (MH+).

Example 32

5-tert-butyl-3-[4-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]-1,2,4-oxadiazole

a) 3-bromo-4-(cyclopropylmethoxy)pyridine 1-oxide

(97) ##STR00080##

(98) In a 250 mL pear-shaped flask, 3-bromo-4-(cyclopropylmethoxy)pyridine, previously described as Example 1a, (3.7 g, 16.2 mmol, Eq: 1.00) was combined with DCM (81.1 mL) to give a colorless solution. m-CPBA (5.45 g, 24.3 mmol, Eq: 1.5) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured into 250 mL DCM and extracted with 1M NaHCO.sub.3. The organic layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude material was purified by flash chromatography (SiO.sub.2, 120 g, gradient MeOH in DCM) giving 3.39 g of the title compound as a white solid (Yield 85%). MS (ESI, m/z): 244.2 (M).

b) 5-bromo-4-(cyclopropylmethoxy)picolinonitrile

(99) ##STR00081##

(100) To a solution of 3-bromo-4-(cyclopropylmethoxy)pyridine 1-oxide (9.5 g, 38.9 mmol, Eq: 1.00) in dry DCM (160 mL) cooled down to 0 C. and under argon atmosphere was slowly added TMS-CN (5.79 g, 7.83 mL, 58.4 mmol, Eq: 1.5) followed by addition of dimethylcarbamoyl chloride (6.28 g, 5.37 mL, 58.4 mmol, Eq: 1.5). The reaction mixture was then stirred at RT overnight and monitored by LC-MS which showed complete consumption of the starting material. Addition of aqueous Na.sub.2CO.sub.3 2M solution and mixture was stirred for 10 min, then poured into a separatory funnel, addition of water and extraction. Organic phase collected, dried over Na.sub.2SO.sub.4 and evaporated down to dryness. Flash chromatography with a 120 g SiO.sub.2 column, eluent mixture of heptane and ethyl acetate giving 3.52 g of the desired isomer (Yield 36%). MS (ESI, m/z): 253.4 (M).

c) 5-bromo-4-(cyclopropylmethoxy)-N-hydroxypicolinimidamide

(101) ##STR00082##

(102) To a solution of 5-bromo-4-(cyclopropylmethoxy)picolinonitrile (0.75 g, 2.96 mmol, Eq: 1.00) in EtOH (8 mL) was added hydroxylamine hydrochloride (309 mg, 4.44 mmol, Eq: 1.5) and triethylamine (450 mg, 620 L, 4.44 mmol, Eq: 1.5). The reaction mixture was then stirred at 70 C. for 45 min under microwave radiation and reaction monitored by TLC (eluent: ethyl acetate). Reaction mixture was poured into a separatory funnel, diluted with ethyl acetate, extracted with aqueous NaHCO.sub.3 1M. Organic phase dried over Na.sub.2SO.sub.4 and evaporated down to dryness. Flash chromatography with a 50 g SiO.sub.2 column, eluent mixture of heptane and ethyl acetate giving 482 mg of the desired product (Yield 57%). MS (ESI, m/z): 286.3 (M).

d) 3-(5-bromo-4-(cyclopropylmethoxy)pyridin-2-yl)-5-tert-butyl-1,2,4-oxadiazole

(103) ##STR00083##

(104) To a solution of 5-bromo-4-(cyclopropylmethoxy)-N-hydroxypicolinimidamide (2.1 g, 7.34 mmol, Eq: 1.00) in dry DMF (25 mL) under argon atmosphere at 0 C. was added potassium carbonate (1.12 g, 8.07 mmol, Eq: 1.1) followed by slow addition of pivaloyl chloride (CAS 3282-30-2) (929 mg, 948 L, 7.71 mmol, Eq: 1.05). The resulting reaction was stirred for 15 min at 0 C. and then stirred for 30 min at RT, reaction was monitored by LC-MS. The reaction was then stirred at 130 C. under microwave radiation for 30 min and controlled by LC-MS which showed complete conversion to the desired product. Removal of DMF in vacuo, residue redissolved in ethyl acetate and solution was poured into a separatory funnel. Extraction with aqueous NaHCO.sub.3 1M, organic phase dried over Na.sub.2SO.sub.4 and evaporated down to dryness. Flash chromatography with a 70 g SiO.sub.2 column, eluent mixture of heptane and ethyl acetate giving 2.4 g of the desired product (Yield 93%). MS (ESI, m/z): 352.4 (M).

e) 5-tert-butyl-3-[4-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]-1,2,4-oxadiazole

(105) ##STR00084##

(106) To a solution of 3-(5-bromo-4-(cyclopropylmethoxy)pyridin-2-yl)-5-tert-butyl-1,2,4-oxadiazole (0.06 g, 170 mol, Eq: 1.00) in dry toluene (1 mL) under argon atmosphere was added 3,3-difluoroazetidine hydrochloride (CAS 288315-03-7) (24.3 mg, 187 mol, Eq: 1.1), Pd(OAc).sub.2 (3.82 mg, 17.0 mol, Eq: 0.1), BINAP (10.6 mg, 17.0 mol, Eq: 0.1) and Cs.sub.2CO.sub.3 (111 mg, 341 mol, Eq: 2.0). The reaction mixture was stirred at 130 C. for 60 min under microwave radiation and monitored by LC-MS. The reaction mixture was filtered over a pad of Celite, filtrate was evaporated down and dissolved in 1 mL DMSO. Purification was done by preparative HPLC without any prior work-up. MS (ESI, m/z): 365.5 (MH+).

Example 33

5-tert-butyl-3-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole

a) 5-cyclopropyl-N-hydroxy-4-(2,2,2-trifluoroethoxy)picolinimidamide

(107) ##STR00085##

(108) To a solution of 5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinonitrile, previously described as Example 7d, (1.62 g, 6.69 mmol, Eq: 1.00) in EtOH (13.0 mL) the following was added hydroxylamine hydrochloride (465 mg, 6.69 mmol, Eq: 1.0) and triethylamine (677 mg, 932 L, 6.69 mmol, Eq: 1.0). The reaction was stirred for 3 h at 70 C. and monitered with LC-MS. Another 0.5 Eq. of Hydroxylamine hydrochloride (232 mg) and triethylamine (465 L) were added as complete conversion had not taken place. The reaction was stirred for a further 3 h at 70 C. The reaction mixture was poured into a separating funnel, ethyl acetate was added and the mixture was extracted with aqueous NaHCO.sub.3 1M. The organic phase was dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude material was purified by flash chromatography on SiO.sub.2, 20 g, gradient ethyl acetate in heptane giving 650 mg of the title compound as a white powder (yield 35%). MS (ESI, m/z): 276.5 (MH+).

b) 5-tert-butyl-3-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole

(109) ##STR00086##

(110) To a solution of 5-cyclopropyl-N-hydroxy-4-(2,2,2-trifluoroethoxy)picolinimidamide (0.080 g, 291 mol, Eq: 1.00) in dry DMF (1.29 mL) under argon atmosphere was added K.sub.2CO.sub.3 (40.2 mg, 291 mol, Eq: 1.0) followed by pivaloyl chloride (CAS 3282-30-2) (35.0 mg, 35.8 L, 291 mol, Eq: 1.0). The reaction was stirred at RT for 45 min and controlled by LC-MS which showed complete conversion to the intermediate. The reaction mixture was stirred overnight at 120 C. and controlled by LC-MS which showed complete conversion to the desired product. The reaction mixture was diluted with ethyl acetate, poured into a separatory funnel and extracted with water. The organic phase was dried over Na.sub.2SO.sub.4 and evaporated down to dryness. The crude material was purified by flash chromatography (SiO.sub.2, 10 g, gradient ethyl acetate in heptane) giving 55 mg of the title compound as a light yellow waxy solid (Yield 55%). MS (ESI, m/z): 342.5 (MH+).

Example 34

3-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-5-(1-methylcyclopropyl)-1,2,4-oxadiazole

(111) ##STR00087##

(112) The title compound was synthesized in analogy to Example 9b, using 1-methylcyclopropanecarboxylic acid (CAS 6914-76-7) and 5-cyclopropyl-N-hydroxy-4-(2,2,2-trifluoroethoxy)picolinimidamide, described as Example 33a, as starting materials, and directly purified by preparative HPLC without any work-up. MS (ESI, m/z): 340.4 (MH+).

Example 35

1-[6-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-4-(cyclopropylmethoxy)pyridin-3-yl]-6-oxa-1-azaspiro[3.3]heptane

(113) ##STR00088##

(114) The title compound was synthesized in analogy to Example 32e, using 3-(5-bromo-4-(cyclopropylmethoxy)pyridin-2-yl)-5-tert-butyl-1,2,4-oxadiazole and 6-oxa-1-azaspiro[3.3]heptane hemioxalate (CAS 1359655-43-8) as starting materials, and purified by preparative HPLC. MS (ESI, m/z): 371.4 (MH+).

Example 36

3-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-5-propan-2-yl-1,2,4-oxadiazole

(115) ##STR00089##

(116) The title compound was synthesized in analogy to Example 33b, using 5-cyclopropyl-N-hydroxy-4-(2,2,2-trifluoroethoxy)picolinimidamide and isobutyryl chloride (CAS 79-30-1) as starting materials, and purified by purified by flash chromatography. MS (ESI, m/z): 328.1 (MH+).

Example 37

1-[3-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazol-5-yl]cyclopropan-1-ol

(117) ##STR00090##

(118) The title compound was synthesized in analogy to Example 9b, using 1-hydroxycyclopropanecarboxylic acid (CAS 17994-25-1) and 5-cyclopropyl-N-hydroxy-4-(2,2,2-trifluoroethoxy)picolinimidamide (described as Example 33a) as starting materials, and directly purified by preparative HPLC without any work-up. MS (ESI, m/z): 342.1 (MH+).

Example 38

3-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-5-(3-methyloxetan-3-yl)-1,2,4-oxadiazole

(119) ##STR00091##

(120) The title compound was synthesized in analogy to Example 9b, using 3-methyloxetane-3-carboxylic acid (CAS 28562-68-7) and 5-cyclopropyl-N-hydroxy-4-(2,2,2-trifluoroethoxy)picolinimidamide (described as Example 33a) as starting materials, and purified by purified by flash chromatography. MS (ESI, m/z): 356.5 (MH+).

Example 39

3-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole

(121) ##STR00092##

(122) 5-cyclopropyl-N-hydroxy-4-(2,2,2-trifluoroethoxy)picolinimidamide, described as Example 33a, (60 mg, 218 mol, Eq: 1.00) was combined with DCM (2.6 mL) and treated with triethyl orthoformate (129 mg, 145 L, 872 mol, Eq: 4.0) under Nitrogen. The resulting solution was then treated with boron trifluoride etherate (3.09 mg, 2.76 L, 21.8 mol, Eq: 0.1) and allowed to stire for 2 h at RT. 0.5 more equivalents of triethyl orthoformate (16.1 mg) and 0.1 equivalents of boron triflouride etherate (0.773 mg) were added and the mixture left to stir overnight. The mixture was brought up to a basic pH with NaHCO.sub.3 and extracted with DCM. The aqueous layer was then extracted with ethyl acetate two times. The organic layers were combined, dried and concentrated in vacuo. The crude material was purified by flash chromatography (SiO.sub.2, 10 g, gradient ethyl acetate in heptane) giving 48 mg of the title compound as a white solid (Yield 77%). MS (ESI, m/z): 286.4 (MH+).

Example 40

3-tert-butyl-5-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole

(123) ##STR00093##

(124) The title compound was synthesized in analogy to Example 7f, using 5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinic acid and N-hydroxypivalimidamide (CAS 42956-75-2) as starting materials, and directly purified by preparative HPLC without any work-up. MS (ESI, m/z): 342.5 (MH+).

Example 41

2-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-5,5-dimethyl-4H-1,3-oxazole

(125) ##STR00094##

(126) The title compound was synthesized in a similar manner as Example 11, using 5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinic acid (previously described as Example 7e) and 1-amino-2-methylpropan-2-ol (CAS 2854-16-2) as starting materials for the first step. The second step differs as follow: To a solution of 5-cyclopropyl-N-(2-hydroxy-2-methylpropyl)-4-(2,2,2-trifluoroethoxy)picolinamide (60 mg, 0.181 mmol, Eq: 1.00) in DCM (900 L) was added methanesulfonic acid (59 L, 0.9 mmol, Eq: 5.0). Reaction was heated at 40 C. 2 h. LC-MS showed reaction was complete. Extraction with DCM/NaHCO.sub.3 saturated aqueous solution Organic layer was dried on MgSO.sub.4 and evaporated. Column on SiO.sub.2 with a gradient heptane/ethyl acetate. MS (ESI, m/z): 315.5 (MH.sup.+) to give 5.9 mg of the title compound as colorless viscous oil.

Example 42

5-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-3-propan-2-yl-1,2,4-oxadiazole

(127) ##STR00095##

(128) The title compound was synthesized in analogy to Example 7f, using 5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinic acid and N-hydroxyisobutyrimidamide (CAS 35613-84-4) as starting materials, and directly purified by preparative HPLC without any work-up. MS (ESI, m/z): 328.4 (MH+).

Example 43

5-tert-butyl-3-[4-(cyclopropylmethoxy)-5-methylsulfonylpyridin-2-yl]-1,2,4-oxadiazole

a) 5-tert-butyl-3-(4-(cyclopropylmethoxy)-5-(methylthio)pyridin-2-yl)-1,2,4-oxadiazole

(129) ##STR00096##

(130) To a solution of 3-(5-bromo-4-(cyclopropylmethoxy)pyridin-2-yl)-5-tert-butyl-1,2,4-oxadiazole, previously described as Example 32d, (0.08 g, 227 mol, Eq: 1.00) in dry DMF (1.5 mL) under argon atmosphere was added methanethiol, sodium salt (CAS 5188-07-8) (19.4 mg, 273 mol, Eq: 1.2) and the resulting reaction mixture was stirred at 100 C. overnight and controlled by TLC. Reaction mixture poured into a separatory funnel, dilution with ethlycetate, extraction with aqueous NaHCO.sub.3 1M. The aqueous phase was back-extracted with ethyl acetate, organic phase combined, dried over Na.sub.2SO.sub.4 and evaporated down to dryness. Flash chromatography with a 10 g SiO.sub.2 column, eluent mixture of heptane and ethyl acetate gave 49 mg of the desired product (Yield 67%). MS (ESI, m/z): 319.9 (MH+).

b) 5-tert-butyl-3-[4-(cyclopropylmethoxy)-5-methylsulfonylpyridin-2-yl]-1,2,4-oxadiazole

(131) ##STR00097##

(132) To a solution of 5-tert-butyl-3-(4-(cyclopropylmethoxy)-5-(methylthio)pyridin-2-yl)-1,2,4-oxadiazole (0.045 g, 141 mol, Eq: 1.00) in DCM (1 mL) was added m-CPBA (63.1 mg, 282 mol, Eq: 2.0). The reaction mixture was stirred at RT overnight and controlled by LC-MS. Only partial conversion to the sulfone and no more starting material but major product is the sulfoxide. Addition of m-CPBA (12.2 mg, 70.4 mol, Eq: 0.5) to the reaction mixture was stirred at RT for 2 h, control by LC-MS showed change in conversion but not total. The reaction was stopped anyway. Evaporation of the volatiles and residue was redissolved in DMSO for purification by preparative HPLC without any work-up giving 18.3 mg of the desired product (Yield 37%). MS (ESI, m/z): 352.5 (MH+).

Example 44

5-tert-butyl-3-[5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole

a) 5-(3,3-difluoroazetidin-1-yl)-N-hydroxy-4-(2,2,2-trifluoroethoxy)picolinimidamide

(133) ##STR00098##

(134) To a solution of 5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)picolinonitrile, previously described as Example 15c, (1 g, 3.41 mmol, Eq: 1.00) in EtOH (16.6 mL) was added hydroxylamine hydrochloride (261 mg, 156 L, 3.75 mmol, Eq: 1.1) and triethylamine (380 mg, 524 L, 3.75 mmol, Eq: 1.1). The reaction mixture was heated up to 70 C. and left for half an hour. LC-MS showed the reaction was complete. The reaction mixture was poured into a separatory funnel, ethyl acetate was added and the mixture was extracted with aqueous saturated NaHCO.sub.3 1M. The organic phase was dried over Na.sub.2SO.sub.4 and evaporated down to dryness to give 1.09 g of the desired compound as a white powder (yield 98%). MS (ESI, m/z): 327.2 (MH+).

b) 5-tert-butyl-3-[5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole

(135) ##STR00099##

(136) To a solution of 5-(3,3-difluoroazetidin-1-yl)-N-hydroxy-4-(2,2,2-trifluoroethoxy)picolinimidamide (0.08 g, 245 mol, Eq: 1.00) in dry DMF (1.09 mL) under argon atmosphere was added K.sub.2CO.sub.3 (37.3 mg, 270 mol, Eq: 1.1) followed by pivaloyl chloride (CAS 3282-30-2) (32.5 mg, 33.2 L, 270 mol, Eq: 1.1). The reaction was stirred at RT for 45 min and controlled by LC-MS which showed complete conversion to the intermediate. The reaction mixture was stirred overnight at 120 C. and controlled by LC-MS which showed complete conversion to the desired product. The reaction mixture was diluted with ethyl acetate, poured into a separatory funnel and extracted with water. The organic phase was dried over Na.sub.2SO.sub.4 and evaporated down to dryness. The crude material was purified by flash chromatography (SiO.sub.2, gradient ethyl acetate in heptane) giving 44 mg of the title compound as a white powder (Yield 45%). MS (ESI, m/z): 393.1 (MH+).

Example 45

3-[5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-5-propan-2-yl-1,2,4-oxadiazole

(137) ##STR00100##

(138) The title compound was synthesized in analogy to Example 44b, using 5-(3,3-difluoroazetidin-1-yl)-N-hydroxy-4-(2,2,2-trifluoroethoxy)picolinimidamide and isobutyryl chloride (CAS 79-30-1) as starting materials, and purified by purified by flash chromatography. MS (ESI, m/z): 379.1 (MH+).

Example 46

1-[3-[5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazol-5-yl]cyclopropan-1-ol

(139) ##STR00101##

(140) To a solution of 1-hydroxycyclopropanecarboxylic acid (CAS 17994-25-1) (27.5 mg, 270 mol, Eq: 1.1) in DMF (1.44 mL) was added CDI (43.7 mg, 270 mol, Eq: 1.1) and the resulting reaction mixture was stirred at RT for 45 min, followed by the addition of 5-(3,3-difluoroazetidin-1-yl)-N-hydroxy-4-(2,2,2-trifluoroethoxy)picolinimidamide, previously described as Example 44a, (80 mg, 245 mol, Eq: 1.00). The reaction was then stirred at RT for 2 h and monitored by LC-MS which showed complete consumption of the starting material to form the intermediate. The reaction mixture was then heated to 130 C. and left to stir overnight. The reaction was diluted with ethyl acetate and extracted with water. The organic layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude material was purified by flash chromatography (SiO.sub.2, 10 g, gradient ethyl acetate in heptane) giving 41.7 mg of the title compound as a white powder (Yield 43%). MS (ESI, m/z): 393.4 (MH+).

Example 47

3-[5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-5-(3-methyloxetan-3-yl)-1,2,4-oxadiazole

(141) ##STR00102##

(142) The title compound was synthesized in analogy to Example 46, using 3-methyloxetane-3-carboxylic acid (CAS 28562-68-7) and 5-(3,3-difluoroazetidin-1-yl)-N-hydroxy-4-(2,2,2-trifluoroethoxy)picolinimidamide as starting materials, and purified by purified by flash chromatography. MS (ESI, m/z): 407.5 (MH+).

Example 48

5-tert-butyl-3-[5-cyclopropyl-4-[(2S)-1,1,1-trifluoropropan-2-yl]oxypyridin-2-yl]-1,2,4-oxadiazole

a) 2,4-dichloro-5-cyclopropylpyridine

(143) ##STR00103##

(144) To a solution of 5-bromo-2,4-dichloropyridine (CAS 849937-96-8) (22.95 g, 96.1 mmol, Eq: 1.00) in Toluene (352 mL) and Water (48.0 mL) was added Pd(OAc).sub.2 (431 mg, 1.92 mmol, Eq: 0.02), butyldi-1-adamantylphosphine (1.03 g, 2.88 mmol, Eq: 0.03), potassium cyclopropyltrifluoroborate (CAS 1065010-87-8) (14.9 g, 101 mmol, Eq: 1.05) and Cs.sub.2CO.sub.3 (62.6 g, 192 mmol, Eq: 2.0). The resulting reaction mixture was stirred at 110 C. overnight and controlled by TLC. The reaction was found to be only partially complete so 0.5 more equivalents (7.5 g) of potassium cyclopropyltrifluororate were added (3 times). Reaction mixture concentrated in vacuo then diluted with ethyl acetate and the solution poured into a separatory funnel. Extraction with aqueous saturated NaHCO.sub.3, organic phase dried over NaSO.sub.4 and evaporated down to dryness. Flash chromatography with a 330 g SiO.sub.2 column, eluent mixture of heptane and ethyl acetate giving 7.39 g of the desired product (Yield 40%). MS (ESI, m/z): 188.2 (M).

b) 4-chloro-5-cyclopropylpicolinonitrile

(145) ##STR00104##

(146) To a solution of 2,4-dichloro-5-cyclopropylpyridine (7.35 g, 39.1 mmol, Eq: 1.00) dissolved in dry DMF (130 mL), dppf (1.73 g, 3.13 mmol, Eq: 0.08) was added followed by dicyanozinc (2.75 g, 23.5 mmol, Eq: 0.6) and Pd.sub.2dba.sub.3 (1.95 mmol, Eq: 0.05). Reaction was stirred at 100 C. for 2 h, controlled by TLC. Reaction mixture filtered on a pad of Celite, filtrate diluted with ethyl acetate, extraction with water, aqueous phase back-extracted with ethyl acetate, organic phase dried over Na.sub.2SO.sub.4 and concentrated in vacuo. Purification with a 330 g SiO.sub.2 column, eluent mixture of Heptane and EtOAc giving 6.82 g of the title compound as a yellow solid (Yield 97%). MS (ESI, m/z): 179.2 (MH+).

c) 4-chloro-5-cyclopropyl-N-hydroxypicolinimidamide

(147) ##STR00105##

(148) To a solution of 4-chloro-5-cyclopropylpicolinonitrile (3.2 g, 17.9 mmol, Eq: 1.00) in EtOH (120 mL) was added hydroxylamine hydrochloride (1.87 g, 26.9 mmol, Eq: 1.5) and triethylamine (5 mL, 35.8 mmol, Eq: 2.0). The reaction was heated at 90 C. and monitered with LC-MS. The reaction mixture was poured into a separating funnel, diluted with DCM and the mixture extracted with aqueous NaHCO.sub.3 saturated solution. The organic phase was dried over Na.sub.2SO.sub.4 and concentrated in vacuo to give a white crystalline solid (Yield 96%). MS (ESI, m/z): 212.5 (MH+).

d) 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole

(149) ##STR00106##

(150) To a solution of 4-chloro-5-cyclopropyl-N-hydroxypicolinimidamide (3.64 g, 17.2 mmol, Eq: 1.00) in dry DMF (115 mL) was added pivaloyl chloride (CAS 3282-30-2) (2.7 g, 2.75 mL, 22.4 mmol, Eq: 1.3) and triethylamine (4.79 mL, 34.4 mmol, Eq: 2.0). The reaction was stirred at RT 30 min. LC-MS showed formation of the intermediate. Reaction mixture was then heated at 110 C. overnight. Solvent was partially evaporated the crude extracted with ethyl acetate and NaHCO.sub.3 aqueous saturated solution. Organic layer was dried on Na.sub.2SO.sub.4 and evaporated. Column on SiO.sub.2 column using MPLC ISCO with a gradient ethyl acetate in heptane gave the title product as yellow viscous oil (Yield 77%). MS (ESI, m/z): 278.6 (MH+).

e) 5-tert-butyl-3-[5-cyclopropyl-4-[(2S)-1,1,1-trifluoropropan-2-yl]oxypyridin-2-yl]-1,2,4-oxadiazole

(151) ##STR00107##

(152) To a solution of 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole (0.05 g, 180 mol, Eq: 1.00) in dry DMF (1.5 mL) was added (S)-1,1,1-trifluoropropan-2-ol (CAS 3539-97-7) (30.8 mg, 270 mol, Eq: 1.5) followed by NaH (10.8 mg, 270 mol, Eq: 1.5). The reaction mixture was stirred at RT for 15 min, then stirred under microwave radiation for 30 min at 100 C. and monitored by LC-MS. The reaction mixture was quenched with water and directly purified by preparative HPLC without any work-up giving 44.2 mg of the desired product (Yield 69%). MS (ESI, m/z): 356.5 (MH+).

Example 49

5-tert-butyl-3-[5-cyclopropyl-4-[(2R)-1,1,1-trifluoropropan-2-yl]oxypyridin-2-yl]-1,2,4-oxadiazole

(153) ##STR00108##

(154) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and (R)-1,1,1-trifluoropropan-2-ol (75% in TBME) (CAS 17628-73-8) as starting materials, and purified by preparative HPLC without any work-up. MS (ESI, m/z): 356.5 (MH+).

Example 50

3-[5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-5-(1-methylcyclopropyl)-1,2,4-oxadiazole

(155) ##STR00109##

(156) The title compound was synthesized in analogy to Example 46, using 1-methylcyclopropanecarboxylic acid (CAS 6914-76-7) and 5-(3,3-difluoroazetidin-1-yl)-N-hydroxy-4-(2,2,2-trifluoroethoxy)picolinimidamide as starting materials, and purified by purified by flash chromatography. MS (ESI, m/z): 391.1 (MH+).

Example 51

3-tert-butyl-5-[5-cyclopropyl-4-[(2R)-1,1,1-trifluoropropan-2-yl]oxypyridin-2-yl]-1,2,4-oxadiazole

a) 4-chloro-3-cyclopropylpyridine

(157) ##STR00110##

(158) To a solution of 3-bromo-4-chloropyridine (7.1 g, 36.9 mmol, Eq: 1.00) in toluene/water (153 mL/18 mL) was added Potassium Cyclopropyltrifluoroborate (CAS 1065010-87-8) (8.41 g, 38.7 mmol, Eq: 1.05), palladium (II) acetate (331 mg, 1.48 mmol, Eq: 0.04), cesium carbonate (30.1 g, 92.2 mmol, Eq: 2.5) and Butyldi-1-Adamantylphosphine (661 mg, 1.84 mmol, Eq: 0.05). Reaction was stirred at 115 C. overnight under argon. LC-MS showed product. Extraction with water/ethyl acetate (3 times). Organic layer was dried on MgSO.sub.4 and evaporated. Column on SiO.sub.2 with a gradient heptane/ethyl acetate gave 3.8 g of the desired compound as a yellow oil (Yield 67%). MS (ESI, m/z): 154.0 (MH+).

b) 4-Chloro-5-cyclopropyl-pyridine-2-carboxylic acid

(159) ##STR00111##

(160) To a solution of N,N-Dimethylethanolamine (2.18 g, 2.46 mL, 24.4 mmol, Eq: 2.5) in Hexane at 15 C. under argon was slowly added BuLi 1.6M in Hexane (30.5 mL, 48.8 mmol, Eq: 5.0). The reaction was stirred at 15 C. during 20 min. The reaction was cooled down to 78 C. before addition of 4-chloro-3-cyclopropylpyridine (1.5 g, 9.77 mmol, Eq: 1.0). Reaction was stirred 1 h at 78 C. before pellets of dry ice addition. The reaction was slowly allowed to reach 20 C. LC-MS confirmed product formation. Reaction was quenched with water and stirred 5 min. Extraction with HCl 4M aqueous solution and ethyl acetate (3 times). Organic layer was dried on MgSO.sub.4 and evaporated to give yellow oil. Diethyl ether was poured on the crude, giving a white suspension, and placed in the fridge. Filtration and washed with ether. Mother liquor was concentrated and again ether was added. Precipitate was filtered and dried under high vacuum giving 850 mg of title compound as white powder (Yield 44%). MS (ESI, m/z): 196.0 (MH).

c) 3-tert-butyl-5-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole

(161) ##STR00112##

(162) To a solution of 4-chloro-5-cyclopropylpicolinic acid (300 mg, 1.52 mmol, Eq: 1.00) in dry DMF (6 mL) was added CDI (369 mg, 2.28 mmol, Eq: 1.5) and reaction stirred for 30 min at RT. N-hydroxypivalimidamide (CAS 42956-75-2) (265 mg, 2.28 mmol, Eq: 1.5) was then added, stirred for 1 h at RT and heated to 100 C. over night. The reaction mixture was controlled by LC-MS. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The extraction was accomplished with 1M NaHCO.sub.3, dried over Na.sub.2SO.sub.4 and concentrated. The crude material was purified by flash chromatography (SiO.sub.2, 10 g, eluent: heptane/ethyl acetate) giving 100 mg of the title compound as light yellow liquid (Yield 23%). MS (ESI, m/z): 278.4 (MH+).

d) 3-tert-butyl-5-[5-cyclopropyl-4-[(2R)-1,1,1-trifluoropropan-2-yl]oxypyridin-2-yl]-1,2,4-oxadiazole

(163) ##STR00113##

(164) To a solution of 3-tert-butyl-5-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole (48 mg, 173 mol, Eq: 1.00) in dry DMF (100 mL) were added (R)-1,1,1-trifluoropropan-2-ol (84.5 mg, 518 mol, Eq: 3.0) (CAS 17628-73-8) and NaH (20.7 mg, 518 mol, Eq: 3.0) and reaction stirred at RT for 30 min. The reaction mixture was then heated to 100 C. for 30 min in the microwave. The reaction was directly purified by preparative HPLC without any work-up giving the title compound as a white solid. MS (ESI, m/z): 356.3 (MH+).

Example 52

3-tert-butyl-5-[5-cyclopropyl-4-[(2S)-1,1,1-trifluoropropan-2-yl]oxypyridin-2-yl]-1,2,4-oxadiazole

(165) ##STR00114##

(166) The title compound was synthesized in analogy to Example 51d, using 3-tert-butyl-5-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and (S)-1,1,1-trifluoropropan-2-ol (CAS 3539-97-7) as starting materials, and purified by preparative HPLC without any work-up. MS (ESI, m/z): 356.4 (MH+).

Example 53

5-tert-butyl-3-[5-cyclopropyl-4-[(4-fluorophenyl)methoxy]pyridin-2-yl]-1,2,4-oxadiazole

(167) ##STR00115##

(168) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and (4-fluorophenyl)methanol (CAS 459-56-3) as starting materials, and purified by preparative HPLC without any work-up. MS (ESI, m/z): 368.6 (MH+).

Example 54

5-tert-butyl-3-[5-cyclopropyl-4-(oxetan-3-yloxy)pyridin-2-yl]-1,2,4-oxadiazole

(169) ##STR00116##

(170) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and oxetan-3-ol (CAS 7748-36-9) as starting materials, and purified by preparative HPLC without any work-up. MS (ESI, m/z): 316.5 (MH+).

Example 55

5-tert-butyl-3-[5-cyclopropyl-4-[(3-methyloxetan-3-yl)methoxy]pyridin-2-yl]-1,2,4-oxadiazole

(171) ##STR00117##

(172) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and (3-methyloxetan-3-yl)methanol (CAS 3143-02-0) as starting materials, and purified by preparative HPLC without any work-up. MS (ESI, m/z): 344.5 (MH+).

Example 56

5-tert-butyl-3-[5-cyclopropyl-4-(oxolan-2-ylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole

(173) ##STR00118##

(174) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and (tetrahydrofuran-2-yl)methanol (CAS 97-99-4) as starting materials, and purified by preparative HPLC without any work-up. MS (ESI, m/z): 344.6 (MH+).

Example 57

5-tert-butyl-3-[5-cyclopropyl-4-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]pyridin-2-yl]-1,2,4-oxadiazole

(175) ##STR00119##

(176) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and (S)-(1-methylpyrrolidin-2-yl)methanol (CAS 34381-71-0) as starting materials, and purified by preparative HPLC without any work-up. MS (ESI, m/z): 357.2 (MH+).

Example 58

5-tert-butyl-3-[5-cyclopropyl-4-(oxetan-2-ylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole

(177) ##STR00120##

(178) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and oxetan-2-ylmethanol (CAS 61266-70-4) as starting materials, and purified by preparative HPLC without any work-up. MS (ESI, m/z): 330.5 (MH+).

Example 59

5-tert-butyl-3-[5-cyclopropyl-4-(1-methylpyrrolidin-3-yl)oxypyridin-2-yl]-1,2,4-oxadiazole

(179) ##STR00121##

(180) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and 1-methylpyrrolidin-3-ol (CAS 13220-33-2) as starting materials, and purified by preparative HPLC without any work-up. MS (ESI, 111/Z): 343.5 (MH+).

Example 60

3-[3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazol-5-yl]oxetan-3-amine

a) N-(3-(3-(5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl)-1,2,4-oxadiazol-5-yl)oxetan-3-yl)-2,2,2-trifluoroacetamide

(181) ##STR00122##

(182) The title compound was synthesized in analogy to Example 9b, using 3-(2,2,2-trifluoroacetamido)oxetane-3-carboxylic acid (CAS 1392072-19-3) and 5-cyclopropyl-4-(cyclopropylmethoxy)-N-hydroxypicolinimidamide as starting materials. DMF was evaporated, residue redissolved in ethyl acetate and poured into a separatory funnel, extraction with aqueous NaHCO.sub.3 1M, organic phase dried over Na.sub.2SO.sub.4 and evaporated down to dryness. Flash chromatography with SiO.sub.2 column, eluent mixture of heptane and ethyl acetate. MS (ESI, m/z): 425.2 (MH+).

b) 3-[3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazol-5-yl]oxetan-3-amine

(183) ##STR00123##

(184) To a solution of N-(3-(3-(5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl)-1,2,4-oxadiazol-5-yl)oxetan-3-yl)-2,2,2-trifluoroacetamide (0.06 g, 141 mol, Eq: 1.00) in ammonia 7N in MeOH (1.01 mL, 7.07 mmol, Eq: 50.0) was stirred at 100 C. for 30 min under microwave radiation and reaction was monitored by LC-MS. When the reaction was completed, volatiles were removed in vacuo and the residue was resdissolved in DMF. Purification was done by preparative HPLC without any work-up procedure and gave 9 mg of the desired product. MS (ESI, m/z): 329.4 (MH+).

Example 61

5-tert-butyl-3-[5-cyclopropyl-4-(4-fluorophenoxy)pyridin-2-yl]-1,2,4-oxadiazole

(185) ##STR00124##

(186) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and 4-fluorophenol (CAS 371-41-5) as starting materials, and purified by preparative HPLC without any work-up. MS (ESI, m/z): 354.5 (MH+).

Example 62

5-tert-butyl-3-[5-cyclopropyl-4-(oxolan-3-yloxy)pyridin-2-yl]-1,2,4-oxadiazole

(187) ##STR00125##

(188) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and tetrahydrofuran-3-ol (CAS 453-20-3) as starting materials, and purified by preparative HPLC without any work-up. MS (ESI, m/z): 330.5 (MH+).

Example 63

5-tert-butyl-3-[5-cyclopropyl-4-(oxan-4-yloxy)pyridin-2-yl]-1,2,4-oxadiazole

(189) ##STR00126##

(190) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and tetrahydro-2H-pyran-4-ol (CAS 2081-44-9) as starting materials, and purified by preparative HPLC without any work-up. MS (ESI, m/z): 344.5 (MH+).

Example 64

2-(5-tert-butyl-1H-imidazol-2-yl)-5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridine

a) 5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)picolinimidamide

(191) ##STR00127##

(192) To a solution of ammonium chloride (47.4 mg, 887 mol, Eq: 2) in toluene (0.56 mL) was added at 0 C. for 10 minutes trimethylaluminum (443 L, 887 mol, Eq: 2.0). Reaction was then brought at RT for 20 minutes. 5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)picolinonitrile (130 mg, 443 mol, Eq: 1.00), previously described as Example 15c, dissolved in toluene was then added and the reaction mixture heated up to 80 C. and stirred for 1 h. The reaction mixture was then cooled down to RT, quenched with water and poured into a DCM/silica slurry. This was then filtered and washed through with methanol to give 250 mg of a yellow solid. The crude material was purified by flash chromatography on SiO.sub.2, 10 g, gradient methanol in DCM giving 21 mg of the title compound as light yellow powder (Yield 15%). MS (ESI, m/z): 311.4 (MH+).

b) 2-(5-tert-butyl-1H-imidazol-2-yl)-5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridine

(193) ##STR00128##

(194) 5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)picolinimidamide (20 mg, 64.5 mol, Eq: 1.00), 1-bromo-3,3-dimethylbutan-2-one (24.2 mg, 18.2 L, 135 mol, Eq: 2.1) and DBU (49.1 mg, 48.6 L, 322 mol, Eq: 5.0) were combined with Ethanol (0.77 mL). The reaction mixture was heated up to 115 C. and stirred overnight. The crude material was purified by preparative HPLC giving 5 mg of the title compound as white powder (Yield 19%). MS (ESI, m/z): 391.5 (MH+).

Example 65

5-tert-butyl-2-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,3-oxazole

a) 5-cyclopropyl-4-(cyclopropylmethoxy)-N-(2-hydroxy-3,3-dimethylbutyl)picolinamide

(195) ##STR00129##

(196) To a solution of 5-cyclopropyl-4-(cyclopropylmethoxy)picolinic acid, previously described as Example 1e, (200 mg, 0.857 mmol, Eq: 1.00) in 8.5 mL DCM was added HATU (158 mg, 1.03 mmol, Eq: 1.2) and DIPEA (449 L, 2.57 mmol, Eq: 3.0). Reaction was stirred 15 min at 40 C., then 1-amino-3,3-dimethylbutan-2-ol hydrochloride (158 mg, 1.03 mmol, Eq: 1.2) (CAS 1438-15-9) was added. Reaction was stirred 2 h at 40 C. Extraction with DCM/NaHCO.sub.3 saturated aqueous solution. Organic layer was dried on sodium sulfate and evaporated. Column on SiO.sub.2 with a gradient heptane/ethyl acetate gave 126 mg of the title compound as colorless viscous oil (Yield 44%). MS (ESI, m/z): 333.5 (MH+).

b) 5-cyclopropyl-4-(cyclopropylmethoxy)-N-(3,3-dimethyl-2-oxobutyl)picolinamide

(197) ##STR00130##

(198) To a solution of 5-cyclopropyl-4-(cyclopropylmethoxy)-N-(2-hydroxy-3,3-dimethylbutyl)picolinamide (125 mg, 0.376 mmol, Eq: 1.00) in DCM (3.8 mL) was added Dess-Martin periodinane (181 mg, 0.414 mmol, Eq: 1.1) and the reaction was stirred overnight at RT. LC-MS showed reaction was complete. Sodium thiosulfate solution was added to the crude and stirred for 10 min before extraction with NaHCO.sub.3 saturated aqueous solution and DCM. Column on SiO.sub.2 with a gradient heptane/ethyl acetate gave 116 mg of the title compound as white waxy solid (Yield 93%). MS (ESI, m/z): 331.5 (MH+).

c) 5-tert-butyl-2-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,3-oxazole

(199) ##STR00131##

(200) Hexachloroethane was dissolved in anhydrous acetonitrile. Then 5-cyclopropyl-4-(cyclopropylmethoxy)-N-(3,3-dimethyl-2-oxobutyl)picolinamide was dissolved in Acetonitrile and added. The reaction mixture was cooled to 0 C. and triethylamine followed by triphenylphosphine were added. The ice bath was removed and the reaction mixture was stirred for 2 hours. LC-MS showed some SM left. Another 3 Eq. hexachloroethane, triethylamine and finally triphenylphosphine were added at 0 C. Acetonitrile was evaporated and the crude extracted with DCM/brine 3 times. Organic layer was dried on Na.sub.2SO.sub.4 and evaporated. Column on SiO.sub.2 with a gradient heptane/ethyl acetate to give 14 mg of the title compound (Yield 60%). MS (ESI, m/z): 313.5 (MH+).

Example 66

2-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-4-methyl-4-propan-2-yl-1H-imidazol-5-one

(201) ##STR00132##

(202) 5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinic acid, previously described as Example 7e, (100 mg, 383 mol, Eq: 1.00) in 1,2-Dichloroethane (1.91 mL) had thionyl chloride (68.3 mg, 41.9 L, 574 mol, Eq: 1.5) added to it. The reaction mixture was heated up to 90 C. and left to reflux for 3 h. The reaction mixture was concentrated in vacuo. Product was used immediately in the next step and dissolved in THF (526 L). A mixture of 2-amino-2,3-dimethylbutanamide (46.6 mg, 358 mol, Eq: 1.00) and triethylamine (36.2 mg, 49.8 L, 358 mol, Eq: 1.0) in 130 L of tetrahydrofuran was added and the reaction stirred at 4 h at RT. The reaction mixture was poured into water, extracted with ethyl acetate and the organic layers combined, dried, and concentrated in vacuo to give a solid which was used immediately in the next step and dissolved in THF (536 L). This was added to a solution of potassium hydroxide (40.3 mg, 718 mol, Eq: 2.0) and water (15 L) and the reaction was refluxed for 2 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layers were combined before being dried on Na.sub.2SO.sub.4 and concentrated in vacuo. The crude material was purified by flash chromatography (SiO.sub.2, 10 g, gradient ethyl acetate in heptane) giving 43 mg of the title compound as a white solid (Yield 34%). MS (ESI, m/z): 356.1 (MH+).

Example 67

5-tert-butyl-3-[5-methylsulfonyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole

a) 2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-(methylsulfonyl)pyridin-4-ol

(203) ##STR00133##

(204) To a solution of 5-tert-butyl-3-(4-(cyclopropylmethoxy)-5-(methylsulfonyl)pyridin-2-yl)-1,2,4-oxadiazole, described as Example 43, (330 mg, 939 mol, Eq: 1.00) in dry DCM (5 ml) under an argon atmosphere was added BBr.sub.3 1M solution in DCM (1.88 mL, 1.88 mmol, Eq: 2.0). The reaction mixture was stirred at RT overnight and monitored by LC-MS until complete conversion. The reaction mixture was quenched by addition of water, stirred for 10 min and the mixture was then poured into a separatory funnel and pH was adjusted to 7 and extracted with DCM and then ethyl acetate. All the organic layers were dried over Na.sub.2SO.sub.4 and evaporated down to dryness giving 140 mg of the title compound as white solid (Yield 50%). MS (ESI, m/z): 296.4 (MH).

b) 5-tert-butyl-3-[5-methylsulfonyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole

(205) ##STR00134##

(206) To a solution of 2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-(methylsulfonyl)pyridin-4-ol (40 mg, 135 mol, Eq: 1.00) in DMF (1 mL) was added Cs2CO3 (65.7 mg, 202 mol, Eq: 1.5) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (CAS 6226-25-1) (62.4 mg, 38.8 L, 269 mol, Eq: 2.0). Reaction was heated at 90 C. during 1.5 h in the microwave and purified by preparative HPLC without any work-up. MS (ESI, m/z): 380.5 (MH+).

Example 68

2-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-4-ethyl-4-methyl-1H-imidazol-5-one

(207) ##STR00135##

(208) The title compound was synthesized in a similar manner as Example 66, using 5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinic acid (Eq: 1.0), previously described as Example 7e, with CDI (Eq: 1.1), DIPEA (Eq: 2.2) and 1-amino-2-methyl-1-oxobutan-2-aminium chloride (CAS 18305-22-1) as starting materials for the amide coupling step. MS (ESI, m/z): 342.1 (MH+).

Example 69

2-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-4-methyl-4-(2-methylpropyl)-1H-imidazol-5-one

(209) ##STR00136##

(210) The title compound was synthesized in analogy to Example 68, using 5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinic acid (Eq: 1.0), previously described as Example 7e, with CDI (Eq: 1.1), DIPEA (Eq: 2.2) and 2-amino-2,4-dimethylpentanamide (CAS 113509-60-7) as starting materials for the amide coupling step. MS (ESI, m/z): 370.5 (MH+).

Example 70

5-tert-butyl-3-[5-chloro-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole

a) 2,5-dichloro-4-(2,2,2-trifluoroethoxy)pyridine

(211) ##STR00137##

(212) To a solution of 2,5-dichloropyridin-4-ol (CAS 847664-65-7) (5 g, 30.5 mmol, Eq: 1.00) in DMF (51 mL) was added cesium carbonate (14.9 g, 45.7 mmol, Eq: 1.5) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (6.59 mL, 45.7 mmol, Eq: 1.5). Reaction was heated at 90 C. overnight. Reaction was filtered to remove Cs.sub.2CO.sub.3 (cake washed with ethyl acetate) and solvent evaporated. Extraction of the crude using ethyl acetate/water. Organic layer was dried on Na.sub.2SO.sub.4 and evaporated. Column on SiO.sub.2 using MPLC Isco with a gradient heptane/ethyl acetate gave 6.64 g of title compound as off-white solid (Yield 88%). MS (ESI, m/z): 246.3 (MH+).

b) 5-chloro-4-(2,2,2-trifluoroethoxy)picolinonitrile

(213) ##STR00138##

(214) 2,5-dichloro-4-(2,2,2-trifluoroethoxy)pyridine (4 g, 16.3 mmol, Eq: 1.00), Dicyanozinc (2.1 g, 17.9 mmol, Eq: 1.1), 1,1-bis(diphenylphosphino)ferrocene (721 mg, 1.3 mmol, Eq: 0.08) and Pd.sub.2(dba).sub.3 (744 mg, 0.813 mmol, Eq: 0.05) were combined in DMF and the reaction heated at 100 C. 2 days. Evaporation of the solvent, extraction with ethyl acetate/NaHCO.sub.3 saturated aqueous solution Organic layer dried on sodium sulfate and evaporated. Column on SiO.sub.2 with MPLC Isco with a gradient heptane/ethyl acetate gave 2.1 g of title compound as white solid (Yield 54%). MS (ESI, m/z): 237.3 (MH+).

c) 5-chloro-N-hydroxy-4-(2,2,2-trifluoroethoxy)picolinimidamide

(215) ##STR00139##

(216) To a solution of 5-chloro-4-(2,2,2-trifluoroethoxy)picolinonitrile (200 mg, 0.845 mmol, Eq: 1.00) in EtOH (5.6 mL) was added hydroxylamine hydrochloride (65 mg, 0.93 mmol, Eq: 1.1) and triethylamine (128 mg, 177 L, 1.27 mmol, Eq: 1.5). The reaction was heated with microwave 30 min at 80 C. and monitered with LC-MS. The reaction mixture was poured into a separating funnel, DCM was added and the mixture was extracted with aqueous NaHCO.sub.3 saturated solution. The organic phase was dried over Na.sub.2SO.sub.4 and concentrated in vacuo to give 223 mg of title compound as white powder (Yield 97%). MS (ESI, m/z): 270.4 (MH+).

d) 5-tert-butyl-3-[5-chloro-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole

(217) ##STR00140##

(218) To a solution of 5-chloro-N-hydroxy-4-(2,2,2-trifluoroethoxy)picolinimidamide (0.1 g, 371 mol, Eq: 1.00) in dry DMF (2.5 mL) under argon atmosphere was added DIPEA (130 L, 742 mol, Eq: 2.0) followed by pivaloyl chloride (CAS 3282-30-2) (53.7 mg, 54.8 L, 445 mol, Eq: 1.2). The reaction was stirred at RT for 45 min and controlled by LC-MS which showed complete conversion to the intermediate. The reaction mixture was heated with microwave 30 min at 120 C. and controlled by LC-MS which showed complete conversion to the desired product. The solvent was evaporated and the crude diluted with ethyl acetate, poured into a separatory funnel and extracted with NaHCO.sub.3 aqueous saturated solution. The organic phase was dried over Na.sub.2SO.sub.4 and evaporated down to dryness. The crude material was purified by flash chromatography (SiO.sub.2, 20 g, gradient ethyl acetate in heptane) gave 92 mg of the title compound as white powder (Yield 73%). MS (ESI, m/z): 336.4 (MH+).

Example 71

3-[5-chloro-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-5-cyclopropyl-1,2,4-oxadiazole

(219) ##STR00141##

(220) The title compound was synthesized in analogy to Example 70d, using 5-chloro-N-hydroxy-4-(2,2,2-trifluoroethoxy)picolinimidamide and cyclopropanecarboxylic acid (CAS 1759-53-1) as starting materials, with HATU (Eq: 1.2) and DIPEA (Eq: 2.0), and heated with microwave 30 min at 120 C. MS (ESI, m/z): 320.4 (MH+).

Example 72

5-cyclopropyl-3-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole

(221) ##STR00142##

(222) The title compound was synthesized in analogy to Example 33b, using 5-cyclopropyl-N-hydroxy-4-(2,2,2-trifluoroethoxy)picolinimidamide and cyclopropanecarbonyl chloride (CAS 4023-34-1) as starting materials, and purified by purified by flash chromatography. MS (ESI, 111/Z): 326.6 (MH+).

Example 73

1-[2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-cyclopropylpyridin-4-yl]pyrrolidin-3-ol

(223) ##STR00143##

(224) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and 3-pyrrolidinol (CAS 40499-83-0) (Eq: 2.0) as starting materials in NMP with K.sub.2CO.sub.3 (Eq: 3.0), heated 1 h30 at 200 C. with microwave, and purified by preparative HPLC without any work-up. MS (ESI, m/z): 329.6 (MH+).

Example 74

5-tert-butyl-3-[5-cyclopropyl-4-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyridin-2-yl]-1,2,4-oxadiazole

(225) ##STR00144##

(226) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and 3,3,4,4-tetrafluoropyrrolidine hydrochloride (CAS 1810-13-5) (Eq: 2.0) as starting materials in Sulfolane with K.sub.2CO.sub.3 (Eq: 3.0), heated 2 h at 180 C. with microwave, and purified by preparative HPLC without any work-up. MS (ESI, m/z): 385.6 (MH+).

Example 75

5-tert-butyl-3-[5-cyclopropyl-4-(4-methylsulfonylphenoxy)pyridin-2-yl]-1,2,4-oxadiazole

(227) ##STR00145##

(228) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and 4-methylsulfonylphenol (CAS 14763-60-1) (Eq: 1.2) as starting materials in NMP, heated 1 h at 180 C. with microwave, and purified by preparative HPLC without any work-up. MS (ESI, m/z): 414.6 (MH+).

Example 76

7-[2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-cyclopropylpyridin-4-yl]-2-oxa-7-azaspiro[3.4]octane

(229) ##STR00146##

(230) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and 2-oxa-6-azaspiro[3.4]octane (CAS 220290-68-6) (Eq: 2.0) as starting materials in NMP with K.sub.2CO.sub.3 (Eq: 3.0), heated 1 h30 at 200 C. with microwave, and purified by preparative HPLC without any work-up. MS (ESI, m/z): 355.6 (MH+).

Example 77

5-tert-butyl-3-[5-cyclopropyl-4-(3,3-difluoropyrrolidin-1-yl)pyridin-2-yl]-1,2,4-oxadiazole

(231) ##STR00147##

(232) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and 3,3-difluoropyrrolidine hydrochloride (CAS 163457-23-6) (Eq: 2.0) as starting materials in Sulfolane with K.sub.2CO.sub.3 (Eq: 3.0), heated 30 min at 220 C. with microwave, and purified by preparative HPLC without any work-up. MS (ESI, m/z): 349.6 (MH+).

Example 78

4-[2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-cyclopropylpyridin-4-yl]morpholine

(233) ##STR00148##

(234) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and morpholine (CAS 110-91-8) (Eq: 1.2) as starting materials in DMSO with CsF (Eq: 1) and triethylamine (Eq: 2.0), heated 24 h at 150 C., and purified by preparative HPLC without any work-up. MS (ESI, m/z): 329.6 (MH+).

Example 79

5-tert-butyl-3-(5-cyclopropyl-4-pyrrolidin-1-ylpyridin-2-yl)-1,2,4-oxadiazole

(235) ##STR00149##

(236) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and pyrrolidine (CAS 123-75-1) (Eq: 2) as starting materials in NMP with K.sub.2CO.sub.3 (Eq: 3.0), heated 1 h30 at 200 C. with microwave, and purified by preparative HPLC without any work-up. MS (ESI, m/z): 313.3 (MH+).

Example 80

5-tert-butyl-3-(5-cyclopropyl-4-cyclopropylsulfonylpyridin-2-yl)-1,2,4-oxadiazole

(237) ##STR00150##

(238) To a solution of 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole (50 mg, 0.18 mmol), previously described as Example 48d, in DMA (2 mL) in a microwave vial, was added sodium cyclopropanesulfinate (CAS 910209-21-1) (46.1 mg, 0.36 mmol, Eq: 2.0) and DMAP (44 mg, 0.36 mmol, Eq: 2.0). Tube was sealed and reaction heated 2 days at 140 C. DMA was evaporated. Crude was then extracted with ethyl acetate/NaHCO.sub.3 aqueous saturated solution. Organic layer was dried on Na.sub.2SO.sub.4 and evaporated. Column on SiO.sub.2 with a gradient ethyl acetate/heptane gave 37 mg of the title compound as colorless viscous oil (Yield 59%). MS (ESI, m/z): 348.6 (MH+).

Example 81

5-tert-butyl-3-[5-cyclopropyl-4-(3-methoxyazetidin-1-yl)pyridin-2-yl]-1,2,4-oxadiazole

(239) ##STR00151##

(240) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and 3-methoxyazetidine (CAS 110925-17-2) (Eq: 2.0) as starting materials in ethylene glycol with Cs.sub.2CO.sub.3 (Eq: 3.0), heated 6 h at 100 C., and purified by preparative HPLC after filtration. MS (ESI, m/z): 329.6 (MH+).

Example 82

6-[2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-cyclopropylpyridin-4-yl]-2-oxa-6-azaspiro[3.3]heptane

(241) ##STR00152##

(242) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and 2-oxa-6-azaspiro[3.3]heptane (CAS 174-78-7) (Eq: 2) as starting materials in ethylene glycol with Cs.sub.2CO.sub.3 (Eq: 3), heated 6 h at 100 C., and purified by preparative HPLC after filtration. MS (ESI, m/z): 341.6 (MH+).

Example 83

5-tert-butyl-3-[5-cyclopropyl-4-(2-ethoxyethoxy)pyridin-2-yl]-1,2,4-oxadiazole

(243) ##STR00153##

(244) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and 2-ethoxyethanol (CAS 110-80-5) as starting materials, and purified by preparative HPLC without any work-up. MS (ESI, m/z): 332.6 (MH+).

Example 84

5-tert-butyl-3-[5-cyclopropyl-4-(1-methoxybutan-2-yloxy)pyridin-2-yl]-1,2,4-oxadiazole

(245) ##STR00154##

(246) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and 1-methoxybutan-2-ol (CAS 53778-73-7) as starting materials, and purified by preparative HPLC without any work-up. MS (ESI, m/z): 346.6 (MH+).

Example 85

5-tert-butyl-3-[5-cyclopropyl-4-[2-[(2-methylpropan-2-yl)oxy]ethoxy]pyridin-2-yl]-1,2,4-oxadiazole

(247) ##STR00155##

(248) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and ethylene glycol mono-tert-butyl ether (CAS 7580-85-0) as starting materials, and purified by preparative HPLC without any work-up. MS (ESI, m/z): 360.7 (MH+).

Example 86

5-tert-butyl-3-[5-cyclopropyl-4-[1-[(2-methylpropan-2-yl)oxy]propan-2-yloxy]pyridin-2-yl]-1,2,4-oxadiazole

(249) ##STR00156##

(250) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and 1-tert-butoxy-propan-2-ol (CAS 57018-52-7) as starting materials, and purified by preparative HPLC without any work-up. MS (ESI, m/z): 374.8 (MH+).

Example 87

5-tert-butyl-3-[5-cyclopropyl-4-(1-methoxypropan-2-yloxy)pyridin-2-yl]-1,2,4-oxadiazole

(251) ##STR00157##

(252) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and 1-methoxy-propan-2-ol (CAS 107-98-2) as starting materials, and purified by preparative HPLC without any work-up. MS (ESI, m/z): 332.7 (MH+).

Example 88

5-tert-butyl-3-[5-cyclopropyl-4-(oxan-3-yloxy)pyridin-2-yl]-1,2,4-oxadiazole

(253) ##STR00158##

(254) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and tetrahydro-pyran-3-ol (CAS 19752-84-2) as starting materials, and purified by preparative HPLC without any work-up. MS (ESI, m/z): 344.6 (MH+).

Example 89

5-tert-butyl-3-[5-cyclopropyl-4-(3-methoxybutoxy)pyridin-2-yl]-1,2,4-oxadiazole

(255) ##STR00159##

(256) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and 3-methoxy-butanol (CAS 2517-43-3) as starting materials, and purified by preparative HPLC without any work-up. MS (ESI, m/z): 346.6 (MH+).

Example 90

5-tert-butyl-3-[5-cyclopropyl-4-(oxetan-3-ylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole

(257) ##STR00160##

(258) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and 3-oxetanemethanol (CAS 6246-06-6) as starting materials, and purified by preparative HPLC without any work-up. MS (ESI, m/z): 330.6 (MH+).

Example 91

5-cyclopropyl-3-[5-cyclopropyl-4-[(2S)-1,1,1-trifluoropropan-2-yl]oxypyridin-2-yl]-1,2,4-oxadiazole

(259) ##STR00161##

(260) The title compound was synthesized in analogy to Example 33b, using (S,Z)-5-cyclopropyl-N-hydroxy-4-(1,1,1-trifluoropropan-2-yloxy)picolinimidamide (prepared in analogy to Example 33a but with (S)-1,1,1-trifluoropropan-2-ol for the first Example 7a) and isobutyryl chloride (CAS 79-30-1) as starting materials, and purified by purified by flash chromatography. MS (ESI, m/z): 340.1 (MH+).

Example 92

5-tert-butyl-3-[5-cyclopropyl-4-(1-ethylpyrrolidin-3-yl)oxypyridin-2-yl]-1,2,4-oxadiazole

(261) ##STR00162##

(262) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and 1-ethyl-3-pyrrolidinol (CAS 30727-14-1) as starting materials, and purified by preparative HPLC without any work-up. MS (ESI, m/z): 357.6 (MH+).

Example 93

5-tert-butyl-3-[5-cyclopropyl-4-(1-propan-2-ylpyrrolidin-3-yl)oxypyridin-2-yl]-1,2,4-oxadiazole

(263) ##STR00163##

(264) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and 1-isopropyl-pyrrolidinol (CAS 42729-56-6) as starting materials, and purified by preparative HPLC without any work-up. MS (ESI, m/z): 371.7 (MH+).

Example 94

5-tert-butyl-3-[5-cyclopropyl-4-(2-pyrrolidin-1-ylethoxy)pyridin-2-yl]-1,2,4-oxadiazole

(265) ##STR00164##

(266) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and 1-(2-hydroxyethyl)pyrrolidine (CAS 2955-88-6) as starting materials, and purified by preparative HPLC without any work-up. MS (ESI, m/z): 357.6 (MH+).

Example 95

5-tert-butyl-3-[5-cyclopropyl-4-(2-piperidin-1-ylethoxy)pyridin-2-yl]-1,2,4-oxadiazole

(267) ##STR00165##

(268) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and 1-(2-hydroxyethyl)piperidine (CAS 3040-44-6) as starting materials, and purified by preparative HPLC without any work-up. MS (ESI, m/z): 371.7 (MH+).

Example 96

5-tert-butyl-3-[5-cyclopropyl-4-(1-piperidin-1-ylpropan-2-yloxy)pyridin-2-yl]-1,2,4-oxadiazole

(269) ##STR00166##

(270) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and alpha-methyl-1-piperidineethanol (CAS 934-90-7) as starting materials, and purified by preparative HPLC without any work-up. MS (ESI, m/z): 385.7 (MH+).

Example 97

5-tert-butyl-3-[5-cyclopropyl-4-[(1-methylpiperidin-2-yl)methoxy]pyridin-2-yl]-1,2,4-oxadiazole

(271) ##STR00167##

(272) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and 1-methyl-2-piperidinemethanol (CAS 20845-34-5) as starting materials, and purified by preparative HPLC without any work-up. MS (ESI, m/z): 371.7 (MH+).

Example 98

2-tert-butyl-5-[5-cyclopropyl-4-(oxan-4-yloxy)pyridin-2-yl]-1,3,4-oxadiazole

a) 5-cyclopropyl-4-(tetrahydro-2H-pyran-4-yloxy)picolinonitrile

(273) ##STR00168##

(274) To a solution of 4-chloro-5-cyclopropylpicolinonitrile (300 mg, 1.68 mmol, Eq: 1.00), previously described as Example 48b, in dry DMF (11 mL) with tetrahydro-2H-pyran-4-ol (CAS 2081-44-9) (189 mg, 176 L, 1.85 mmol, Eq: 1.1) was added NaH (60% in oil, 73.9 mg, 1.85 mmol, Eq: 1.1). The reaction was stirred at RT 15 min then 30 min at 110 C. with microwave. The solvent was partially evaporated. Extraction with ethyl acetate/NaHCO.sub.3 saturated aqueous solution Organic layer dried on Na.sub.2SO.sub.4 and evaporated. Column on SiO.sub.2 using MPLC ISCO with a gradient heptane/ethyl acetate gave 245 mg of the title compound as off-white powder (Yield 59%). MS (ESI, m/z): 245.6 (MH+).

b) 5-cyclopropyl-4-(tetrahydro-2H-pyran-4-yloxy)picolinic acid

(275) ##STR00169##

(276) 5-cyclopropyl-4-(tetrahydro-2H-pyran-4-yloxy)picolinonitrile (240 mg, 0.982 mmol, Eq: 1.00) was dissolved in HCl 25% aqueous solution (9 mL). Reaction was heated at 110 C. After 3 h reaction was complete and cooled down to RT. HCl was neutralized using 6M NaOH aqueous solution followed by NaOH pellets. Then pH adjusted to 1-2 with HCl 2M. The precipitate formed was filtered off to give 140 mg of the title compound as light yellow powder (Yield 54%). MS (ESI, m/z): 264.6 (MH+).

c) 5-cyclopropyl-N-pivaloyl-4-(tetrahydro-2H-pyran-4-yloxy)picolinohydrazide

(277) ##STR00170##

(278) 5-cyclopropyl-4-(tetrahydro-2H-pyran-4-yloxy)picolinic acid (70 mg, 266 mol, Eq: 1.00) in 1,2-Dichloroethane (1.33 mL) had thionyl chloride (47.4 mg, 29.1 L, 399 mol, Eq: 1.5) added to it. The reaction mixture was heated up to 90 C. and left to reflux for 3 h. The reaction was complete and the reaction mixture was concentrated in vacuo. The product was used immediately in the next step and dissolved in THF (391 L) to be reacted with pivalohydrazide (35.0 mg, 292 mol, Eq: 1.1) and triethylamine (40.4 mg, 55.6 L, 399 mol, Eq: 1.5) at RT overnight. The reaction mixture was then diluted with ethyl acetate, poured into NaHCO.sub.3 aqueous solution (1M). It was then extracted with ethyl acetate and the organic layers were combined, dried, and concentrated in vacuo to be used as a crude. MS (ESI, m/z): 362.6 (MH+).

d) 2-tert-butyl-5-[5-cyclopropyl-4-(oxan-4-yloxy)pyridin-2-yl]-1,3,4-oxadiazole

(279) ##STR00171##

(280) Trifluoromethanesulfonic anhydride (97.7 mg, 58.5 L, 346 mol, Eq: 1.5) was added slowly to a solution of triphenylphosphine oxide (193 mg, 692 mol, Eq: 3.0) in dry DCM (0.231 mL) at 0 C. The reaction mixture was stirred for 5 minutes at this temperature before it was adjusted to room temperature and 5-cyclopropyl-N-pivaloyl-4-(tetrahydro-2H-pyran-4-yloxy)picolinohydrazide (83.4 mg, 231 mol, Eq: 1.00), first azeotropically dried with toluene, was added. The reaction mixture was then stirred for a further 30 minutes at RT before monitoring via LC-MS showed the reaction as complete. The reaction mixture was then diluted with DCM and poured into NaHCO.sub.3 saturated aqueous solution and extracted with DCM. The aqueous layer was then back-extracted with DCM before the organic layers were combined, dried, and concentrated in vacuo. The crude material was purified by flash chromatography (SiO.sub.2, 10 g, gradient ethyl acetate in heptane) to give 33.9 mg of the title compound (Yield 42%). MS (ESI, m/z): 344.6 (MH+).

Example 99

5-tert-butyl-3-[5-cyclopropyl-4-(1-methylpiperidin-3-yl)oxypyridin-2-yl]-1,2,4-oxadiazole

(281) ##STR00172##

(282) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and 3-hydroxy-N-methylpiperidine (CAS 3554-74-3) as starting materials, and purified by preparative HPLC without any work-up. MS (ESI, m/z): 357.7 (MH+).

Example 100

5-tert-butyl-3-[5-cyclopropyl-4-(1-ethylpiperidin-3-yl)oxypyridin-2-yl]-1,2,4-oxadiazole

(283) ##STR00173##

(284) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and 3-hydroxy-N-ethylpiperidine (CAS 13444-24-1) as starting materials, and purified by preparative HPLC without any work-up. MS (ESI, m/z): 371.7 (MH+).

Example 101

2-[2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-cyclopropylpyridin-4-yl]oxy-N,N-diethylpropan-1-amine

(285) ##STR00174##

(286) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and 1-diethylamino-2-propanol (CAS 4402-32-8) as starting materials, and purified by preparative HPLC without any work-up. MS (ESI, m/z): 373.7 (MH+).

Example 102

3-[[2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-cyclopropylpyridin-4-yl]oxymethyl]morpholine

(287) ##STR00175##

(288) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and 3-hydroxymethylmorpholine (CAS 103003-01-6) as starting materials, and purified by preparative HPLC without any work-up. MS (ESI, m/z): 359.6 (MH+).

Example 103

4-[2-[2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-cyclopropylpyridin-4-yl]oxyethyl]morpholine

(289) ##STR00176##

(290) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and N-(2-hydroxyethyl)morpholine (CAS 622-40-2) as starting materials, and purified by preparative HPLC without any work-up. MS (ESI, m/z): 373.7 (MH+).

Example 104

5-tert-butyl-3-(5-cyclopropyl-4-piperidin-3-yloxypyridin-2-yl)-1,2,4-oxadiazole

(291) ##STR00177##

(292) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and (R,S)-Boc-3-hydroxypiperidine (CAS 85275-45-2) as starting materials. The reaction was then diluted with ethyl acetate and washed with water. Organic layer was dried on Na.sub.2SO.sub.4 and evaporated. Product was used as a crude and directly dissolved in HCl (4M) in dioxane and stirred at RT for 2 h. The reaction mixture was purified by preparative HPLC after evaporation of the solvent. MS (ESI, m/z): 343.7 (MH+).

Example 105

5-tert-butyl-3-[5-cyclopropyl-4-[(3-fluorooxetan-3-yl)methoxy]pyridin-2-yl]-1,2,4-oxadiazole

(293) ##STR00178##

(294) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and (3-fluoro-oxetane) methanol (CAS 865451-85-0) as starting materials, and purified by preparative HPLC without any work-up. MS (ESI, m/z): 348.5 (MH+).

Example 106

5-tert-butyl-3-[5-cyclopropyl-4-[(2,5-dimethyl-1,3-oxazol-4-yl)methoxy]pyridin-2-yl]-1,2,4-oxadiazole

(295) ##STR00179##

(296) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and (2,5-dimethyloxazol-4-yl)methanol (CAS 92901-94-5) as starting materials, and purified by preparative HPLC without any work-up. MS (ESI, m/z): 369.6 (MH+).

Example 107

5-tert-butyl-3-[5-cyclopropyl-4-[(5-methyl-1,2-oxazol-3-yl)methoxy]pyridin-2-yl]-1,2,4-oxadiazole

(297) ##STR00180##

(298) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and (5-methylisoxazol-3-yl)methanol (CAS 35166-33-7) as starting materials, and purified by preparative HPLC without any work-up. MS (ESI, m/z): 355.6 (MH+).

Example 108

5-tert-butyl-3-[5-cyclopropyl-4-(3-methylsulfonylphenoxy)pyridin-2-yl]-1,2,4-oxadiazole

(299) ##STR00181##

(300) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and 3-(methylsulfonyl)phenol (CAS 14763-61-2) as starting materials with Cs.sub.2CO.sub.3 (Eq: 1.5), and purified by preparative HPLC without any work-up. MS (ESI, m/z): 414.5 (MH+).

Example 109

5-tert-butyl-3-[5-(3-fluorooxetan-3-yl)-4-(oxan-4-yloxy)pyridin-2-yl]-1,2,4-oxadiazole

a) 3-(4,6-dichloropyridin-3-yl)oxetan-3-ol

(301) ##STR00182##

(302) To a solution of 5-bromo-2,4-dichloropyridine (15 g, 66.1 mmol, Eq: 1.00) (CAS 849937-96-8) in dry THF (300 mL) cooled down to 15 C. under an argon atmosphere was added isopropyl magnesium chloride, lithium chloride complex (53.4 mL, 69.4 mmol, Eq: 1.05) and the mixture was stirred at 15 C. for 1 h. Slow addition of neat oxetan-3-one (5.24 g, 72.7 mmol, Eq: 1.1) to the reaction mixture cooled at 15 C. and reaction mixture was let to warm up to RT overnight. Reaction was monitored by LC-MS. Reaction was quenched by addition of water and was transferred into a separatory funnel. Dilution with ethyl acetate, extraction with saturated aqueous NH.sub.4Cl and organic phase was collected. Aqueous phase was back-extracted with ethyl acetate; organic phases were combined, dried over Na.sub.2SO.sub.4 and evaporated down to dryness. Flash chromatography with a 330 g SiO.sub.2 column, eluent mixture of heptane and ethyl acetate gave 10.5 g of the desired product as a white solid (yield 72%). MS (ESI, m/z): 220.4 (MH+).

b) 4-chloro-5-(3-hydroxyoxetan-3-yl)nicolinonitrile

(303) ##STR00183##

(304) To a solution of 3-(4,6-dichloropyridin-3-yl)oxetan-3-ol (5.0 g, 22.7 mmol, Eq: 1.00) in dry DMF (100 mL) under argon atmosphere was added dicyanozinc (1.47 g, 12.5 mmol, Eq: 0.55), dppf (1.26 g, 2.27 mmol, Eq: 0.1) and Pd.sub.2(dba).sub.3 (1.04 g, 1.14 mmol, Eq: 0.05). The reaction mixture was stirred at 100 C. for 2 h and monitored by LC-MS. Evaporation of DMF, residue was diluted with ethyl acetate and poured into a separatory funnel. Extraction with saturated aqueous NH.sub.4Cl. Pd colloids were formed and removed by filtration through Celite. Organic phase was collected; aqueous phase was back-extracted with ethyl acetate. Organic phases were combined, dried over Na.sub.2SO.sub.4 and evaporated down to dryness. Flash chromatography with a 120 g SiO.sub.2 column, eluent mixture of heptane and ethyl acetate gave 4.1 g of the desired product (Yield 86%). MS (ESI, m/z): 209.0 (MH).

c) 4-chloro-5-(3-fluorooxetan-3-yl)pyridine-2-carbonitrile

(305) ##STR00184##

(306) To a solution of 4-chloro-5-(3-hydroxyoxetan-3-yl)picolinonitrile (0.2 g, 950 mol, Eq: 1.00) in dry DCM (6 mL) cooled down to 78 C. was added DAST (161 mg, 132 L, 997 mol, Eq: 1.05). The reaction was stirred at 78 C. for 15 min, let to warm up to 0 C. and stirred at 0 C. for 1 h. Reaction was then quenched by addition of aqueous Na.sub.2CO.sub.3 2M, the mixture was stirred at RT for 15 min and poured into a separatory funnel. Extraction, organic phase was collected, dried over Na.sub.2SO.sub.4 and evaporated down to dryness. Flash chromatography with a 20 g SiO.sub.2 column, eluent mixture of heptane and ethyl acetate gave 184 mg of the desired product (Yield 91%). MS (ESI, m/z): 213.0 (MH+).

d) 4-chloro-5-(3-fluorooxetan-3-yl)-N-hydroxypyridine-2-carboximidamide

(307) ##STR00185##

(308) To a solution of 4-chloro-5-(3-fluorooxetan-3-yl)picolinonitrile (500 mg, 2.35 mmol, Eq: 1.00) in Ethanol (15 mL) was added hydroxylamine hydrochloride (196 mg, 2.82 mmol, Eq: 1.2) and triethylamine (476 mg, 656 L, 4.7 mmol, Eq: 2.0). The reaction mixture was heated to 50 C. and stirred for 3 hours. Evaporation of volatiles, residue redissolved in ethyl acetate, poured into a separatory funnel and extracted with aqueous NaHCO.sub.3 1M, The organic layers were dried over Na.sub.2SO.sub.4 and evaporated down to dryness. Flash chromatography with a 20 g SiO.sub.2 column, eluent mixture of heptane and ethyl acetate gave 490 mg of desired compound (Yield 84%). MS (ESI, m/z): 246.4 (MH+).

e) 5-tert-butyl-3-[4-chloro-5-(3-fluorooxetan-3-yl)pyridin-2-yl]-1,2,4-oxadiazole

(309) ##STR00186##

(310) To a solution of 4-chloro-5-(3-fluorooxetan-3-yl)-N-hydroxypicolinimidamide (490 mg, 1.99 mmol, Eq: 1.00) in dry DMF (7 mL) under argon atmosphere was added K.sub.2CO.sub.3 (358 mg, 2.59 mmol, Eq: 1.3) and slowly pivaloyl chloride (CAS 3282-30-2) (265 mg, 270 L, 2.19 mmol, Eq: 1.1). The reaction mixture was stirred for 1 h at RT and controlled by LC-MS. The reaction was then stirred at 130 C. for 1 h30 and monitored by LC-MS. The reaction mixture was poured into a separatory funnel, diluted with EtOAc and extracted with aqueous NaHCO.sub.3 1M. The organic layer was dried over Na.sub.2SO.sub.4 and evaporated down to dryness. Purification by flash chromatography gave 374 mg of the title compound (Yield 54%). MS (ESI, m/z): 312.5 (MH+).

f) 5-tert-butyl-3-[5-(3-fluorooxetan-3-yl)-4-(oxan-4-yloxy)pyridin-2-yl]-1,2,4-oxadiazole

(311) ##STR00187##

(312) To a solution of 5-tert-butyl-3-(4-chloro-5-(3-fluorooxetan-3-yl)pyridin-2-yl)-1,2,4-oxadiazole (50 mg, 144 mol, Eq: 1.00) in dry DMF (1 mL) were added NaH (6.35 mg, 159 mol, Eq: 1.1) and tetrahydropyran-4-ol (16.2 mg, 159 mol, Eq: 1.1) (CAS 2081-44-9). The reaction was stirred at RT for 15 min and then stirred at 110 C. for 30 min under microwave radiation, reaction was monitored by LC-MS. Reaction was quenched by addition of few drops of water, and mixture was directly purified by preparative HPLC with any work-up procedure giving 43 mg of the title compound. MS (ESI, m/z): 378.6 (MH+).

Example 110

5-tert-butyl-3-[5-(3-fluorooxetan-3-yl)-4-(4-fluorophenoxy)pyridin-2-yl]-1,2,4-oxadiazole

(313) ##STR00188##

(314) The title compound was synthesized in analogy to Example 109f, using 5-tert-butyl-3-(4-chloro-5-(3-fluorooxetan-3-yl)pyridin-2-yl)-1,2,4-oxadiazole and 4-fluorophenol (CAS 371-41-5) as starting materials, and purified by preparative HPLC without any work-up. MS (ESI, m/z): 388.5 (MH+).

Example 111

3-[2-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-4-methyl-5H-1,3-oxazol-4-yl]-5-methyl-1,2,4-oxadiazole

a) N-(1-(benzyloxy)propan-2-ylidene)-2-methylpropane-2-sulfinamide

(315) ##STR00189##

(316) To a solution of 1-(benzyloxy)propan-2-one (4.0 g, 21.9 mmol, Eq: 1.00) (CAS 22539-93-1) in dry THF (100 mL) under argon atmosphere was added 2-methylpropane-2-sulfinamide (2.79 g, 23.0 mmol, Eq: 1.05) (CAS 146374-27-8) and Titanium(IV) ethoxide (5.25 g, 4.83 mL, 23.0 mmol, Eq: 1.05). The reaction mixture was stirred at 70 C. overnight. Reaction was cooled down to RT and stirred during quenching by addition of 10 mL of aqueous saturated NaCl solution. The heterogenous mixture was stirred for 20 min, then filtered through a pad of Celite and finally the filtrate was concentrated, diluted with ethyl acetate and extracted with aqueous saturated NaCl solution. Organic phase collected, dried over Na.sub.2SO.sub.4 and evaporated down to dryness. Flash chromatography with a 120 g SiO.sub.2 column, eluent mixture of heptane and ethyl acetate, gave 2.62 g of the title compound as yellow oil (Yield 45%). MS (ESI, m/z): 268.6 (MH+).

b) N-(1-(benzyloxy)-2-cyanopropan-2-yl)-2-methylpropane-2-sulfinamide

(317) ##STR00190##

(318) To a solution of N-(1-(benzyloxy)propan-2-ylidene)-2-methylpropane-2-sulfinamide (2.6 g, 9.72 mmol, Eq: 1.00) in dry THF (45 mL) under argon atmosphere was added CsF (1.62 g, 10.7 mmol, Eq: 1.1) followed by trimethylsilyl cyanide (1.06 g, 1.43 mL, 10.7 mmol, Eq: 1.1). The reaction mixture was stirred at RT overnight and monitored by TLC (ethyl acetate, spray reagent KMnO.sub.4). Concentration in vacuo, dilution with ethyl acetate, extraction with water, organic phase was brined before drying over Na.sub.2SO.sub.4 and evaporated down to dryness. Flash chromatography with a 70 g SiO.sub.2 column, eluent mixture of heptane and ethyl acetate, gave 2.55 g of the desired product (Yield 89%). MS (ESI, m/z): 295.5 (MH+).

c) 3-(benzyloxy)-2-(1,1-dimethylethylsulfinamido)-N-hydroxy-2-methylpropanimidamide

(319) ##STR00191##

(320) To a suspension of potassium carbonate (2.44 g, 17.6 mmol, Eq: 1.5) in dry ethanol (40 mL) under argon atmosphere was added hydroxylamine hydrochloride (858 mg, 12.3 mmol, Eq: 1.05) and the mixture was stirred at RT for 20 min. Addition of a solution of N-(1-(benzyloxy)-2-cyanopropan-2-yl)-2-methylpropane-2-sulfinamide (3.46 g, 11.8 mmol, Eq: 1.00) in dry ethanol (30 mL) to the former reaction mixture. The reaction mixture was stirred at 55 C. overnight and monitored by TLC (ethyl acetate, UV 254 nm and spray reagent KMnO.sub.4). Evaporation of volatiles, residue suspended in ethyl acetate, extraction with aqueous Na.sub.2CO.sub.3 2M, aqueous phase back-extracted with ethyl acetate, organic phase were combined, dried over Na.sub.2SO.sub.4 and evaporated down to dryness. Flash chromatography with a 50 g SiO.sub.2 column, eluent mixture of DCM and methanol, gave 3.1 g of the title compound as a white solid (Yield 81%). MS (ESI, m/z): 328.6 (MH+).

d) N-(1-(benzyloxy)-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-yl)-2-methylpropane-2-sulfinamide

(321) ##STR00192##

(322) To a solution of 3-(benzyloxy)-2-(1,1-dimethylethylsulfinamido)-N-hydroxy-2-methylpropanimidamide (3.1 g, 9.47 mmol, Eq: 1.00) in dry DMF (50 mL) under argon atmosphere was added potassium carbonate (1.57 g, 11.4 mmol, Eq: 1.2) and acetic anhydride (967 mg, 893 L, 9.47 mmol, Eq: 1.0). The reaction mixture was stirred at RT for 1 h and was monitored by LC-MS to control the formation of the acetylated intermediate. The reaction was then stirred at 120 C. for 2 h, monitoring was done by LC-MS. Evaporation of volatiles, residue redissolved in ethyl acetate, extraction with aqueous NaHCO.sub.3 1M, aqueous phase back-extracted with ethyl acetate, organic phases were combined, dried over Na.sub.2SO.sub.4 and evaporated down to dryness. Flash chromatography with a 120 g SiO.sub.2 column, eluent mixture of heptane and ethyl acetate, gave 2.25 g of title compound as yellow oil (Yield 68%). MS (ESI, m/z): 352.6 (MH+).

e) 1-(benzyloxy)-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-amine

(323) ##STR00193##

(324) To a solution of N-(1-(benzyloxy)-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-yl)-2-methylpropane-2-sulfinamide (2.25 g, 6.4 mmol, Eq: 1.00) in MeOH (25 mL) was added HCl 4M in Dioxane (4.8 mL, 19.2 mmol, Eq: 3.0). The reaction mixture was stirred at RT for 1 h and monitored by LC-MS. Evaporation of volatiles, residue redissolved in ethyl acetate, extraction with aqueous Na.sub.2CO.sub.3 2M. Aqueous phase was back-extracted with ethyl acetate and organic phases were combined, dried over Na.sub.2SO.sub.4 and evaporated down to dryness. Flash chromatography with a 50 g SiO.sub.2 column, eluent mixture of heptane and ethyl acetate, gave 1.52 g of desired product as light yellow oil (Yield 96%). MS (ESI, m/z): 248.6 (MH+).

f) N-(1-(benzyloxy)-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-yl)-5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinamide

(325) ##STR00194##

(326) To a solution of 5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinic acid (0.4 g, 1.53 mmol, Eq: 1.00), previously described as Example 7e, in dry DMF (10 mL) under argon atmosphere was added TBTU (516 mg, 1.61 mmol, Eq: 1.05) and triethylamine (186 mg, 256 L, 1.84 mmol, Eq: 1.2). The reaction mixture was stirred at RT for 30 min and 1-(benzyloxy)-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-amine (398 mg, 1.61 mmol, Eq: 1.05) was then added to the reaction. The reaction was then stirred at RT overnight and monitored by LC-MS. Evaporation of DMF. Residue was redissolved in ethyl acetate and extracted with aqueous NaHCO.sub.3 1M. Organic phase dried over Na.sub.2SO.sub.4 and evaporated down to dryness. Flash chromatography with a 50 g SiO.sub.2 column, eluent mixture of heptane and ethyl acetate gave 805 mg of the desired product (Yield 93%). MS (ESI, m/z): 491.5 (MH+).

g) 5-cyclopropyl-N-(1-hydroxy-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-yl)-4-(2,2,2-trifluoroethoxy)picolinamide

(327) ##STR00195##

(328) To a solution of N-(1-(benzyloxy)-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-yl)-5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinamide (0.1 g, 204 mol, Eq: 1.00) in dry DCM (1 mL) cooled down to 0 C. under argon atmosphere was added BBr.sub.3 solution 1.0M in DCM (224 L, 224 mol, Eq: 1.1). The reaction mixture was stirred at 0 C. for 15 min and then stirred at RT for 1 h, reaction was monitored by LC-MS. Reaction was diluted with DCM, quenched by addition of aqueous Na.sub.2CO.sub.3 2M and mixture was stirred for 10 min. Mixture was poured into a separatory funnel, organic phase was collected, aqueous phase was back-extracted with DCM, organic phases were combined, dried over Na.sub.2SO.sub.4 and evaporated down to dryness. Flash chromatography with a 10 g SiO.sub.2 column, eluent mixture of heptane and ethyl acetate, gave 80 mg of the desired product (Yield 92%). MS (ESI, m/z): 401.5 (MH+).

h) 2-(5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinamido)-2-(5-methyl-1,2,4-oxadiazol-3-yl)propyl 4-methylbenzenesulfonate

(329) ##STR00196##

(330) To a solution of 5-cyclopropyl-N-(1-hydroxy-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-yl)-4-(2,2,2-trifluoroethoxy)picolinamide (0.1 g, 250 mol, Eq: 1.00) in dry DCM (2 ml) was added DMAP (15.3 mg, 125 mol, Eq: 0.5), K.sub.2CO.sub.3 (48.3 mg, 350 mol, Eq: 1.4) followed by addition of 4-methylbenzene-1-sulfonyl chloride (47.6 mg, 250 mol, Eq: 1.0). The reaction mixture was stirred at RT overnight and monitored by LC-MS. Reaction diluted with DCM and water, poured into a separatory funnel, extracted and organic phase was collected. Organic phase was dried over Na.sub.2SO.sub.4 and evaporated down to dryness. Crude was used for the next step without any purification. MS (ESI, m/z): 555.4 (MH+).

i) 3-(2-(5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)-4-methyl-4,5-dihydrooxazol-4-yl)-5-methyl-1,2,4-oxadiazole

(331) ##STR00197##

(332) To a solution of 2-(5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinamido)-2-(5-methyl-1,2,4-oxadiazol-3-yl)propyl 4-methylbenzenesulfonate (0.06 g, 108 mol, Eq: 1.00) in dry DMF (1 mL) was added triethylamine (16.4 mg, 22.6 l, 162 mol, Eq: 1.5) and 3,3-difluoroazetidine hydrochloride (CAS 288315-03-7) (16.8 mg, 130 mol, Eq: 1.2). The reaction mixture was stirred at 80 C. for 45 min under microwave radiation and reaction was monitored by LC-MS which showed conversion to a side product from an intramolecular ring closure to an oxazolidine. Reaction was directly purified by preparative HPLC without any purification and gave 6.2 mg of the title compound. MS (ESI, m/z): 383.5 (MH+).

Example 112

5-tert-butyl-3-(6-chloro-5-cyclopropyl-4-(4-fluorobenzyloxy)pyridin-2-yl)-1,2,4-oxadiazole

a) 2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-cyclopropyl-4-(4-fluorobenzyloxy)pyridine 1-oxide

(333) ##STR00198##

(334) To a solution of 5-tert-butyl-3-(5-cyclopropyl-4-(4-fluorobenzyloxy)pyridin-2-yl)-1,2,4-oxadiazole (326 mg, 887 mol, Eq: 1.00), previously described as Example 53, in dry DCM (4.93 mL) was added m-CPBA (459 mg, 1.33 mmol, Eq: 1.5) and the reaction stirred overnight at RT. Extraction with NaHCO.sub.3/DCM. Organic layer was dried on Na.sub.2SO.sub.4 and evaporated. Purification by flash chromatography on SiO.sub.2 column with a gradient DCM and methanol gave 445 mg of the title compound (Yield 78%). MS (ESI, m/z): 384.6 (MH+).

b) 5-tert-butyl-3-(6-chloro-5-cyclopropyl-4-(4-fluorobenzyloxy)pyridin-2-yl)-1,2,4-oxadiazole

(335) ##STR00199##

(336) 2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-cyclopropyl-4-(4-fluorobenzyloxy)pyridine 1-oxide (123 mg, 321 mol, Eq: 1.00) was dissolved in a mixture of DCM/DMF: 1/1 (2.8 mL). The mixture was cooled down to 0 C. and oxalyl chloride (204 mg, 139 L, 1.6 mmol, Eq: 5.0) was slowly added. Reaction was stirred at 0 C. for 30 min and then the temperature was allowed to reach RT and reacted overnight. The reaction was cooled down to 0 C. and quenched by in addition of aqueous Na.sub.2CO.sub.3 and stirred for 15 min at 0 C. The mixture was diluted with ethyl acetate and extracted with aqueous Na.sub.2CO.sub.3. Organic phase was collected; aqueous phase was back-extracted with ethyl acetate. Organic phases were combined, dried over Na.sub.2SO.sub.4 and evaporated down to dryness. The crude material was purified by flash chromatography on SiO.sub.2 using MPLC ISCO with a gradient heptane/ethyl acetate giving 15 mg of the title compound as colorless viscous oil. MS (ESI, m/z): 402.5 (MH+).

Example 113

2-tert-butyl-5-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,3,4-oxadiazole

a) 5-cyclopropyl-N-pivaloyl-4-(2,2,2-trifluoroethoxy)picolinohydrazide

(337) ##STR00200##

(338) 5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinic acid (100 mg, 383 mmol, Eq: 1.00), previously described as Example 7e, in DCM (1.91 mL) had oxalyl chloride (50 L, 0.574 mmol, Eq: 1.5) and DMF (2 L, 0.019 mmol, Eq: 0.05) added to it. The reaction was deemed to be complete and the reaction mixture was concentrated in vacuo. The product was used immediately in the next step and dissolved in THF (563 L) to be reacted with pivalohydrazide (55.0 mg, 459 mol, Eq: 1.2) (CAS 42826-42-6) and triethylamine (58.1 mg, 80.0 L, 574 mol, Eq: 1.5) at RT overnight. The reaction mixture was then diluted with ethyl acetate, poured into NaHCO.sub.3 1M solution. It was then extracted with ethyl acetate and the organic layers were combined, dried, and concentrated in vacuo to give 130 mg of the title compound used as crude (Yield 94%). MS (ESI, m/z): 360.6 (MH+).

b) 2-tert-butyl-5-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,3,4-oxadiazole

(339) ##STR00201##

(340) Trifluoromethanesulfonic anhydride (153 mg, 91.7 L, 543 mol, Eq: 1.5) was added slowly to a solution of triphenylphosphine oxide (302 mg, 1.09 mmol, Eq: 3.0) in dry DCM (0.231 mL) at 0 C. The reaction mixture was stirred for 5 minutes at this temperature before it was adjusted to room temperature and 5-cyclopropyl-N-pivaloyl-4-(2,2,2-trifluoroethoxy)picolinohydrazide (130 mg, 362 mol, eq: 1.00) previously azeotropically dried with toluene, was added. The reaction mixture was then stirred for a further 30 minutes at RT before monitoring via LC-MS showed the reaction as complete. The reaction mixture was then diluted with DCM and poured into NaHCO.sub.3 saturated aqueous solution and extracted with DCM. The aqueous layer was then back-extracted with DCM before the organic layers were combined, dried, and concentrated in vacuo. The crude material was purified by flash chromatography (SiO.sub.2, 10 g, gradient ethyl acetate in heptane) to give 56 mg of the title product as white solid (45% yield). MS (ESI, m/z): 342.6 (MH+).

Example 114

5-tert-butyl-3-[6-chloro-5-cyclopropyl-4-(oxan-4-yloxy)pyridin-2-yl]-1,2,4-oxadiazole

a) 2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-cyclopropyl-4-(tetrahydro-2H-pyran-4-yloxy)pyridine 1-oxide

(341) ##STR00202##

(342) To a solution of 5-tert-butyl-3-(5-cyclopropyl-4-(tetrahydro-2H-pyran-4-yloxy)pyridin-2-yl)-1,2,4-oxadiazole (64 mg, 186 mol, Eq: 1.00), previously described as Example 63, in dry DCM (1.04 mL) was added m-CPBA (96.5 mg, 280 mol, Eq: 1.5). The reaction was stirred for 1 h at RT. Extraction NaHCO.sub.3/DCM. Organic layer was dried on Na.sub.2SO.sub.4 and evaporated. Purification by flash chromatography (SiO.sub.2, 70 g, eluent: ethyl acetate/heptane) gave 59 mg of the desired compound (Yield 88%). MS (ESI, m/z): 360.6 (MH+).

b) 5-tert-butyl-3-[6-chloro-5-cyclopropyl-4-(oxan-4-yloxy)pyridin-2-yl]-1,2,4-oxadiazole

(343) ##STR00203##

(344) 2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-cyclopropyl-4-(tetrahydro-2H-pyran-4-yloxy)pyridine 1-oxide (56 mg, 0.156 mmol, Eq: 1.00) was dissolved in a mixture of DCM/DMF: 1/1 (1.3 mL). The mixture was cooled down to 0 C. and oxalyl chloride (98.9 mg, 67.3 L, 779 mol, Eq: 5.0) was slowly added. Reaction was stirred at 0 C. for 20 min and then the temperature was allowed to reach RT and reacted overnight. Another 1.5 eq of oxalyl chloride was added and stirred for 1.5 h. The reaction was then cooled down to 0 C. and quenched by addition of aqueous Na.sub.2CO.sub.3 and stirred for 15 min at 0 C. The mixture was diluted with ethyl acetate and extracted with aqueous Na.sub.2CO.sub.3. Organic phase was collected; aqueous phase was back-extracted with ethyl acetate. Organic phases were combined, dried over Na.sub.2SO.sub.4 and evaporated down to dryness. The crude material was purified by flash chromatography (SiO.sub.2, 5 g, ethyl acetate/heptane) giving 21 mg of the title compound as colorless oil (Yield 35%). MS (ESI, m/z): 378.5 (MH+).

Example 115

5-tert-butyl-3-[5-cyclopropyl-4-(2,2-difluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole

a) 5-cyclopropyl-4-(2,2-difluoroethoxy)picolinonitrile

(345) ##STR00204##

(346) Sodium hydride (123 mg, 3.08 mmol, Eq: 1.1) was added to a solution of 4-chloro-5-cyclopropylpicolinonitrile (500 mg, 2.8 mmol, Eq: 1.00), previously described as Example 48b, and 2,2-difluoroethanol (253 mg, 3.08 mmol, Eq: 1.1) (CAS 359-13-7) in DMF (10 mL) at RT. and stirred for 3 hours. The 5-fold volume of water was added, followed by extraction with EtOAc, washing with brine. Organic layer was dried on MgSO.sub.4, concentrated in vacuo and chromatographied on SiO.sub.2 with DCM to afford 508 mg of the title compound as a dark-yellow solid (Yield 80%). MS (ESI, m/z): 225.2 (MH+).

b) 5-tert-butyl-3-[5-cyclopropyl-4-(2,2-difluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole

(347) ##STR00205##

(348) To a solution of 5-cyclopropyl-4-(2,2-difluoroethoxy)picolinonitrile (120 mg, 0.535 mmol, Eq: 1.00) in EtOH (3.5 mL) was added triethylamine (149 L, 1.07 mmol, Eq: 2.0) and hydroxylamine hydrochloride (55.8 mg, 0.803 mmol, Eq: 1.5) and the mixture heated 30 min at 90 C. with microwave. 1 M NaHCO.sub.3 was added and it was extracted with DCM. Drying on MgSO.sub.4 and concentration in vacuo afforded 60 mg of the compound as light-yellow solid, this was used without further purification and dissolved in DMF (2.00 mL). Then triethylamine (29.0 mg, 40.0 L, 287 mol, Eq: 1.2) and pivaloyl chloride (31.4 mg, 32 L, 260 mol, Eq: 1.1) were added at RT and after 30 minutes stirring, the solution was heated at 130 C. with microwave for 30 minutes. The mixture was diluted with water and extracted with ethyl acetate, washed with brine, dried on MgSO.sub.4 and concentration in vacuo followed by column chromatography (SiO.sub.2, ethyl acetate in heptane) afforded 45 mg of the title compound (Yield 59%). MS (ESI, m/z): 324.5 (MH+).

Example 116

5-tert-butyl-3-[5-cyclopropyl-4-(2-fluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole

(349) ##STR00206##

(350) The title compound was synthesized in analogy to Example 115, using 4-chloro-5-cyclopropylpicolinonitrile, previously described as Example 48b, and 2-fluoroethanol (CAS 371-62-0) as starting materials. MS (ESI, m/z): 306.5 (MH+).

Example 117

5-tert-butyl-3-[5-cyclopropyl-4-(pyridin-2-ylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole

(351) ##STR00207##

(352) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and 2-(hydroxymethyl)pyridine (CAS 586-98-1) as starting materials, heated 30 min at 120 C. with microwave and purified by preparative HPLC without any work-up. MS (ESI, m/z): 351.6 (MH+).

Example 118

5-tert-butyl-3-[5-cyclopropyl-4-[(5-fluoropyridin-2-yl)methoxy]pyridin-2-yl]-1,2,4-oxadiazole

(353) ##STR00208##

(354) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and 5-fluoro-2-hydroxylmethylpyridine (CAS 802325-29-7) as starting materials, heated 30 min at 110 C. under microwave radiation. The mixture was diluted with ethyl acetate and extracted with aqueous Na.sub.2CO.sub.3. Organic phase was collected and the aqueous phase was back-extracted with ethyl acetate. The organic phases were combined, dried over Na.sub.2SO.sub.4 and evaporated down to dryness. The crude material was purified by flash chromatography (SiO.sub.2, 5 g, ethyl acetate/heptane). MS (ESI, m/z): 369.6 (MH+).

Example 119

5-tert-butyl-3-[5-cyclopropyl-4-(pyridin-3-ylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole

(355) ##STR00209##

(356) The title compound was synthesized in analogy to Example 48e, using 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and 3-(hydroxymethyl)pyridine (CAS 100-55-0) as starting materials, heated 30 min at 110 C. under microwave radiation. The mixture was diluted with ethyl acetate and extracted with aqueous Na.sub.2CO.sub.3. The organic phase was collected and the aqueous phase was back-extracted with ethyl acetate. The organic phases were combined, dried over Na.sub.2SO.sub.4 and evaporated down to dryness. The crude material was purified by flash chromatography (SiO.sub.2, 5 g, ethyl acetate/heptane). MS (ESI, m/z): 351.6 (MH+).

Example 120

2-tert-butyl-5-[5-cyclopropyl-4-[(2S)-1,1,1-trifluoropropan-2-yl]oxypyridin-2-yl]-1,3,4-oxadiazole

(357) ##STR00210##

(358) The title compound was synthesized in a similar manner to Example 98, using the corresponding nitrile 5-cyclopropyl-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carbonitrile generated from (S)-1,1,1-Trifluoropropan-2-ol (CAS 3539-97-7) according to example 7a-d. MS (ESI, m/z): 356.6 (MH+).

Example 121

3-tert-butyl-5-(5-cyclopropyl-4-(tetrahydro-2H-pyran-4-yloxy)pyridin-2-yl)-1,2,4-oxadiazole

(359) ##STR00211##

(360) The title compound was synthesized in analogy to Example 51c, using 5-cyclopropyl-4-(tetrahydro-2H-pyran-4-yloxy)picolinic acid from example 98b. MS (ESI, m/z): 344.5 (MH+).

Example 122

3-tert-butyl-5-[5-cyclopropyl-4-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]pyridin-2-yl]-1,2,4-oxadiazole

a) tert-butyl (2S)-2-[[2-(3-tert-butyl-1,2,4-oxadiazol-5-yl)-5-cyclopropylpyridin-4-yl]oxymethyl]pyrrolidine-1-carboxylate

(361) ##STR00212##

(362) The title compound was synthesized in analogy to Example 51d using Boc-L-prolinol (CAS 69610-40-8). MS (ESI, m/z): 443.7 (MH+).

b) 3-tert-butyl-5-[5-cyclopropyl-4-[[(2S)-pyrrolidin-2-yl]methoxy]pyridin-2-yl]-1,2,4-oxadiazole

(363) ##STR00213##

(364) tert-butyl (2S)-2-[[2-(3-tert-butyl-1,2,4-oxadiazol-5-yl)-5-cyclopropylpyridin-4-yl]oxymethyl]pyrrolidine-1-carboxylate (364 mg, 823 mol, Eq: 1.00) was dissolved in a 4M solution of hydrochloric acid in 1,4-dioxane (19.5 ml, 78.1 mmol, Eq: 95) and then stirred at rt for 1.5 hours and monitored by LC-MS. The solvent was evaporated and the reaction mixture was diluted with ethyl acetate and washed with NaHCO3 and the organic phase was collected, dried over Na.sub.2SO.sub.4 and evaporated. The crude material was purified by flash chromatography (SiO.sub.2, 20 g, ethyl acetate/heptane) to afford 104 mg of the title compound as a light yellow powder (Yield 37%). MS (ESI, m/z): 343.6 (MH+).

c) 3-tert-butyl-5-[5-cyclopropyl-4-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]pyridin-2-yl]-1,2,4-oxadiazole

(365) ##STR00214##

(366) To a solution of 3-tert-butyl-5-[5-cyclopropyl-4-[[(2S)-pyrrolidin-2-yl]methoxy]pyridin-2-yl]-1,2,4-oxadiazole (95 mg, 277 mol, Eq: 1.00) and formaldehyde (295 mg, 360 l, 3.63 mmol, Eq: 13.1) in dichloromethane (1.8 mL) was added sodium triacetoxyborohydride (300 mg, 1.42 mmol, Eq: 5.1). The reaction was stirred 3 hours at rt, and monitored by LC-MS. The mixture was diluted with dichloromethane and washed with 1 N NaOH. The organic phase was dried over Na.sub.2SO.sub.4 and evaporated. The crude material was purified by flash chromatography (SiO.sub.2, 10 g, ethyl acetate/heptane) to afford 54 mg of the title compound as light yellow oil (Yield 54%). MS (ESI, m/z): 357.6 (MH+).

Example 123

3-tert-butyl-5-(5-cyclopropyl-4-(2,2-difluoroethoxy)pyridin-2-yl)-1,2,4-oxadiazole

a) 5-cyclopropyl-4-(2,2-difluoroethoxy)picolinic acid

(367) 5-cyclopropyl-4-(2,2-difluoroethoxy)picolinonitrile (350 mg, 1.56 mmol, Eq: 1.00, previously described as Example 115a, was dissolved in aqueous HCl 25% (16.8 g, 15 ml, 115 mmol, Eq: 73.8). Reaction was heated at 110 C. for 1 hour and then cooled down to rt. HCl was neutralized using 6M NaOH aq. sol. Then pH adjusted to 1-2 with HCl 2M. The precipitate formed was then filtered. The remaining salt was precipitated with ethanol and filtered giving the title compound as a light yellow solid. MS (ESI, m/z): 244.3 (MH+).

b) 3-tert-butyl-5-(5-cyclopropyl-4-(2,2-difluoroethoxy)pyridin-2-yl)-1,2,4-oxadiazole

(368) ##STR00215##

(369) The title compound was synthesized in analogy to Example 51c, using 5-cyclopropyl-4-(2,2-difluoroethoxy)picolinic acid. MS (ESI, m/z): 324.6 (MH+).

Example 124

(370) Pharmacological Tests

(371) The following tests were carried out in order to determine the activity of the compounds of formula I:

(372) Radioligand Binding Assay

(373) The affinity of the compounds of the invention for cannabinoid CB1 receptors was determined using recommended amounts of membrane preparations (PerkinElmer) of human embryonic kidney (HEK) cells expressing the human CNR1 or CNR2 receptors in conjunction with 1.5 or 2.6 nM [3H]-CP-55,940 (Perkin Elmer) as radioligand, respectively. Binding was performed in binding buffer (50 mM Tris, 5 mM MgCl2, 2.5 mM EDTA, and 0.5% (wt/vol) fatty acid free BSA, pH 7.4 for CB1 receptor and 50 mM Tris, 5 mM MgCl.sub.2, 2.5 mM EGTA, and 0.1% (wt/vol) fatty acid free BSA, pH 7.4 for CB2 receptor) in a total volume of 0.2 ml for 1 h at 30 C. shaking. The reaction was terminated by rapid filtration through microfiltration plates coated with 0.5% polyethylenimine (UniFilter GF/B filter plate; Packard). Bound radioactivity was analyzed for Ki using nonlinear regression analysis (Activity Base, ID Business Solution, Limited), with the Kd values for [3H]CP55,940 determined from saturation experiments. The compounds of formula (I) show an excellent affinity for the CB2 receptor with affinities below 10 M, more particularly of 1 nM to 3 M and most particularly of 1 nM to 100 nM.

(374) cAMP Assay

(375) CHO cells expressing human CB1 or CB2 receptors are seeded 17-24 hours prior to the experiment 50.000 cells per well in a black 96 well plate with flat clear bottom (Corning Costar #3904) in DMEM (Invitrogen No. 31331), 1HT supplement, with 10% fetal calf serum and incubated at 5% CO.sub.2 and 37 C. in a humidified incubator. The growth medium was exchanged with Krebs Ringer Bicarbonate buffer with 1 mM IBMX and incubated at 30 C. for 30 min. Compounds were added to a final assay volume of 100 l and incubated for 30 min at 30 C. Using the cAMP-Nano-TRF detection kit the assay (Roche Diagnostics) was stopped by the addition of 50 l lysis reagent (Tris, NaCl, 1.5% Triton X100, 2.5% NP40, 10% NaN.sub.3) and 50 l detection solutions (20 M mAb Alexa700-cAMP 1:1, and 48 M Ruthenium-2-AHA-cAMP) and shaken for 2 h at room temperature. The time-resolved energy transfer is measured by a TRF reader (Evotec Technologies GmbH), equipped with a ND:YAG laser as excitation source. The plate is measured twice with the excitation at 355 nm and at the emission with a delay of 100 ns and a gate of 100 ns, total exposure time 10 s at 730 (bandwidth30 nm) or 645 nm (bandwidth 75 nm), respectively. The FRET signal is calculated as follows: FRET=T730-Alexa730-P(T645-B645) with P=Ru730-B730/Ru645-B645, where T730 is the test well measured at 730 nM, T645 is the test well measured at 645 nm, B730 and B645 are the buffer controls at 730 nm and 645 nm, respectively. cAMP content is determined from the function of a standard curve spanning from 10 M to 0.13 nM cAMP.

(376) EC.sub.50 values were determined using Activity Base analysis (ID Business Solution, Limited). The EC.sub.50 values for a wide range of cannabinoid agonists generated from this assay were in agreement with the values published in the scientific literature.

(377) The compounds of the invention are CB2 agonists with EC.sub.50 below 0.5 M and selectivity versus CB1 in the corresponding assay of at least 10 fold. Particular compound of the invention are CB2 agonists with EC.sub.50 below 0.05 M and selectivity versus CB1 in the corresponding assay of at least 500 fold.

(378) For example, the following compounds showed the following human EC.sub.50 values in the functional cAMP assay described above (in M):

(379) TABLE-US-00001 EC50 EC50 CB2 CB1 Example human human 1 0.0257 >10 2 0.0231 >10 3 0.0012 >10 4 0.0021 >10 5 0.0691 >10 6 0.001 0.0092 7 0.0111 >10 8 0.0213 >10 9 0.0158 >10 10 0.0008 >10 11 0.0006 >10 12 0.0466 >10 13 0.0319 >10 14 0.0037 >10 15 0.0198 >10 16 0.3426 >10 17 0.0205 >10 18 0.1104 >10 19 0.0137 >10 20 0.0037 >10 21 0.07 >10 22 0.0042 3.67542 23 0.0352 >10 24 0.0043 0.58087 25 0.135 >10 26 0.0308 >10 27 0.0035 >10 28 0.016 >10 29 0.7967 >10 30 0.0026 >10 31 0.0194 >10 32 0.0086 >10 33 0.0069 >10 34 0.0147 >10 35 0.0328 >10 36 0.0209 >10 37 0.2359 >10 38 0.1283 >10 39 0.4344 >10 40 0.0022 >10 41 0.0539 >10 42 0.0023 >10 43 0.0409 >10 44 0.0159 >10 45 0.0778 >10 46 0.1798 >10 47 0.1659 >10 48 0.019 >10 49 0.0515 >10 50 0.0458 >10 51 0.0618 >10 52 0.0131 >10 53 0.0014 0.05506 54 0.0331 >10 55 0.0077 >10 56 0.0447 >10 57 0.0134 >10 58 0.0156 >10 59 0.0481 >10 60 0.4476 >10 61 0.0062 >10 62 0.0178 >10 63 0.0043 >10 64 0.0875 >10 65 0.0017 0.17031 66 0.009 >10 67 0.4343 >10 68 0.0726 >10 69 0.009 >10 70 0.0057 >10 71 0.2795 >10 72 0.0454 >10 73 0.0572 >10 74 0.0047 >10 75 0.2877 >10 76 0.0193 >10 77 0.0021 >10 78 0.0422 >10 79 0.009 >10 80 0.0475 >10 81 0.0211 >10 82 0.0379 >10 83 0.0301 >10 84 0.0501 >10 85 0.0356 1.33751 86 0.0482 1.40191 87 0.1127 >10 88 0.0529 >10 89 0.0162 >10 90 0.0118 >10 91 0.6412 >10 92 0.0751 0.76771 93 0.0119 0.23504 94 0.0602 >10 95 0.0261 >10 96 0.0759 1.01189 97 0.019 >10 98 0.042 >10 99 0.3174 >10 100 0.5179 >10 101 0.1423 >10 102 0.0718 >10 103 0.0289 >10 104 0.0698 >10 105 0.0291 >10 106 0.1279 >10 107 0.0958 >10 108 0.0698 >10 109 0.162 >10 110 0.103 >10 111 0.0576 >10 112 0.0048 0.07317 113 0.0225 >10 114 0.0037 0.45539 115 0.002 >10 116 0.0155 >10 117 0.0539 >10 118 0.035 >10 119 0.047 >10 120 0.063 >10 121 0.001 >10 122 0.146 >10 123 0.002 >10

Example A

(380) Film coated tablets containing the following ingredients can be manufactured in a conventional manner:

(381) TABLE-US-00002 Ingredients Per tablet Kernel: Compound of formula (I) 10.0 mg 200.0 mg Microcrystalline cellulose 23.5 mg 43.5 mg Lactose hydrous 60.0 mg 70.0 mg Povidone K30 12.5 mg 15.0 mg Sodium starch glycolate 12.5 mg 17.0 mg Magnesium stearate 1.5 mg 4.5 mg (Kernel Weight) 120.0 mg 350.0 mg Film Coat: Hydroxypropyl methyl cellulose 3.5 mg 7.0 mg Polyethylene glycol 6000 0.8 mg 1.6 mg Talc 1.3 mg 2.6 mg Iron oxide (yellow) 0.8 mg 1.6 mg Titan dioxide 0.8 mg 1.6 mg

(382) The active ingredient is sieved and mixed with microcrystalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidone in water. The granulate is then mixed with sodium starch glycolate and magnesium stearate and compressed to yield kernels of 120 or 350 mg respectively. The kernels are lacquered with an aq. solution/suspension of the above mentioned film coat.

Example B

(383) Capsules containing the following ingredients can be manufactured in a conventional manner:

(384) TABLE-US-00003 Ingredients Per capsule Compound of formula (I) 25.0 mg Lactose 150.0 mg Maize starch 20.0 mg Talc 5.0 mg

(385) The components are sieved and mixed and filled into capsules of size 2.

Example C

(386) Injection solutions can have the following composition:

(387) TABLE-US-00004 Compound of formula (I) 3.0 mg Polyethylene glycol 400 150.0 mg Acetic acid q.s. ad pH 5.0 Water for injection solutions ad 1.0 ml

(388) The active ingredient is dissolved in a mixture of Polyethylene glycol 400 and water for injection (part). The pH is adjusted to 5.0 by addition of acetic acid. The volume is adjusted to 1.0 ml by addition of the residual amount of water. The solution is filtered, filled into vials using an appropriate overage and sterilized.