Pyridine and pyrazine derivatives as preferential cannabinoid 2 agonists

Abstract

The invention relates to a compound of formula (I) ##STR00001##
wherein A.sup.1, A.sup.2 and R.sup.1-R.sup.5 are as defined in the description and in the claims. The compound of formula (I) can be used as a medicament.

Claims

1. A compound of formula (I) ##STR00107## wherein A.sup.1 is —CH— or nitrogen; A.sup.2 is —CH.sub.2— or carbonyl; R.sup.1 is haloalkoxyalkylcycloalkyl, haloalkylcycloalkyl, haloalkoxyalkyl, hydroxyalkylcycloalkyl, oxetanyl, haloalkoxyalkyloxetanyl, hydroxyalkyloxetanyl, haloalkyloxetanyl, 1-fluoroethyl, 1-fluoro-prop-2-yl, fluoro-tert.-butyl, cyclopropylfluoromethyl, fluorocyclopropyl, halooxanyl, halotetrahydrofuranyl, phenylalkoxyalkylcycloalkyl, 1-fluoro-1,1-dideuteroprop-2-yl, fluorodideuteromethyl, fluorodideuteromethyloxyalkylcycloalkyl, 2-fluoro-2,2-dideuteroethyloxyalkylcycloalkyl, fluorodideuteromethylcycloalkyl, fluorodideuteromethyloxyalkyl, fluorodideuteromethylalkyl, fluorodideuteromethyloxyalkyloxetanyl, 2-fluoro-2,2-dideuteroethyloxyalkyloxetanyl, 3-fluoro-3,3-dideuteropropyloxyalkyloxetanyl or fluorodideuteromethyloxetanyl; R.sup.2 is alkoxyazetidinyl, haloazetidinyl, dihaloazetidinyl, pyrrolidinyl or alkylphenylsulfonyloxyazetidinyl; R.sup.3 and R.sup.4 are independently selected from hydrogen, alkyl, alkenyl and deuterioalkyl; R.sup.5 is hydrogen, alkyl, haloalkyl, deuterioalkyl, alkylphenylsulfonyloxyalkyl, alkylphenylsulfonyloxydeuterioalkyl or hydroxyalkyl; and X is oxygen or —NH—; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein A.sup.1 is —CH—.

3. The compound of claim 1, wherein A.sup.2 is carbonyl.

4. The compound of claim 1, wherein R.sup.1 is haloalkoxyalkylcycloalkyl, haloalkylcycloalkyl or hydroxyalkylcycloalkyl.

5. The compound of claim 4, wherein R.sup.1 is fluoromethoxymethylcyclopropyl, fluoromethylcyclopropyl or hydroxmethylcyclopropyl.

6. The compound of claim 1, wherein R.sup.2 is alkoxyazetidinyl or haloazetidinyl.

7. The compound of claim 6, wherein R.sup.2 is methoxyazetidinyl or fluoroazetidinyl.

8. The compound of claim 1, wherein R.sup.3 and R.sup.4 are both alkyl at the same time or both deuterioalkyl at the same time.

9. The compound claim 8, wherein R.sup.3 and R.sup.4 are both ethyl at the same time or both dideuterioethyl at the same time.

10. The compound of claim 1, wherein R.sup.5 is alkyl, haloalkyl or halodeuterioalkyl.

11. The compound of claim 10, wherein R.sup.5 is ethyl, fluoromethyl, fluoropropyl, fluorobutyl or fluorohexadeuteriopropyl.

12. The compound of claim 1, wherein X is oxygen.

13. The compound of claim 1 selected from the group consisting of: Ethyl 2-ethyl-2-{[6-({(1S,2S)-2-[(fluoromethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; ethyl 2-ethyl-2-{[6-({(1R,2R)-2-[(fluoromethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-caronyl]amino}butanoate; Ethyl 2-ethyl-2-{[6({(1S,2S)-2-[(2-fluoroethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; ethyl 2-ethyl-2-{[6-({(1R,2R)-2-[(2-fluoroethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; Ethyl 2-ethyl-2-{[6-{[(1S,2S)-2-(fluoromethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate and ethyl 2-ethyl-2-{[6-{[(1R,R)-2-(fluoromethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; Ethyl 2-ethyl-2-{[6-{[(1R,2S)-2-(fluoromethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate and ethyl 2-ethyl-2-{[6-{[(1S,2R)-2-(fluoromethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; Ethyl 2-ethyl-2-{[6-({(1R,2S)-2-[(fluoromethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; ethyl 2-ethyl-2-{[6({(1S,2R)-2-[(fluoromethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; Ethyl 2-ethyl-2-{[6-({(1R,2S)-2-[(2-fluoroethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; ethyl 2-ethyl-2-{[6({(1S,2R)-2-[(2-fluoroethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; Ethyl 2-ethyl-2-({6-[3-(fluoromethoxy)-2,2-dimethylpropoxy]-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl}amino)butanoate; (+)-trans-Ethyl 2-ethyl-2-{[6-({-2-[(fluoromethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; (−)-trans-Ethyl 2-ethyl-2-{[6-({-2-[(fluoromethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; ethyl 2-ethyl-2-{[6-({(1R,2S)-2-[(fluoromethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate ethyl 2-ethyl-2-{[6-({(1S,2R)-2-[(fluoromethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; (−)-trans-Fluoromethyl 2-ethyl-2-{[6-{[(1R,2R)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; (+)-trans-Fluoromethyl 2-ethyl-2-{[6-{[-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; (+)-trans-2-Fluoroethyl 2-ethyl-2-{[6-{[-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; (−)-trans-2-Fluoroethyl 2-ethyl-2-{[6-{[-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; 3-Fuoropropyl 2-ethyl-2-{[6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; 3-Fuoropropyl 2-ethyl-2-{[6-{[(1R,2R)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; N-[(2S)-1-(fluoromethoxy)propan-2-yl]-6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; N-[(2S)-1-(2-fluoroethoxy)propan-2-yl]-6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; N-[(2S)-1-(3-fluoropropoxy)propan-2-yl]-6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; N-[(2S)-1-(fluoromethoxy)-3-methylbutan-2-yl]-6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; N-[(2S)-1-(2-fluoroethoxy)-3-methylbutan-2-yl]-6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; N-[(2S)-1-(3-fluoropropoxy)-3-methylbutan-2-yl]-6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; N-[(2S)-1-(fluoromethoxy)-4-methylpentan-2-yl]-6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; N-[(2S)-1-(2-fluoroethoxy)-4-methylpentan-2-yl]-6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; N-[(2S)-1-(3-fluoropropoxy)-4-methylpentan-2-yl]-6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; N-{3-[(fluoromethoxy)methyl]pentan-3-yl}-6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; N-{3-[(2-fluoroethoxy)methyl]pentan-3-yl}-6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; N-{3-[(3-fluoropropoxy)methyl]pentan-3-yl}-6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; fluoromethyl 2-ethyl-2-{[6-{[(1R,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; 2-fluoroethyl 2-ethyl-2-{[6-{[(1R,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; 3-fluoropropyl 2-ethyl-2-{[6-{[(1R,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; N-[(2S)-1-(fluoromethoxy)propan-2-yl]-6-{[(1R,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; N-[(2S)-1-(2-fluoroethoxy)propan-2-yl]-6-{[(1R,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; N-[(2S)-1-(3-fluoropropoxy)propan-2-yl]-6-{[(1R,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; N-[(2S)-1-(fluoromethoxy)-3-methylbutan-2-yl]-6-{[(1R,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; N-[(2S)-1-(2-fluoroethoxy)-3-methylbutan-2-yl]-6-{[(1R,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; N-[(2S)-1-(3-fluoropropoxy)-3-methylbutan-2-yl]-6-{[(1R,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; N-[(2S)-1-(fluoromethoxy)-4-methylpentan-2-yl]-6-{[(1R,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; N-[(2S)-1-(2-fluoroethoxy)-4-methylpentan-2-yl]-6-{[(1R,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; N-[(2S)-1-(3-fluoropropoxy)-4-methylpentan-2-yl]-6-{[(1R,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; N-{3-[(fluoromethoxy)methyl]pentan-3-yl}-6-{[(1R,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; N-{3-[(2-fluoroethoxy)methyl]pentan-3-yl}-6-{[(1R,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; N-{3-[(3-fluoropropoxy)methyl]pentan-3-yl}-6-{[(1R,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; fluoromethyl 2-ethyl-2-({5-(3-methoxyazetidin-1-yl)-6-[(oxetan-3-yl)methoxy]pyridine-2-carbonyl}amino)butanoate; 2-fluoroethyl 2-ethyl-2-({5-(3-methoxyazetidin-1-yl)-6-[(oxetan-3-yl)methoxy]pyridine-2-carbonyl}amino)butanoate; 3-fluoropropyl 2-ethyl-2-({5-(3-methoxyazetidin-1-yl)-6-[(oxetan-3-yl)methoxy]pyridine-2-carbonyl}amino)butanoate; N-[(2S)-1-(fluoromethoxy)propan-2-yl]-5-(3-methoxyazetidin-1-yl)-6-[(oxetan-3-yl)methoxy]pyridine-2-carboxamide; N-[(2S)-1-(2-fluoroethoxy)propan-2-yl]-5-(3-methoxyazetidin-1-yl)-6-[(oxetan-3-yl)methoxy]pyridine-2-carboxamide; N-[(2S)-1-(3-fluoropropoxy)propan-2-yl]-5-(3-methoxyazetidin-1-yl)-6-[(oxetan-3-yl)methoxy]pyridine-2-carboxamide; N-[(2S)-1-(fluoromethoxy)-3-methylbutan-2-yl]-5-(3-methoxyazetidin-1-yl)-6-[(oxetan-3-yl)methoxy]pyridine-2-carboxamide; N-[(2S)-1-(2-fluoroethoxy)-3-methylbutan-2-yl]-5-(3-methoxyazetidin-1-yl)-6-[(oxetan-3-yl)methoxy]pyridine-2-carboxamide; N-[(2S)-1-(3-fluoropropoxy)-3-methylbutan-2-yl]-5-(3-methoxyazetidin-1-yl)-6-[(oxetan-3-yl)methoxy]pyridine-2-carboxamide; N-[(2S)-1-(fluoromethoxy)-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)-6-[(oxetan-3-yl)methoxy]pyridine-2-carboxamide; N-[(2S)-1-(2-Fluoroethoxy)-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)-6-[(oxetan-3-yl)methoxy]pyridine-2-carboxamide; N-[(2S)-1-(3-fluoropropoxy)-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)-6-[(oxetan-3-yl)methoxy]pyridine-2-carboxamide; N-{3-[(fluoromethoxy)methyl]pentan-3-yl}-5-(3-methoxyazetidin-1-yl)-6-[(oxetan-3-yl)methoxy]pyridine-2-carboxamide; N-{3-[(2-fluoroethoxy)methyl]pentan-3-yl}-5-(3-methoxyazetidin-1-yl)-6-[(oxetan-3-yl)methoxy]pyridine-2-carboxamide; N-{3-[(3-fluoropropoxy)methyl]pentan-3-yl}-5-(3-methoxyazetidin-1-yl)-6-[(oxetan-3-yl)methoxy]pyridine-2-carboxamide; N-[(2S)-1-(2-Fluoroethoxy)-4-methylpentan-2-yl]-6-[(oxetan-3-yl)methoxy]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide; ethyl 2-ethyl-2-{[6-({3-[(fluoromethoxy)methyl]oxetan-3-yl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; ethyl 2-ethyl-2-{[6-({3-[(2-fluoroethoxy)methyl]oxetan-3-yl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; ethyl 2-ethyl-2-{[6-({3-[(3-fluoropropoxy)methyl]oxetan-3-yl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; fluoromethyl 2-ethyl-2-{[6-{[3-(hydroxymethyl)oxetan-3-yl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; 2-fluoroethyl 2-ethyl-2-{[6-{[3-(hydroxymethyl)oxetan-3-yl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; 3-fluoropropyl 2-ethyl-2-{[6-{[3-(hydroxymethyl)oxetan-3-yl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; N-[(2S)-1-(fluoromethoxy)propan-2-yl]-6-{[3-(hydroxymethyl)oxetan-3-yl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; N-[(2S)-1-(2-fluoroethoxy)propan-2-yl]-6-{[3-(hydroxymethyl)oxetan-3-yl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; N-[(2S)-1-(3-fluoropropoxy)propan-2-yl]-6-{[3-(hydroxymethyl)oxetan-3-yl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; N-[(2S)-1-(fluoromethoxy)-3-methylbutan-2-yl]-6-{[3-(hydroxymethyl)oxetan-3-yl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; N-[(2S)-1-(2-fluoroethoxy)-3-methylbutan-2-yl]-6-{[3-(hydroxymethyl)oxetan-3-yl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; N-[(2S)-1-(3-fluoropropoxy)-3-methylbutan-2-yl]-6-{[3-(hydroxymethyl)oxetan-3-yl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; N-[(2S)-1-(fluoromethoxy)-4-methylpentan-2-yl]-6-{[3-(hydroxymethyl)oxetan-3-yl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; N-[(2S)-1-(2-fluoroethoxy)-4-methylpentan-2-yl]-6-{[3-(hydroxymethyl)oxetan-3-yl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; N-[(2S)-1-(3-fluoropropoxy)-4-methylpentan-2-yl]-6-{[3-(hydroxymethyl)oxetan-3-yl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; N-{3-[(fluoromethoxy)methyl]pentan-3-yl}-6-{[3-(hydroxymethyl)oxetan-3-yl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; N-{3-[(2-fluoroethoxy)methyl]pentan-3-yl}-6-{[3-(hydroxymethyl)oxetan-3-yl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; N-{3-[(3-fluoropropoxy)methyl]pentan-3-yl}-6-{[3-(hydroxymethyl)oxetan-3-yl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-({(1S,2S)-2-[(fluoromethoxy)methyl]cyclopropyl}methoxy)-N-[(2S)-1-hydroxy-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-({(1S,2S)-2-[(2-fluoroethoxy)methyl]cyclopropyl}methoxy)-N-[(2S)-1-hydroxy-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-({(1S,2S)-2-[(3-fluoropropoxy)methyl]cyclopropyl}methoxy)-N-[(2S)-1-hydroxy-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-{[(1S,2S)-2-(fluoromethyl)cyclopropyl]methoxy}-N-[(2S)-1-hydroxy-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-({(1R,2S)-2-[(fluoromethoxy)methyl]cyclopropyl}methoxy)-N-[(2S)-1-hydroxy-3-methylbutan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-({(1R,2S)-2-[(2-fluoroethoxy)methyl]cyclopropyl}methoxy)-N-[(2S)-1-hydroxy-3-methylbutan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-({(1R,2S)-2-[(3-fluoropropoxy)methyl]cyclopropyl}methoxy)-N-[(2S)-1-hydroxy-3-methylbutan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-{[(1R,2S)-2-(fluoromethyl)cyclopropyl]methoxy}-N-[(2S)-1-hydroxy-3-methylbutan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-({3-[(fluoromethoxy)methyl]oxetan-3-yl}methoxy)-N-[(2S)-1-hydroxypropan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-({3-[(2-fluoroethoxy)methyl]oxetan-3-yl}methoxy)-N-[(2S)-1-hydroxypropan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-({3-[(3-fluoropropoxy)methyl]oxetan-3-yl}methoxy)-N-[(2S)-1-hydroxypropan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-{[3-(fluoromethyl)oxetan-3-yl]methoxy}-N-[(2S)-1-hydroxypropan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-({3-[(fluoromethoxy)methyl]oxetan-3-yl}methoxy)-N-[3-(hydroxymethyl)pentan-3-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-({3-[(2-fluoroethoxy)methyl]oxetan-3-yl}methoxy)-N-[3-(hydroxymethyl)pentan-3-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-({3-[(3-fluoropropoxy)methyl]oxetan-3-yl}methoxy)-N-[3-(hydroxymethyl)pentan-3-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-{[3-(fluoromethyl)oxetan-3-yl]methoxy}-N-[3-(hydroxymethyl)pentan-3-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; ethyl 2-ethyl-2-{[6-({(1S,2S)-2-[(fluoromethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyrazine-2-carbonyl]amino}butanoate; ethyl 2-ethyl-2-{[6-({(1R,2S)-2-[(fluoromethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyrazine-2-carbonyl]amino}butanoate; 6-({(1S,2S)-2-[(3-fluoropropoxy)methyl]cyclopropyl}methoxy)-N-[(2S)-1-hydroxy-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)pyrazine-2-carboxamide; 6-({(1R,2S)-2-[(3-fluoropropoxy)methyl]cyclopropyl}methoxy)-N-[(2S)-1-hydroxy-3-methylbutan-2-yl]-5-(3-methoxyazetidin-1-yl)pyrazine-2-carboxamide; ethyl 2-ethyl-2-({6-[(3-fluorooxan-4-yl)methoxy]-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl}amino)butanoate; 1,4-anhydro-2,3-dideoxy-5-O-[6-{[3-(ethoxycarbonyl)pentan-3-yl]carbamoyl}-3-(3-methoxyazetidin-1-yl)pyridin-2-yl]-2-fluoropentitol; ethyl 2-ethyl-2-{[6-{[3-fluoro-2-methyl(3,3-dideuterio)propyl]oxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; ethyl 2-ethyl-2-{[6-{[2-fluoro(2,2-dideuterio)ethyl]oxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; ethyl 2-ethyl-2-({6-[(3-fluorooxan-4-yl)methoxy]-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl}amino)butanoate; 1,4-anhydro-2,3-dideoxy-5-O-[6-{[3-(ethoxycarbonyl)pentan-3-yl]carbamoyl}-3-(3-methoxyazetidin-1-yl)pyridin-2-yl]-2-fluoropentitol; ethyl 2-ethyl-2-{[6-{[(1S,2S)-2-({[fluoro(dideuterio)methyl]oxy}methyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; ethyl 2-ethyl-2-{[6-{[(1S,2S)-2-({[2-fluoro(2,2-˜2˜H_2_)ethyl]oxy}methyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; ethyl 2-ethyl-2-{[6-({(1S,2S)-2-[fluoro(dideuterio)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; ethyl 2-ethyl-2-{[6-({(1R,2S)-2-[fluoro(dideuterio)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; ethyl 2-ethyl-2-{[6-{[(1R,2S)-2-({[fluoro(dideuterio)methyl]oxy}methyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; ethyl 2-ethyl-2-{[6-{[(1R,2S)-2-({[2-fluoro(2,2-dideuterio)ethyl]oxy}methyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; ethyl 2-ethyl-2-{[6-(3-{[fluoro(dideuterio)methyl]oxy}-2,2-dimethylpropoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; ethyl 2-ethyl-2-{[6-{[3-fluoro-2,2-dimethyl(3,3-dideuterio)propyl]oxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; ethyl 2-ethyl-2-{[6-{[(1S,2S)-2-({[fluoro(dideuterio)methyl]oxy}methyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; ethyl 2-ethyl-2-{[6-{[(1R,2R)-2-({[fluoro(dideuterio)methyl]oxy}methyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; ethyl 2-ethyl-2-{[6-{[3-fluoro-2-methyl(3,3-dideuterio)propyl]oxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; ethyl 2-ethyl-2-{[6-{[2-fluoro(2,2-dideuterio)ethyl]oxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; ethyl 2-ethyl-2-{[6-{[3-fluoro-2-methyl(3,3-dideuterio)propyl]oxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; ethyl 2-ethyl-2-{[6-{[3-fluoro-2-methyl(3,3-dideuterio)propyl]oxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; ethyl 2-ethyl-2-{[6-{[2-fluoro(2,2-dideuterio)ethyl]oxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; ethyl 2-ethyl-2-{[6-{[3-fluoro-2-methyl(3,3-dideuterio)propyl]oxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; 6-{[3-({[fluoro(dideuterio)methyl]oxy}methyl)oxetan-3-yl]methoxy}-N-[(2S)-1-hydroxypropan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-{[3-({[2-fluoro(2,2-dideuterio)ethyl]oxy}methyl)oxetan-3-yl]methoxy}-N-[(2S)-1-hydroxypropan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-{[3-({[3-fluoro(3,3-dideuterio)propyl]oxy}methyl)oxetan-3-yl]methoxy}-N-[(2S)-1-hydroxypropan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-({3-[fluoro(dideuterio)methyl]oxetan-3-yl}methoxy)-N-[(2S)-1-hydroxypropan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-{[3-({[fluoro(dideuterio)methyl]oxy}methyl)oxetan-3-yl]methoxy}-N-[3-(hydroxymethyl)pentan-3-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-{[3-({[2-fluoro(2,2-dideuterio)ethyl]oxy}methyl)oxetan-3-yl]methoxy}-N-[3-(hydroxymethyl)pentan-3-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-{[3-({[3-fluoro(3,3-dideuterio)propyl]oxy}methyl)oxetan-3-yl]methoxy}-N-[3-(hydroxymethyl)pentan-3-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-({3-[fluoro(dideuterio)methyl]oxetan-3-yl}methoxy)-N-[3-(hydroxymethyl)pentan-3-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 3-Fluoropropyl 3,4-dideuterio-2-(1,2-dideuterioethyl)-2-[[6-[[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy]-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino]butanoate; fluoromethyl 2-ethyl-2-(6-((3-(hydroxymethyl)oxetan-3-yl)methoxy)-5-(pyrrolidin-1-yl)picolinamido)butanoate; 2-fluoroethyl 2-ethyl-2-(6-((3-(hydroxymethyl)oxetan-3-yl)methoxy)-5-(pyrrolidin-1-yl)picolinamido)butanoate; 3-fluoropropyl 2-ethyl-2-(6-((3-(hydroxymethyl)oxetan-3-yl)methoxy)-5-(pyrrolidin-1-yl)picolinamido)butanoate; (1,1,2,2,3,3-Hexadeuterio-3-fluoro-propyl) 2-ethyl-2-[[6-[[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy]-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino]butanoate; 3-Fluoropropyl 2-[[6-[[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy]-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino]-2-vinyl-but-3-enoate; 3-Fluoropropyl 3,4-dideuterio-2-(1,2-dideuterioethyl)-2-[[6-[[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy]-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino]butanoate; (Rac)-trans-3-Fluoropropyl 2-[[6-[[(1S,2S)-2-(benzyloxymethyl)cyclopropyl]methoxy]-5-(3-hydroxyazetidin-1-yl)pyridine-2-carbonyl]amino]-2-ethyl-butanoate; 3-(p-Tolylsulfonyloxy)propyl 2-ethyl-2-[[6-[[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy]-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino]butanoate; [1,1,2,2,3,3-Hexadeuterio-3-(p-tolylsulfonyloxy)propyl]2-ethyl-2-[[6-[[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy]-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino]butanoate; 4-Fluorobutyl 2-ethyl-2-[[6-[[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy]-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino]butanoate; N-[1-Ethyl-1-[[(1S)-1-(hydroxymethyl)-3-methyl-butyl]carbamoyl]propyl]-6-[[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; N-[1-ethyl-1-[[(1S)-1-(hydroxymethyl)-3-methyl-butyl]carbamoyl]propyl]-5-(3-fluoroazetidin-1-yl)-6-[[(1R,2R)-2-(hydroxymethyl)cyclopropyl]methoxy]pyridine-2-carboxamide; N-[1-Ethyl-1-[[(1S)-1-(hydroxymethyl)-3-methyl-butyl]carbamoyl]propyl]-5-(3-fluoroazetidin-1-yl)-6-[[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy]pyridine-2-carboxamide; 3-Fluoropropyl 2-ethyl-2-{[5-(3-fluoroazetidin-1-yl)-6-{[(1R,2R)-2-(hydroxymethyl)cyclopropyl]methoxy}pyridin-2-yl]formamido}butanoate; 3-Fluoropropyl 2-ethyl-2-{[5-(3-fluoroazetidin-1-yl)-6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}pyridin-2-yl]formamido}butanoate; (Rac)-trans-3-fluoropropyl 2-ethyl-2-[[6-[[-2-(hydroxymethyl)cyclopropyl]methoxy]-5-[3-(p-tolylsulfonyloxy)azetidin-1-yl]pyridine-2-carbonyl]amino]butanoate; 3-Fluoropropyl 2-[[6-[[(1S,2S)-2-(benzyloxymethyl)cyclopropyl]methoxy]-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino]-2-ethyl-butanoate; ethyl 2-ethyl-2-{[6-(2-fluoropropoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; ethyl 2-ethyl-2-{[6-(3-fluoro-2-methylpropoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; ethyl 2-ethyl-2-{[6-(3-fluoro-2,2-dimethylpropoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; ethyl 2-ethyl-2-{[6-(3-fluoro-2-methylpropoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; ethyl 2-ethyl-2-({6-[(1-fluorocyclopropyl)methoxy]-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl}amino)butanoate; ethyl 2-ethyl-2-({6-[(2-fluorocyclopropyl)methoxy]-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl}amino)butanoate; ethyl 2-ethyl-2-{[6-(2-fluoropropoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; ethyl 2-ethyl-2-{[6-(3-fluoro-2-methylpropoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; ethyl 2-ethyl-2-{[6-(3-fluoro-2-methylpropoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; ethyl 2-ethyl-2-({6-[(1-fluorocyclopropyl)methoxy]-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl}amino)butanoate; and ethyl 2-ethyl-2-({6-[(2-fluorocyclopropyl)methoxy]-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl}amino)butanoate; or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1 selected from the group consisting of: Ethyl 2-ethyl-2-{[6-({(1S,2S)-2-[(fluoromethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate and ethyl 2-ethyl-2-{[6-({(1R,2R)-2-[(fluoromethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; Ethyl 2-ethyl-2-{[6-({(1S,2S)-2-[(2-fluoroethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; ethyl 2-ethyl-2-{[6-({(1R,2R)-2-[(2-fluoroethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; Ethyl 2-ethyl-2-{[6-{[(1R,2S)-2-(fluoromethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; ethyl 2-ethyl-2-{[6-{[(1S,2R)-2-(fluoromethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; Ethyl 2-ethyl-2-{[6-({(1R,2S)-2-[(fluoromethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; ethyl 2-ethyl-2-{[6-({(1S,2R)-2-[(fluoromethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; (+)-trans-Ethyl 2-ethyl-2-{[6({-2-[(fluoromethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; (+)-trans-Fluoromethyl 2-ethyl-2-{[6-{[-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; 3-Fuoropropyl 2-ethyl-2-{[6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; and 3-Fuoropropyl 2-ethyl-2-{[6-{[(1R,2R)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; or a pharmaceutically acceptable salt thereof.

15. A process for the preparation of the compound of claim 1, comprising one of the following steps: (a) the reaction of a compound of formula (A1) ##STR00108## with a compound of formula (A2) ##STR00109## in the presence of a coupling agent and a base; (b) the reaction of a compound of formula (B) ##STR00110## in the presence of R.sup.2M, a palladium catalyst and a base; wherein: A.sup.1 is —CH— or nitrogen; A.sup.2 is —CH.sub.2— or carbonyl; R.sup.1 is haloalkoxyalkylcycloalkyl, haloalkylcycloalkyl, haloalkoxyalkyl, hydroxyalkylcycloalkyl, oxetanyl, haloalkoxyalkyloxetanyl, hydroxyalkyloxetanyl, haloalkyloxetanyl, 1-fluoroethyl, 1-fluoro-prop-2-yl, fluoro-tert.-butyl, cyclopropylfluoromethyl, fluorocyclopropyl, halooxanyl, halotetrahydrofuranyl, phenylalkoxyalkylcycloalkyl, 1-fluoro-1,1-dideuteroprop-2-yl, fluorodideuteromethyl, fluorodideuteromethyloxyalkylcycloalkyl, 2-fluoro-2,2-dideuteroethyloxyalkylcycloalkyl, fluorodideuteromethylcycloalkyl, fluorodideuteromethyloxyalkyl, fluorodideuteromethylalkyl, fluorodideuteromethyloxyalkyloxetanyl, 2-fluoro-2,2-dideuteroethyloxyalkyloxetanyl, 3-fluoro-3,3-dideuteropropyloxyalkyloxetanyl or fluorodideuteromethyloxetanyl; R.sup.2 is alkoxyazetidinyl, haloazetidinyl, dihaloazetidinyl, pyrrolidinyl or alkylphenylsulfonyloxyazetidinyl; R.sup.3 and R.sup.4 are independently selected from hydrogen, alkyl, alkenyl and deuterioalkyl; R.sup.5 is hydrogen, alkyl, haloalkyl, deuterioalkyl, alkylphenylsulfonyloxyalkyl, alkylphenylsulfonyloxydeuterioalkyl or hydroxyalkyl; X is oxygen or —NH—; and Y is halogen.

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

Description

EXAMPLES

Abbreviations

(1) AcOH=acetic acid; rac-BINAP=racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl); CAN=chemical abstracts service number; DCM=dichloromethane; DEA=diethanolamine; DIPEA=N-ethyl-N-isopropylpropan-2-amine; DMF=dimethylformamide; DPPA=diphenylphosphoryl azide; EDC=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; EI=electron impact; EtOAc=ethyl acetate; 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; HOBt=hydroxybenzotriazole; HPLC=LC=high performance liquid chromatography; ISP=ion spray, corresponds to ESI (electrospray); LAH=Lithiumaluminiumhydrid; LC=liquid chromatography; LiTMP=lithium tetramethylpiperidide; MS=mass spectrometry; NMR data are reported in parts per million (S) relative to internal tetramethylsilane and are referenced to the deuterium lock signal from the sample solvent (d.sub.6-DMSO unless otherwise stated); coupling constants (J) are in Hertz; m-CPBA=meta-chloroperoxybenzoic acid; mp=melting point; PTSA=p-toluenesulfonic acid; RT=room temperature; Rt=retention time; SFC=supercritical fluid chromatography; SOR=specific optical rotation; TBAF=tetra-n-butylammonium fluoride; TBTU=O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uronium-tetrafluoroborate; THF=tetrahydrofuran.

Example 1

Ethyl 2-ethyl-2-{[6-({(1S,2S)-2-[(fluoromethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate and ethyl 2-ethyl-2-{[6-({(1R,2R)-2-[(fluoromethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate

(2) ##STR00009##

a) (Rac)-trans-5-bromo-6-((-2-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)picolinic Acid

(3) ##STR00010##

(4) In a 250 mL round-bottomed flask, sodium hydride in mineral oil (507 mg, 12.7 mmol, Eq: 2) was combined with DMF (50 mL) to give a grey suspension, which was cooled to 0° C. (Rac)-trans-(-2-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methanol (2.06 g, 9.52 mmol, Eq: 1.5) was dissolved in DMF (100 mL) and added to the reaction mixture, which was stirred at 0° C. for 1 h. 5-Bromo-6-chloropicolinic acid (CAN 959958-25-9, 1500 mg, 6.34 mmol, Eq: 1) was dissolved in DMF (20 mL) and added to the reaction mixture. Stirring was continued at RT for 20 h. 250 mg of sodium hydride was added and stirring was continued for 3 h. Another portion of 450 mg NaH and 300 mg of (rac)-trans-(-2-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methanol were added. After 3 h of stirring at RT the reaction mixture was quenched by the addition of water and concentrated in vacuo. The residue was carefully acidified by the addition of HCl (1 M). The mixture was diluted with EtOAc and washed with brine (3×250 mL). The organic layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo resulting in a colorless oil. The crude product was purified by column chromatography (SiO.sub.2, 50 g, hept./EtOAc) to give enriched title compound (1 g) which was sufficiently pure to be carried on to the next step, MS (ISP): 416.3 [MH.sup.+].

b) (Rac)-trans-ethyl 2-(5-bromo-6-((-2-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)picolinamido)-2-ethylbutanoate

(5) ##STR00011##

(6) In a 50 mL round-bottomed flask, (rac)-trans-5-bromo-6-((-2-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)picolinic acid (1.02 g, 2.45 mmol, Eq: 1.5) was combined with DMF (28.2 mL) to give a colorless solution. DIPEA (1.06 g, 1.43 mL, 8.18 mmol, Eq: 5) and TBTU (788 mg, 2.45 mmol, Eq: 1.5) were added. Ethyl 2-amino-2-ethylbutanoate hydrochloride (CAN 1135219-29-2, 320 mg, 1.64 mmol, Eq: 1) was added and the reaction mixture was stirred at RT for 1 h. The solvent was removed under reduced pressure and the residue dissolved in EtOAc. The organic layers were combined, washed with sat. NaHCO.sub.3(3×20 mL), 1 M HCl (3×20 mL), and sat. NaCl (3×20 mL). The organic layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude product was purified by column chromatography (SiO.sub.2, 50 g, hept./EtOAc) to give the title compound (235 mg, 26%) as colorless oil, MS (ISP): 556.8 [M−H.sup.−].

c) (Rac)-trans-ethyl 2-(6-((-2-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamido)-2-ethylbutanoate

(7) ##STR00012##

(8) In a 20 mL sealed tube (rac)-trans-ethyl 2-(5-bromo-6-((-2-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)picolinamido)-2-ethylbutanoate (228 mg, 409 μmol, Eq: 1) was combined with toluene (15 mL) to give a colorless solution. Cs.sub.2CO.sub.3 (400 mg, 1.23 mmol, Eq: 3) and 3-methoxyazetidine hydrochloride (CAN 148644-09-1, 75.5 mg, 613 μmol, Eq: 1.5) were added, rac-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl(50.9 mg, 81.8 μmol, Eq: 0.2) and palladium(II) acetate (18.4 mg, 81.8 μmol, Eq: 0.2) were added. The reaction mixture was stirred at 110° C. for 4 h, diluted with EtOAc and filtered through celite. The organic solvent was removed under reduced pressure and the residue dissolved in EtOAc. The organic layers were combined, washed with 1 M HCl (3×25 mL) and sat. NaCl (1×25 mL). The organic layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude product was purified by column chromatography (SiO.sub.2, 20 g, hept./EtOAc) to give the title compound (207 mg, 90%) as colorless oil.

d) (Rac)-trans-ethyl 2-ethyl-2-(6-((-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamido)butanoate

(9) ##STR00013##

(10) In a 50 mL round-bottomed flask, (rac)-trans-ethyl 2-(6-((-2-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamido)-2-ethylbutanoate (200 mg, 355 μmol, Eq: 1) was combined with AcOH (3 mL), water (1 mL) and THF (1 mL) to give a colorless solution. The reaction mixture was stirred at RT for 1 h. The organic solvent was removed under reduced pressure and the residue diluted with EtOAc. The organic layers were combined, washed with sat. NaHCO.sub.3 (3×10 mL) and sat. NaCl (1×25 mL). The organic layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo to give the title compound (186 mg, quant.) as coloreless oil which was used in the next step without further purification, MS (ISP): 450.343 [MH.sup.+].

e) Ethyl 2-ethyl-2-{[6-({(1S,2S)-2-[(fluoromethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate and ethyl 2-ethyl-2-{[6-({(1R,2R)-2-[(fluoromethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate

(11) In a 5 mL round-bottomed flask, (rac)-trans-ethyl 2-ethyl-2-(6-((-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamido)butanoate (31 mg, 69 μmol, Eq: 1) was combined with DMF (1 mL) to give a light yellow solution. Sodium hydride on mineral oil (13.8 mg, 345 μmol, Eq: 5) was added and the reaction mixture was stirred for 30 min at RT. Fluoro-iodo-methane (55.1 mg, 23.3 μL, 345 μmol, Eq: 5) was added. The reaction mixture was stirred for 12 h at RT, diluted with EtOAc and washed with brine (3×10 mL). The organic layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo to give the title compounds (2.5 mg, 5.19 μmol, 8%) as colorless oil, MS (ISP): 482.370 [MH.sup.+].

Example 2

Ethyl 2-ethyl-2-{[6-({(1S,2S)-2-[(2-fluoroethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate and ethyl 2-ethyl-2-{[6-({(1R,2R)-2-[(2-fluoroethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate

(12) ##STR00014##

(13) In analogy to the procedure described in example 1 e, (rac)-trans-ethyl 2-ethyl-2-(6-((-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamido)butanoate (example 1 d) was reacted with fluoro-iodo-ethane to give the title compounds as colorless oil, MS (ISP): 492.359 [MH.sup.+].

Example 3

Ethyl 2-ethyl-2-{[6-{[(1S,2S)-2-(fluoromethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate and ethyl 2-ethyl-2-{[6-{[(1R,R)-2-(fluoromethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate

(14) ##STR00015##

a) (Rac)-trans-ethyl 2-ethyl-2-(5-(3-methoxyazetidin-1-yl)-6-((-2-(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)picolinamido)butanoate

(15) ##STR00016##

(16) In a 5 mL round-bottomed flask, (rac)-trans-ethyl 2-ethyl-2-(6-((-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamido)butanoate (example 1 d, 50 mg, 111 μmol, Eq: 1) was combined with CH.sub.2Cl.sub.2 (1000 μL) to give a colorless solution. The reaction mixture was cooled to 0° C. and triethylamine (33.8 mg, 46.5 μL, 334 μmol, Eq: 3) and methanesulfonyl chloride (25.5 mg, 17.3 μL, 222 μmol, Eq: 2) were added. The reaction mixture was stirred at RT for 2 h. Additional 10 uL of methanesulfonyl chloride were added and stirring was continued for 30 min. The reaction mixture was diluted with EtOAc and the organic layers were washed with 1 M HCl (3×10 mL), sat NaHCO.sub.3(3×10 mL), and sat NaCl (1×20 mL). The organic layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo to give crude title compound which was used in the next step without further purification, LC-MS: 528.3 [MH.sup.+].

b) Ethyl 2-ethyl-2-{[6-{[(1S,2S)-2-(fluoromethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate and ethyl 2-ethyl-2-{[6-{[(1R,R)-2-(fluoromethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate

(17) In a 20 mL sealed tube (rac)-trans-ethyl 2-ethyl-2-(5-(3-methoxyazetidin-1-yl)-6-((-2-(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)picolinamido)butanoate (64 mg, 121 μmol, Eq: 1) was combined with acetonitrile (10 mL) under an atmosphere of argon to give a colorless solution. TBAF in THF (606 μL, 606 μmol, Eq: 5) was added and the reaction mixture was heated to 80° C. for 1 h. The mixture was diluted with EtOAc and washed with 1 M HCl (3×25 mL) and brine (1×25 mL). The crude product was purified by column chromatography (SiO.sub.2, 5 g, hept./EtOAc) to give the title compounds (19 mg, 35%) as colorless oil, MS (ISP): 452.351 [MH.sup.+].

Example 4

Ethyl 2-ethyl-2-{[6-{[(1R,2S)-2-(fluoromethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate and ethyl 2-ethyl-2-{[6-{[(1S,2R)-2-(fluoromethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate

(18) ##STR00017##

a) (Rac)-cis-5-bromo-6-((-2-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)picolinic Acid

(19) ##STR00018##

(20) In analogy to the procedure described in example 1 a, 5-bromo-6-chloropicolinic acid (CAN 959958-25-9) was reacted with (rac)-trans-(-2-((tert-butyldimethylsilyl)methoxy)cyclopropyl)methanol (CAN 124200-37-9) to give the title compound as light yellow oil, MS (ISP): 418.162 [MH.sup.+].

b) (Rac)-cis-ethyl 2-(5-bromo-6-((-2-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)picolinamido)-2-ethylbutanoate

(21) ##STR00019##

(22) In analogy to the procedure described in example 1 b, (rac)-cis-5-bromo-6-((-2-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)picolinic acid was reacted with ethyl 2-amino-2-ethylbutanoate hydrochloride (CAN 1135219-29-2) to give the title compound as colorless oil, LC-MS (UV peak area/ESI) 90%, 559.2032 [MH.sup.+].

c) (Rac)-cis-ethyl 2-(6-((-2-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamido)-2-ethylbutanoate

(23) ##STR00020##

(24) In analogy to the procedure described in example 1 c, (rac)-cis-ethyl 2-(5-bromo-6-((-2-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)picolinamido)-2-ethylbutanoate was reacted with 3-methoxyazetidine hydrochloride (CAN 148644-09-1) to give the title compound (60 mg, 85%) as light yellow oil, LC-MS (UV peak area/ESI) 100%, 564.3469 [MH.sup.+].

d) (Rac)-cis-ethyl 2-ethyl-2-(6-((-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamido)butanoate

(25) ##STR00021##

(26) In analogy to the procedure described in example 1 d, (rac)-cis-ethyl 2-(6-((-2-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamido)-2-ethylbutanoate was treated with AcOH to obtain crude title compound which was used in the next reaction step without further purification, MS (ISP): 550.343 [MH.sup.+].

e) (Rac)-cis-ethyl 2-ethyl-2-(5-(3-methoxyazetidin-1-yl)-6-((-2-(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)colinamido)butanoate

(27) ##STR00022##

(28) In analogy to the procedure described in example 3 a, (rac)-cis-ethyl 2-ethyl-2-(6-((-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamido)butanoate was reacted with methanesulfonyl chloride to obtain crude title compound which was used in the next reaction step without further purification, MS (ISP): 528.300 [MH.sup.+].

f) Ethyl 2-ethyl-2-{[6-{[(1R,2S)-2-(fluoromethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate and ethyl 2-ethyl-2-{[6-{[(1S,2R)-2-(fluoromethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate

(29) In analogy to the procedure described in example 3 b, (rac)-cis-ethyl 2-ethyl-2-(5-(3-methoxyazetidin-1-yl)-6-((-2-(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)picolinamido)butanoate was reacted with TBAF to obtain the title compounds as coloreless oil, MS (ISP): 452.351 [MH.sup.+].

Example 5

Ethyl 2-ethyl-2-{[6-({(1R,2S)-2-[(fluoromethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate and ethyl 2-ethyl-2-{[6-({(1S,2R)-2-[(fluoromethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate

(30) ##STR00023##

(31) In analogy to the procedure described in example 1 e, (rac)-cis-ethyl 2-ethyl-2-(6-((-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamido)butanoate (example 4 d) was reacted with fluoro-iodo-methane to give the title compounds as colorless oil, MS (ISP): 482.370 [MH.sup.+].

Example 6

Ethyl 2-ethyl-2-{[6-({(1R,2S)-2-[(2-fluoroethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate and ethyl 2-ethyl-2-{[6-({(1S,2R)-2-[(2-fluoroethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate

(32) ##STR00024##

(33) In analogy to the procedure described in example 1 e, (rac)-cis-ethyl 2-ethyl-2-(6-((-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamido)butanoate (example 4 d) was reacted with fluoro-iodo-ethane to give the title compounds as colorless oil, MS (ISP): 496.324 [MH.sup.+].

Example 7

Ethyl 2-{[6-(cyclopropylmethoxy)-4-fluoro-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate

(34) ##STR00025##

a) Ethyl 2-(4-bromo-6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)picolinamido)-2-ethylbutanoate

(35) ##STR00026##

(36) In a 5 mL round-bottomed flask, ethyl 2-(6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)picolinamido)-2-ethylbutanoate (CAN 1778678-14-0.28 mg, 66.7 μmol, Eq: 1) was combined with DMF (1.5 mL) to give a light yellow solution. N-Bromosuccinimide (23.8 mg, 133 μmol, Eq: 2) was added and the reaction was stirred at RT for 30 min. The mixture was diluted with EtOAc and washed with water/brine (1×15 mL) and brine (2×15 mL). The organic layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude product was purified by column chromatography (SiO.sub.2, 5 g, hept.EtOAc) to give the title compound (21 mg, 63%) as colorless oil, MS (ISP): 498.229 [MH.sup.+].

b) Ethyl 2-{[6-(cyclopropylmethoxy)-4-fluoro-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate

(37) In a 5 mL round-bottomed flask, ethyl 2-(4-bromo-6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)picolinamido)-2-ethylbutanoate (21 mg, 42.1 μmol, Eq: 1) and CsF (128 mg, 843 μmol, Eq: 20) were combined with DMSO (500 μL) to give a white suspension. The reaction mixture was heated to 120° C. for 7 d, diluted with EtOAc and washed with brine (3×15 mL). The organic layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude product was purified by prep. HPLC to give the title compound (0.7 mg, 4%) as white solid, LC-MS (UV peak area/ESI) 100%, 438.2417 [MH.sup.+].

Example 8

Ethyl 2-ethyl-2-({6-[3-(fluoromethoxy)-2,2-dimethylpropoxy]-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl}amino)butanoate

(38) ##STR00027##

a) 6-(3-(Benzyloxy)-2,2-dimethylpropoxy)-5-bromopicolinic Acid

(39) ##STR00028##

(40) In analogy to the procedure described in example 1 a, 5-bromo-6-chloropicolinic acid (CAN 959958-25-9) was reacted with 3-(benzyloxy)-2,2-dimethylpropan-1-ol (CAN 66582-32-9) to give the title compound as white solid, MS (ISP): 394.060 [MH.sup.+].

b) Ethyl 2-(6-(3-(benzyloxy)-2,2-dimethylpropoxy)-5-bromopicolinamido)-2-ethylbutanoate

(41) ##STR00029##

(42) In analogy to the procedure described in example 1 b, 6-(3-(benzyloxy)-2,2-dimethylpropoxy)-5-bromopicolinic acid was reacted with ethyl 2-amino-2-ethylbutanoate hydrochloride (CAN 1135219-29-2) to give the title compound as yellow oil, MS (ISP): 535.200 [MH.sup.+].

c) Ethyl 2-(6-(3-(benzyloxy)-2,2-dimethylpropoxy)-5-(3-methoxyazetidin-1-yl)picolinamido)-2-ethylbutanoate

(43) ##STR00030##

(44) In analogy to the procedure described in example 1 c, ethyl 2-(6-(3-(benzyloxy)-2,2-dimethylpropoxy)-5-bromopicolinamido)-2-ethylbutanoate was reacted with 3-methoxyazetidine hydrochloride (CAN 148644-09-1) to give the title compound (680 mg, 88%) as light yellow oil, MS (ISP): 542.357 [MH.sup.+].

d) Ethyl 2-ethyl-2-(6-(3-hydroxy-2,2-dimethylpropoxy)-5-(3-methoxyazetidin-1-yl)picolinamido)butanoate

(45) ##STR00031##

(46) In a 100 mL round-bottomed flask, ethyl 2-(6-(3-(benzyloxy)-2,2-dimethylpropoxy)-5-(3-methoxyazetidin-1-yl)picolinamido)-2-ethylbutanoate (665 mg, 1.23 mmol, Eq: 1) was combined with EtOAc (30 mL) and MeOH (3 mL) to give a light yellow solution. Pd—C on charcoal (600 mg, 5.64 mmol, Eq: 4.59) was added. The mixture was stirred under hydrogen atmosphere for 48 h. The reaction mixture was filtered through celite and the organic solvent was removed under reduced pressure to give the target compound (523 mg, 94%) as white solid, MS (ISP): 452.351 [MH.sup.+].

e) Ethyl 2-ethyl-2-({6-[3-(fluoromethoxy)-2,2-dimethylpropoxy]-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl}amino)butanoate

(47) In analogy to the procedure described in example 1 e, ethyl 2-ethyl-2-(6-(3-hydroxy-2,2-dimethylpropoxy)-5-(3-methoxyazetidin-1-yl)picolinamido)butanoate was reacted with fluoro-iodo-methane to give the title compound as colorless oil, MS (ISP): 484.237 [MH.sup.+].

Example 9

(+)-trans-Ethyl 2-ethyl-2-{[6-({-2-[(fluoromethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate

(48) ##STR00032##

a) (+)-trans-Ethyl 2-ethyl-2-(6-((-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamido)butanoate

(49) ##STR00033##

(50) (Rac)-trans-ethyl 2-ethyl-2-(6-((-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamido)butanoate (example 1 d) was subjected to preparative chiral HPLC (column Chiralpak AD, 90% heptane/10% ethanol and NH.sub.4OAc). The organic solvent was removed under reduced pressure and the residue diluted with EtOAc. The organic phase was washed with water (3×50 mL) and brine (1×50 mL). The organic layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo to give the title compound as light yellow oil, LC-MS (UV peak area/ESI) 100%, 450.2624 [MH.sup.+].

b) (+)-trans-Ethyl 2-ethyl-2-{[6-({-2-[(fluoromethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate

(51) In a 5 mL round-bottomed flask, (+)-trans-ethyl 2-ethyl-2-(6-((-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamido)butanoate (56 mg, 125 μmol, Eq: 1) was combined with DMF (1 mL) to give a light yellow solution. Sodium hydride on mineral oil (24.9 mg, 623 μmol, Eq: 5) was added and the reaction mixture was stirred for 30 min at RT. Fluoro-iodo-methane (99.6 mg, 42 μL, 623 μmol, Eq: 5) was added and stirring was continued for 90 min. The reaction mixture was diluted with EtOAc and washed with brine (3×10 mL). The organic layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude product was purified by column chromatography (SiO.sub.2, 5 g, hept./EtOAc) to give the title compound (10 mg, 17%) as colorless oil, MS (ISP): 482.319 [MH.sup.+].

Example 10

(−)-trans-Ethyl 2-ethyl-2-{[6-({-2-[(fluoromethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate

(52) ##STR00034##

a) (−)-trans-Ethyl 2-ethyl-2-(6-((-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamido)butanoate or Enantiomer

(53) ##STR00035##

(54) In analogy to the procedure described in example 9 a, (rac)-trans-ethyl 2-ethyl-2-(6-((-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamido)butanoate (example 1 d) was subjected to preparative chiral HPLC to give the title compound as light yellow oil, LC-MS (UV peak area/ESI) 99%, 450.2631 [MH.sup.+].

b) (−)-trans-Ethyl 2-ethyl-2-{[6-({-2-[(fluoromethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate

(55) In analogy to the procedure described in example 9 b, (−)-trans-ethyl 2-ethyl-2-(6-((-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamido)butanoate was reacted with fluoro-iodo-methane to give the title compound as colorless oil, MS (ISP): 482.319 [MH.sup.+].

Example 11

(−)-trans-Fluoromethyl 2-ethyl-2-{[6-{[(1R,2R)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate

(56) ##STR00036##

a) (−)-trans-2-Ethyl-2-(6-((-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamido)butanoic Acid

(57) ##STR00037##

(58) In a 10 mL round-bottomed flask, (−)-trans-ethyl 2-ethyl-2-(6-((-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamido)butanoate (example 10 a, 117 mg, 260 μmol, Eq: 1) was combined with THF (2 mL), MeOH (2.2 mL) and water (2 mL) to give a colorless solution. KOH (73 mg, 1.3 mmol, Eq: 5) was added. The mixture was stirred at 90° C. for 18 h. The organic solvent was removed under reduced pressure. The aqueous phase was adjusted to pH 2 (1 M HCl) and extracted with EtOAc (3×5 mL). The combined extracts were washed with brine (1×10 mL), dried over Na.sub.2SO.sub.4 and filtered. The solvent was removed under reduced pressure to give crude title compound (110 mg, quant.) as colorless oil which was used in the next reaction step without further purification, LC-MS (ES): 420.3 [M−H.sup.−].

b) (−)-trans-Fluoromethyl 2-ethyl-2-{[6-{[-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate

(59) In a 50 mL test tube K.sub.2CO.sub.3 (32.5 mg, 235 μmol, Eq: 3) was combined with DMF (2 mL) to give a white suspension. (−)-trans-2-Ethyl-2-(6-((-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamido)butanoic acid (33 mg, 78.3 μmol, Eq: 1) and fluoro-iodo-methane (37.6 mg, 15.9 μL, 235 μmol, Eq: 3) were added. Stirring was continued for 2 h. The solvent was removed under reduced pressure. The crude product was purified by column chromatography (SiO.sub.2, 5 g, hept./EtOAc) to give the title compound (23 mg, 65%) as colorless oil, MS (ISP): 454.308 [MH.sup.+].

Example 12

(60) (+)-trans-Fluoromethyl 2-ethyl-2-{[6-{[-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate

(61) ##STR00038##

a)(+)-trans-2-Ethyl-2-(6-((-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamido)butanoic Acid

(62) ##STR00039##

(63) In analogy to the procedure described in example 11 a, (+)-trans-ethyl 2-ethyl-2-(6-((-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamido)butanoate (example 9 a) was treated with KOH to give the title compound as white solid, MS (ISP): 422.281 [MH.sup.+].

b) (+)-trans-Fluoromethyl 2-ethyl-2-{[6-{[-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate

(64) In analogy to the procedure described in example 11 b, (+)-trans-2-ethyl-2-(6-((-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamido)butanoic acid was reacted with fluoro-iodo-methane to give the title compound as colorless oil, MS (ISP): 454.308 [MH.sup.+].

Example 13

(+)-trans-2-Fluoroethyl 2-ethyl-2-{[6-{[-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate

(65) ##STR00040##

(66) In analogy to the procedure described in example 11 b, (+)-trans-2-ethyl-2-(6-((-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamido)butanoic acid (example 12 a) was reacted with fluoro-iodo-ethane to give the title compound as colorless oil, MS (ISP): 468.313 [MH.sup.+].

Example 14

(−)-trans-2-Fluoroethyl 2-ethyl-2-{[6-{[-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate

(67) ##STR00041##

(68) In analogy to the procedure described in example 11 b, (−)-trans-2-ethyl-2-(6-((-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamido)butanoic acid (example 11 a) was reacted with fluoro-iodo-ethane to give the title compound as colorless oil, MS (ISP): 468.313 [MH.sup.+].

Example 15

3-Fluoropropyl 2-ethyl-2-{[6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate

(69) ##STR00042##

a) Bis(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl Butanedioate

(70) ##STR00043##

(71) A 2 L one-necked, round bottom flask was equipped with a stirrer, a Dean-Stark trap and a condenser. The flask was charged with succinic anhydride (64 g, 0.64 mol, 1 eq.), 1-menthol (199.88 g, 1.3 mol, 2 eq.), p-toluenesulfonic acid monohydrate (1.1 g, 6.39 mmol, 0.01 eq.) and tolune (576 mL). The mixture was heated under reflux for 24 h, cooled to 25° C., diluted with hexane (640 mL) and poured into a mixture of aqueous saturated sodium bicarbonate (800 mL), methanol (320 mL) and water (320 mL). The layers were separated and the aqueous phase was extracted with hexane (2×320 mL). The organic phases were combined, washed with brine (640 mL), dried over sodium sulphate and filtered. The solvent was removed under reduced pressure and the crude product was dissolved in methanol (240 mL). The solution was cooled to +4° C. for 16 h to form colorless crystals which were collected by filtration with suction. The crystals were purified by recrystallization from methanol (240 mL) to afford pure bis(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl butanedioate (212 g, 84%).

(72) SOR value: [−87.64°] at ≅25° C., 1.0132% solution in CHCl.sub.3.

b) 1,2-Bis(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl (1S,2S)-cyclopropane-1,2-dicarboxylate

(73) ##STR00044##

(74) A 1.8 M solution of butyllithium in THF (152.2 mmol, 84 mL) was added to 225 mL of THF at 0° C. under a N.sub.2 atmosphere. Under stirring lithium tetramethylpiperidide (28.2 mL, 167 mmol) was added drop wise over a 20 min period. Stirring was continued at 0° C. for 1 h. Then the reaction mixture was cooled to −78° C. A solution of Bis(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl butanedioate (30 g, 76.1 mmol) in THF (60 mL) was added drop wise over a 20 min period. The yellow solution was stirred for 1 h.

(75) Bromochloromethane (4.08 mL, 60.91 mmol) was added drop wise over a 20 min period. The mixture was stirred for 3 h at −78° C. A saturated aqueous solution of NH.sub.4Cl (120 mL) was added. After stirring for 30 min at 25° C. the mixture was extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine (200 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The crude was purified by column chromatography (SiO.sub.2, 100-200 mesh, 0.5-1% of ethyl acetate and hexane) to afford the title compound (38 g, 42%) as colorless crystals. Recrystallization of this material from methanol (380 mL) provided pure 1,2-bis(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl (1S,2S)-cyclopropane-1,2-dicarboxylate (27 g, 36%).

(76) SOR value: [+18.18°] at ≅25° C., 1.0288% solution in CHCl.sub.3.

c)(1S,2S)-Cyclopropane-1,2-dicarboxylic acid mono-((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl) ester

(77) ##STR00045##

(78) To a solution of 1,2-bis(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl (1S,2S)-cyclopropane-1,2-dicarboxylate (25 g, 61.58 mmol) in isopropanol (250 mL) was added a 5 M solution of NaOH (13.54 mL, 67.73 mmol) at 25° C. The mixture was stirred at 70° C. for 16 h. The organic solvent was removed under reduced pressure. Water (200 mL) was added and the mixture was washed with diethyl ether (2×150 mL). The aqueous layer was acidified with 2 N HCl (pH˜2) and extracted with ethyl acetate (3×250 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to get (1S,2S)-2-({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)cyclopropane-1-carboxylic acid (11.4 g, 69%) as off white semisolid.

d) (1R,2S,5R)-5-Methyl-2-(propan-2-yl)cyclohexyl(1S,2S)-2-(hydroxymethyl) cyclopropane-1-carboxylate

(79) ##STR00046##

(80) To a stirred solution of (S,2S)-cyclopropane-1,2-dicarboxylic acid mono-((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl) ester (20 g, 74.63 mmol) in THF (200 mL) was added a 1 M solution of borane in THF (56 mL) drop wise at −78° C. The mixture was stirred for 1 h at 25° C. and quenched with aq. NH.sub.4Cl solution (150 mL). The organic solvent was removed under reduced pressure. Water was added (50 mL) and the mixture was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (80 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude was purified by silica gel column chromatography (15-19% ethyl acetate/hexane) to get (1R,2S,5R)-5-methyl-2-(propan-2-yl) cyclohexyl (1S,2S)-2-(hydroxymethyl)cyclopropane-1-carboxylate (13.66 g, 72%) as yellowish semi solid.

e) (1R,2S,5R)-5-Methyl-2-(propan-2-yl)cyclohexyl(1S,2S)-2-[(benzyloxy) methyl]cyclopropane-1-carboxylate

(81) ##STR00047##

(82) To a stirred solution of (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl (1S,2S)-2-(hydroxymethyl) cyclopropane-1-carboxylate (20 g, 78.74 mmol) in DMF (140 mL) was added NaH (4.72 g, 118.11 mmol) at 0° C. The mixture was stirred at 25° C. for 30 min. Benzylbromide (18.70 mL, 157.48 mmol) was added and stirring was continued at 25° C. for 30 min. Aqueous NH.sub.4Cl solution (150 mL) was added and the mixture was extracted with EtOAc (2×150 mL). The combined organic layers were washed with water (3×120 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude was purified by silica gel column chromatography (1.9% EtOAc/hexane) to get (R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl (1S,2S)-2-[(benzyloxy)methyl]cyclopropane-1-carboxylate (22 g, 81%) as light yellow oil.

f) [(1S,2S)-2-[(Benzyloxy)methyl]cyclopropyl]methanol

(83) ##STR00048##

(84) To a stirred solution of (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl (1S,2S)-2-[(benzyloxy) methyl] cyclopropane-1-carboxylate (10 g, 29.07 mmol) in THF (200 mL) was added LAH (58.14 mL, 1 M in THF) at 0° C. The reaction mixture was stirred for 40 min at 0° C. and quenched with aq NH.sub.4Cl solution (100 mL). The organic solvent was removed under reduced pressure. The solution was extracted with ethyl acetate (3×100 mL). The combined organic layers were brought to dryness and the crude was purified using silica gel column chromatography (30-35% ethyl acetate/hexane) to get [(1S,2S)-2-[(benzyloxy)methyl]cyclopropyl]methanol (5.33 g, 95%) as light yellow oil.

g) 6-{[(1S,2S)-2-[(Benzyloxy)methyl]cyclopropyl]methoxy}-5-bromopyridine-2-carboxylic Acid

(85) ##STR00049##

(86) To a solution of 5-bromo-6-chloropyridine-2-carboxylic acid (CAN 959958-25-9, 4 g, 19.80 mmol) in DMF (45 mL) was added NaH (2.77 g, 69.31 mmol) portion wise at 0° C. and stirred for 20 min at 0° C. [(S,2S)-2-[(Benzyloxy)methyl]cyclopropyl]methanol (4.18 g, 21.78 mmol) in DMF (15 mL) was added drop wise at 0° C. The mixture was stirred for 15 min at 25° C., heated to 80° C. for 3 h, cooled to 25° C. and quenched with 2 N aq. HCl to pH˜2. Waster (100 mL) was added and the mixture was extracted with EtOAc (3×150 mL). The combined organic layers were washed with water (4×50 mL) and brine (50 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to get 6-{[(S,2S)-2-[(benzyloxy)methyl]cyclopropyl]methoxy}-5-bromopyridine-2-carboxylic acid (7.7 g, 99%) as off white sticky liquid.

(87) LCMS:

(88) Column Zorbax Ext C 18 (50×4.6 mm), 5μ, (mobile phase: from 90% [10 mM NH.sub.4OAc in water] and 10% [CH.sub.3CN] to 70% [10 mM NH.sub.4OAc in water] and 30% [CH.sub.3CN] in 1.5 min, further to 10% [10 mM NH.sub.4OAc in water] and 90% [CH.sub.3CN] in 3.0 min, held this mobile phase composition to 4 min and finally back to initial condition in 5 min). Purity is 76.78%, Rt=2.60 min, MS calculate: 391, MS found: 391.8[M+H.sup.+].

h) Ethyl 2-[(6-{[(1S,2S)-2-[(benzyloxy)methyl]cyclopropyl]methoxy}-5-bromopyridin-2-yl)formamido]-2-ethylbutanoate

(89) ##STR00050##

(90) To a solution of 6-{[(1S,2S)-2-[(benzyloxy)methyl]cyclopropyl]methoxy}-5-bromopyridine-2-carboxylic acid (15.5 g, 39.54 mmol) in DMF (100 mL) were added DIPEA (27.49 mL, 158.16 mmol), ethyl 2-amino-2-ethylbutanoate (CAN 189631-96-7, 7.73 g, 39.54 mmol) and TBTU (15.25 g, 47.449 mmol). The reaction mixture was stirred at 25° C. for 16 h, poured into water (170 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with water (4×120 mL) and brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and brought to dryness. The crude was purified via silica gel column chromatography (25% ethyl acetate/hexanes) to get ethyl 2-[(6-{[(1S,2S)-2-[(benzyloxy)methyl]cyclopropyl]methoxy}-5-bromopyridin-2-yl)formamido]-2-ethylbutanoate (20.5 g, 97%) as light brown oil.

(91) LCMS:

(92) Column Zorbax Ext C 18 (50×4.6 mm), 5μ, (mobile phase: from 90% [10 mM NH.sub.4OAc in water] and 10% [CH.sub.3CN] to 70% [10 mM NH.sub.4OAc in water] and 30% [CH.sub.3CN] in 1.5 min, further to 10% [10 mM NH.sub.4OAc in water] and 90% [CH.sub.3CN] in 3.0 min, held this mobile phase composition to 4 min and finally back to initial condition in 5 min). Purity is 91.47%, Rt=2.58 min, MS calculate: 533, MS found: 533.0 [M+H.sup.+].

i) Ethyl 2-[(6-{[(1S,2S)-2-[(benzyloxy) methyl]cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridin-2-yl)formamido]-2-ethylbutanoate

(93) ##STR00051##

(94) To a solution ethyl 2-[(6-{[(1S,2S)-2-[(benzyloxy)methyl]cyclopropyl]methoxy}-5-bromopyridin-2-yl)formamido]-2-ethylbutanoate (4 g, 7.50 mmol) in toluene (160 mL) were added 3-methoxyazetidine (1.39 g, 11.26 mmol) and cesium carbonate (7.33 g, 22.51 mmol). The mixture was degassed with argon for 10 min. Rac-BINAP (0.935 g, 1.50 mmol) and Pd(II)acetate (0.34 g, 1.50 mmol) were added. The mixture was heated to 110° C. for 3 h, diluted with EtOAc (100 mL), filtered through a celite bed and washed with EtOAc (3×100 mL). The filtrate was concentrated and the crude purified through silica gel column chromatography (42-50% ethyl acetate/hexanes) to get ethyl 2-[(6-{[(1S,2S)-2-[(benzyloxy)methyl]cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridin-2-yl)formamido]-2-ethylbutanoate (3.1 g, 76%) as light brown oil.

(95) LCMS:

(96) Column Zorbax Ext C 18 (50×4.6 mm), 5μ, (mobile phase: from 90% [10 mM NH.sub.4OAc in water] and 10% [CH.sub.3CN] to 70% [10 mM NH.sub.4OAc in water] and 30% [CH.sub.3CN] in 1.5 min, further to 10% [10 mM NH.sub.4OAc in water] and 90% [CH.sub.3CN] in 3.0 min, held this mobile phase composition to 4 min and finally back to initial condition in 5 min). Purity is 96.74%, Rt=2.37 min, MS calculate: 539, MS found: 539.9 [M+H.sup.+].

j) Ethyl 2-ethyl-2-[(6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridin-2-yl)formamido]butanoat

(97) ##STR00052##

(98) A stirred solution of ethyl 2-[(6-{[(S,2S)-2-[(benzyloxy) methyl]cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridin-2-yl)formamido]-2-ethylbutanoate (26 g, 48.24 mmol) in 735 mL EtOAc:MeOH (10:1) was degassed for 30 min. Pd/C (10%) (6.5 g) was added. The mixture was hydrogenated under a hydrogen atmosphere at 40 PSI for 28 h at 25° C., filtered through a celite bed and washed with 10% MeOH/EtOAc (4×200 mL). The filtrate was evaporated under reduced pressure to get the crude. The crude was purified applying silica gel column chromatography (10-50% EtOAc:hexanes) to get ethyl 2-ethyl-2-[(6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridin-2-yl)formamido] butanoate (19.3 g, 89%) as colorless sticky liquid.

(99) SOR value:

(100) [+15.51°] at ≅20° C., 0.2514% in MeOH.

(101) LCMS:

(102) Column Zorbax Ext C 18 (50×4.6 mm), 5μ, (mobile phase: from 90% [10 mM NH.sub.4OAc in water] and 10% [CH.sub.3CN] to 70% [10 mM NH.sub.4OAc in water] and 30% [CH.sub.3CN] in 1.5 min, further to 10/a [10 mM NH.sub.4OAc in water] and 90/[CH.sub.3CN] in 3.0 min, held this mobile phase composition to 4 min and finally back to initial condition in 5 min). Purity is 98.93%, Rt=3.26 min, MS calculate: 449, MS found: 449.9 [M+H.sup.+].

k) 2-Ethyl-2-[(6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridin-2-yl)formamido]butanoic Acid

(103) ##STR00053##

(104) In a 25 ml round-bottomed flask, ethyl 2-ethyl-2-[(6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridin-2-yl)formamido]butanoate (100 mg, 0.22 mmol) was combined with THF (2.0 mL), MeOH (2.2 mL) and water (2.0 mL) to give a light yellow solution. KOH pellets (62 mg, 1.11 mmol) were added. The mixture was heated to 90° C. After 18 h the organic solvent was removed under reduced pressure. The aqueous phase was diluted with water (20 mL) and extracted with diethyl ether (2×10 mL). The combined organic layers were discarded. The aqueous phase was adjusted to pH˜2 (1 M HCl) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (10 mL), dried, filtered and brought to dryness under reduced pressure to get pure 2-ethyl-2-[(6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridin-2-yl)formamido]butanoic acid (90 mg, 96%) as colorless sticky mass.

(105) LCMS:

(106) Column Zorbax Ext C 18 (50×4.6 mm), 5μ, (mobile phase: from 90% [10 mM NH.sub.4OAc in water] and 10% [CH.sub.3CN] to 70% [10 mM NH.sub.4OAc in water] and 30% [CH.sub.3CN] in 1.5 min, further to 10% [10 mM NH.sub.4OAc in water] and 90% [CH.sub.3CN] in 3.0 min, held this mobile phase composition to 4 min and finally back to initial condition in 5 min). Purity is 95.49%, Rt=2.00 min, MS calculate: 419, MS found: 420.4 [M+H.sup.+].

l) 3-{[(4-Methylbenzene)sulfonyl]oxy}propyl 2-ethyl-2-[(6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridin-2-yl)formamido]butanoate

(107) ##STR00054##

(108) To a solution of 2-ethyl-2-{[(6-[(S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridin-2-yl)formamido]butanoic acid (260 mg. 0.62 mmol) in DMF (5 mL) were added K.sub.2CO.sub.3 (256 mg, 1.85 mmol) and 3-{[(4-methylbenzene)sulfonyl]oxy}propyl 4-methylbenzene-1-sulfonate (711 mg, 1.85 mmol). The reaction mixture was stirred for 16 h at 25° C., poured into water, quenched with aq. 1 (N) HCl and extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine (30 mL), dried, filtered and concentrated in vacuo to get crude product which was purified by combiflash using silica column and 20-80% EtOAc in hexane to get pure 3-{[(4-methylbenzene)sulfonyl]oxy}propyl 2-ethyl-2-[(6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridin-2-yl)formamido]butanoate (255 mg, 65%) as colorless sticky mass.

(109) LCMS:

(110) Column Zorbax Ext C 18 (50×4.6 mm), 5μ, (mobile phase: from 90% [10 mM NH.sub.4OAc in water] and 10% [CH.sub.3CN] to 70% [10 mM NH.sub.4OAc in water] and 30% [CH.sub.3CN] in 1.5 min, further to 10% [10 mM NH.sub.4OAc in water] and 90% [CH.sub.3CN] in 3.0 min, held this mobile phase composition to 4 min and finally back to initial condition in 5 min). Purity is 90.68%, Rt=3.48 min, MS calculate: 633, MS found: 634.4 [M+H.sup.+].

m) 3-Fluoropropyl 2-ethyl-2-{[6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate

(111) In analogy to the procedure described in example 11 b, 2-ethyl-2-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamido)butanoic acid (example 12 a) was reacted with fluoro-iodo-propane to give the title compound as colorless oil, MS (ISP): 482.370 [MH.sup.+].

Example 16

3-Fluoropropyl 2-ethyl-2-{[6-{[(1R,2R)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate

(112) ##STR00055##

(113) In analogy to the procedure described in example 11 b, (−)-trans-2-ethyl-2-(6-((-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamido)butanoic acid (example 11 a) was reacted with fluoro-iodo-propane to give the title compound as colorless oil, MS (ISP): 482.319 [MH.sup.+].

Example 17

N-[(2S)-1-(2-Fluoroethoxy)-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)-6-[(oxetan-3-yl)methoxy]pyridine-2-carboxamide

(114) ##STR00056##

a) 5-Bromo-6-(oxetan-3-ylmethoxy)picolinic Acid

(115) ##STR00057##

(116) In analogy to the procedure described in example 1 a, 5-bromo-6-chloropicolinic acid (CAN 959958-25-9) was reacted with 3-oxetanemethanol (CAN 6246-06-6) to give the title compound as light brown solid, MS (ISP): 287.998 [MH.sup.+].

b) Methyl 5-bromo-6-(oxetan-3-ylmethoxy)picolinate

(117) ##STR00058##

(118) In analogy to the procedure described in example 11 b, 5-bromo-6-(oxetan-3-ylmethoxy)picolinic acid was reacted with iodomethane to give the title compound as colorless oil, MS (ISP): 302.003 [MW].

c) Methyl 5-(3-methoxyazetidin-1-yl)-6-(oxetan-3-ylmethoxy)picolinate

(119) ##STR00059##

(120) In analogy to the procedure described in example 1 c, methyl 5-bromo-6-(oxetan-3-ylmethoxy)picolinate was reacted with 3-methoxyazetidine hydrochloride (CAN 148644-09-1) to give the title compound as light yellow oil, MS (ISP): 309.209 [MH.sup.+].

d) 5-(3-Methoxyazetidin-1-yl)-6-(oxetan-3-ylmethoxy)picolinic Acid

(121) ##STR00060##

(122) In analogy to the procedure described in example 1 a, methyl 5-(3-methoxyazetidin-1-yl)-6-(oxetan-3-ylmethoxy)picolinate was treated with KOH to give crude title compound which was used in the next reaction step without further purification.

e) (S)-N-(1-Hydroxy-4-methylpentan-2-yl)-5-(3-methoxyazetidin-1-yl)-6-(oxetan-3-ylmethoxy)picolinamide

(123) ##STR00061##

(124) In a 5 mL round-bottomed flask, 5-(3-methoxyazetidin-1-yl)-6-(oxetan-3-ylmethoxy)picolinic acid (45 mg, 153 μmol, Eq: 1) was combined with DMF (1 mL) to give a light yellow solution. TBTU (58.9 mg, 183 μmol, Eq: 1.2) and DIPEA (98.8 mg, 134 μL, 765 μmol, Eq: 5) were added. L-Leucinol (CAN 7533-40-6, 53.8 mg, 58.6 μL, 459 μmol, Eq: 3) was added and the mixture was stirred at RT for 30 min. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (SiO.sub.2, 10 g, hept./EtOAc) to give the title compound (44 mg, 73%) as colorless solid, MS (ISP): 394.326 [MH.sup.+].

f) N-[(2S)-1-(2-Fluoroethoxy)-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)-6-[(oxetan-3-yl)methoxy]pyridine-2-carboxamide

(125) In a 10 mL round-bottomed flask, (S)-N-(1-hydroxy-4-methylpentan-2-yl)-5-(3-methoxyazetidin-1-yl)-6-(oxetan-3-ylmethoxy)picolinamide (45 mg, 114 μmol, Eq: 1) was combined with DMF (1 mL) to give a yellow solution which was cooled to 0° C. Sodium hydride, disperision on mineral oil (13.7 mg, 343 μmol, Eq: 3) was added and the mixture was allowed to warm to RT. After 15 min 1-fluoro-2-iodoethane (99.5 mg, 47.4 μL, 572 μmol, Eq: 5) was added and stirring was continued at RT. The addition of sodium hydride (Eq: 3) and 1-fluoro-2-iodoethane (Eq: 5) was repeated after 15, 17 and 20 h. After additional 2 h stirring at RT the reaction mixture was diluted with EtOAc and washed with brine (3×10 mL). The organic layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude product was purified by prep. HPLC to obtain the title compound (6 mg, 12%) as colorless oil, LC-MS (UV peak area/ESI) 99%, 440.2561 [MH.sup.+].

Example 18

N-[(2S)-1-(2-Fluoroethoxy)-4-methylpentan-2-yl]-6-[(oxetan-3-yl)methoxy]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide

(126) ##STR00062##

a) Methyl 6-(oxetan-3-ylmethoxy)-5-(pyrrolidin-1-yl)picolinate

(127) ##STR00063##

(128) In analogy to the procedure described in example 1 c, methyl 5-bromo-6-(oxetan-3-ylmethoxy)picolinate (example 17 b) was reacted with pyrrolidine (CAN 123-75-1) to give the title compound as light yellow oil, MS (ISP): 293.162 [MH.sup.+].

b) 5-(3-Methoxyazetidin-1-yl)-6-(oxetan-3-ylmethoxy)picolinic Acid

(129) ##STR00064##

(130) In analogy to the procedure described in example 11 a, methyl 6-(oxetan-3-ylmethoxy)-5-(pyrrolidin-1-yl)picolinate was treated with KOH to give crude title compound which was used in the next reaction step without further purification, LC-MS (ES): 279.2 [MH.sup.+].

c) (S)-N-(1-Hydroxy-4-methylpentan-2-yl)-6-(oxetan-3-ylmethoxy)-5-(pyrrolidin-1-yl)picolinamide

(131) ##STR00065##

(132) In analogy to the procedure described in example 17 e, 5-(3-methoxyazetidin-1-yl)-6-(oxetan-3-ylmethoxy)picolinic acid was reacted with L-leucinol to give the title compound as light yellow oil, MS (ISP): 378.327 [MH.sup.+].

d) N-[(2S)-1-(2-Fluoroethoxy)-4-methylpentan-2-yl]-6-[(oxetan-3-yl)methoxy]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide

(133) In analogy to the procedure described in example 17 f, (S)-N-(1-hydroxy-4-methylpentan-2-yl)-6-(oxetan-3-ylmethoxy)-5-(pyrrolidin-1-yl)picolinamide was reacted with 1-fluoro-2-iodoethane to obtain the title compound as as colorless oil, MS (ISP): 424.387 [MH.sup.+].

Example 19

(1,1,2,2,3,3-Hexadeuterio-3-fluoro-propyl) 2-ethyl-2-[[6-[[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy]-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino]butanoate

(134) ##STR00066##

a) (1,1,2,2,3,3-Hexadeuterio-3-hydroxy-propyl) 4-methylbenzenesulfonate

(135) ##STR00067##

(136) To a solution of 1,1,2,2,3,3-hexadeuteriopropane-1,3-diol (46 mg, 0.55 mmol) in DCM (1 mL) were added 2,6-lutidine (0.2 mL, 1.64 mmol) and tosyl chloride (156 mg, 0.82 mmol, 1.5 eq.). The reaction mixture was stirred for 17 h at 25° C., diluted with DCM (15 mL), washed with aq. 1 N HCl (10 mL and water (10 mL), dried, filtered and concentrated in vacuo. The crude was purified by column chromatography on silica gel (5-30% EtOAc in hexane) to get the title compound (50 mg, 41%) as colorless liquid.

(137) LCMS:

(138) Column Zorbax Ext C 18 (50×4.6 mm), 5μ, (mobile phase: from 90% [10 mM NH.sub.4OAc in water] and 10% [CH.sub.3CN] to 70% [10 mM NH.sub.4OAc in water] and 30% [CH.sub.3CN] in 1.5 min, further to 10% [10 mM NH.sub.4OAc in water] and 90% [CH.sub.3CN] in 3.0 min, held this mobile phase composition to 4 min and finally back to initial condition in 5 min). Purity is 99.72%, Rt=2.75 min, MS calculate: 236, MS found: 237.1 [M+H.sup.+].

b) (1,1,2,2,3,3-Hexadeuterio-3-fluoro-propyl) 4-methylbenzenesulfonate

(139) ##STR00068##

(140) Triethylamine.3HF (0.09 mL, 0.55 mmol) and XtalFluor-E® (94 mg, 0.41 mmol) were added to dichloromethane (5.0 mL). (1,1,2,2,3,3-Hexadeuterio-3-hydroxy-propyl) 4-methylbenzenesulfonate (65 mg, 0.27 mmol) was added and the reaction mixture was stirred for 17 h at 25° C. The reaction was quenched with 5% aq. NaHCO.sub.3 solution. The layers were separated and the aqueous layer was extracted with DCM (2×10 mL). The combined organic layers were washed with brine (10 mL), dried, filtered and concentrated in vacuo. The crude was purified by column chromatography on silica gel (5-10% EtOAc in hexane) to get the title compound (50 mg, 80%) as colorless liquid which was used in the next reaction step without further purification.

c) (1,1,2,2,3,3-Hexadeuterio-3-fluoro-propyl) 2-ethyl-2-[[6-[[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy]-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino]butanoate

(141) To a solution of 2-ethyl-2-[(6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridin-2-yl)formamido]butanoic acid (example 15 k, 40 mg, 0.09 mmol) in DMF (1.5 mL) were added K.sub.2CO.sub.3 (39 mg, 0.29 mmol) and (1,1,2,2,3,3-hexadeuterio-3-fluoro-propoxy)methylbenzene (45 mg, 0.19 mmol). The reaction mixture was stirred for 17 h, quenched with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL), dried, filtered and concentrated in vacuo. The crude was purified by column chromatography on silica gel (20-80% EtOAc in hexane) to obtain the title compound (35 mg, 77%) as colorless liquid.

(142) LCMS:

(143) Column Zorbax Ext C 18 (50×4.6 mm), 5μ, (mobile phase: from 90% [10 mM NH.sub.4OAc in water] and 10% [CH.sub.3CN] to 70% [10 mM NH.sub.4OAc in water] and 30% [CH.sub.3CN] in 1.5 min, further to 10% [10 mM NH.sub.4OAc in water] and 90% [CH.sub.3CN] in 3.0 min, held this mobile phase composition to 4 min and finally back to initial condition in 5 min). Purity is 83.98%, Rt=3.21 min, MS calculate: 487, MS found: 488.2 [M+H.sup.+].

Example 20

3-Fluoropropyl 2-[6-[[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy]-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonylamino]-2-vinyl-but-3-enoate

(144) ##STR00069##

a) 2-Ethyl-2-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamido)butanoyl Azide

(145) ##STR00070##

(146) In a 30 mL round bottom flask 2-ethyl-2-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamido)butanoic acid (example 15 k, 338 mg, 802 μmol, 1 eq.) was dissolved in toluene (14 mL). Triethylamine (81 mg, 116 μL, 802 μmol, 1 eq.) and DPPA (221 mg, 173 μL, 802 μmol, 1 eq.) were added. The reaction mixture was stirred for 24 h at ambient temperature, poured onto water (20 mL) and extracted with AcOEt (3×30 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (SiO.sub.2, 120 g, 10-70% AcOEt in heptane) to give the title compound (177 mg, 0.396 mmol, 48%) as a off white solid.

(147) .sup.1H NMR (600 MHz, CDCl.sub.3): δ ppm 8.32 (s, 2H, NH), 7.54-7.59 (d, .sup.3J=7.9 Hz, 1H, N.sub.Py—C.sub.q—CH—CH), 6.46-6.53 (d, .sup.3J=7.9 Hz, 1H, N.sub.Py—C.sub.q—C.sub.H), 4.09-4.30 (m, 8H, m, O—CH.sub.2, CH.sub.2—N—CH.sub.2, PO.sub.3-O—CH.sub.2, O—CH), 3.72-3.84 (m, 2H, CH.sub.2—N—CH.sub.2), 3.23 (s, 3H, O—CH.sub.3), 2.35-2.51 (m, 2H, N.sub.3—CO—C.sub.q—CH.sub.2), 1.68-1.89 (m, 2H, N.sub.3—CO—C.sub.q—CH.sub.2), 1.24-1.34 (m, 2H, CH—CH.sub.2—CH), 0.74 (t, 3-7.5 Hz, 6H, N.sub.3—CO—C.sub.q—CH.sub.2—CH.sub.3), 0.63-0.72 (m, 2H, CH—CH.sub.2—CH)

(148) HRMS (ESI): C.sub.21H.sub.30N.sub.6O.sub.5 [M+H].sup.+ calculated=447.2304; found=447.2296.

b) 6-(((1S,2S)-2-(Hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamide

(149) ##STR00071##

(150) In a 25 mL round bottom flask 2-ethyl-2-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamido)butanoyl azide (177 mg, 0.396 mmol, 1 eq.) was dissolved in toluene (10.0 mL). The reaction mixture was heated to 110° C. upon stirring for 3 h and then concentrated in vacuo. THF (3 mL) and 3N NaOH (7 mL) were added. The reaction mixture was heated to 90° C. for 1 h upon stirring, poured onto water (10 mL) and extracted with AcOEt (3×40 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give the title compound (85 mg, 0.277 mmol, 70%) as a light orange oil. The crude material was used in the next step without further purification.

(151) .sup.1H NMR (600 MHz, CDCl.sub.3): δ ppm 8.18 (CO—NH.sub.2), 7.74 (d, .sup.3J=8.0 Hz, 1H, N.sub.Py—C.sub.q—CH—CH), 6.56 (d, .sup.3J=8.0 Hz, 1H, N.sub.Py—C.sub.q—CH), 3.99-4.41 (m, 7H, O—CH.sub.2, CH.sub.2—N—CH.sub.2, O—CH, HO—CH), 3.95-4.00 (m, 2H, CH.sub.2—N—CH.sub.2), 3.29 (m, 3H, O—CH.sub.3), 1.20-1.36 (CH—CH.sub.2—CH), 0.54-0.79 (m, 2H, CH—CH.sub.2—CH)

(152) MS (ESI): C.sub.15H.sub.21N.sub.3O.sub.4 [M+H].sup.+ calculated=308.14; found=308.20.

c) 6-(((1S,2S)-2-(Hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinic Acid

(153) ##STR00072##

(154) In a 25 mL round bottom flask 6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamide (85 mg, 0.277 mmol, 1 eq.) was dissolved in methanol (3 mL) and water (5 mL). Sodium hydroxide (55 mg, 1.38 mmol, 5 eq.) was added. The reaction mixture was heated to 85° C. for 12 h upon stirring, poured onto water (10 mL) and 1N HCl (3 mL) and extracted with AcOEt (3×20 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (SiO.sub.2, 12 g, 40-100% AcOEt in heptane) to give the title compound (64 mg, 0.207 mmol, 75%) as a light orange solid.

(155) .sup.1H NMR (600 MHz, CDCl.sub.3): δ ppm 7.72 (dd, 3J=7.9 Hz, 4J=2.9 Hz, H, N.sub.Py—C.sub.q—CH—CH), 6.56 (d, .sup.3J=7.9 Hz, 1H, N.sub.Py—C.sub.q—CH), 3.99-4.41 (m, 7H, O—CH.sub.2, CH.sub.2—N—CH.sub.2, O—CH, HO—CH), 3.97-3.99 (m, 2H, CH.sub.2—N—CH.sub.2), 3.28 (m, 3H, O—CH.sub.3), 1.18-1.32 (CH—CH.sub.2—CH), 0.56-0.81 (m, 2H, CH—CH.sub.2—CH)

(156) HRMS (ESI): C.sub.15H.sub.20N.sub.2O.sub.5 [M+H].sup.+ calculated=309.1379; found=309.1451.

d) 3-Fluoropropyl 2-amino-2-vinylbut-3-enoate

(157) ##STR00073##

(158) 3-Fluoropropan-1-ol (1.55 g, 1.61 mL, 19.8 mmol, Eq.: 18) and 2-amino-2-vinylbut-3-enoic acid hydrochloride (CAN 1865695-91-5, 180 mg, 1.1 mmol, Eq.: 1) were added to a round bottom flask. Sulfurous dichloride (1.31 g, 798 μL, 11 mmol, Eq.: 10) was added. The reaction mixture was stirred for 1 h at 80° C., poured onto water (10 mL) and extracted with CH.sub.2Cl.sub.2 (2×20 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 20% to 70% AcOEt in heptane) to give the title compound as colorless oil, LC-MS (UV peak area/ESI) 94%, 187.1083 [MH+].

e) 3-Fluoropropyl 2-(1,2-ditritioethyl)-2-[[6-[[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy]-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino]-3,4-ditritio-butanoate

(159) 6-(((1S,2S)-2-(Hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinic acid (19.8 mg, 64.1 μmol, Eq.: 0.8) and 3-fluoropropyl 2-amino-2-vinylbut-3-enoate (15 mg, 80.1 μmol, Eq.: 1) were dissolved in CH.sub.2Cl.sub.2 (1.34 mL). N-Ethyl-N-isopropylpropan-2-amine (41.4 mg, 55.2 μL, 320 μmol, Eq.: 4) followed by 1-(bis(dimethylamino)methylene)-1H-[1,2,3]triazolo[4,5-b]pyridine-1-ium 3-oxide hexafluorophosphate(V) (36.6 mg, 96.1 μmol, Eq.: 1.2) were added. The reaction mixture was stirred for 1 h at ambient temperature, poured onto water (10 mL) and extraced with CH.sub.2Cl.sub.2 (4×20 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 20% to 70% AcOEt in heptane) to give the title compound as colorless oil, LC-MS (UV peak area/ESI) 98%, 478.2399 [MH+].

Example 21

3-Fluoropropyl 3,4-didenterio-2-(1,2-dideterioethyl)-2-[[6-[[(S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy]-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino]butanoate

(160) ##STR00074##

(161) In a 2 ml deuteration flask, 3-Fluoropropyl 2-[[6-[[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy]-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino]-2-vinyl-but-3-enoate (1.0 mg, 2.09 μmol, 1.0 eq.) and Pd/C (10%) (1.11 mg, 1.05 μmol, 0.5 eq.) was suspended in dimethylformamide (0.5 ml). The flask was attached to the deuterium manifold (RC-TRITEC) and degassed by freeze-pump-thaw.

(162) Deuterium gas was introduced, and the black suspension was vigorously stirred for 2.5 hours under an atmosphere of deuterium at 600 mbar. The black suspension was filtered over a 17 mm Titan HPLC filter (0.45 μm, PTFE) and washed with methanol (3×2 ml). The colorless solution was concentrated to give 1 mg of the titel compound in >98% purity, as determined by HPLC (SunFire C18, 5 μm, 4.6×250 mm; eluent: acetonitrile [A], 5% acetonitrile in water [B]; gradient: 10% [A], 90% [B] to 99% [A], 1%[B] in 12 min, hold for 3 min, then back to initial conditions for 5 min). MS m/z: 483.4 [M(.sup.2H)+H].sup.+ (4%), 484.4 [M(.sup.2H.sub.2)+H].sup.+ (9%), 485.4 [M(.sup.2H.sub.3)+H].sup.+ (14%), 486.4 [M(.sup.2H.sub.4)+H].sup.+ (27%), 487.4 [M(.sup.2H.sub.5)+H].sup.+ (21%), 488.4 [M(.sup.2H.sub.6)+H].sup.+ (18%), 489.4 [M(.sup.2H.sub.7)+H].sup.+ (7%).

Example 22

(Rac)-trans-3-Fluoropropyl 2-[[6-[[-2-(benzyloxymethyl)cyclopropyl]methoxy]-5-(3-hydroxyazetidin-1-yl)pyridine-2-carbonyl]amino]-2-ethyl-butanoate

(163) ##STR00075##

a) (Rac)-trans-6-(-2-benzyloxymethyl-cyclopropylmethoxy)-5-bromo-pyridine-2-carboxylic Acid

(164) ##STR00076##

(165) A solution of 5-bromo-6-chloro-pyridine-2-carboxylic acid (2.0 g, 8.5 mmol) in DMF (35 mL) was cooled to 0° C. under argon. NaH (60% oil suspension, 1.01 g, 25.4 mmol) was added and the mixture was stirred for 20 minutes at 0° C. A solution of (rac)-trans-[-2-[(benzyloxy)methyl]cyclopropyl]methanol (2.277 g, 11.8 mmol) in DMF (5 mL) was slowly added. The mixture was heated to 80° C. for 3 h, cooled to 25° C. and adjusted to pH-2 with 2 N aq. HC solution. Water was added (400 mL) and the mixture was extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (150 mL), dried, filtered and concentrated in vacuo to give crude title compound as light yellow gum which was used in the next step without further purification.

(166) LCMS:

(167) Column Zorbax Ext C 18 (50×4.6 mm), 5μ, (mobile phase: from 90% [10 mM NH.sub.4OAc in water] and 10% [CH.sub.3CN] to 70% [10 mM NH.sub.4OAc in water] and 30% [CH.sub.3CN] in 1.5 min, further to 10% [10 mM NH.sub.4OAc in water] and 90% [CH.sub.3CN] in 3.0 min, held this mobile phase composition to 4 min and finally back to initial condition in 5 min). Purity is 71.32%, Rt=2.67 min, MS calculate: 392, MS found: 392.1 [M−H.sup.−].

b) (Rac)-trans-ethyl 2-[[6-[[-2-(benzyloxymethyl)cyclopropyl]methoxy]-5-bromo-pyridine-2-carbonyl]amino]-2-ethyl-butanoate

(168) ##STR00077##

(169) To a solution of (rac)-trans-6-(-2-benzyloxymethyl-cyclopropylmethoxy)-5-bromo-pyridine-2-carboxylic acid (3.3 g, 8.4 mmol) in DMF (15 mL) were added DIPEA (5.9 mL, 33.7 mmol), ethyl 2-amino-2-ethylbutanoate hydrochloride (1.646 g, 8.4 mmol) and TBTU (2.701 g, 8.4 mmol). The reaction mixture was stirred at 25° C. for 16 h, poured into water (200 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (100 mL), dried, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 5% AcOEt in hexane) to give the title compound (2.95 g, 66%) as colorless gum.

(170) LCMS:

(171) Column Zorbax Ext C 18 (50×4.6 mm), 5μ, (mobile phase: from 90% [10 mM NH.sub.4OAc in water] and 10% [CH.sub.3CN] to 70% [10 mM NH.sub.4OAc in water] and 30% [CH.sub.3CN] in 1.5 min, further to 10% [10 mM NH.sub.4OAc in water] and 90% [CH.sub.3CN] in 3.0 min, held this mobile phase composition to 4 min and finally back to initial condition in 5 min). Purity is 96.75%, Rt=4.65 min, MS calculate: 533, MS found: 534.8 [M+H.sup.+].

c) (Rac)-trans-2-[[6-[[-2-(benzyloxymethyl)cyclopropyl]methoxy]-5-bromo-pyridine-2-carbonyl]amino]-2-ethyl-butanoic Acid

(172) ##STR00078##

(173) KOH (282 mg, 2.34 mmol) was added to a solution of (rac)-trans-ethyl 2-[(6-{[-2-[(benzyloxy)methyl]cyclopropyl]methoxy}-5-bromopyridin-2-yl)formamido]-2-ethylbutanoate (250 mg, 0.46 mmol) in THF (4 mL), MeOH (4.4 mL) and water (4.0 mL).

(174) The mixture was heated to 90° C. for 18 h. The organic solvents were removed under reduced pressure. The pH of the remaining aqueous phase was adjusted to 2 using 1 M HC. Extraction with EtOAc (3×25 mL) followed. The combined organic layers were washed with brine (1×30 mL), dried, filtered and brought to dryness under reduced pressure to obtain the title compound (230 mg, 97%) as light yellow sticky mass.

(175) LCMS:

(176) Column Zorbax Ext C 18 (50×4.6 mm), 5μ, (mobile phase: from 90% [10 mM NH.sub.4OAc in water] and 10% [CH.sub.3CN] to 70% [10 mM NH.sub.4OAc in water] and 30% [CH.sub.3CN] in 1.5 min, further to 10% [10 mM NH.sub.4OAc in water] and 90% [CH.sub.3CN] in 3.0 min, held this mobile phase composition to 4 min and finally back to initial condition in 5 min). Purity is 99.03%, Rt=2.8 min, MS calculate: 505, MS found: 503.3[M+H.sup.+].

d) (Rac)-trans-3-fluoropropyl 2-[(6-{[-2-[(benzyloxy)methyl]cyclopropyl]methoxy}-5-bromopyridin-2-yl)formamido]-2-ethylbutanoate

(177) ##STR00079##

(178) In a Round bottom flask K.sub.2CO.sub.3 (230 mg, 1.66 mmol) was suspended in DMF (8 mL). (Rac)-trans-2-[(6-{[-2-[(benzyloxy)methyl]cyclopropyl]methoxy}-5-bromopyridin-2-yl)formamido]-2-ethylbutanoic acid (280 mg, 0.55 mmol) and 1-iodo-3-fluoro-propane (313 mg, 1.66 mmol) were added. The mixture was stirred for 2 h at 25° C. Ice cold water was added and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (20 mL), dried, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 30% AcOEt in hexane) to give the title compound (225 mg, 72%) as colorless sticky mass.

(179) LCMS:

(180) Column Zorbax Ext C 18 (50×4.6 mm), 5μ, (mobile phase: from 90% [10 mM NH.sub.4OAc in water] and 10% [CH.sub.3CN] to 70% [10 mM NH.sub.4OAc in water] and 30% [CH.sub.3CN] in 1.5 min, further to 10% [10 mM NH.sub.4OAc in water] and 90% [CH.sub.3CN] in 3.0 min, held this mobile phase composition to 4 min and finally back to initial condition in 5 min). Purity is 99.38%, Rt=2.41 min, MS calculate: 565, MS found: 565.3 [M+H.sup.+].

e) 3-Fluoropropyl 2-amino-2-vinylbut-3-enoate

(181) To a solution of (rac)-trans-3-fluoropropyl 2-[(6-{[-2-[(benzyloxy)methyl]cyclopropyl]methoxy}-5-bromopyridin-2-yl)formamido]-2-ethylbutanoate (225 mg, 0.39 mmol) in toluene (5 mL) were added azetidin-3-ol-HCl (87 mg, 0.79 mmol) and cesium carbonate (519 mg, 1.59 mmol). The mixture was degassed with argon for 10 minutes. BINAP (100 mg, 0.16 mmol) and Pd(H) acetate (36 mg, 0.16 mmol) were added and the mixture was heated at 110° C. for 3 h. The reaction mixture was diluted with EtOAc (30 mL), filtered through a bed of celite and the celite bad was washed with EtOAc (30 mL). The solvent was removed in vacuo. The crude material was purified by flash chromatography (silica gel, 10% to 70% EtOAc in heptane) followed by SFC purification to give the title compound (130 mg, 59%) as yellowish sticky solid.

(182) LCMS:

(183) Column Zorbax Ext C 18 (50×4.6 mm), 5μ, (mobile phase: from 90% [10 mM NH.sub.4OAc in water] and 10% [CH.sub.3CN] to 70% [10 mM NH.sub.4OAc in water] and 30% [CH.sub.3CN] in 1.5 min, further to 10% [10 mM NH.sub.4OAc in water] and 90% [CH.sub.3CN] in 3.0 min, held this mobile phase composition to 4 min and finally back to initial condition in 5 min). Purity is 98.28%, Rt=3.63 min, MS calculate: 557, MS found: 558.0 [M+H.sup.+].

Example 23

3-(p-Tolylsulfonyloxy)propyl 2-ethyl-2-[[6-[[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy]-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino]butanoate

(184) ##STR00080##

a) 3-{[(4-Methylbenzene)sulfonyl]oxy}propyl 4-methylbenzene-1-sulfonate

(185) ##STR00081##

(186) To a solution of propane-1,3-diol (500 mg, 6.58 mmol) in DCM (5 mL) were added 2,6-lutidine (2.3 mL, 19.74 mmol) and tosyl chloride (2.508 g, 13.16 mmol). The reaction mixture was stirred for 17 h at 25° C., diluted with DCM (50 mL), washed with aq. 1 HCl, water (20 mL), dried, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 5% to 30% EtOAc in heptane) to obtain the title compound (1000 mg, 40%) as as white solid.

(187) LCMS:

(188) Column Zorbax Ext C 18 (50×4.6 mm), 5μ, (mobile phase: from 90% [10 mM NH.sub.4OAc in water] and 10% [CH.sub.3CN] to 70% [10 mM NH.sub.4OAc in water] and 30% [CH.sub.3CN] in 1.5 min, further to 10% [10 mM NH.sub.4OAc in water] and 90% [CH.sub.3CN] in 3.0 min, held this mobile phase composition to 4 min and finally back to initial condition in 5 min). Purity is 97.88%, Rt=3.56 min, MS calculate: 384, MS found: 402.1 [M+NH.sub.4.sup.+].

b) 3-(p-Tolylsulfonyloxy)propyl 2-ethyl-2-[[6-[[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy]-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino]butanoate

(189) To a solution of 2-ethyl-2-[(6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridin-2-yl)formamido]butanoic acid (example 15 k, 260 mg, 0.62 mmol) in DMF (5 mL) were added K.sub.2CO.sub.3 (256 mg, 1.85 mmol) and 3-{[(4-methylbenzene)sulfonyl]oxy}propyl 4-methylbenzene-1-sulfonate (711 mg, 1.85 mmol). The reaction mixture was stirred for 16 h at 25° C., poured onto water, quenched with aq. 1 N HCl and extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine (30 mL), dried, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 20% to 80% EtOAc in heptane) to obtain the title compound (255 mg, 65%) as colorless sticky mass.

(190) LCMS:

(191) Column Zorbax Ext C 18 (50×4.6 mm), 5μ, (mobile phase: from 90% [10 mM NH.sub.4OAc in water] and 10% [CH.sub.3CN] to 70% [10 mM NH.sub.4OAc in water] and 30% [CH.sub.3CN] in 1.5 min, further to 10% [10 mM NH.sub.4OAc in water] and 90% [CH.sub.3CN] in 3.0 min, held this mobile phase composition to 4 min and finally back to initial condition in 5 min). Purity is 90.68%, Rt=3.48 min, MS calculate: 633, MS found: 634.4 [M+H.sup.+].

Example 24

[1,1,2,2,3,3-Hexadeuterio-3-(p-tolylsulfonyloxy)propyl] 2-ethyl-2-[[6-[[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy]-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino]butanoate

(192) ##STR00082##

a) [1,1,2,2,3,3-Hexadeuterio-3-(p-tolylsulfonyloxy)propyl] 4-methylbenzenesulfonate

(193) ##STR00083##

(194) To a solution of propane-1,3-diol (d.sub.6) (73 mg, 0.87 mmol) in DCM (1 mL) were added 2,6-lutidine (0.5 mL, 4.34 mmol) and tosyl chloride (496 mg, 2.6 mmol, 3 eq.). The reaction mixture was stirred for 17 h at 25° C., diluted with DCM (20 mL), washed with aq. 1 N HCl solution and water (10 mL), dried, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 5% to 30% EtOAc in hexane) to obtain the title compound (205 mg, 61%) as white solid.

(195) LCMS:

(196) Column Zorbax Ext C 18 (50×4.6 mm), 5μ, (mobile phase: from 90% [10 mM NH.sub.4OAc in water] and 10% [CH.sub.3CN] to 70% [10 mM NH.sub.4OAc in water] and 30% [CH.sub.3CN] in 1.5 min, further to 10% [10 mM NH.sub.4OAc in water] and 90% [CH.sub.3CN] in 3.0 min, held this mobile phase composition to 4 min and finally back to initial condition in 5 min). Purity is 99.84%, Rt=3.48 min, MS calculate: 390, MS found: 408.1 [M+NH.sub.4.sup.+].

b) [1,1,2,2,3,3-Hexadeuterio-3-(p-tolylsulfonyloxy)propyl] 2-ethyl-2-[[6-[[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy]-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino]butanoate

(197) To a solution of 2-ethyl-2-[(6-{[(S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridin-2-yl)formamido]butanoic acid (example 15 k, 50 mg, 0.12 mmol) in DMF (5.0 mL) were added K.sub.2CO.sub.3 (49 mg, 0.35 mmol) and [1,1,2,2,3,3-hexadeuterio-3-(p-tolylsulfonyloxy)propyl] 4-methylbenzenesulfonate (93 mg, 0.24 mmol). The reaction mixture was stirred for 17 h at 25° C., quenched with water (30 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL), dried, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 30% a to 80% EtOAc in hexane) to obtain the title compound (50 mg, 67%) as colorless liquid.

(198) LCMS:

(199) Column Zorbax Ext C 18 (50×4.6 mm), 5μ, (mobile phase: from 90% [10 mM NH.sub.4OAc in water] and 10% [CH.sub.3CN] to 70% [10 mM NH.sub.4OAc in water] and 30% [CH.sub.3CN] in 1.5 min, further to 10% [10 mM NH.sub.4OAc in water] and 90% [CH.sub.3CN] in 3.0 min, held this mobile phase composition to 4 min and finally back to initial condition in 5 min). Purity is 95.50%, Rt=3.47 min, MS calculate: 639, MS found: 640.3 [M+H.sup.+].

Example 25

4-Fluorobutyl 2-ethyl-2-[[6-[[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy]-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino]butanoate

(200) ##STR00084##

(201) To a solution of 2-ethyl-2-[(6-{[(S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridin-2-yl)formamido]butanoic acid (example 15 k, 60 mg, 0.14 mmol) in DMF (5 mL) were added K.sub.2CO.sub.3 (59 mg, 0.43 mmol) and 1-bromo-4-fluorobutane (66 mg, 0.43 mmol). The reaction mixture was stirred for 2 h at 25° C., poured into water, quenched with aq. 1 N HCl solution and extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (10 mL), dried, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10% to 40% EtOAc in hexane) to obtain the title compound (26 mg, 37%) as colorless liquid.

(202) LCMS:

(203) Column Zorbax Ext C 18 (50×4.6 mm), 5μ, (mobile phase: from 90% [10 mM NH.sub.4OAc in water] and 10% [CH.sub.3CN] to 70% [10 mM NH.sub.4OAc in water] and 30% [CH.sub.3CN] in 1.5 min, further to 10% [10 mM NH.sub.4OAc in water] and 90% [CH.sub.3CN] in 3.0 min, held this mobile phase composition to 4 min and finally back to initial condition in 5 min). Purity is 92.73%, Rt=1.39 min, MS calculate: 495, MS found: 495.6 [M+H.sup.+].

Example 26

N-[1-Ethyl-1-[[(1S)-1-(hydroxymethyl)-3-methyl-butyl]carbamoyl]propyl]-6-[[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide

(204) ##STR00085##

(205) To a solution of 2-ethyl-2-[(6-{[(S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridin-2-yl)formamido]butanoic acid (example 15 k, 30 mg, 0.06 mmol) in DCM (5.0 mL) were added EDC.HCl (18 mg, 0.09 mmol) and HOBt (8 mg, 0.06 mmol). The reaction mixture was stirred at 25° C. for 30 min. (2S)-2-Amino-4-methylpentan-1-ol (11 mg, 0.09 mmol) and DIPEA (0.02 mL, 0.09 mmol) were added. The mixture was stirred at 25° C. for 12 h, diluted with DCM (10 mL) and washed with water (2×5 mL) and brine (5 mL). The combined extracts were dried, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 70% EtOAc in hexane) to obtain the title compound (14 mg, 45%) as colorless sticky mass.

(206) LCMS:

(207) Column Zorbax Ext C 18 (50×4.6 mm), Sp, (mobile phase: from 90% [10 mM NH.sub.4OAc in water] and 10% [CH.sub.3CN] to 70% [10 mM NH.sub.4OAc in water] and 30% [CH.sub.3CN] in 1.5 min, further to 10% [10 mM NH.sub.4OAc in water] and 90% [CH.sub.3CN] in 3.0 min, held this mobile phase composition to 4 min and finally back to initial condition in 5 min). Purity is 78.15%, Rt=3.06 min, MS calculate: 520, MS found: 521.2 [M+H.sup.+].

Example 27

N-[1-Ethyl-1-[[(1S)-1-(hydroxymethyl)-3-methyl-butyl]carbamoyl]propyl]-5-(3-fluoroazetidin-1-yl)-6-[[(1R,2R)-2-(hydroxymethyl)cyclopropyl]methoxy]pyridine-2-carboxamide or N-[1-ethyl-1-[[(1S)-1-(hydroxymethyl)-3-methyl-butyl]carbamoyl]propyl]-5-(3-fluoroazetidin-1-yl)-6-[[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy]pyridine-2-carboxamide

(208) ##STR00086##

a) (Rac)-trans-ethyl 2-[(6-{[-2-[(benzyloxy)methyl] cyclopropyl]methoxy}-5-(3-fluoroazetidin-1-yl) pyridin-2-yl) formamido]-2-ethylbutanoate

(209) ##STR00087##

(210) To a solution of (rac)-trans-ethyl 2-[(6-{[-2-[(benzyloxy)methyl]cyclopropyl]methoxy}-5-bromopyridin-2-yl)formamido]-2-ethylbutanoate (example 22 b, 250 mg, 0.47 mmol) in toluene (12 mL) were added 3-fluorozetidine hydrochloride (78 mg, 0.70 mmol) and cesium carbonate (458 mg, 1.41 mmol). The mixture was degassed with argon for 10 minutes. Rac-BINAP (58 mg, 0.09 mmol) and Pd(II) acetate (21 mg, 0.09 mmol) were added and the mixture was heated to 110° C. for 3 h. The reaction mixture was diluted with EtOAc (30 mL), filtered through a celite bed and the bed was washed with EtOAc (30 mL). The filtrate was concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10% to 20% EtOAc in hexane) to obtain the title compound (205 mg, 83%) as brown liquid.

(211) LCMS:

(212) Column Zorbax Ext C 18 (50×4.6 mm), 5μ, (mobile phase: from 90% [10 mM NH.sub.4OAc in water] and 10% [CH.sub.3CN] to 70% [10 mM NH.sub.4OAc in water] and 30% [CH.sub.3CN] in 1.5 min, further to 10% [10 mM NH.sub.4OAc in water] and 90% [CH.sub.3CN] in 3.0 min, held this mobile phase composition to 4 min and finally back to initial condition in 5 min). Purity is 98.26%, Rt=4.21 min, MS calculate: 527, MS found: 527.9 [M+H.sup.+].

b) (Rac)-trans-2-[(6-{[-2-[(benzyloxy)methyl]cyclopropyl]methoxy}-5-(3-fluoroazetidin-1-yl)pyridin-2-yl) formamido]-2-ethylbutanoic Acid

(213) ##STR00088##

(214) In a 25 mL round-bottomed flask (rac)-trans-ethyl 2-[(6-{[-2-[(benzyloxy)methyl]cyclopropyl]methoxy}-5-(3-fluoroazetidin-1-yl) pyridin-2-yl) formamido]-2-ethylbutanoate (290 mg, 0.55 mmol) was combined with THF (2.5 mL), MeOH (2.8 mL) and water (2.5 mL) to give a light yellow solution. KOH pellets (154 mg, 2.75 mmol) were added. The mixture was heated to 90° C. for 18 h. The organic solvent was removed under reduced pressure. The aqueous phase was diluted with water (30 mL) and extracted with diethyl ether (2×10 mL). The organic part was discarded, the aqueous phase was adjusted to pH˜2 (1 M HCl) and extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine (1×20 mL), dried, filtered and concentrated in vacuo to obtain the title compound (260 mg, 95%) as brown sticky mass.

(215) LCMS:

(216) Column Zorbax Ext C 18 (50×4.6 mm), 5μ, (mobile phase: from 90% [10 mM NH.sub.4OAc in water] and 10% [CH.sub.3CN] to 70% [10 mM NH.sub.4OAc in water] and 30% [CH.sub.3CN] in 1.5 min, further to 10% [10 mM NH.sub.4OAc in water] and 90% [CH.sub.3CN] in 3.0 min, held this mobile phase composition to 4 min and finally back to initial condition in 5 min). Purity is 100%, Rt=2.70 min, MS calculate: 497, MS found: 498.4 [M+H.sup.+].

c) trans-2-[(6-{[-2-[(Benzyloxy)methyl]cyclopropyl]methoxy}-5-(3-fluoroazetidin-1-yl)pyridin-2-yl) formamido]-2-ethyl-N-[(2S)-1-hydroxy-4-methylpentan-2-yl]butanamide

(217) ##STR00089##

(218) To a solution of (rac)-trans-2-[(6-{[-2-[(benzyloxy)methyl]cyclopropyl]methoxy}-5-(3-fluoroazetidin-1-yl)pyridin-2-yl) formamido]-2-ethylbutanoic acid (180 mg, 0.36 mmol) in DCM (12 mL) were added EDC.HCl (104 mg, 0.54 mmol) and HOBt (49 mg, 0.36 mmol). The reaction mixture was stirred at 25° C. for 30 min. (S)-2-Amino-4-methyl-pentan-1-ol (63 mg, 0.54 mmol) and DIPEA (0.09 mL, 0.54 mmol) were added. The mixture was stirred at 25° C. for 12 h, diluted with DCM (30 mL) and washed with water (20 mL) and brine (10 mL). The combined extracts were dried, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 70% EtOAc in hexane) to obtain the title compound (160 mg, 74%) as sticky solid.

(219) LCMS:

(220) Column Zorbax Ext C 18 (50×4.6 mm), 5μ, (mobile phase: from 90% [10 mM NH.sub.4OAc in water] and 10% [CH.sub.3CN] to 70% [10 mM NH.sub.4OAc in water] and 30% [CH.sub.3CN] in 1.5 min, further to 10% [10 mM NH.sub.4OAc in water] and 90% [CH.sub.3CN] in 3.0 min, held this mobile phase composition to 4 min and finally back to initial condition in 5 min). Purity is 89.65%, Rt=3.77 min, MS calculate: 598, MS found: 599.1 [M+H.sup.+].

d) N-[1-Ethyl-1-[[(1S)-1-(hydroxymethyl)-3-methyl-butyl]carbamoyl]propyl]-5-(3-fluoroazetidin-1-yl)-6-[[(1R,2R)-2-(hydroxymethyl)cyclopropyl]methoxy]pyridine-2-carboxamide or N-[1-ethyl-1-[[(1S)-1-(hydroxymethyl)-3-methyl-butyl]carbamoyl]propyl]-5-(3-fluoroazetidin-1-yl)-6-[[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy]pyridine-2-carboxamide

(221) A solution of trans-2-[(6-{[-2-[(benzyloxy)methyl]cyclopropyl]methoxy}-5-(3-fluoroazetidin-1-yl)pyridin-2-yl) formamido]-2-ethyl-N-[(2S)-1-hydroxy-4-methylpentan-2-yl]butanamide (160 mg, 0.27 mmol) in EtOAc (6 mL) and methanol (0.6 mL) was degassed for 10 minutes. Pd—C (10%) (80 mg) was added and degassing was continued for another 2 minutes. The mixture was then put under a hydrogen atmosphere at balloon pressure and stirred for 17 h at 25° C., filtered through a celite bed and concentrated in vacuo to get crude trans-2-ethyl-2-{[5-(3-fluoroazetidin-1-yl)-6-{[-2-(hydroxymethyl)cyclopropyl]methoxy}pyridin-2-yl] formamido}-N-[(2S)-1-hydroxy-4-methylpentan-2-yl]butanamide (130 mg, 86%) as colorless gum. The crude was purified by preparative chiral HPLC (column: Chiralpak IE (250×4.6 mm), Si; mobile phase: hexane/EtOH/DEA: 90/10/0.1; flow rate: 1.0 mL/min) to obtain the title compound (27 mg, 20/a, 100% ee).

(222) LCMS:

(223) Column Zorbax Ext C 18 (50×4.6 mm), 5μ, (mobile phase: from 90% [10 mM NH.sub.4OAc in water] and 10% [CH.sub.3CN] to 70% [10 mM NH.sub.4OAc in water] and 30% [CH.sub.3CN] in 1.5 min, further to 10% [10 mM NH.sub.4OAc in water] and 90% [CH.sub.3CN] in 3.0 min, held this mobile phase composition to 4 min and finally back to initial condition in 5 min). Purity is 97.62%, Rt=3.09 min, MS calculate: 508, MS found: 509.1 [M+H.sup.+].

Example 28

N-[1-Ethyl-1-[[(1S)-1-(hydroxymethyl)-3-methyl-butyl]carbamoyl]propyl]-5-(3-fluoroazetidin-1-yl)-6-[[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy]pyridine-2-carboxamide or N-[1-ethyl-1-[[(1S)-1-(hydroxymethyl)-3-methyl-butyl]carbamoyl]propyl]-5-(3-fluoroazetidin-1-yl)-6-[[(1R,2R)-2-(hydroxymethyl)cyclopropyl]methoxy]pyridine-2-carboxamide

(224) ##STR00090##

(225) A solution of trans-2-[(6-{[-2-[(benzyloxy)methyl]cyclopropyl]methoxy}-5-(3-fluoroazetidin-1-yl)pyridin-2-yl) formamido]-2-ethyl-N-[(2S)-1-hydroxy-4-methylpentan-2-yl]butanamide (160 mg, 0.27 mmol) in EtOAc (6 mL) and methanol (0.6 mL) was degassed for 10 minutes. Pd—C (10%) (80 mg) was added and degassing was continued for another 2 minutes. The mixture was then put under a hydrogen atmosphere at balloon pressure and stirred for 17 h at 25° C., filtered through a celite bed and concentrated in vacuo to get crude trans-2-ethyl-2-{[5-(3-fluoroazetidin-1-yl)-6-{[-2-(hydroxymethyl)cyclopropyl]methoxy}pyridin-2-yl] formamido}-N-[(2S)-1-hydroxy 4-methylpentan-2-yl]butanamide (130 mg, 86%) as colorless gum. The crude was purified by preparative chiral HPLC (column: Chiralpak IE (250×4.6 mm), 51; mobile phase: hexane/EtOH/DEA: 90/10/0.1; flow rate: 1.0 mL/min) to obtain the title compound (27 mg, 20%, 89% ee).

(226) LCMS:

(227) Column Zorbax Ext C 18 (50×4.6 mm), 5μ, (mobile phase: from 90% [10 mM NH.sub.4OAc in water] and 10% [CH.sub.3CN] to 70% [10 mM NH.sub.4OAc in water] and 30% [CH.sub.3CN] in 1.5 min, further to 10% [10 mM NH.sub.4OAc in water] and 90% [CH.sub.3CN] in 3.0 min, held this mobile phase composition to 4 min and finally back to initial condition in 5 min). Purity is 95.79%, Rt=3.09 min, MS calculate: 508, MS found: 509.3 [M+H.sup.+].

Example 29

3-Fluoropropyl 2-ethyl-2-{[5-(3-fluoroazetidin-1-yl)-6-{[(1R,2R)-2-(hydroxymethyl)cyclopropyl]methoxy}pyridin-2-yl]formamido}butanoate or 3-fluoropropyl 2-ethyl-2-{[5-(3-fluoroazetidin-1-yl)-6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}pyridin-2-yl]formamido}butanoate

(228) ##STR00091##

a) (Rac)-trans-3-fluoropropyl 2-[(6-{[-2-[(benzyloxy)methyl]cyclopropyl]methoxy}-5-(3-fluoroazetidin-1-yl)pyridin-2-yl)formamido]-2-ethylbutanoate

(229) ##STR00092##

(230) To a solution of (rac)-trans-2-[(6-{[-2-[(benzyloxy)methyl]cyclopropyl]methoxy}-5-(3-fluoroazetidin-1-yl)pyridin-2-yl)formamido]-2-ethylbutanoic acid (example 27 b, 170 mg, 0.34 mmol) in DMF (10 mL) were added K.sub.2CO.sub.3 (141 mg, 1.02 mmol) and 1-fluoro-3-iodo-propane (192 mg, 1.02 mmol). The mixture was stirred for 2 h at 25° C., diluted with water (100 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (30 mL), dried, filtered and concentrated in vacuo to obtain the title compound (170 mg) as yellow gum which was used in the next reaction step without further purification.

(231) LCMS:

(232) Column Zorbax Ext C 18 (50×4.6 mm), 5μ, (mobile phase: from 90% [10 mM NH.sub.4OAc in water] and 10% [CH.sub.3CN] to 70% [10 mM NH.sub.4OAc in water] and 30% [CH.sub.3CN] in 1.5 min, further to 10% [10 mM NH.sub.4OAc in water] and 90% [CH.sub.3CN] in 3.0 min, held this mobile phase composition to 4 min and finally back to initial condition in 5 min). Purity is 63.82%, Rt=4.02 min, MS calculate: 559, MS found: 560.1 [M+H.sup.+].

b) 3-Fluoropropyl 2-ethyl-2-{[5-(3-fluoroazetidin-1-yl)-6-{[(1R,2R)-2-(hydroxymethyl)cyclopropyl]methoxy}pyridin-2-yl]formamido}butanoate or 3-fluoropropyl 2-ethyl-2-{[5-(3-fluoroazetidin-1-yl)-6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}pyridin-2-yl]formamido}butanoate

(233) A solution of (rac)-trans-3-fluoropropyl 2-[(6-{[-2-[(benzyloxy)methyl]cyclopropyl]methoxy}-5-(3-fluoroazetidin-1-yl)pyridin-2-yl)formamido]-2-ethylbutanoate (160 mg, 0.29 mmol) in EtOAc (6 mL) and methanol (0.6 mL) was degassed for 10 minutes. Pd—C (10%, 80 mg) was added and degassing was continued for another 2 minutes. The mixture was put under a hydrogen atmosphere at balloon pressure and stirred for 17 h at 25° C. The reaction mixture was filtered through a celite bed and concentrated in vacuo to get crude (rac)-trans-3-fluoropropyl 2-ethyl-2-{[5-(3-fluoroazetidin-1-yl)-6-{[-2-(hydroxymethyl) cyclopropyl]methoxy}pyridin-2-yl]formamido}butanoate (140 mg) as colorless gum. The crude was purified by preparative chiral HPLC (column: Chiralpak IC (250×4.6 mm), 51; mobile phase: hexane/EtOH/isopropylamine: 80/20/0.1; flow rate: 1.0 mL/min) to obtain the title compound (34 mg, 24%) as colorless sticky mass.

(234) LCMS:

(235) Column Zorbax Ext C 18 (50×4.6 mm), 5μ, (mobile phase: from 90% [10 mM NH.sub.4OAc in water] and 10% [CH.sub.3CN] to 70% [10 mM NH.sub.4OAc in water] and 30% [CH.sub.3CN] in 1.5 min, further to 10% [10 mM NH.sub.4OAc in water] and 90% [CH.sub.3CN] in 3.0 min, held this mobile phase composition to 4 min and finally back to initial condition in 5 min). Purity is 98.47%, Rt=3.26 min, MS calculate: 469, MS found: 470.1 [M+H.sup.+].

Example 30

3-Fluoropropyl 2-ethyl-2-{[5-(3-fluoroazetidin-1-yl)-6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}pyridin-2-yl]formamido}butanoate or 3-fluoropropyl 2-ethyl-2-{[5-(3-fluoroazetidin-1-yl)-6-{[(1R,2R)-2-(hydroxymethyl)cyclopropyl]methoxy}pyridin-2-yl]formamido}butanoate

(236) ##STR00093##

(237) A solution of (rac)-trans-3-fluoropropyl 2-[(6-[{-2-[(benzyloxy)methyl]cyclopropyl]methoxy}-5-(3-fluoroazetidin-1-yl)pyridin-2-yl)formamido]-2-ethylbutanoate (160 mg, 0.29 mmol) in EtOAc (6 mL) and methanol (0.6 mL) was degassed for 10 minutes. Pd—C (10%, 80 mg) was added and degassing was continued for another 2 minutes. The mixture was put under a hydrogen atmosphere at balloon pressure and stirred for 17 h at 25° C. The reaction mixture was filtered through a celite bed and concentrated in vacuo to get crude (rac)-trans-3-fluoropropyl 2-ethyl-2-{[5-(3-fluoroazetidin-1-yl)-6-{[-2-(hydroxymethyl) cyclopropyl]methoxy}pyridin-2-yl]formamido}butanoate (140 mg) as colorless gum. The crude was purified by preparative chiral HPLC (column: Chiralpak IC (250×4.6 mm), 51; mobile phase: hexane/EtOH/isopropylamine: 80/20/0.1; flow rate: 1.0 mL/min) to obtain the title compound (37 mg, 26%) as colorless sticky mass.

(238) LCMS:

(239) Column Zorbax Ext C 18 (50×4.6 mm), 5μ, (mobile phase: from 90% [10 mM NH.sub.4OAc in water] and 10% [CH.sub.3CN] to 70% [10 mM NH.sub.4OAc in water] and 30% [CH.sub.3CN] in 1.5 min, further to 10% [10 mM NH.sub.4OAc in water] and 90% [CH.sub.3CN] in 3.0 min, held this mobile phase composition to 4 min and finally back to initial condition in 5 min). Purity is 98.46%, Rt=3.28 min, MS calculate: 469, MS found: 470.1 [M+H.sup.+].

Example 31

(Rac)-trans-3-fluoropropyl 2-ethyl-2-[[6-[[-2-(hydroxymethyl)cyclopropyl]methoxy]-5-[3-(p-tolylsulfonyloxy)azetidin-1-yl]pyridine-2-carbonyl]amino]butanoate

(240) ##STR00094##

a) (Rac)-trans-3-fluoropropyl 2-[(6-{[-2-[(benzyloxy)methyl] cyclopropyl]methoxy}-5-(3-{[(4-methylbenzene)sulfonyl]oxy}azetidin-1-yl)pyridin-2-yl)formamido]-2-ethylbutanoate

(241) ##STR00095##

(242) To a solution of (rac)-trans-3-fluoropropyl 2-[(6-{[-2-[(benzyloxy)methyl]cyclopropyl]methoxy}-5-(3-hydroxyazetidin-1-yl)pyridin-2-yl)formamido]-2-ethylbutanoate (example 22 e, 225 mg, 0.40 mmol) in DCM (5 mL) in a sealed tube were added 2,6-lutidine (0.25 mL, 2.02 mmol) and tosyl chloride (230 mg, 1.21 mmol). The reaction mixture was stirred for 16 h at 50° C., diluted with DCM (20 mL) and washed with aq. 1 N HCl and water (10 mL). The organic layer was dried, filtered and concentrated in vacuo. The crude purified by prep. HPLC to obtain the title compound as yellowish solid (16 mg, 6%).

(243) LCMS:

(244) Column Zorbax Ext C 18 (50×4.6 mm), 5μ, (mobile phase: from 90/a [10 mM NH.sub.4OAc in water] and 10% [CH.sub.3CN] to 70% [10 mM NH.sub.4OAc in water] and 30% [CH.sub.3CN] in 1.5 min, further to 10% [10 mM NH.sub.4OAc in water] and 90% [CH.sub.3CN] in 3.0 min, held this mobile phase composition to 4 min and finally back to initial condition in 5 min). Purity:crude material, Rt=2.44 min, MS calculate: 711, MS found: 712.5 [M+H.sup.+].

b) (Rac)-trans-3-fluoropropyl 2-ethyl-2-[[6-[[-2-(hydroxymethyl)cyclopropyl]methoxy]-5-[3-(p-tolylsulfonyloxy)azetidin-1-yl]pyridine-2-carbonyl]amino]butanoate

(245) A solution of (rac)-trans-3-fluoropropyl 2-[(6-{[-2-[(benzyloxy)methyl]cyclopropyl]methoxy}-5-(3-{[(4-methylbenzene)sulfonyl]oxy}azetidin-1-yl)pyridin-2-yl)formamido]-2-ethylbutanoate (16.0 mg, 0.02 mmol) in EtOAc (2 mL) was degassed. Pd/C (10 wt %, 8.0 mg) was added. The mixture was degassed, charged with H.sub.2, and stirred for 16 h at ambient temperature. The mixture was filtered through celite and the celite bed was washed with EtOAc. The filtrate was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to yield the title compound (10.1 mg, 72%) as colourless sticky mass.

(246) LCMS:

(247) Column Zorbax Ext C 18 (50×4.6 mm), 5μ, (mobile phase: from 90% [10 mM NH.sub.4OAc in water] and 10% [CH.sub.3CN] to 70% [10 mM NH.sub.4OAc in water] and 30% [CH.sub.3CN] in 1.5 min, further to 10% [10 mM NH.sub.4OAc in water] and 90% [CH.sub.3CN] in 3.0 min, held this mobile phase composition to 4 min and finally back to initial condition in 5 min). Purity is 89.55%, Rt=3.53 min, MS calculate: 621, MS found: 622.2 [M+H.sup.+].

Example 32

3-Fluoropropyl 2-[[6-[[(1S,2S)-2-(benzyloxymethyl)cyclopropyl]methoxy]-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino]-2-ethyl-butanoate

(248) ##STR00096##

a) 2-[(6-{[(1S,2S)-2-[(Benzyloxy)methyl]cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridin-2-yl)formamido]-2-ethylbutanoic Acid

(249) ##STR00097##

(250) To a solution of 3-fluoropropyl 2-ethyl-2-[(6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridin-2-yl)formamido]butanoate (example 15 m, 20 mg, 0.04 mmol) in DMF (1.0 mL) was added benzyl bromide (7 mg, 0.04 mmol). The mixture was cooled to 0° C. and put under an argon atmosphere. Sodium hydride (3 mg, 0.08 mmol) was added. The reaction mixture was stirred at ambient temperature for 15 h, poured onto water (10 mL), acidified with aqueous HCl and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL), dried, filtered and concentrated in vacuo to obtain the title compound (20 mg, 94%) as yellow sticky mass.

(251) LCMS:

(252) Column Zorbax Ext C 18 (50×4.6 mm), 5μ, (mobile phase: from 90% [10 mM NH.sub.4OAc in water] and 10% [CH.sub.3CN] to 70% [10 mM NH.sub.4OAc in water] and 30% [CH.sub.3CN] in 1.5 min, further to 10/a [10 mM NH.sub.4OAc in water] and 90% [CH.sub.3CN] in 3.0 min, held this mobile phase composition to 4 min and finally back to initial condition in 5 min). Purity is 84.14%, Rt=0.54 min, MS calculate: 511, MS found: 512.0 [M+H.sup.+].

b) 3-Fluoropropyl 2-[[6-[[(1S,2S)-2-(benzyloxymethyl)cyclopropyl]methoxy]-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino]-2-ethyl-butanoate

(253) To a solution of 2-[(6-{[(1S,2S)-2-[(benzyloxy)methyl]cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridin-2-yl)formamido]-2-ethylbutanoic acid (20 mg, 0.04 mmol) in DMF (1.0 mL) were added K.sub.2CO.sub.3 (16 mg, 0.12 mmol) and 1-iodo-3-fluoro-propane (22 mg, 0.12 mmol). The reaction mixture was stirred for 2 h at 25° C., poured onto water and quenched with aq. 1 N HCl solution and extracted with EtOAc (3×15 mL). The combined extracts were washed with brine (10 mL), dried, filtered and concentrated in vacuo. The crude was purified by preparative TLC (20% EtOAc in hexane) to obtain the title compound (11 mg, 49%) as colorless liquid.

(254) LCMS:

(255) Column Zorbax Ext C 18 (50×4.6 mm), 5μ, (mobile phase: from 90% [10 mM NH.sub.4OAc in water] and 10% [CH.sub.3CN] to 70% [10 mM NH.sub.4OAc in water] and 30% [CH.sub.3CN] in 1.5 min, further to 10% [10 mM NH.sub.4OAc in water] and 90% [CH.sub.3CN] in 3.0 min, held this mobile phase composition to 4 min and finally back to initial condition in 5 min). Purity is 98.02%, Rt=4.07 min, MS calculate: 571, MS found: 572.1 [M+H.sup.+].

Example 33

Fluoromethyl 2-ethyl-2-[[6-[[3-(hydroxymethyl)oxetan-3-yl]methoxy]-5-pyrrolidin-1-yl-pyridine-2-carbonyl]amino]butanoate

(256) ##STR00098##

a) Methyl 6-((3-((benzyloxy)methyl)oxetan-3-yl)methoxy)-5-bromopicolinate

(257) ##STR00099##

(258) In a 250 mL three-necked flask, 5-bromo-6-chloropicolinic acid (CAN 959958-25-9, 1.8 g, 7.61 mmol, Eq: 1) was combined with DMF (100 mL) to give a colorless solution. The mixture was cooled to 0° C. and sodium hydride (913 mg, 22.8 mmol, Eq: 3) was added. The reaction mixture was stirred at 0° C. for 20 min. In a 10 mL round-bottomed flask, (3-((benzyloxy)methyl)oxetan-3-yl)methanol (CAN 142731-84-8, 2.06 g, 9.9 mmol, Eq: 1.3) was combined with DMF (10 mL) to give a colorless solution, which was slowly added to the reaction mixture. The reaction mixture was heated to 80° C. for 4 h and cooled to ambient temperature. Methyl iodide (3.24 g, 1.43 mL, 22.8 mmol, Eq: 3) was added and stirring was continued for 18 h. The solvent was removed under reduced pressure. The residue was diluted with EtOAc (100 mL) and water (100 mL). The layers were separated and the aqueous phase was extracted with EtOAc (2×40 mL). The combined organic layers were washed with brine (1×100 mL), dried over Na.sub.2SO.sub.4, filtered and brought to dryness under reduced pressure. The crude product was purified by column chromatography (SiO.sub.2, 50 g, hept./EtOAc) to give the title compound (2.82 g, 88%) as colorless oil, MS (ISP): 424.121 [MH.sup.+].

b) Methyl 6-((3-((benzyloxy)methyl)oxetan-3-yl)methoxy)-5-(pyrrolidin-1-yl)picolinate

(259) ##STR00100##

(260) In analogy to the procedure described in example 1 c, methyl 6-((3-((benzyloxy)methyl)oxetan-3-yl)methoxy)-5-bromopicolinate was reacted with pyrrolidine to give the title compound as light brown oil, MS (ISP): 413.365 [MH.sup.+].

c) 6-((3-((Benzyloxy)methyl)oxetan-3-yl)methoxy)-5-(pyrrolidin-1-yl)picolinic acid

(261) ##STR00101##

(262) In analogy to the procedure described in example 11 a, methyl 6-((3-((benzyloxy)methyl)oxetan-3-yl)methoxy)-5-(pyrrolidin-1-yl)picolinate was hydrolyzed with KOH to give the title compound as white solid which was used in the next reaction step without further purification, MS (ISP): 399.305 [MH.sup.+].

d) Ethyl 2-(6-((3-((benzyloxy)methyl)oxetan-3-yl)methoxy)-5-(pyrrolidin-1-yl)picolinamido)-2-ethylbutanoate

(263) ##STR00102##

(264) In a 25 mL round-bottomed flask, 6-((3-((benzyloxy)methyl)oxetan-3-yl)methoxy)-5-(pyrrolidin-1-yl)picolinic acid (660 mg, 1.66 mmol, Eq: 1) was combined with DMF (10 mL) to give a light yellow solution. TBTU (532 mg, 1.66 mmol, Eq: 1) and DIPEA (856 mg, 1.16 mL, 6.63 mmol, Eq: 4) were added. Ethyl 2-amino-2-ethylbutanoate hydrochloride (CAN 1135219-29-2, 389 mg, 1.99 mmol, Eq: 1.2) was added and the reaction mixture was stirred at ambient temperature for 17 h. Additional 0.12 equivalents of ethyl 2-amino-2-ethylbutanoate hydrochloride and 0.1 equivalents of TBTU were added and stirring was continued for 2 h. The reaction mixture was diluted with EtOAc and washed with sat. NaHCO.sub.3 (3×25 mL), 1 M HCl (3×25 mL) and sat. NaCl (1×25 mL). The organic layer was dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude product was purified by column chromatography (SiO.sub.2, 50 g, hept./EtOAc) to give the title compound (587 mg, 66%) as colorless oil, MS (ISP): 540.432 [MH.sup.+].

e) Ethyl 2-ethyl-2-(6-((3-(hydroxymethyl)oxetan-3-yl)methoxy)-5-(pyrrolidin-1-yl)picolinamido)butanoate

(265) ##STR00103##

(266) In a 25 mL round-bottomed flask, ethyl 2-(6-((3-((benzyloxy)methyl)oxetan-3-yl)methoxy)-5-(pyrrolidin-1-yl)picolinamido)-2-ethylbutanoate (556 mg, 1.03 mmol, Eq: 1) was combined with ethyl acetate (5 mL) and MeOH (5 mL) to give a colorless solution. Pd/C (250 mg, 235 μmol, Eq: 0.228) was added and the reaction mixture was stirred under and atmosphere of hydrogen gas for 44 h. Another portion of Pd/C (200 mg) was added and stirring was continued under an atmosphere of hydrogen gas for 16 h. The mixture was filtered through Celite and the organic solvent was removed under reduced pressure to give the title compound (370 mg, 80%) as white solid, MS (ISP): 450.3% [MH.sup.+].

f) 2-Ethyl-2-(6-((3-(hydroxymethyl)oxetan-3-yl)methoxy)-5-(pyrrolidin-1-yl)picolinamido)butanoic Acid

(267) ##STR00104##

(268) In analogy to the procedure described in example 11 a, ethyl 2-ethyl-2-(6-((3-(hydroxymethyl)oxetan-3-yl)methoxy)-5-(pyrrolidin-1-yl)picolinamido)butanoate was hydrolyzed with KOH to give the title compound as brown oil which was used in the next reaction step without further purification.

g) Fluoromethyl 2-ethyl-2-[[6-[[3-(hydroxymethyl)oxetan-3-yl]methoxy]-5-pyrrolidin-1-yl-pyridine-2-carbonyl]amino]butanoate

(269) In analogy to the procedure described in example 11 b, 2-ethyl-2-(6-((3-(hydroxymethyl)oxetan-3-yl)methoxy)-5-(pyrrolidin-1-yl)picolinamido)butanoic acid was reacted with fluoro-iodo-methane to give the title compound as colorless oil, MS (ESI): 454.4 [MH.sup.+].

Example 34

2-Fluoroethyl 2-ethyl-2-(6-((3-(hydroxymethyl)oxetan-3-yl)methoxy)-5-(pyrrolidin-1-yl)picolinamide)butanoate

(270) ##STR00105##

(271) In analogy to the procedure described in example 11 b, 2-ethyl-2-(6-((3-(hydroxymethyl)oxetan-3-yl)methoxy)-5-(pyrrolidin-1-yl)picolinamido)butanoic acid (example 33 f) was reacted with 1-fluoro-2-iodoethane to give the title compound as colorless oil, MS (ESI): 468.4 [MH.sup.+].

Example 35

(272) 3-Fluoropropyl 2-ethyl-2-(6-((3-(hydroxymethyl)oxetan-3-yl)methoxy)-5-(pyrrolidin-1-yl)picolinamido)butanoate

(273) ##STR00106##

(274) In analogy to the procedure described in example 11 b, 2-ethyl-2-(6-((3-(hydroxymethyl)oxetan-3-yl)methoxy)-5-(pyrrolidin-1-yl)picolinamido)butanoic acid (example 33 f) was reacted with 1-iodo-3-fluoropropane to give the title compound as colorless oil, MS (ESI): 482.4 [MH.sup.+].

Example 36

(275) Pharmacological Tests

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

(277) Radioligand Binding Assay

(278) 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 MgCl2, 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 GFB 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.

(279) The compounds according to formula (I) have an activity in the above assay (Ki) between 0.5 nM and 10 μM. Particular compounds of formula (I) have an activity in the above assay (Ki) between 0.5 nM and 3 μM. Other particular compounds of formula (I) have an activity in the above assay (Ki) between 0.5 nM and 100 nM.

(280) cAMP Assay

(281) 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), 1×HT 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 μl 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 μl lysis reagent (Tris, NaCl, 1.5% Triton X100, 2.5% NP40, 10% NaN.sub.3) and 50 μl detection solutions (20 μM mAb Alexa700-cAMP 1:1, and 48 μM 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 (bandwidth 30 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 μM to 0.13 nM cAMP.

(282) 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 for reference compounds were in agreement with the values published in the scientific literature.

(283) In the foregoing assay, the compounds according to the invention have a human CB2 EC.sub.50 which is between 0.5 nM and 10 μM. Particular compounds according to the invention have a human CB2 EC.sub.50 between 0.5 nM and μM. Further particular compounds according to the invention have a human CB2 EC.sub.50 between 0.5 nM and 100 nM. They exhibit at least 10 fold selectivity against the human CB1 receptor in, either both of the radioligand and cAMP assay, or in one of these two assays.

(284) Results obtained for representative compounds of the invention are given in the following table.

(285) TABLE-US-00001 Binding assay human CB2 Ki Example [μM]  1 0.0018  2 0.0037  3 0.0005  4 0.0007  5 0.0046  6 0.013  7 0.0025  8 0.1429  9 0.0002 10 0.0082 11 0.0097 12 0.0004 13 0.0003 14 0.0114 15 0.0007 16 0.0188 17 0.3311 18 0.021 19 0.0008 20 0.5251 22 0.7551 23 0.0216 24 0.0655 25 0.0018 26 0.1295 27 4.1533 28 3.945 29 0.0109 30 0.0017 31 0.0117 32 0.2462 33 0.348 34 0.6069 35 1.388

Example A

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

(287) 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

(288) The active ingredient is sieved and mixed with microcystalline 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

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

(290) 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

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

Example C

(292) Injection solutions can have the following composition:

(293) 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

(294) 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.