NZ715284B2 - Pyridin-2-amides useful as cb2 agonists - Google Patents

Pyridin-2-amides useful as cb2 agonists Download PDF

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Publication number
NZ715284B2
NZ715284B2 NZ715284A NZ71528412A NZ715284B2 NZ 715284 B2 NZ715284 B2 NZ 715284B2 NZ 715284 A NZ715284 A NZ 715284A NZ 71528412 A NZ71528412 A NZ 71528412A NZ 715284 B2 NZ715284 B2 NZ 715284B2
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New Zealand
Prior art keywords
pyridinecarboxylic acid
amide
methyl
phenyl
chloro
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NZ715284A
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NZ715284A (en
Inventor
Caterina Bissantz
Uwe Grether
Paul Hebeisen
Atsushi Kimbara
Qingping Liu
Matthias Nettekoven
Marco Prunotto
Stephan Roever
Mark Rogersevans
Tanja Schulzgasch
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F Hoffmannla Roche Ag
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Application filed by F Hoffmannla Roche Ag filed Critical F Hoffmannla Roche Ag
Publication of NZ715284A publication Critical patent/NZ715284A/en
Publication of NZ715284B2 publication Critical patent/NZ715284B2/en

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Abstract

Provided are compounds of the general formula (I) wherein the variables are as defined in the specification. Examples of the compounds include Methyl 2-(6-(3-chlorophenyl)picolinamido)-2-methylpropanoate, 6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid piperidin-1-ylamide, 5-Chloro-6-(3-chloro-phenyl)-pyridine-2-carboxylic acid (1-methyl-1-oxazol-2-yl-ethyl)-amide and (S)-N-(3,3-Dimethyl-1-(methylamino)-1-oxobutan-2-yl)-6-phenylpicolinamide. The compounds are agonists of Cannabinoid Receptor 2 (CB2). The compounds may be useful in the treatment of pain, atherosclerosis, regulation of bone mass, inflammation, ischemia, reperfusion injury, systemic fibrosis, liver fibrosis, lung fibrosis, kidney fibrosis, chronic allograft nephropathy, congestive heart failure, myocardial infarction, systemic sclerosis, glomerulonephropathy, thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors. )-pyridine-2-carboxylic acid (1-methyl-1-oxazol-2-yl-ethyl)-amide and (S)-N-(3,3-Dimethyl-1-(methylamino)-1-oxobutan-2-yl)-6-phenylpicolinamide. The compounds are agonists of Cannabinoid Receptor 2 (CB2). The compounds may be useful in the treatment of pain, atherosclerosis, regulation of bone mass, inflammation, ischemia, reperfusion injury, systemic fibrosis, liver fibrosis, lung fibrosis, kidney fibrosis, chronic allograft nephropathy, congestive heart failure, myocardial infarction, systemic sclerosis, glomerulonephropathy, thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors.

Description

PYRIDINAMIDES USEFUL AS CB2 AGONISTS The present invention relates to organic compounds useful for therapy and/or prophylaxis in a mammal, and in particular to compounds that are preferential agonists of the Cannabinoid Receptor 2. The compound of formula (I) is particularly useful in the treatment or prophylaxis of e.g. pain, in particular chronic pain, atherosclerosis, regulation of bone mass, inflammation, ischemia, reperfusion injury, systemic fibrosis, liver fibrosis, lung fibrosis, kidney fibrosis, chronic allograft nephropathy, congestive heart failure, myocardial infarction, systemic sclerosis, glomerulonephropathy, thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors.
The invention is as defined in the claims. However, the description which follows refers to additional compounds and other subject matter outside the scope of the current claims. This description is retained for technical information.
Described herein is a compound of formula (I) N N O R 3 R 4 R 1 R 2 (I) wherein R1 is cycloalkyl, cycloalkylalkoxy, haloalkoxy, alkoxyalkoxy, phenyl, halophenyl, haloalkylphenyl, phenylalkyl, halophenylalkyl, phenylhydroxyalkyl, phenyloxyalkyl, phenylalkoxy, alkoxyphenyl, halophenyloxy, piperidinylsulfonyl, tetrahydropyranyl, 3-alkoxy-azetidinyl, tetrahydropyranylalkyl, tetrahydropyranylalkoxy, tetrahydrothiopyranyl 1,1- dioxide, 1,1-dioxo-[1,2]thiazinanyl, piperidinonyl, tetrahydrofuranylalkoxy, pyridinylalkoxy, alkyloxetanylalkoxy, hydroxylhaloalkyloxy, halophenylhydroxyalkyl, alkylsulfonyl, alkylsulfanyl or (halo)(haloalkyl)phenyl; R2 is hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, hydroxycycloalkyl, alkoxy, haloalkoxy, alkylamino, haloalkylamino, tetrahydropyranyl, 1H-pyrazolyl, pyrrolidinyl, alkylpyrrolidinyl, halopyrrolidinyl, oxopyrrolidinyl, haloazetidinyl, hydroxyazetidinyl, 1,1- dioxidoisothioazolidinyl, tetrahydrofuranyl, cycloalkylamino, hydroxyoxetanyl, alkylsulfonyl, oxetanyl, 6-oxaaza-spiro[3.3]heptyl, 3,3- difluorooxo-azetidinyl, oxo-azetidinyl or oxo-pyrrolidinyl; or R1 and R2 10 together with the ring to which they are attached form tetrahydroquinolinyl or alkyltetrahydroquinolinyl; one of R3 and R4 is hydrogen and the other one is -(CR5R 6 )m(CR7R 8 )n-R9 ; or R3 and R4 together with the nitrogen atom to which they are attached form piperidinyl, 1,1-dioxidotetrahydro-2H-thiopyranyl, thiomorpholinyl, 2-oxa aza-spiro[3.3]heptyl or 1-hydroxyalkylpyrrolidinyl; R5 and R6 are independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, phenyl, pyridazinyl, halophenyl, pyrimidinyl, alkylsulfanylalkyl and alkylsulfonylalkyl; or R5 and R6 together with the carbon atom to which they are attached form cycloalkyl, tetrahydropyranyl or oxetanyl; R7 and R8 are independently selected from hydrogen, alkyl and cycloalkyl; R9 is alkyl, hydroxyl, cyano, carboxyl, alkoxycarbonyl, alkyl[1,2,4]oxadiazolyl, oxazolyl, thiazolyl, [1,3,4]oxadiazolyl, cycloalkyl, phenyl, pyridinyl, tetrahydropyranyl, alkyl[1,2,4]thiadiazolyl, [1,2,4]thiadiazolyl, alkylaminocarbonyl, alkyltetrahydropyranyl, alkylisoxazolyl, aminocarbonyl, morpholinyl, dihydro-oxazolyl, [1,2,4]oxadiazolyl, hydroxycycloalkyl, alkoxycarbonylcycloalkyl, alkoxyalkoxy, hydroxyalkylcycloalkyl, alkoxypyridinyl, piperidinyl, hydroxypiperidinyl, hydroxyalkylpiperidinyl, isoxazolyl, azetidine-carbonyl, alkoxyalkylaminocarbonyl, cycloalkyl30 alkylaminocarbonyl, haloazetidinylcarbonyl, alkyloxopyrrolidinyl, 1,1-dioxotetrahydro-1λ6-thiophenyl, 1,1-dioxo-tetrahydro-1λ6-thiophenylamino, amino[1,2,4]oxadiazolyl, 4-alkyloxo-4,5-dihydro-[1,2,4]oxadiazolyl, nitrobenzo[1,2,5]oxadiazolyl, alkylsulfonyl, alkyl[1,2,4]thiazolyl, hydroxyalkylaminocarbonyl, oxotetrahydrofuranyl, (cycloalkylalkyl)(alkoxycarbonyl)amino, 2-oxo-[1,3]oxazinanyl, haloalkyl or hydroxypyrrolidinylaminocarbonyl; m is 0 or 1; and n is 0, 1 or 2; or a pharmaceutically acceptable salt or ester thereof.
The cannabinoid receptors are a class of cell membrane receptors belonging to the G protein-coupled receptor superfamily. There are currently two known subtypes, termed Cannabinoid Receptor 1 (CB1) and Cannabinoid Receptor 2 (CB2). The CB1 receptor is mainly expressed in the central nervous (i.e. amygdala cerebellum, hippocampus) system and to a lesser amount in the periphery. CB2, which is encoded by the CNR2 gene, is mostly expressed peripherally, on cells of the immune system, such as macrophages and T-cells (Ashton, J. C. et al. Curr Neuropharmacol 2007, 5(2), 73-80; Miller, A. M. et al. Br J Pharmacol 2008, 153(2), 299-308; Centonze, D., et al. Curr Pharm Des 2008, 14(23), 2370-42), and in the gastrointestinal system (Wright, K. L. et al. Br J Pharmacol 2008, 153(2), 263-70). The CB2 receptor is also widely distributed in the brain where it is found primarily on microglia and not neurons (Cabral, G. A. et al. Br J Pharmacol 2008, 153(2): 240-51).
The interest in CB2 receptor agonists has been steadily on the rise during the last decade (currently 30-40 patent applications/year) due to the fact that several of the early compounds have been shown to have beneficial effects in pre-clinical models for a number of human diseases including chronic pain (Beltramo, M. Mini Rev Med Chem 2009, 9(1), 11-25), atherosclerosis (Mach, F. et al. J Neuroendocrinol 2008, 20 Suppl 1, 53-7), regulation of bone mass (Bab, I. et al. Br J Pharmacol 2008, 153(2), 182-8), neuroinflammation (Cabral, G. A. et al. J Leukoc Biol 2005, 78(6), 1192-7), ischemia/reperfusion injury (Pacher, P. et al. Br J Pharmacol 2008, 153(2), 252-62), systemic fibrosis (Akhmetshina, A. et al. Arthritis Rheum 2009, 60(4), 1129-36; GarciaGonzalez, E. et al. Rheumatology (Oxford) 2009, 48(9), 1050-6), liver fibrosis (Julien, B. et al. Gastroenterology 2005, 128(3), 742-55; Munoz-Luque, J. et al. J Pharmacol Exp Ther 2008, 324(2), 475-83).
Ischemia/reperfusion (I/R) injury is the principal cause of tissue damage occurring in conditions such as stroke, myocardial infarction, cardiopulmonary bypass and other vascular surgeries, and organ transplantation, as well as a major mechanism of end-organ damage complicating the course of circulatory shock of various etiologies. All these conditions are characterized by a disruption of normal blood supply resulting in an insufficient tissue oxygenation. Re-oxygenation e.g., reperfusion is the ultimate treatment to restore normal tissue oxygenation. However the absence of oxygen and nutrients from blood creates a condition in which the restoration of circulation results in further tissue damage. The damage of reperfusion injury is due in part to the inflammatory response of damaged tissues. White blood cells, carried to the area by the newly returning blood, release a host of inflammatory factors such as interleukins as well as free radicals in response to tissue damage. The restored blood flow reintroduces oxygen within cells that damages cellular proteins, DNA, and the plasma membrane.
Remote ischemic preconditioning (RIPC) represents a strategy for harnessing the body’s endogenous protective capabilities against the injury incurred by ischemia and reperfusion. It describes the intriguing phenomenon in which transient non-lethal ischemia and reperfusion of one organ or tissue confers resistance to a subsequent episode of “lethal” ischemia reperfusion injury in a remote organ or tissue. The actual mechanism through which transient ischemia and reperfusion of an organ or tissue confers protection is currently unknown although several hypotheses have been proposed.
The humoral hypothesis proposes that the endogenous substance (such as adenosine, bradykinin, opioids, CGRP, endocannabinoids, Angiotensin I or some other as yet unidentified humoral factor) generated in the remote organ or tissue enters the blood stream and activates its respective receptor in the target tissue and thereby recruiting the various intracellular pathways of cardioprotection implicated in ischemic preconditioning.
Recent data indicates that endocannabinnoids and their receptors, in particular CB2 might be involved in pre-conditioning and contribute to prevent reperfusion injury by downregulation of the inflammatory response (Pacher, P. et al. Br J Pharmacol 2008, 153(2), 252-62). Specifically, recent studies using CB2 tool agonists demonstrated the efficacy of this concept for reducing the I/R injury in the heart (Defer, N. et al. Faseb J 2009, 23(7), 2120-30), the brain (Zhang, M. et al. J Cereb Blood Flow Metab 2007, 27(7), 1387-96), the liver (Batkai, S. et al. Faseb J 2007, 21(8), 1788-800) and the kidney (Feizi, A. et al. Exp Toxicol Pathol 2008, 60(4-5), 405-10).
Moreover, over the last few years, a growing body of literature indicates that CB2 can also be of interest in sub-chronic and chronic setting. Specific upregulation of CB1 and CB2 has been shown to be associated in animal models of chronic diseases associated with fibrosis (Garcia-Gonzalez, E. et al. Rheumatology (Oxford) 2009, 48(9), 1050-6; Yang, Y. Y. et al. Liver Int 2009, 29(5), 678-85) with a relevant expression of CB2 in myofibroblasts, the cells responsible for fibrosis progression.
Activation of CB2 receptor by selective CB2 agonist has in fact been shown to exert anti-fibrotic effect in diffuse systemic sclerosis (Garcia-Gonzalez, E. et al. Rheumatology (Oxford) 2009, 48(9), 1050-6) and CB2 receptor has emerged as a critical target in experimental dermal fibrosis (Akhmetshina, A. et al. Arthritis Rheum 2009, 60(4), 1129- 36) and in in liver pathophysiology, including fibrogenesis associated with chronic liver diseases (Lotersztajn, S. et al. Gastroenterol Clin Biol 2007, 31(3), 255-8; Mallat, A. et al.
Expert Opin Ther Targets 2007, 11(3), 403-9; Lotersztajn, S. et al. Br J Pharmacol 2008, 153(2), 286-9).
The compounds of the invention bind to and modulate the CB2 receptor and have lower CB1 receptor activity.
In the present description the term “alkyl”, alone or in combination with other groups, signifies a straight-chain or branched-chain alkyl group with 1 to 8 carbon atoms, particularly a straight or branched-chain alkyl group with 1 to 6 carbon atoms and more particularly a straight or branched-chain alkyl group with 1 to 4 carbon atoms. Examples of straight-chain and branched-chain C1-C8 alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, the isomeric pentyls, the isomeric hexyls, the isomeric heptyls and the isomeric octyls, particularly methyl, ethyl, propyl, butyl and pentyl more particularly methyl, ethyl, propyl, isopropyl, isobutyl, tert.-butyl and isopentyl.
The term “cycloalkyl”, alone or in combination with other groups, signifies a cycloalkyl ring with 3 to 8 carbon atoms and particularly a cycloalkyl ring with 3 to 6 carbon atoms. Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, cycloheptyl and cyclooctyl. Particular cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cyclopropyl, cyclobutyl and cyclopentyl are particular examples.
The term “alkoxy”, alone or in combination with other groups, signifies a group of the formula alkyl-O- in which the term "alkyl" has the previously given significance, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy, particularly methoxy and ethoxy.
The terms “cycloalkyloxy” or “cycloalkoxy”, alone or in combination with other groups, signify a group of the formula cycloalkyl-O- in which the term "cycloalkyl" has the previously given significance, such as cyclobutyloxy, cyclopentyloxy or cyclohexyloxy.
The term “phenyloxy”, alone or in combination with other groups, signifies a phenyl-O- group.
The term “oxy”, alone or in combination with other groups, signifies the -O- group.
The terms “halogen” or “halo”, alone or in combination with other groups, signifies fluorine, chlorine, bromine or iodine and particularly fluorine, chlorine or bromine, more particularly fluorine and chlorine. The term “halo”, in combination with another group, denotes the substitution of said group with at least one halogen, particularly substituted with one to five halogens, particularly one to three halogens.
The terms “haloalkyl”, “halocycloalkyl” and “haloalkoxy”, alone or in combination with other groups, denote an alkyl group, a cycloalkyl group and an alkoxy group respectively, substituted with at least one halogen, particularly substituted with one to five halogens, particularly one to three halogens. Particular “haloalkyl” are trifluoromethyl, trifluoroethyl and trifluoropropyl. Particular “haloalkoxy” is trifluoroethoxy.
The terms “halophenyl”, “halopyrrolidinyl”, “halopyridinyl” and “haloazetidinyl”, alone or in combination with other groups, denote a phenyl group, a pyrrolidinyl group, a pyridinyl group and an azetidinyl group respectively, substituted with at least one halogen, particularly substituted with one to three halogens. Particular “halophenyl” are chlorophenyl, fluorophenyl, dichlorophenyl and chlorofluorophenyl. Particular “halopyrrolidinyl” is difluoropyrrolidinyl. Particular “haloazetidinyl” is difluoroazetidinyl.
The terms “hydroxyl” or “hydroxy”, alone or in combination with other groups, signify the -OH group.
The term “carbonyl”, alone or in combination with other groups, signifies the -C(O)- group.
The term “carboxy” or “carboxyl”, alone or in combination with other groups, signifies the -COOH group.
The term “amino”, alone or in combination with other groups, signifies the primary amino group (-NH2), the secondary amino group (-NH-) or the tertiary amino group (-N-).
The term “sulfonyl”, alone or in combination, signifies the -SO2- group.
The term “sulfanyl”, alone or in combination, signifies the -SO- group.
The term “pharmaceutically acceptable salts” refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, particularly hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcystein. In addition these salts may be prepared form addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts. Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyamine resins. The compound of formula (I) can also be present in the form of zwitterions. Particularly preferred pharmaceutically acceptable salts of compounds of formula (I) are the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and methanesulfonic acid.
If one of the starting materials or compounds of formula (I) contain one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups (as described e.g. in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wutts, 3rd Ed., 1999, Wiley, New York) can be introduced before the critical step applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature. Examples of protecting groups are tert-butoxycarbonyl (Boc), 9-fluorenylmethyl carbamate (Fmoc), 2-trimethylsilylethyl carbamate (Teoc), carbobenzyloxy (Cbz) and p-methoxybenzyloxycarbonyl (Moz).
The compound of formula (I) can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.
The term “asymmetric carbon atom” means a carbon atom with four different substituents. According to the Cahn-Ingold-Prelog Convention an asymmetric carbon atom can be of the “R” or “S” configuration.
Described herein is a compound of formula (I) wherein: R1 is cycloalkyl, cycloalkylalkoxy, haloalkoxy, alkoxyalkoxy, phenyl, halophenyl, haloalkylphenyl, phenylalkyl, halophenylalkyl, phenylhydroxyalkyl, phenyloxyalkyl, phenylalkoxy, alkoxyphenyl, halophenyloxy, piperidinylsulfonyl, tetrahydropyranyl, 3-alkoxy-azetidinyl, tetrahydropyranylalkyl, tetrahydropyranylalkoxy, tetrahydrothiopyranyl 1,1- dioxide, 1,1-dioxo-[1,2]thiazinanyl, piperidinonyl, tetrahydrofuranylalkoxy or pyridinylalkoxy; R2 is hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, hydroxycycloalkyl, alkoxy, haloalkoxy, alkylamino, haloalkylamino, tetrahydropyranyl, 1H-pyrazolyl, pyrrolidinyl, alkylpyrrolidinyl, halopyrrolidinyl, oxopyrrolidinyl, haloazetidinyl, hydroxyazetidinyl, 1,1- dioxidoisothioazolidinyl, tetrahydrofuranyl, cycloalkylamino, hydroxyoxetanyl, alkylsulfonyl or oxetanyl; or R1 and R2 together with the ring to which they are attached form a tetrahydroquinolinyl or alkyltetrahydroquinolinyl; one of R3 and R4 is hydrogen and the other one is -(CR5R 6 )m(CR7R 8 )n-R9 ; or R3 and R4 together with the nitrogen atom to which they are attached form piperidinyl, 1,1-dioxidotetrahydro-2H-thiopyranyl, thiomorpholinyl, 2-oxa aza-spiro[3.3]heptyl or 1-hydroxyalkylpyrrolidinyl; R5 and R6 20 are independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl and phenyl; or R5 and R6 together with the carbon atom to which they are attached form cycloalkyl or tetrahydropyranyl; R7 and R8 are independently selected from hydrogen, alkyl and cycloalkyl; R9 25 is alkyl, hydroxyl, cyano, carboxyl, alkoxycarbonyl, alkyl[1,2,4]oxadiazolyl, oxazolyl, thiazolyl, [1,3,4]oxadiazolyl, cycloalkyl, phenyl, pyridinyl, tetrahydropyranyl, alkyl[1,2,4]thiadiazolyl, [1,2,4]thiadiazolyl, alkylaminocarbonyl, alkyltetrahydropyranyl, alkylisoxazolyl, aminocarbonyl, morpholinyl, alkylaminocarbonyl, dihydro-oxazolyl, [1,2,4]oxadiazolyl, hydroxycycloalkyl, alkoxycarbonylcycloalkyl, alkoxyalkoxy, hydroxyalkylcycloalkyl, alkoxypyridinyl, piperidinyl, hydroxypiperidinyl, hydroxyalkylpiperidinyl, isoxazolyl or piperidinyl; m is 0 or 1; and n is 0, 1 or 2; or a pharmaceutically acceptable salt or ester thereof.
Also described herein is a compound of formula (I) wherein R1 is cycloalkyl, cycloalkylalkoxy, haloalkoxy, alkoxyalkoxy, phenyl, halophenyl, haloalkylphenyl, halophenylalkyl, halophenyloxy, piperidinylsulfonyl, tetrahydropyranyl, tetrahydropyranylalkoxy, tetrahydrofuranylalkoxy or pyridinylalkoxy.
Also described herein is a compound of formula (I) wherein R1 is cycloalkyl, cycloalkylalkoxy, haloalkoxy, alkoxyalkoxy, halophenyl, halophenylalkyl, alkoxyphenyl, halophenyloxy, piperidinylsulfonyl, tetrahydropyranyl, tetrahydropyranylalkoxy or tetrahydrofuranylalkoxy.
Also described herein is a compound of formula (I) wherein R1 is cycloalkylalkoxy, halophenyl, halophenylalkyl, tetrahydropyranylmethoxy or tetrahydrofuranylalkoxy.
Also described herein is a compound of formula (I) wherein R1 is cyclopropylmethoxy, chlorophenyl, fluorophenylmethyl, fluorochlorophenyl or tetrahydrofuranylalkoxy.
Also described herein is a compound of formula (I) wherein R2 is hydrogen, halogen, alkyl, haloalkyl, cycloalkyl, hydroxycycloalkyl, alkoxy, haloalkylamino, tetrahydropyranyl, 1H-pyrazolyl, pyrrolidinyl, alkylpyrrolidinyl, halopyrrolidinyl, oxopyrrolidinyl, haloazetidinyl, hydroxyazetidinyl, 1,1-dioxidoisothioazolidinyl, tetrahydrofuranyl, cycloalkylamino or hydroxyoxetanyl is of particular interest.
Also described herein is a compound of formula (I) wherein R2 is hydrogen, alkyl, haloalkyl, cycloalkyl, haloalkylamino, tetrahydropyranyl, pyrrolidinyl, alkylpyrrolidinyl, halopyrrolidinyl, haloazetidinyl, tetrahydrofuranyl or cycloalkylamino is of further particular interest.
Also described herein is a compound of formula (I) wherein R2 is hydrogen, methyl, trifluoromethyl, cyclopropyl, cyclopentyl, bis(trifluoroethyl)amino, tetrahydropyranyl, pyrrolidinyl, methylpyrrolidinyl, difluoropyrrolidinyl, difluoroazetidinyl, tetrahydrofuranyl or cyclopropylamino is a particular embodiment of the invention.
Also described herein is a compound of formula (I) wherein R1 and R2 30 together with the ring to which they are attached form dimethyltetrahydroquinolinyl is a further particular embodiment of the invention.
Also described herein is a compound of formula (I) wherein R5 and R6 are independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, trifluoromethyl, cyclopropyl, cyclopropylmethyl and phenyl or R5 and R6 together with the carbon atom to which they are attached form cyclobutyl or tetrahydropyranyl.
Also described herein is a compound of formula (I) wherein R7 and R8 5 are independently selected from hydrogen and methyl.
Also described herein is a compound of formula (I) wherein R9 is hydroxyl, cyano, carboxyl, alkoxycarbonyl, alkyl[1,2,4]oxadiazolyl, oxazolyl, thiazolyl, [1,3,4]oxadiazolyl, cycloalkyl, phenyl, pyridinyl, tetrahydropyranyl, alkyl[1,2,4]thiadiazolyl, alkylaminocarbonyl, alkyltetrahydropyranyl, alkylisoxazolyl, aminocarbonyl, morpholinyl, alkylaminocarbonyl, dihydro-oxazolyl, [1,2,4]oxadiazolyl, hydroxycycloalkyl, alkoxycarbonylcycloalkyl, alkoxyalkoxy, hydroxyalkylcycloalkyl or piperidinyl.
Also described herein is a compound of formula (I) wherein R9 is hydroxyl, carboxyl, alkyl[1,2,4]oxadiazolyl, thiazolyl, alkylaminocarbonyl, aminocarbonyl, morpholinyl, alkoxyalkoxy or piperidinyl is a particular embodiment of the invention.
Also described herein is a compound of formula (I) wherein R9 is hydroxyl, methyl[1,2,4]oxadiazolyl, thiazolyl, methylaminocarbonyl, aminocarbonyl, morpholinyl, methoxymethoxy or piperidinyl is another particular embodiment of the invention.
In a first aspect, the invention provides: a compound selected from Methyl 2-(6-(3-chlorophenyl)picolinamido)methylpropanoate; Methyl 2-(6-(2-chlorophenyl)picolinamido)methylpropanoate; 6-(4-Chloro-phenyl)-pyridinecarboxylic acid [1-methyl(5-methyl25 [1,2,4]oxadiazolyl)-ethyl]-amide; Methyl 2-(5-cyclopropyl(2,4-dichlorophenylamino)picolinamido) methylpropanoate; Methyl 2-(6-(2,4-dichlorophenylamino)methylpicolinamido) methylpropanoate; 6-(3-Chloro-phenyl)-pyridinecarboxylic acid (1-methyloxazolyl-ethyl)- amide; 6-(3-Chloro-phenyl)-pyridinecarboxylic acid piperidinylamide; 6-(3-Chloro-phenyl)-pyridinecarboxylic acid (1-methylthiazolyl-ethyl)- amide; 6-(3-Chloro-phenyl)-pyridinecarboxylic acid (1-methyl[1,3,4]oxadiazolylethyl)-amide; 6-(3-Chloro-phenyl)-pyridinecarboxylic acid cyclohexylamide; 6-(3-Chloro-phenyl)-pyridinecarboxylic acid phenylamide; 6-(3-Chloro-phenyl)-pyridinecarboxylic acid pyridinylamide; 6-(3-Chloro-phenyl)-pyridinecarboxylic acid (tetrahydro-pyranyl)-amide; 6-(3-Chloro-phenyl)-pyridinecarboxylic acid [1-methyl(3-methyl- [1,2,4]thiadiazolyl)-ethyl]-amide; 6-(3-Chloro-phenyl)-pyridinecarboxylic acid (1-dimethylcarbamoylethyl15 propyl)-amide; 6-(3-Chloro-phenyl)-pyridinecarboxylic acid (2-methyl-tetrahydro-pyranyl)- amide; 6-(3-Chloro-phenyl)-pyridinecarboxylic acid [1-methyl(3-methyl-isoxazol yl)-ethyl]-amide; 6-(3-Chloro-phenyl)-pyridinecarboxylic acid (1-ethylhydroxymethyl-propyl)- amide; 6-(3-Chloro-phenyl)-pyridinecarboxylic acid (tetrahydro-pyranyl)-amide; 6-(3-Chloro-phenyl)-pyridinecarboxylic acid [(S)cyclopropyl(5-methyl- [1,2,4]oxadiazolyl)-ethyl]-amide; 6-(3-Chloro-phenyl)-pyridinecarboxylic acid [1-methyl(5-methyl- [1,2,4]oxadiazolyl)-ethyl]-amide; 6-(4-Chloro-phenyl)-pyridinecarboxylic acid piperidinylamide; [6-(3-Chloro-phenyl)cyclopropyl-pyridinyl]-(1,1-dioxidotetrahydro-2Hthiopyranyl)-methanone; 6-(3-Chloro-phenyl)methyl-pyridinecarboxylic acid (1-methyloxazolylethyl)-amide; 6-(3-Chloro-phenyl)methyl-pyridinecarboxylic acid (1-methylthiazolylethyl)-amide; 6-(3-Chloro-phenyl)methyl-pyridinecarboxylic acid [1-methyl(5-methyl- [1,2,4]oxadiazolyl)-ethyl]-amide; 6-(3-Chloro-phenyl)methyl-pyridinecarboxylic acid piperidinylamide; 6-(3-Chloro-phenyl)-pyridinecarboxylic acid ((S)methylthiazolyl-butyl)- amide; -Chloro(3-chloro-phenyl)-pyridinecarboxylic acid (1-methylthiazolylethyl)-amide; 6-(3-Chloro-phenyl)-pyridinecarboxylic acid ((S)cyclopropylthiazolyl15 ethyl)-amide; -Chloro(3-chloro-phenyl)-pyridinecarboxylic acid piperidinylamide; 6-(3-Chloro-phenyl)cyclopropyl-pyridinecarboxylic acid (1-methyl methylcarbamoyl-ethyl)-amide; 6-(3-Chloro-phenyl)methyl-pyridinecarboxylic acid (1-ethyl methylcarbamoyl-propyl)-amide; 6-(3-Chloro-phenyl)cyclopropyl-pyridinecarboxylic acid (1-ethyl methylcarbamoyl-propyl)-amide; 6-(3-Chloro-phenyl)-pyridinecarboxylic acid (1-methyl[1,2,4]oxadiazolylethyl)-amide; 6-(4-Chloro-phenyl)-pyridinecarboxylic acid (1-ethylmethylcarbamoylpropyl)-amide; 6-(3-Chloro-phenyl)methoxy-pyridinecarboxylic acid (1-ethyl methylcarbamoyl-propyl)-amide; 6-(3-Chloro-phenyl)methoxy-pyridinecarboxylic acid (1-methylthiazol yl-ethyl)-amide; -Chloro(3-chloro-phenyl)-pyridinecarboxylic acid (1-methyl [1,2,4]oxadiazolyl-ethyl)-amide; 6-(3-Chloro-phenyl)methoxy-pyridinecarboxylic acid [1-methyl(5-methyl- [1,2,4]oxadiazolyl)-ethyl]-amide; 6-(3-Chloro-phenyl)methoxy-pyridinecarboxylic acid (1-methyloxazolylethyl)-amide; -Chloro(3-chloro-phenyl)-pyridinecarboxylic acid (1-ethyl methylcarbamoyl-propyl)-amide; 6-(3-Chloro-phenyl)cyclopropyl-pyridinecarboxylic acid (1-methyloxazol2-yl-ethyl)-amide; 6-(3-Chloro-phenyl)cyclopropyl-pyridinecarboxylic acid [1-methyl(5- methyl-[1,2,4]oxadiazolyl)-ethyl]-amide; 6-(3-Chloro-phenyl)cyclopropyl-pyridinecarboxylic acid ((S)carbamoyl cyclopropyl-ethyl)-amide; 6-(3-Chloro-phenyl)(tetrahydro-furanyl)-pyridinecarboxylic acid (1-methyl1-thiazolyl-ethyl)-amide; -Chloro(3-chloro-phenyl)-pyridinecarboxylic acid (1-methyloxazolyl20 ethyl)-amide; -Chloro(3-chloro-phenyl)-pyridinecarboxylic acid ((S)carbamoyl methyl-butyl)-amide; 6-(3-Chloro-phenyl)cyclopentyl-pyridinecarboxylic acid [1-methyl(5- methyl-[1,2,4]oxadiazolyl)-ethyl]-amide; 6-(3-Chloro-phenyl)cyclopropyl-pyridinecarboxylic acid (1-methylthiazol2-yl-ethyl)-amide; 6-(3-Chloro-phenyl)(tetrahydro-furanyl)-pyridinecarboxylic acid [1-methyl1-(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide; 6-(3-Chloro-phenyl)(tetrahydro-furanyl)-pyridinecarboxylic acid (1-methyl1-oxazolyl-ethyl)-amide; 6-(3-Chloro-phenyl)(tetrahydro-furanyl)-pyridinecarboxylic acid (1-methyl1-thiazolyl-ethyl)-amide; 6-(3-Chloro-phenyl)cyclopentyl-pyridinecarboxylic acid (1-methylthiazol2-yl-ethyl)-amide; 6-(3-Chloro-phenyl)(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid ((S)- 1-carbamoylmethyl-butyl)-amide; 6-(3-Chloro-phenyl)(tetrahydro-furanyl)-pyridinecarboxylic acid [1-methyl10 1-(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide; 6-(3-Chloro-phenyl)(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid [2-(2- methoxy-ethoxy)-1,1-dimethyl-ethyl]-amide; 6-(3-Chloro-phenyl)(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (1- methylthiazolyl-ethyl)-amide; 6-(3-Chloro-phenyl)(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid [(S)- 2-cyclopropyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide; (S)(3-chlorophenyl)-N-(3,3-dimethyl(methylamino)oxobutan yl)picolinamide; (S)(3-chlorophenyl)-N-(4,4-dimethyl(methylamino)oxopentan yl)picolinamide; (S)-N-(3,3-Dimethyl(methylamino)oxobutanyl)phenylpicolinamide; (S)-N-(4-Methyl(methylamino)oxopentanyl)phenylpicolinamide; (S)(3-Fluorophenyl)-N-(4-methyl(methylamino)oxopentanyl) picolinamide; (S)(3-Chlorofluorophenyl)-N-(4-methyl(methylamino)oxopentan yl)picolinamide; (S)-N-(3,3-Dimethyl(methylamino)oxobutanyl)(3-fluorophenyl) picolinamide; (S)-N-(3,3-Dimethyl(methylamino)oxobutanyl)(3-methoxyphenyl) picolinamide; (S)(3-Chlorofluorophenyl)-N-(3,3-dimethyl(methylamino)oxobutan yl)picolinamide; 6-(3-Chlorofluoro-phenyl)-pyridinecarboxylic acid [cyclopropyl-(5-methyl- [1,2,4]oxadiazolyl)-methyl]-amide; 6-(3-Chlorofluoro-phenyl)-pyridinecarboxylic acid [(-)-cyclopropyl-(5-methyl- [1,2,4]oxadiazolyl)-methyl]-amide; 6-(3-Chlorofluoro-phenyl)-pyridinecarboxylic acid [(+)-cyclopropyl-(5- methyl-[1,2,4]oxadiazolyl)-methyl]-amide; 6-(4-Chlorofluoro-phenyl)-pyridinecarboxylic acid [1-methyl(5-methyl- [1,2,4]oxadiazolyl)-ethyl]-amide; 6-(3-Chlorofluoro-phenyl)-pyridinecarboxylic acid [1-methyl(5-methyl- [1,2,4]oxadiazolyl)-ethyl]-amide; 6-(3-Chlorofluoro-phenyl)-pyridinecarboxylic acid [(S)cyclopropyl(5- methyl-[1,2,4]oxadiazolyl)-ethyl]-amide; and 6-(3-Fluoro-phenyl)-pyridinecarboxylic acid [(S)cyclopropyl(5-methyl- [1,2,4]oxadiazolyl)-ethyl]-amide.
Also described herein are the following: A compound of formula (I) wherein wherein R1 20 is cycloalkyl, cycloalkylalkoxy, haloalkoxy, alkoxyalkoxy, phenyl, halophenyl, haloalkylphenyl, halophenylalkyl, halophenyloxy, piperidinylsulfonyl, tetrahydropyranyl, tetrahydropyranylalkoxy, tetrahydrofuranylalkoxy, pyridinylalkoxy, hydroxyhaloalkyloxy, halophenylhydroxyalkyl, alkylsulfanyl or alkylsulfonyl; A compound of formula (I) wherein R1 25 is cycloalkyl, cycloalkylalkoxy, haloalkoxy, alkoxyalkoxy, halophenyl, halophenylalkyl, alkoxyphenyl, halophenyloxy, piperidinylsulfonyl, tetrahydropyranyl, tetrahydropyranylalkoxy, tetrahydrofuranylalkoxy, hydroxyhaloalkyloxy, halophenylhydroxyalkyl, alkylsulfanyl or alkylsulfonyl; A compound of formula (I) wherein R1 is cycloalkylalkoxy, halophenyl, halophenylalkyl, tetrahydropyranylalkoxy, tetrahydrofuranylalkoxy, haloalkoxy, hydroxylhaloalkyloxy, halophenylhydroxyalkyl, alkylsulfanyl or alkylsulfonyl; A compound of formula (I) wherein R1 is cyclopropylmethoxy, chlorophenyl, fluorophenylmethyl, fluorochlorophenyl, tetrahydropyranylmethoxy, tetrahydrofuranylmethoxy, pentafluoropopyloxy, trifluorohydroxybutyloxy, fluorophenylhydroxymethyl, butylsulfanyl or butylsulfonyl; A compound of formula (I) wherein R2 is hydrogen, halogen, alkyl, haloalkyl, cycloalkyl, hydroxycycloalkyl, alkoxy, haloalkylamino, tetrahydropyranyl, 1H-pyrazolyl, pyrrolidinyl, alkylpyrrolidinyl, halopyrrolidinyl, oxopyrrolidinyl, haloazetidinyl, hydroxyazetidinyl, 1,1-dioxidoisothioazolidinyl, tetrahydrofuranyl, cycloalkylamino, hydroxyoxetanyl or 6-oxaaza-spiro[3.3]heptyl; A compound of formula (I) wherein R2 is hydrogen, alkyl, haloalkyl, cycloalkyl, haloalkylamino, tetrahydropyranyl, pyrrolidinyl, alkylpyrrolidinyl, halopyrrolidinyl, haloazetidinyl, tetrahydrofuranyl, cycloalkylamino or 6-oxaaza-spiro[3.3]heptyl; A compound of formula (I) wherein R2 is hydrogen, methyl, trifluoromethyl, cyclopropyl, cyclopentyl, bis(trifluoroethyl)amino, tetrahydropyranyl, pyrrolidinyl, methylpyrrolidinyl, difluoropyrrolidinyl, difluoroazetidinyl, tetrahydrofuranyl or cyclopropylamino or 6-oxaaza-spiro[3.3]heptyl; A compound of formula (I) wherein R5 and R6 20 are independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, trifluoromethyl, cyclopropyl, cyclopropylmethyl, phenyl, fluorophenyl and pyridazinyl, or R5 and R6 together with the carbon atom to which they are attached form cyclobutyl, tetrahydropyranyl or cyclopropyl; A compound of formula (I) wherein R9 is hydroxyl, cyano, carboxyl, alkoxycarbonyl, alkyl[1,2,4]oxadiazolyl, oxazolyl, thiazolyl, [1,3,4]oxadiazolyl, cycloalkyl, phenyl, pyridinyl, tetrahydropyranyl, alkyl[1,2,4]thiadiazolyl, alkylaminocarbonyl, alkyltetrahydropyranyl, alkylisoxazolyl, aminocarbonyl, morpholinyl, dihydro-oxazolyl, [1,2,4]oxadiazolyl, hydroxycycloalkyl, alkoxycarbonylcycloalkyl, alkoxyalkoxy, hydroxyalkylcycloalkyl, piperidinyl, haloazetidinylcarbonyl, nitro30 benzo[1,2,5]oxadiazolyl or alkyl; A compound of formula (I) wherein R9 is hydroxyl, carboxyl, alkyl[1,2,4]oxadiazolyl, thiazolyl, alkylaminocarbonyl, aminocarbonyl, morpholinyl, alkoxyalkoxy, piperidinyl, cyano, pyridinyl, haloazetidinylcarbonyl, nitrobenzo[1,2,5]oxadiazolyl, alkoxycarbonyl or alkyl; A compound of formula (I) wherein R9 is hydroxyl, methyl[1,2,4]oxadiazolyl, thiazolyl, methylaminocarbonyl, aminocarbonyl, morpholinyl, methoxymethoxy piperidinyl, cyano, pyridinyl, nitro-benzo[1,2,5]oxadiazolyl, dimethylaminocarbonyl, methoxycarbonyl, N-methyl-N-ethylaminocarbonyl, difluoroazetidinylcarbonyl or methyl; A compound of formula (I) wherein m is 1; and A compound of formula (I) wherein n is 0.
Also described herein are the following compounds of formula (I): -Cyclopropyl(tetrahydro-pyranylmethoxy)-pyridinecarboxylic acid [cyclopropyl- (5-methyl-[1,2,4]oxadiazolyl)-methyl]-amide; 2-({5-[Bis-(2,2,2-trifluoro-ethyl)-amino]cyclopropylmethoxy-pyridinecarbonyl}- amino)ethyl-butyric acid methyl ester; 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazolyl)-methyl]-amide; -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid ((S)cyclopropyl dimethylcarbamoyl-ethyl)-amide; -Cyclopropyl(tetrahydro-pyranylmethoxy)-pyridinecarboxylic acid (2,2,2- trifluoropyridinyl-ethyl)-amide; 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (2,2,2- trifluoropyridinyl-ethyl)-amide; 5-Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid ((-)-methylcarbamoylphenyl-methyl)-amide; -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid ((+)-dimethylcarbamoylphenyl-methyl)-amide; -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid ((-)-dimethylcarbamoyl25 phenyl-methyl)-amide; 6-Cyclopropylmethoxytrifluoromethyl-pyridinecarboxylic acid ((S)-3,3-dimethyl methylcarbamoyl-butyl)-amide; 6-Cyclopropylmethoxytrifluoromethyl-pyridinecarboxylic acid [cyclopropyl-(5- methyl-[1,2,4]oxadiazolyl)-methyl]-amide; 6-(Tetrahydro-pyranylmethoxy)trifluoromethyl-pyridinecarboxylic acid ((S)-3,3- dimethylmethylcarbamoyl-butyl)-amide; -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid ((S) dimethylcarbamoylmethyl-butyl)-amide; 6-(3-Chlorofluoro-phenyl)-pyridinecarboxylic acid [cyclopropyl-(5-methyl- [1,2,4]oxadiazolyl)-methyl]-amide; 2-{[5-Cyclopropyl(tetrahydro-furanylmethoxy)-pyridinecarbonyl]-amino} ethyl-butyric acid methyl ester; 6-Cyclopropylmethoxy(6-oxaaza-spiro[3.3]heptyl)-pyridinecarboxylic acid ((S)-3,3-dimethylmethylcarbamoyl-butyl)-amide; 6-Cyclopropylmethoxy(6-oxaaza-spiro[3.3]heptyl)-pyridinecarboxylic acid [1- methyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide; 6-Cyclopropylmethoxy(6-oxaaza-spiro[3.3]heptyl)-pyridinecarboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazolyl)-methyl]-amide; 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid ((R)- 2,2,2-trifluoropyridinyl-ethyl)-amide; 2-Ethyl{[6-(tetrahydro-pyranylmethoxy)trifluoromethyl-pyridinecarbonyl]- amino}-butyric acid methyl ester; (S)[(5-Cyclopropylcyclopropylmethoxy-pyridinecarbonyl)-amino]-3,3-dimethyl20 butyric acid methyl ester; -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid ((S)-2,2,2-trifluoro pyridinyl-ethyl)-amide; -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [(-)(5-methyl- [1,2,4]oxadiazolyl)-ethyl]-amide; 5-Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [(+)methyl(5- methyl-[1,2,4]oxadiazolyl)-butyl]-amide; -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [(-)methyl(5- methyl-[1,2,4]oxadiazolyl)-butyl]-amide; -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [(+)(5-methyl- [1,2,4]oxadiazolyl)-propyl]-amide; -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [(-)(5-methyl- [1,2,4]oxadiazolyl)-propyl]-amide; 5-Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid ((-)-cyano-methylmethyl)-amide; -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid ((-)cyanomethylbutyl)-amide; -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid ((+)-cyano-cyclopropyl10 methyl)-amide; 2-[(6-Cyclopropylmethoxytrifluoromethyl-pyridinecarbonyl)-amino]ethyl-butyric acid methyl ester; -Cyclopropyl(tetrahydro-furanylmethoxy)-pyridinecarboxylic acid (1-ethyl methylcarbamoyl-propyl)-amide; 2-[(5-Cyclopropylcyclopropylmethoxy-pyridinecarbonyl)-amino]ethyl-butyric acid methyl ester; 2-[(6-Cyclopropylmethoxytrifluoromethyl-pyridinecarbonyl)-amino]ethyl-butyric acid; 6-(Tetrahydro-pyranylmethoxy)trifluoromethyl-pyridinecarboxylic acid (1-ethyl20 1-methylcarbamoyl-propyl)-amide; 2-Ethyl{[6-(tetrahydro-furanylmethoxy)trifluoromethyl-pyridinecarbonyl]- amino}-butyric acid ethyl ester; 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (dimethylcarbamoyl-phenyl-methyl)-amide; 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid ((S) cyclopropyldimethylcarbamoyl-ethyl)-amide; 2-[(5-Cyclopropylcyclopropylmethoxy-pyridinecarbonyl)-amino]ethyl-butyric acid ethyl ester; (S)Cyclopropyl[(5-cyclopropylcyclopropylmethoxy-pyridinecarbonyl)-amino]- propionic acid methyl ester; 6-Cyclopropylmethoxytrifluoromethyl-pyridinecarboxylic acid (1-ethyl methylcarbamoyl-propyl)-amide; 6-(3-Chlorofluoro-phenyl)-pyridinecarboxylic acid [(-)-cyclopropyl-(5-methyl- [1,2,4]oxadiazolyl)-methyl]-amide; 6-(3-Chlorofluoro-phenyl)-pyridinecarboxylic acid [(+)-cyclopropyl-(5-methyl- [1,2,4]oxadiazolyl)-methyl]-amide; 6-(Tetrahydro-pyranylmethoxy)trifluoromethyl-pyridinecarboxylic acid (1- dimethylcarbamoylethyl-propyl)-amide; 2-{[6-Cyclopropylmethoxy(6-oxaaza-spiro[3.3]heptyl)-pyridinecarbonyl]- amino}ethyl-butyric acid ethyl ester; 6-(Tetrahydro-furanylmethoxy)trifluoromethyl-pyridinecarboxylic acid (1- dimethylcarbamoylethyl-propyl)-amide; 2-[(5-Bromocyclopropylmethoxy-pyridinecarbonyl)-amino]ethyl-butyric acid ethyl ester; 2-{[6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarbonyl]-amino} ethyl-butyric acid ethyl ester; 6-(4-Chlorofluoro-phenyl)-pyridinecarboxylic acid [1-methyl(5-methyl20 [1,2,4]oxadiazolyl)-ethyl]-amide; 6-(3-Chlorofluoro-phenyl)-pyridinecarboxylic acid [1-methyl(5-methyl- [1,2,4]oxadiazolyl)-ethyl]-amide; 2-{[6-Cyclopropylmethoxy(3,3-difluorooxo-azetidinyl)-pyridinecarbonyl]- amino}ethyl-butyric acid methyl ester; (S)[(5-Cyclopropylcyclopropylmethoxy-pyridinecarbonyl)-amino]methylpentanoic acid methyl ester; 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (1- cyanomethyl-butyl)-amide; 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid [3- methyl(5-methyl-[1,2,4]oxadiazolyl)-butyl]-amide; 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (1- hydroxymethyl-1,3-dimethyl-butyl)-amide; 5-Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [1-(azetidine carbonyl)ethyl-propyl]-amide; -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [1-ethyl(2-methoxyethylcarbamoyl)-propyl]-amide; -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [1-ethyl(ethyl10 methyl-carbamoyl)-propyl]-amide; 6-(4-Fluoro-benzyl)-pyridinecarboxylic acid ((S)carbamoylmethyl-butyl)-amide; 6-(4-Fluoro-benzyl)-pyridinecarboxylic acid ((R)-2,2,2-trifluoropyridinyl-ethyl)- amide; -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid ((S)hydroxymethyl15 1,2-dimethyl-propyl)-amide; -Bromo(3-methyl-oxetanylmethoxy)-pyridinecarboxylic acid (1-methyl thiazolyl-ethyl)-amide; -Bromo(3-methyl-oxetanylmethoxy)-pyridinecarboxylic acid (3-thiazolyloxetanyl)-amide; 5-Bromo(2,2,2-trifluoro-ethoxy)-pyridinecarboxylic acid (3-thiazolyl-oxetan yl)-amide; -Bromo(3-methyl-oxetanylmethoxy)-pyridinecarboxylic acid (2,2,2-trifluoro pyridinyl-ethyl)-amide; -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [1-(cyclopropylmethyl25 carbamoyl)ethyl-propyl]-amide; -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid (1-methylpyridin yl-ethyl)-amide; 6-(4-Fluoro-benzyl)-pyridinecarboxylic acid ((S)-3,3-dimethylmethylcarbamoylbutyl)-amide; -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [1-(3,3-difluoroazetidinecarbonyl)ethyl-propyl]-amide; -(3,3-Difluoro-azetidinyl)(2,2,2-trifluoro-ethoxy)-pyridinecarboxylic acid (1- methylthiazolyl-ethyl)-amide; 2-[(6-Cyclopropylmethoxypyrrolidinyl-pyridinecarbonyl)-amino]ethyl-butyric acid ethyl ester; 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (1- methyloxo-pyrrolidinyl)-amide; 2-[(6-Cyclopropylmethoxypyrrolidinyl-pyridinecarbonyl)-amino]ethyl-butyric acid; 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (1,1- dioxo-tetrahydro-1λ6 -thiophenyl)-amide; 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid N'-(1,1- dioxo-tetrahydro-1λ6 -thiophenyl)-hydrazide; 5-Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [1-methyl(4-methylthiazolyl)-ethyl]-amide; -(3,3-Difluoro-azetidinyl)(3-methyl-oxetanylmethoxy)-pyridinecarboxylic acid (1-methylthiazolyl-ethyl)-amide; -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [1-(5-amino20 [1,2,4]oxadiazolyl)methyl-ethyl]-amide; 6-(2,2,3,3,3-Pentafluoro-propoxy)-pyridinecarboxylic acid (1-ethyl methylcarbamoyl-propyl)-amide; -Cyclopropyl(2,2,3,3,3-pentafluoro-propoxy)-pyridinecarboxylic acid (1-ethyl methylcarbamoyl-propyl)-amide; 5-Cyclopropyl(2,2,3,3,3-pentafluoro-propoxy)-pyridinecarboxylic acid ((S)-3,3- dimethylmethylcarbamoyl-butyl)-amide; -Cyclopropyl(2,2,3,3,3-pentafluoro-propoxy)-pyridinecarboxylic acid [(S) cyclopropyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide; -Cyclopropyl(2,2,2-trifluoro-ethoxy)-pyridinecarboxylic acid ((S)-carbamoylphenyl-methyl)-amide; -Cyclopropyl(2,2,2-trifluoro-ethoxy)-pyridinecarboxylic acid (2,2,2-trifluoro pyridinyl-ethyl)-amide; 5-Cyclopropyl(2,2,2-trifluoro-ethoxy)-pyridinecarboxylic acid ((S) hydroxymethylmethyl-butyl)-amide; -Cyclopropyl(2,2,2-trifluoro-ethoxy)-pyridinecarboxylic acid (3-thiazolyloxetanyl)-amide; -Cyclopropyl(2,2,2-trifluoro-ethoxy)-pyridinecarboxylic acid (1-methylthiazol10 2-yl-ethyl)-amide; -Cyclopropyl(2,2,2-trifluoro-ethoxy)-pyridinecarboxylic acid (2,2-dimethyl thiazolyl-propyl)-amide; 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid [1-(3,3- difluoro-azetidinecarbonyl)ethyl-propyl]-amide; 6-(4-Fluoro-benzyl)-pyridinecarboxylic acid N'-(1,1-dioxo-tetrahydro-1λ6 15 -thiophen yl)-hydrazide; -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [1-(3-amino- [1,2,4]oxadiazolyl)methyl-ethyl]-amide; 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid [(S) (3,3-difluoro-azetidinecarbonyl)-2,2-dimethyl-propyl]-amide; 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid [(S) (3,3-difluoro-azetidinecarbonyl)methyl-butyl]-amide; 2-[(6-Cyclopropylmethoxytrifluoromethyl-pyridinecarbonyl)-amino]ethyl-butyric acid ethyl ester; 5-Cyclopropyl((R)hydroxytrifluoromethyl-propoxy)-pyridinecarboxylic acid (1-ethylmethylcarbamoyl-propyl)-amide; -Cyclopropyl((R)-4,4,4-trifluorohydroxy-butoxy)-pyridinecarboxylic acid (1- ethylmethylcarbamoyl-propyl)-amide; 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (3- methylpyridinyl-butyl)-amide; 6-Cyclopropylmethoxytrifluoromethyl-pyridinecarboxylic acid [1-(3,3-difluoroazetidinecarbonyl)ethyl-propyl]-amide; 6-[(4-Fluoro-phenyl)-hydroxy-methyl]-pyridinecarboxylic acid ((S)carbamoyl methyl-butyl)-amide; 6-[(4-Fluoro-phenyl)-hydroxy-methyl]-pyridinecarboxylic acid [(S)methyl(5- methyl-[1,2,4]oxadiazolyl)-butyl]-amide; -Cyclopropyl((S)hydroxytrifluoromethyl-propoxy)-pyridinecarboxylic acid (1-ethylmethylcarbamoyl-propyl)-amide; -Cyclopropyl((S)-4,4,4-trifluorohydroxy-butoxy)-pyridinecarboxylic acid (1- ethylmethylcarbamoyl-propyl)-amide; 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (3- methylpyridazinyl-butyl)-amide; 6-Cyclopropylmethoxy(3-oxo-azetidinyl)-pyridinecarboxylic acid [1-methyl(5- methyl-[1,2,4]oxadiazolyl)-ethyl]-amide; -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [(+)cyclopropyl(5- methyl-[1,2,4]oxadiazolyl)-ethyl]-amide; -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [(-)cyclopropyl(5- methyl-[1,2,4]oxadiazolyl)-ethyl]-amide; 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (3- methylpyridinyl-butyl)-amide; -Cyclopropyl(4-fluoro-benzyl)-pyridinecarboxylic acid ((S)carbamoyl cyclopropyl-ethyl)-amide; 5-Cyclopropyl(4-fluoro-benzyl)-pyridinecarboxylic acid [(S)cyclopropyl(5- methyl-[1,2,4]oxadiazolyl)-ethyl]-amide; -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [(S)-carbamoyl-(4- fluoro-phenyl)-methyl]-amide; -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [(S)-carbamoyl-(4- chloro-phenyl)-methyl]-amide; 6-(2-Methyl-propanesulfonyl)-pyridinecarboxylic acid ((S)carbamoylmethylbutyl)-amide; 6-Isobutylsulfanyl-pyridinecarboxylic acid ((S)carbamoylmethyl-butyl)-amide; -Cyclopropyl(4-fluoro-benzyl)-pyridinecarboxylic acid ((S)-2,2,2-trifluoro pyridinyl-ethyl)-amide; 2-{[5-Cyclopropyl(4-fluoro-benzyl)-pyridinecarbonyl]-amino}ethyl-butyric acid; 6-Cyclopropylmethoxy(3-oxo-pyrrolidinyl)-pyridinecarboxylic acid [1-methyl (5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide; 6-(2-Methyl-propanesulfonyl)-pyridinecarboxylic acid [(S)methyl(5-methyl- [1,2,4]oxadiazolyl)-butyl]-amide; (S){[5-Cyclopropyl(4-fluoro-benzyl)-pyridinecarbonyl]-amino}methylpentanoic acid; 2-{[5-Cyclopropyl(tetrahydro-pyranylmethoxy)-pyridinecarbonyl]-amino} ethyl-butyric acid; -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [1-methyl(4-methyl5-oxo-4,5-dihydro-[1,2,4]oxadiazolyl)-ethyl]-amide; 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (3- methylpyrimidinyl-butyl)-amide; 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid [1- cyclopropyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide; 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid [2- cyclopropylmethyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide; 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid ((S) carbamoylmethylsulfanyl-propyl)-amide; 6-(3-Chlorofluoro-phenyl)-pyridinecarboxylic acid [(S)cyclopropyl(5-methyl- [1,2,4]oxadiazolyl)-ethyl]-amide; 6-Cyclopropylmethoxypyrrolidinyl-pyridinecarboxylic acid {(S)methyl[(7- nitro-benzo[1,2,5]oxadiazolylamino)-methyl]-butyl}-amide; 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid ((S) carbamoylmethanesulfonyl-propyl)-amide; 5-Cyclopropylisobutylsulfanyl-pyridinecarboxylic acid ((S)carbamoylmethylbutyl)-amide; 6-(3-Fluoro-phenyl)-pyridinecarboxylic acid [(S)cyclopropyl(5-methyl- [1,2,4]oxadiazolyl)-ethyl]-amide; 6-(4-Fluorotrifluoromethyl-phenyl)-pyridinecarboxylic acid [(S)cyclopropyl(5- methyl-[1,2,4]oxadiazolyl)-ethyl]-amide; -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid (3-methanesulfonyl-1,1- dimethyl-propyl)-amide; -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [1-methyl(5-methylthiazolyl)-ethyl]-amide; 5-Cyclopropyl(2-methyl-propanesulfonyl)-pyridinecarboxylic acid ((S) carbamoylmethyl-butyl)-amide; -Cyclopropyl(2-methyl-propanesulfonyl)-pyridinecarboxylic acid [(S) cyclopropyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide; 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid [1- methyl(5-methyl-thiazolyl)-ethyl]-amide; 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid ((R) methylpyridazinyl-butyl)-amide; 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid ((S) methylpyridazinyl-butyl)-amide; 5-Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [1-ethyl(2-hydroxyethylcarbamoyl)-propyl]-amide; -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [(+)cyclopropyl methyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide; -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [(-)cyclopropyl methyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide; 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid tertbutylamide; 2-{[5-Cyclopropyl(2-methyl-propanesulfonyl)-pyridinecarbonyl]-amino}ethylbutyric acid ethyl ester; -Cyclopropyl(2-methyl-propanesulfonyl)-pyridinecarboxylic acid ((S)-3,3- dimethylmethylcarbamoyl-butyl)-amide; -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid ((S)oxo-tetrahydro10 furanyl)-amide; N'-(5-Cyclopropylcyclopropylmethoxy-pyridinecarbonyl)-N-cyclopropylmethylhydrazinecarboxylic acid tert-butyl ester; -Cyclopropyl(2-methyl-propanesulfonyl)-pyridinecarboxylic acid ((S)-2,2- dimethylmethylcarbamoyl-propyl)-amide; 5-Cyclopropyl(2-methyl-propanesulfonyl)-pyridinecarboxylic acid ((S)-2,2,2- trifluoropyridinyl-ethyl)-amide; (S)[(5-Cyclopropylcyclopropylmethoxy-pyridinecarbonyl)-amino]methylpentanoic acid tert-butyl ester; -Cyclopropyl(2-methyl-propanesulfonyl)-pyridinecarboxylic acid (1-ethyl methylcarbamoyl-propyl)-amide; -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid tert-butylamide; -Cyclopropyl(tetrahydro-furanylmethoxy)-pyridinecarboxylic acid tertbutylamide; 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (3- methyl-oxetanyl)-amide; -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid (2-oxo-[1,3]oxazinan yl)-amide; -Cyclopropyl(2,2,2-trifluoromethyl-ethoxy)-pyridinecarboxylic acid ((S) carbamoylmethyl-butyl)-amide; -Cyclopropyl(2,2,2-trifluoromethyl-ethoxy)-pyridinecarboxylic acid [1-methyl1-(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide; -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid ((+)-carbamoylcyclopropyl-methyl)-amide; 5-Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid ((-)-carbamoylcyclopropyl-methyl)-amide; 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid ((+)- carbamoyl-cyclopropyl-methyl)-amide; 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid ((-)- carbamoyl-cyclopropyl-methyl)-amide; 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (1- trifluoromethyl-cyclopropyl)-amide; (+)Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [(S)cyclopropyl1-(3-hydroxy-pyrrolidinylcarbamoyl)-ethyl]-amide; (-)Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [(S)cyclopropyl (3-hydroxy-pyrrolidinylcarbamoyl)-ethyl]-amide; (+)Cyclopropyl(2-methyl-propanesulfonyl)-pyridinecarboxylic acid [1- cyclopropyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide; and (-)Cyclopropyl(2-methyl-propanesulfonyl)-pyridinecarboxylic acid [1- cyclopropyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide.
Also described herein are the following compounds of formula (I): -Cyclopropyl(tetrahydro-pyranylmethoxy)-pyridinecarboxylic acid [cyclopropyl- (5-methyl-[1,2,4]oxadiazolyl)-methyl]-amide; 5-Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid ((S)cyclopropyl dimethylcarbamoyl-ethyl)-amide; -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid ((+)-dimethylcarbamoylphenyl-methyl)-amide; 6-Cyclopropylmethoxytrifluoromethyl-pyridinecarboxylic acid ((S)-3,3-dimethyl methylcarbamoyl-butyl)-amide; 6-(3-Chlorofluoro-phenyl)-pyridinecarboxylic acid [cyclopropyl-(5-methyl- [1,2,4]oxadiazolyl)-methyl]-amide; 2-{[5-Cyclopropyl(tetrahydro-furanylmethoxy)-pyridinecarbonyl]-amino} ethyl-butyric acid methyl ester; 6-Cyclopropylmethoxy(6-oxaaza-spiro[3.3]heptyl)-pyridinecarboxylic acid ((S)-3,3-dimethylmethylcarbamoyl-butyl)-amide; 2-Ethyl{[6-(tetrahydro-pyranylmethoxy)trifluoromethyl-pyridinecarbonyl]- amino}-butyric acid methyl ester; (S)[(5-Cyclopropylcyclopropylmethoxy-pyridinecarbonyl)-amino]-3,3-dimethyl10 butyric acid methyl ester; -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [(+)(5-methyl- [1,2,4]oxadiazolyl)-butyl]-amide; 5-Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid ((-)cyanomethylbutyl)-amide; (S)Cyclopropyl[(5-cyclopropylcyclopropylmethoxy-pyridinecarbonyl)-amino]- propionic acid methyl ester; 6-Cyclopropylmethoxytrifluoromethyl-pyridinecarboxylic acid (1-ethyl methylcarbamoyl-propyl)-amide; 6-(3-Chlorofluoro-phenyl)-pyridinecarboxylic acid [1-methyl(5-methyl20 [1,2,4]oxadiazolyl)-ethyl]-amide; 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (1- hydroxymethyl-1,3-dimethyl-butyl)-amide; -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [1-ethyl(ethylmethyl-carbamoyl)-propyl]-amide; 6-(4-Fluoro-benzyl)-pyridinecarboxylic acid ((R)-2,2,2-trifluoropyridinyl-ethyl)- amide; -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid ((S)hydroxymethyl1,2-dimethyl-propyl)-amide; -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [1-(3,3-difluoroazetidinecarbonyl)ethyl-propyl]-amide; -Cyclopropyl(2,2,3,3,3-pentafluoro-propoxy)-pyridinecarboxylic acid (1-ethyl methylcarbamoyl-propyl)-amide; 5-Cyclopropyl(2,2,3,3,3-pentafluoro-propoxy)-pyridinecarboxylic acid ((S)-3,3- dimethylmethylcarbamoyl-butyl)-amide; 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid [1-(3,3- difluoro-azetidinecarbonyl)ethyl-propyl]-amide; -Cyclopropyl((R)-4,4,4-trifluorohydroxy-butoxy)-pyridinecarboxylic acid (1- ethylmethylcarbamoyl-propyl)-amide; 6-Cyclopropylmethoxytrifluoromethyl-pyridinecarboxylic acid [1-(3,3-difluoroazetidinecarbonyl)ethyl-propyl]-amide; 6-[(4-Fluoro-phenyl)-hydroxy-methyl]-pyridinecarboxylic acid ((S)carbamoyl methyl-butyl)-amide; 5-Cyclopropyl((S)-4,4,4-trifluorohydroxy-butoxy)-pyridinecarboxylic acid (1- ethylmethylcarbamoyl-propyl)-amide; -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [(+)cyclopropyl(5- methyl-[1,2,4]oxadiazolyl)-ethyl]-amide; 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (3- methylpyridinyl-butyl)-amide; -Cyclopropyl(4-fluoro-benzyl)-pyridinecarboxylic acid ((S)carbamoyl cyclopropyl-ethyl)-amide; -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [(S)-carbamoyl-(4- fluoro-phenyl)-methyl]-amide; 5-Cyclopropyl(4-fluoro-benzyl)-pyridinecarboxylic acid ((S)-2,2,2-trifluoro pyridinyl-ethyl)-amide; 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid [1- cyclopropyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide; 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid [2- cyclopropylmethyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide; 6-(3-Chlorofluoro-phenyl)-pyridinecarboxylic acid [(S)cyclopropyl(5-methyl- [1,2,4]oxadiazolyl)-ethyl]-amide; 6-Cyclopropylmethoxypyrrolidinyl-pyridinecarboxylic acid {(S)methyl[(7- nitro-benzo[1,2,5]oxadiazolylamino)-methyl]-butyl}-amide; -Cyclopropylisobutylsulfanyl-pyridinecarboxylic acid ((S)carbamoylmethylbutyl)-amide; -Cyclopropyl(2-methyl-propanesulfonyl)-pyridinecarboxylic acid ((S) carbamoylmethyl-butyl)-amide; 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid [1- methyl(5-methyl-thiazolyl)-ethyl]-amide; 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid ((R) methylpyridazinyl-butyl)-amide; 5-Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [(+)cyclopropyl methyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide; -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [(-)cyclopropyl methyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide; 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid tert20 butylamide; -Cyclopropyl(2-methyl-propanesulfonyl)-pyridinecarboxylic acid ((S)-2,2,2- trifluoropyridinyl-ethyl)-amide; -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid ((+)-carbamoylcyclopropyl-methyl)-amide; 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (1- trifluoromethyl-cyclopropyl)-amide; and (+)Cyclopropyl(2-methyl-propanesulfonyl)-pyridinecarboxylic acid [1- cyclopropyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide.
The compounds of the present invention can be prepared, for example, by the general synthetic procedures described below.
In the following schemes and description, R1 to R4 have, unless otherwise indicated, the meaning of R1 to R4 as defined above.
Coupling agents for the reaction of compounds of formula II with acids of formula III are for example N,N’-carbonyldiimidazole (CDI), N,N’-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)ethylcarbodiimide hydrochloride (EDCI), 1- [bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridiniumoxide hexafluorophosphate (HATU), 1-hydroxy-1,2,3-benzotriazole (HOBT), O-benzotriazol yl-N,N,N’,N’-tetramethyluronium tetrafluoroborate (TBTU) or O-benzotriazole-N,N,N’,N’- tetramethyl-uronium-hexafluoro-phosphate (HBTU). Particular coupling agent is HBTU.
Suitable bases include triethylamine, diisopropylethylamine and, particularly, Nmethylmorpholine.
The synthesis of the compounds with the general structure I can, for example, be accomplished according to the following schemes.
Following the procedure according to scheme 1, compound AA (X = Cl, Br, I, trifluoromethanesulfonate; R’ = H, methyl, ethyl, isopropyl, tert. butyl or another suitable protecting group described for example in T.W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3rd edition) can be used as starting material. AA is either commercially available, described in the literature, can be synthesized by a person skilled in the art, can be synthesized as described in schemes 3 and 6 or as described in the experimental part.
Scheme 1 N N O R 3 R 4 R 1 R 2 N O R 1 R 2 OH HN R 3 R 4 N O X R 2 O R' N O R 1 R 2 O R' R 1 M N O X R 2 OH R 1 M HN R 3 R 4 N N O R 3 R 4 X R 2 AA AB AC I III II a b b' c AB c' a' III AD AE Compound AC can be prepared from AA by coupling a suitably substituted aryl, heteroaryl or alkenyl metal species of formula AB (step a), particularly an arylboronic acid or arylboronic acid ester in the presence of a suitable catalyst, in particular a palladium catalyst and more particularly palladium(II)acetate / triphenylphosphine mixtures or palladium(II)chloride-dppf (1,1'-bis(diphenylphosphino)ferrocene) complexes and a base such as triethylamine, sodium carbonate or potassium phosphate in an inert solvent such as dimethylformamide, toluene, tetrahydrofuran, acetonitrile and dimethoxyethane.
Optionally, alkenyl containing R1 10 residues can be transformed to the corresponding alkyl congeners AC using conditions described in the literature such as e.g. via a hydrogenation reaction using hydrogen gas in the presence of a catalyst such as palladium on carbon in a solvent such as ethanol or ethyl acetate particularly at ambient temperature.
The saponification of the ester of general formula AC (R’ ≠ H) by methods well known to the ones skilled in the art - using e.g. aqueous LiOH, NaOH or KOH in tetrahydrofuran / ethanol or another suitable solvent at temperatures between 0°C and the reflux temperature of the solvent employed - leads to an acid of general formula II (step b).
Compound I can be prepared from II and the corresponding amine or hydrazine of formula III by suitable amide bond forming reactions (step c). These reactions are known in the art. For example coupling reagents like N,N’-carbonyl-diimidazole (CDI), N,N’- dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)ethylcarbodiimide hydrochloride (EDCI), 1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5- b]pyridiniumoxide hexafluorophosphate (HATU), 1-hydroxy-1,2,3-benzotriazole (HOBT), O-benzotriazolyl-N,N,N’,N’-tetramethyluronium tetrafluoroborate (TBTU), and O-benzotriazole-N,N,N’,N’-tetramethyl-uronium-hexafluoro-phosphate (HBTU) can be employed to affect such transformation. A convenient method is to use for example HBTU and a base, for example N-methylmorpholine in an inert solvent such as for example dimethylformamide at room temperature.
Alternatively esters of general formula AA (R’ ≠ H) can be saponified by methods well known to the ones skilled in the art - using e.g. aqueous LiOH, NaOH or KOH in tetrahydrofuran / ethanol or another suitable solvent at temperatures between 0°C and the reflux temperature of the solvent employed – to give acids of general formula AD (step b’).
Compounds AE can be prepared from AD and the corresponding amine or hydrazine of formula III by suitable amide bond forming reactions (step c’). These reactions are known in the art. For example coupling reagents like N,N’-carbonyl-diimidazole (CDI), N,N’-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)ethylcarbodiimide hydrochloride (EDCI), 1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5- b]pyridiniumoxide hexafluorophosphate (HATU), 1-hydroxy-1,2,3-benzotriazole (HOBT), O-benzotriazolyl-N,N,N’,N’-tetramethyluronium tetrafluoroborate (TBTU), and O-benzotriazole-N,N,N’,N’-tetramethyl-uronium-hexafluoro-phosphate (HBTU) can be employed to affect such transformation. A convenient method is to use for example HBTU and a base, for example N-methylmorpholine in an inert solvent such as for example dimethylformamide at room temperature.
Compound I can be prepared from AE by coupling a suitably substituted aryl, heteroaryl or alkenyl metal species of formula AB (step a’), particularly an arylboronic acid or arylboronic acid ester in the presence of a suitable catalyst, in particular a palladium catalyst and more particularly palladium(II)acetate / triphenylphosphine mixtures or palladium(II)chloride-dppf (1,1'-bis(diphenylphosphino)ferrocene) complexes and a base such as triethylamine, sodium carbonate or potassium phosphate in an inert solvent such as dimethylformamide, toluene, tetrahydrofuran, acetonitrile and dimethoxyethane. Optionally, alkenyl containing R1 residues can be transformed to the corresponding alkyl congeners AE using conditions described in the literature such as e.g. via a hydrogenation reaction using hydrogen gas in the presence of a catalyst such as palladium on carbon in a solvent such as ethanol or ethyl acetate particularly at ambient temperature.
Amines or hydrazines III are either commercially available, described in the literature, can be synthesized by a person skilled in the art or as described in the experimental part.
If one of the starting materials, compounds of formulae AA, AB or III, contains one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups (P) (as described e.g. in T.W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3rd 5 edition) can be introduced before the critical step applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods known in the art.
If one or more compounds of formulae AA to AE, II or III contain chiral centers, picolines of formula I can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art, e.g. (chiral) HPLC or crystallization.
Racemic compounds can e.g. be separated into their antipodes via diastereomeric salts by crystallization or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbent or a chiral eluent.
Following the procedure according to scheme 2, compound BA (R’ = H, methyl, ethyl, isopropyl, tert. butyl or another suitable protecting group described for example in T.W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc.
New York 1999, 3rd edition) can be used as starting material. BA is either commercially available, described in the literature or can be synthesized by a person skilled in the art.
Scheme 2 N N O R 3 R 4 R 1 R 2 N O R 1 R 2 OH HN R 3 R 4 N O R 1 R 2 O R' R 1 H N O R 2 O R' N + O R 2 O R' O N O X R 2 O R' BC BD I III II c e d BA BB a b AA' Compound BB can be prepared from BA by oxidation with a suitable oxidizing reagent under conditions known to a person skilled in the art (step a), e.g. by treatment with 3-chloro perbenzoic acid in dichloromethane at ambient temperature.
Conversion of compound BB to 6-chloro or 6-bromo-picoline AA’ (X = Cl, Br) can be achieved e.g. by treatment with phosphoryl trichloride or tribromide either without an additional solvent or in a suitable solvent such as chloroform at temperatures between °C and the boiling point of the solvent, or by using other conditions known in the literature (step b). 6-Chloro- or bromo-picoline AA’ (X = Cl, Br) can be transformed to compound BD by reaction with a suitably substituted primary or secondary alcohol BC in the presence of a base, for example sodium hydride, with or without an inert solvent, for example dimethylformamide, at temperatures ranging from room temperature to the reflux temperature of the solvent, particularly at room temperature (step c). Alternatively, compound AA’ can be converted to amino derivatives BD by treatment with an amine BC applying methods well known in the art (step c), for example using a palladium promoted amination reaction with palladium(II)acetate / 2-(dicyclohexylphosphino)biphenyl as the catalyst system in the presence of a base such as potassium carbonate in dioxane under reflux conditions.
Compound BD can be further elaborated to compound I by: i) saponification (for compounds BD with R’ ≠ H) as described in step b of scheme 1 (step d); ii) amide bond formation as described in step c of scheme 1 (step e).
Alternatively, compound AA’ (R’ = methyl, ethyl, isopropyl, tert. butyl or another suitable protecting group described for example in T.W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3rd edition) can be: i) converted into its acid congener AA’ (R’ = H) as described in step b of scheme 1; ii) transformed into the corresponding amide or hydrazide by treatment with amine or hydrazine III as described in step c of scheme 1; and iii) reacted with alcohol BC as described in step c to arrive at compound I.
If one of the starting materials, compounds of formulae BA, BC or III, contains one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups (P) (as described e.g. in T.W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3rd edition) can be introduced before the critical step applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods known in the art.
If one or more compounds of formulae BA to BD, AA’, II or III contain chiral centers, picolines of formula I can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art, e.g. (chiral) HPLC or crystallization. Racemic compounds can e.g. be separated into their antipodes via diastereomeric salts by crystallization or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbent or a chiral eluent.
Following the procedure according to scheme 3, compound CA (R’ = H, methyl, ethyl, isopropyl, tert. butyl or another suitable protecting group described for example in T.W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc.
New York 1999, 3rd 10 edition) can be used as starting material. CA is either commercially available (e.g. for R’ = methyl: 5-bromochloro-pyridinecarboxylic acid methyl ester CAN 12143533), described in the literature or can be synthesized by a person skilled in the art.
Scheme 3 N O Cl R 2 O R' R 2 M N O Cl Br O R' N O R 1 R 2 O R' R 2 M N O R 1 Br O R' R 1 H HN R 4 R 3 N O R 1 Br N R 3 R 4 R 2 M N O R 1 R 2 N R 3 R 4 AA'' CB a CA BD CB a BC CC b c CD CB a I Compound AA’’ can be prepared from CA by coupling a suitably substituted aryl, heteroaryl or alkenyl metal species of formula CB (step a), e.g. an organotrifluoroborate potassium salt in the presence of a palladium catalyst such as palladium(II)acetate / butyl1-adamantylphosphine and a base such as cesium carbonate in an inert solvent such as toluene at temperatures between 50°C and the boiling temperature of the solvent, or an arylboronic acid or arylboronic acid ester in the presence of a suitable catalyst, in particular a palladium catalyst and more particularly palladium(II)acetate / triphenylphosphine mixtures or palladium(II)chloride-dppf (1,1'- bis(diphenylphosphino)ferrocene) complexes and a base such as triethylamine, sodium carbonate or potassium phosphate in an inert solvent such as dimethylformamide, toluene, tetrahydrofuran, acetonitrile or dimethoxyethane. Optionally, compound CB can also be an amine or amide which is coupled to CA by methods well known to a person skilled in the art, e.g. using a palladium catalyst such as tris(dibenzylideneacetone)dipalladium / dimethylbisdiphenyl-phosphinoxanthene and a base such as cesium carbonate in a solvent such as 1,4-dioxane, preferentially at the boiling point of the solvent. Alternatively, compound CB can also be a sulfonamide which undergoes a copper(I) mediated reaction with CA to form AA’’ following procedures described in the literature, e.g. using copper(I) iodide and 1,3-di(pyridinyl)propane-1,3-dione in the presence of a base such as potassium carbonate in a solvent such as dimethylformamide at elevated temperatures preferentially at the boiling point of the solvent. Optionally, alkenyl containing R2 20 residues can be transformed to the corresponding alkyl congeners AA’’ using conditions described in the literature such as e.g. a hydrogenation reaction using hydrogen gas in the presence of a catalyst such as palladium on carbon in a solvent such as ethanol or ethyl acetate particularly at ambient temperature.
Compound AA’ can be further elaborated to compound I by: i) reaction with compound BC to form compound BD as described in step c of scheme 2; ii) saponification as described in step b of scheme 1; and iii) amide bond formation as described in step c of scheme 1.
Furthermore, compound CA can be converted into compound CC by treatment with compound BC as described in step c of scheme 2 (step b).
Subsequent transformation of compound CC into compound BD can be achieved as discussed for the conversion of CA into AA’’ (step a).
Compound BD can be further elaborated to compound I by: i) saponification as described in step b of scheme 1; ii) amide bond formation as described in step c of scheme 1.
Alternatively, compound CC (R’ = methyl, ethyl, isopropyl, tert. butyl or another suitable protecting group described for example in T.W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3rd edition) can be: i) converted into its acid congener CC (R’ = H) as described in step b of scheme 1; ii) transformed into the corresponding amide or hydrazide CD by treatment with amine or hydrazine III as described in step c of scheme 1; and iii) reacted with CB as described in step a to arrive at compound I.
Furthermore, compound I can also be synthesized applying the following reaction sequence: i) saponification of compound CA (R’ = methyl, ethyl, isopropyl, tert. butyl or another suitable protecting group described for example in T.W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3rd edition) to its acid congener CC (R’ = H) as described in step b of scheme 1; ii) conversion to the corresponding amide or hydrazide by treatment with amine or hydrazine III as described in step c of scheme 1; iii) reaction with compound CB as described in step a; and iv) reaction with compound BC as described in step c. Optionally step iii) and step iv) can be interchanged.
If one of the starting materials, compounds of formulae CA, CB or BC contains one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups (P) (as described e.g. in T.W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3rd edition) can be introduced before the critical step applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods known in the art.
If one or more compounds of formulae CA, CB or BC contain chiral centers, picolines of formula AA’’ and BD can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art, e.g. (chiral) HPLC or crystallization. Racemic compounds can e.g. be separated into their antipodes via diastereomeric salts by crystallization or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbent or a chiral eluent.
Following the procedure according to scheme 4, compound CC (R’ = H, methyl, ethyl, isopropyl, tert. butyl or another suitable protecting group described for example in T.W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc.
New York 1999, 3rd edition) can be used as starting material. CC is either commercially available, described in the literature, can be synthesized by methods described in scheme 3 or by other methods known to a person skilled in the art.
Scheme 4 N O R 1 R 2 O R' R 2 M N O R 1 Br O R' N O R 1 R 2 O R' R 1 H N O R 1 R 2 O R' R 2' O BD CB a CC BC BD b BD c DA Compound BD can be prepared from CC by coupling a suitably substituted aryl, heteroaryl or alkenyl metal species of formula CB (step a), e.g. an organotrifluoroborate potassium salt in the presence of a palladium catalyst such as palladium(II)acetate / butyl1-adamantylphosphine and a base such as cesium carbonate in an inert solvent such as toluene at temperatures between 50°C and the boiling temperature of the solvent, or an arylboronic acid or arylboronic acid ester in the presence of a suitable catalyst, in particular a palladium catalyst and more particularly palladium(II)acetate / triphenylphosphine mixtures or palladium(II)chloride-dppf (1,1'- bis(diphenylphosphino)ferrocene) complexes and a base such as triethylamine, sodium carbonate or potassium phosphate in an inert solvent such as dimethylformamide, toluene, tetrahydrofuran, acetonitrile and dimethoxyethane. Optionally, alkenyl containing R2 residues can be transformed to the corresponding alkyl congeners BD using conditions described in the literature such as e.g. a hydrogenation reaction using hydrogen gas in the presence of a catalyst such as palladium on carbon in a solvent such as ethanol or ethyl acetate particularly at ambient temperature.
Alternatively, compound CC can be converted to amino derivatives BD by treatment with an amine BC applying methods well known in the art (step b), for example using a palladium promoted amination with palladium(II)acetate /2-(dicyclohexylphosphino) biphenyl in the presence of a base such as potassium carbonate in dioxane under reflux conditions or by using tris(dibenzylideneacetone)dipalladium / rac-BINAP (2,2'- bis(diphenylphosphino)-1,1'-binaphthyl) in the presence of a base such as cesium carbonate in toluene at 100°C. Optionally, compound BC can also be an amide which is coupled to CC by methods well known to a person skilled in the art, e.g. using a palladium catalyst such as tris(dibenzylideneacetone)dipalladium / dimethylbisdiphenylphosphinoxanthene and a base such as cesium carbonate in a solvent such as 1,4-dioxane preferentially at the boiling point of the solvent.
Compound CC can furthermore be reacted with ketone DA (R2’= alkyl, cycloalkyl, or oxyoxetanyl) to obtain compound BD following procedures known to a person skilled in the art, e.g.: i) treatment with n-butyl lithium in a solvent such as tetrahydrofuran at a temperature of -78°C; ii) addition of a ketone DA or optionally another suitable electrophile at temperatures between -78°C and ambient temperature (step c).
Compound BD can be further elaborated to compound I by: i) saponification as described in step b of scheme 1; ii) amide bond formation as described in step c of scheme 1.
If one of the starting materials, compounds of formulae CC, CB, BC or DA, contains one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups (P) (as described e.g. in T.W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3rd edition) can be introduced before the critical step applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods known in the art.
If one or more compounds of formulae CC, CB, BC or DA, contain chiral centers, picolines of formula BD can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art, e.g. (chiral) HPLC or crystallization. Racemic compounds can e.g. be separated into their antipodes via diastereomeric salts by crystallization or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbens or a chiral eluent.
Following the procedure according to scheme 5, compound AA’’ (R’ = H) can be used as starting material. AA’’ is either commercially available, described in the literature, can be synthesized as described in scheme 2 or by other methods known to a person skilled in the art.
Scheme 5 N N O R 3 R 4 R 1 R 2 N O R 1 R 2 OH HN R 3 R 4 N O R 1 R 2 O R' N O Cl R 2 O R' N O S R 2 OH O O HO N O S R 2 O O O HO R' N R 1' R H 1'' EC I ED III II c e d a b AA'' EA EB Compound EA can be prepared from AA’’ e.g. by treatment with sodium sulfite in a mixture of ethanol and water at a temperature of 180°C in a sealed tube or by using alternative conditions known to a person skilled in the art (step a).
Subsequent esterification of EA to compound EB (R’ = methyl, ethyl, isopropyl, tert. butyl or another suitable protecting group (P) as described e.g. in T.W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3rd edition) can e.g. be performed using a solution of hydrogen chloride in methanol at ambient temperature or by alternative methods described for example in T.W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3 rd edition (step b).
Sulfonic acid EB can be converted to sulfonamide ED, after prior activation e.g. by using thionyl chloride and DMF in an inert solvent such as dichloromethane at temperatures between 0°C and the boiling point of the solvent, particularly at 40°C to form the corresponding sulfonic acid chloride, by reaction with a suitable amine EC (R1’ 15 = alkyl, R 1’’ = alkyl or R1’ and R1’’ together with the nitrogen atom to which they are attached form a cyclic amine) particularly at ambient temperature or by using any other method known to a person skilled in the art (step c).
Compound ED can be further elaborated to compound I by: i) saponification as described in step b of scheme 1 (step d); ii) amide bond formation as described in step c of scheme 1 (step e).
If one of the starting materials, compounds of formulae AA’’, EC or III, contains one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups (P) (as described e.g. in T.W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3rd 5 edition) can be introduced before the critical step applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods known in the art.
If one or more compounds of formulae AA’’, EA to ED, II or III contain chiral centers, picolines of formula I can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art, e.g. (chiral) HPLC or crystallization. Racemic compounds can e.g. be separated into their antipodes via diastereomeric salts by crystallization or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbent or a chiral eluent.
Following the procedure according to scheme 6, compound FA (X = Cl, Br, I, trifluoromethanesulfonate; R’ = H, methyl, ethyl, isopropyl, tert. butyl or another suitable protecting group described for example in T.W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3rd edition) can be used as starting material. FA is either commercially available, described in the literature or can be synthesized by a person skilled in the art.
Scheme 6 N N O R 3 R 4 R 1 R 2 N O R 1 R 2 OH HN R 3 R 4 N O R 1 R 2 O R' N O R 2 O R' N + O R 2 O R' O N O X R 2 O N R' O X O R' R 2 M R 1 M I AC III II f e BA BB b c FA AA' CB a AB d Compound BA can be prepared from FA by coupling a suitably substituted aryl, heteroaryl or alkenyl metal species of formula CB (step a), e.g. an organotrifluoroborate potassium salt in the presence of a palladium catalyst such as palladium(II)acetate / butyl1-adamantylphosphine and a base such as cesium carbonate in an inert solvent such as toluene at temperatures between 50°C and the boiling temperature of the solvent, or an arylboronic acid or arylboronic acid ester in the presence of a suitable catalyst, in particular a palladium catalyst and more particularly palladium(II)acetate / triphenylphosphine mixtures or palladium(II)chloride-dppf (1,1'- bis(diphenylphosphino)ferrocene) complexes and a base such as triethylamine, sodium carbonate or potassium phosphate in an inert solvent such as dimethylformamide, toluene, tetrahydrofuran, acetonitrile and dimethoxyethane. Optionally, compound CB can also be an amine or amide which is coupled to FA by methods well known to a person skilled in the art, e.g. using a palladium catalyst such as tris(dibenzylideneacetone)dipalladium / dimethylbisdiphenyl-phosphinoxanthene and a base such as cesium carbonate in a solvent such as 1,4-dioxane preferentially at the boiling point of the solvent. Optionally, alkenyl containing R2 residues can be transformed to the corresponding alkyl congeners BA using conditions described in the literature such as e.g. a hydrogenation reaction using hydrogen gas in the presence of a catalyst such as palladium on carbon in a solvent such as ethanol or ethyl acetate particularly at ambient temperature.
Compound BB can be prepared from BA by oxidation with a suitable oxidizing reagent as described in step a of scheme 2 (step b).
Conversion of compound BB to 6-chloro- or 6-bromo-picoline AA’ (X = Cl, Br) can be achieved as described in step b of scheme 2 (step c).
Compound AC can be prepared from AA’ by coupling a suitably substituted aryl, heteroaryl or alkenyl metal species of formula AB (step d), particularly an arylboronic acid or arylboronic acid ester in the presence of a suitable catalyst, in particular a palladium catalyst and more particularly palladium(II)acetate / triphenylphosphine mixtures or palladium(II)chloride-dppf (1,1'-bis(diphenylphosphino)ferrocene) complexes and a base such as triethylamine, sodium carbonate or potassium phosphate in an inert solvent such as dimethylformamide, toluene, tetrahydrofuran, acetonitrile and dimethoxyethane.
Optionally, alkenyl containing R1 residues can be transformed to the corresponding alkyl congeners AC using conditions described in the literature such as e.g. a hydrogenation reaction using hydrogen gas in the presence of a catalyst such as palladium on carbon in a solvent such as ethanol or ethyl acetate particularly at ambient temperature.
Compound AC can be further elaborated to compound I by: i) saponification as described in step b of scheme 1 (step e); ii) amide bond formation as described in step c of scheme 1 (step f).
If one of the starting materials, compounds of formulae FA, CB, AB or III, contains one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups (P) (as described e.g. in T.W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3rd 5 edition) can be introduced before the critical step applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods known in the art.
If one or more compounds of formulae FA, CB, BA, BB, AA’, AB, AC, II or III contain chiral centers, picolines of formula I can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art, e.g. (chiral) HPLC or crystallization. Racemic compounds can e.g. be separated into their antipodes via diastereomeric salts by crystallization or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbent or a chiral eluent.
Following the procedure according to scheme 7, compound GA can be used as starting material. GA is either commercially available, described in the literature or can be synthesized by a person skilled in the art.
Scheme 7 N N O R 3 R 4 R 1 R 2 N O R 1 R 2 OH HN R 3 R 4 N R 2 N N + R 2 O N X N R 2 N R 1 M X N R 2 OH O I III II e GA GB a b GC AB d c GD Compound GB can be prepared from GA by oxidation with a suitable oxidizing reagent under conditions known to a person skilled in the art (step a), e.g. by treatment with 3-chloro perbenzoic acid in dichloromethane at ambient temperature.
Conversion of compound GB to 6-chloro or 6-bromo compound GC (X = Cl, Br) can be achieved e.g. by treatment with phosphoryl trichloride or tribromide either without an additional solvent or in a suitable solvent such as chloroform at temperatures between °C and the boiling point of the solvent or by using other conditions known in the literature (step b).
Hydrolysis of compound GC leads to picoline GD and can be performed under acidic or basic conditions known to a person skilled in the art, e.g. by treatment with an aqueous solution of sodium hydroxide at 100°C (step c).
Compound II can be prepared from GD by coupling a suitably substituted aryl, heteroaryl or alkenyl metal species of formula AB (step d) as described in step d of scheme 6. Optionally, alkenyl containing R1 residues can be transformed to the corresponding alkyl congeners II using conditions described in the literature such as e.g. a hydrogenation reaction using hydrogen gas in the presence of a catalyst such as palladium on carbon in a solvent such as ethanol or ethyl acetate particularly at ambient temperature. In cases where the acid group of compound GD is not compatible with the conditions applied to introduce the R1 residue, suitable protecting groups such as ester protecting groups e.g. a methyl ester can be introduced prior to step d and removed at a later point of the synthesis.
Protecting group introduction and removal can be carried out by suitable methods known in the art (for more details see T.W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3rd edition).
Further conversion of compound II to compound I can be done by applying amide bond formation conditions as depicted in step c of scheme 1 (step e).
If one of the starting materials, compounds of formulae GA, AB or III, contains one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups (P) (as described e.g. in T.W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3rd 25 edition) can be introduced before the critical step applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods known in the art.
If one or more compounds of formulae GA, to GD, AB, II or III contain chiral centers, picolines of formula I can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art, e.g. (chiral) HPLC or crystallization. Racemic compounds can e.g. be separated into their antipodes via diastereomeric salts by crystallization or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbent or a chiral eluent.
Following the procedure according to scheme 8, compound HA can be used as starting material (R10 = hydrogen or alkyl; R11 = hydrogen or alkyl). HA is either commercially available, described in the literature or can be synthesized by a person skilled in the art.
Scheme 8 O O R 11 R N H O R 11 R N O S CF3 O O R 11 R N O O N R' N O R 3 R 4 R 1 R 2 N O R 1 R 2 OH HN R 3 R 4 R 11 R O a b c NH3 I III II e d HA HB HC HD HE Compound HC can be prepared from HA applying methods described in the literature, e.g. by treatment with methyl propiolate in ammonia at elevated temperatures in an autoclave (step a).
Conversion of compound HC to HD can be performed e.g. using trifluoromethanesulfonic acid anhydride in the presence of a base such as triethylamine in a solvent such as dichloromethane at temperatures preferentially between -50°C and ambient temperature or applying any other suitable method known to the ones skilled in the art (step b). Alternatively, other groups than trifluoromethane sulfonate suitable for the transformation of HD to HE can be introduced following procedures described in the literature.
Compound HE (R’ = methyl, ethyl, isopropyl, tert. butyl or another suitable protecting group) can be synthesized from HD via palladium catalyzed carbonylation using a palladium catalyst such as palladium(II)chloride-dppf (1,1'- bis(diphenylphosphino)ferrocene) complexes under a carbon monoxide atmosphere preferentially under pressures of 70 bar in the presence of an amine such as triethylamine in a solvent system consisting e.g. of methanol and ethyl acetate at elevated temperatures (step c).
Compound HE can be further elaborated to compound I by: i) saponification as described in step b of scheme 1 (step d); ii) amide bond formation as described in step c of scheme 1 (step e).
If one of the starting materials, compounds of formulae HA or III, contains one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups (P) (as described e.g. in T.W.
Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3rd 10 edition) can be introduced before the critical step applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods known in the art.
If one or more compounds of formulae HA, HC to HE, II or III contain chiral centers, picolines of formula I can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art, e.g. (chiral) HPLC or crystallization. Racemic compounds can e.g. be separated into their antipodes via diastereomeric salts by crystallization or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbent or a chiral eluent.
Following the procedure according to scheme 9, commercially available 5-bromo methyl-pyridinecarbonitrile IA (CAN 11738973) can be used as starting material.
In scheme 9, R1 is benzyl or halobenzyl; R1’ is phenyl or halohenyl.
Scheme 9 N N O R 3 R 4 R 1 R 2 N O R 1 R 2 OH HN R 3 R 4 N R 2 N N + R 2 O N N R 2 N OH N Br N R 2 M N R 2 N Y N R 2 N R 1' R 1' M I III II g IB IC b c IA ID CB a d IE e IF f AB' Compound IB can be prepared from IA by treatment with compound CB as described in step a of scheme 6 (step a).
Further transformation of IB to IC can be achieved by oxidation with a suitable oxidizing reagent as described in step a of scheme 7 (step b).
Conversion of N-oxide IC to alcohol ID can be performed under conditions well known to a person skilled in the art, e.g. by reaction with trifluoroacetic acid anhydride in a solvent such as dichloromethane preferentially at ambient temperature and subsequent treatment with a base such as sodium hydroxide (step c).
Reactions how to convert alcohol ID into compound IE containing a leaving group (Y = Cl, Br or another suitable leaving group) are well described in the literature and known to those skilled in the art (step d). For example alcohol ID can be transformed to compound IE with Y = Br by reaction with carbon tetrabromide and triphenylphosphine in a solvent such as tetrahydrofuran at temperatures between 0°C and the boiling point of the solvent, preferentially at 40°C.
Conversion of compound IE to compound IF can e.g. be accomplished by coupling a suitably substituted aryl metal species of formula AB’, particularly an arylboronic acid or arylboronic acid ester in the presence of a suitable catalyst, in particular a palladium catalyst and more particularly palladium(II)acetate / triphenylphosphine mixtures or palladium(II)chloride-dppf (1,1'-bis(diphenylphosphino)ferrocene) complexes and a base such as triethylamine, cesium carbonate or potassium phosphate in an inert solvent such as dimethylformamide, toluene, tetrahydrofuran and 1,4-dioxane (step e).
Nitrile IF can be hydrolyzed to acid II applying the method described in step c of scheme 7 (step f).
Further conversion of compound II to compound I can be done by applying amide bond formation conditions as depicted in step c of scheme 1 (step e).
If one of the starting materials, compounds of formulae IA, CB, AB’ or III, contains one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups (P) (as described e.g. in T.W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3rd 30 edition) can be introduced before the critical step applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods known in the art.
If one or more compounds of formulae IA to IF, CB, AB’, II or III contain chiral centers, picolines of formula I can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art, e.g. (chiral) HPLC or crystallization. Racemic compounds can e.g. be separated into their antipodes via diastereomeric salts by crystallization or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbent or a chiral eluent.
Compounds I may be further processed to give additional compounds of the general structure I by methods known in the art. Some examples are shown in scheme 10. In scheme 10, R12 is isobutyl, n is 0, 1 or 2.
Compounds of the general structure KB (a subgroup of I) can be prepared from compounds of general structure KA (another subgroup of I) by oxidative methods well known in the art, e.g. by Swern-oxidation using DMSO and a suitable activating agent as for example oxalyl chloride in an inert solvent as for example dichloromethane in the presence of a suitable base at temperatures ranging from -70°C to room temperature.
Compounds of the general structure KD (a subgroup of I) can be prepared from compounds of general structure KC (another subgroup of I) by converting an alcohol functionality to an azide functionality by methods known in the art. This transformation can for example be affected by treating a solution of the alcohol in an inert solvent like DMF with sodium azide, triphenylphosphine and carbon tetrachloride at elevated temperatures as for example 90°C. Further elaboration to the corresponding amine KE is done by reduction methods well known in the art as for example by reduction with sodium borohydride in 2-propanol in the presence of 1,3-propanedithiol and triethylamine at ambient temperatures. The amines KD can be further transformed into compounds of general structure KF, by reaction with 7-nitro-2,1,3-benzooxadiazolamine in an inert solvent like THF at temperatures ranging from room temperature to the boiling point of the solvent.
Scheme 10 N N R 1 N O R 3 R 4 HO N N R 1 N O R 3 R 4 O N R 2 R 1 N O R 3 OH R 12 N R 2 R 1 N O R 3 N3 R 12 N R 2 R 1 N O R 3 NH2 R 12 N R 2 R 1 N O R 3 N H N N O NO2 R 12 KA a )n ( KB )n ( KC KD KE KF b c d If one of the starting materials, compounds of formulae KA or KC contains one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups (P) (as described e.g. in T.W.
Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3rd edition) can be introduced before the critical step applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods known in the art.
If one or more compounds of formulae KA or KC contain chiral centers, picolines of formula I can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art, e.g. (chiral) HPLC or crystallization. Racemic compounds can e.g. be separated into their antipodes via diastereomeric salts by crystallization or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbent or a chiral eluent.
Also described is a process for the preparation of a compound of formula (I) comprising the reaction of a compound of formula (A) N OH O R 1 R 2 (A) in the presence of NHR3R 4 , an amide bond forming coupling agent and a base, wherein R1 to R4 are defined above.
Examples of amide bond forming coupling agents are N,N’-carbonyl-diimidazole (CDI), N,N’-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl) ethylcarbodiimide hydrochloride (EDCI), 1-[bis(dimethylamino)-methylene]-1H-1,2,3- triazolo[4,5-b]pyridiniumoxide hexafluorophosphate (HATU), 1-hydroxy-1,2,3- benzotriazole (HOBT), O-benzotriazolyl-N,N,N’,N’-tetramethyluronium tetrafluoroborate (TBTU) and O-benzotriazole-N,N,N’,N’-tetramethyl-uronium10 hexafluoro-phosphate (HBTU).
Examples of suitable bases are tertiary amine bases like triethylamine, Nmethylmorpholine, N,N-diisopropylethylamin or 4-(dimethylamino)-pyridine.
The reaction temperature is for example room temperature.
A convenient method is to use for example HBTU and a base, for example N15 methylmorpholine in an inert solvent such as for example dimethylformamide at room temperature.
The invention further relates to a compound of the first aspect of the invention for use as therapeutically active substance.
The invention further relates to a pharmaceutical composition comprising a compound of the first aspect of the invention and a therapeutically inert carrier.
The use of a compound of formula (I) for the treatment or prophylaxis of pain, in particular chronic pain, atherosclerosis, regulation of bone mass, inflammation, ischemia, reperfusion injury, systemic fibrosis, liver fibrosis, lung fibrosis, kidney fibrosis, chronic allograft nephropathy, congestive heart failure, myocardial infarction, systemic sclerosis, glomerulonephropathy, thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors is also described herein.
The use of a compound of the first aspect of the invention for the preparation of a medicament for the treatment or prophylaxis of chronic pain, in particular chronic pain, atherosclerosis, regulation of bone mass, inflammation, ischemia, reperfusion injury, systemic fibrosis, liver fibrosis, lung fibrosis, kidney fibrosis, chronic allograft nephropathy, congestive heart failure, myocardial infarction, systemic sclerosis, glomerulonephropathy, thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors is a further aspect of the invention.
Also described herein is a compound of formula (I) for the treatment or prophylaxis of pain, in particular chronic pain, atherosclerosis, regulation of bone mass, inflammation, ischemia, reperfusion injury, systemic fibrosis, liver fibrosis, lung fibrosis, kidney fibrosis, chronic allograft nephropathy, congestive heart failure, myocardial infarction, systemic sclerosis, glomerulonephropathy, thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors.
Also described herein is a compound of formula (I) for the treatment or prophylaxis of ischemia, reperfusion injury, liver fibrosis or kidney fibrosis, in particular ischemia or reperfusion injury.
A method for the treatment or prophylaxis of pain, in particular chronic pain, atherosclerosis, regulation of bone mass, inflammation, ischemia, reperfusion injury, systemic fibrosis, liver fibrosis, lung fibrosis, kidney fibrosis, chronic allograft nephropathy, congestive heart failure, myocardial infarction, systemic sclerosis, glomerulonephropathy, thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors, which method comprises administering an effective amount of a compound of formula (I) is also described herein.
Another embodiment of the invention provides pharmaceutical compositions or medicaments containing the compounds of the invention and a therapeutically inert carrier, diluent or excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments. In one example, compounds of formula (I) may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form. The pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8. In one example, a compound of formula (I) is formulated in an acetate buffer, at pH 5. In another embodiment, the compounds of formula (I) are sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.
Compositions are formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.
The compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration.
Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
The compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.
A typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
The invention will now be illustrated by the following examples which have no limiting character.
Examples Abbreviations MS = mass spectrometry; EI = electron impact; ISP = ion spray, corresponds to ESI (electrospray); NMR data are reported in parts per million () relative to internal tetramethylsilane and are referenced to the deuterium lock signal from the sample solvent (d6-DMSO unless otherwise stated); coupling constants (J) are in Hertz, mp = melting point; bp = boiling point; DIEA = N-ethyl-N-isopropylpropanamine; DMF = dimethylformamide; DMSO = dimethyl-sulfoxide; dppf = 1,1'- bis(diphenylphosphino)ferrocene; HATU = 2-(3H-[1,2,3]triazolo[4,5-b]pyridinyl)- 1,1,3,3-tetramethylisouronium hexafluorophosphate(V); HBTU = O-benzotriazoleN,N,N’,N’-tetramethyl-uronium-hexafluoro-phosphate; HPLC = LC = high performance liquid chromatography; m-CPBA = meta-chloroperoxybenzoic acid; Rt = retention time; TBTU = O-(benzotriazolyl)-N,N,N’,N’-tetramethyl-uronium-tetrafluoroborate; TEMPO = 2,2,6,6-tetra-methylpiperidine 1-oxyl radical; THF = tetrahydrofuran; tlc = thin layer chromatography.
Example 1 Methyl 2-(6-(3-chlorophenyl)picolinamido)methylpropanoate A solution of 6-(3-chlorophenyl)pyridinecarboxylic acid (CAN 8637045, 0.2 mmol), 2-methyl-alanine methyl ester (0.2 mmol) and HBTU (CAN 947901, 114 mg, 0.3 mmol) in DMF (0.5 mL) was stirred for 20 h at room temperature. The crude reaction mixture was concentrated in vacuo by centrifugation and purified by flash chromatography (silica gel, 20g, 0% to 100% ethyl acetate in heptane) to give the desired product together with some impurities (73 mg, 116%) as light yellow oil; MS (LC/MS): 333.1 (M+H).
Example 2 Methyl 2-(6-(2-chlorophenyl)picolinamido)methylpropanoate N Cl NH O O O The title compound was synthesized in analogy to Example 1, using 6-(2-chlorophenyl) pyridinecarboxylic acid (CAN 8879820) and 2-methyl-alanine methyl ester as starting materials, MS (LC/MS): 333.1 (M+H).
Example 3 6-(4-Chloro-phenyl)-pyridinecarboxylic acid [1-methyl(5-methyl- [1,2,4]oxadiazolyl)-ethyl]-amide The title compound was synthesized in analogy to Example 1, using 6-(4-chlorophenyl) pyridinecarboxylic acid (CAN 1354328) and α,α,5-trimethyl-1,2,4-oxadiazole methanamine (CAN 11538310) as starting materials, MS (LC/MS): 357.1 (M+H).
Example 4 Methyl 2-methyl(5-methyl(2,2,2-trifluoroethoxy)picolinamido)propanoate a) 5-Methyl(2,2,2-trifluoro-ethoxy)-pyridinecarboxylic acid A mixture of 6-chloromethyl-pyridinecarboxylic acid (CAN 11668282, 200 mg, 1.17 mmol), 2,2,2-trifluoroethanol (466 mg, 336 µl, 4.66 mmol) and 1,8- diazabicyclo(5.4.0)undecene (CAN 833294, 887 mg, 870 µl, 5.83 mmol) was shaken in a sealed tube for 2 days at 140°C and subsequently for additional 5 days at 150°C. The brown solution was poured into 25 mL ice / 0.1 N HCl and extracted with iPrOAc (2 x 25 mL). The organic layers were washed with ice / brine (2 x 25 mL). The organic layers were dried over sodium sulfate and concentrated in vacuo to give the title N Cl NH O O O N O Cl N H N O N O N F F F OH O compound (198 mg, 58%) as off-white solid containing traces of starting material, MS (EI): m/e = 233.9 [M-H]- . b) Methyl 2-methyl(5-methyl(2,2,2-trifluoroethoxy)picolinamido)propanoate A solution of 5-methyl(2,2,2-trifluoro-ethoxy)-pyridinecarboxylic acid (30 mg, 128 µmol), 2-methyl-alanine methyl ester hydrochloride (23.5 mg, 153 µmol), HATU (CAN 1488931, 97.0 mg, 255 µmol) and DIEA (82.4 mg, 109 µl, 638 µmol) in DMF was stirred at ambient temperature for 72 h. The crude reaction mixture was concentrated in vacuo to give 53 mg of a yellow solid. This solid was purified by preparative TLC (silica gel, 2.0 mm, 1:1 heptane/i-PrOAc) and eluted from the silica gel with i-PrOAc. Filtration over speedex and evaporation under reduced pressure provided the title compound (10 mg, 23%) as colorless liquid, MS (EI): m/e = 335.2 [M+H]+ .
Example 5 Methyl 2-(5-cyclopropyl(2,4-dichlorophenylamino)picolinamido) methylpropanoate a) 6-Chlorocyclopropyl-pyridinecarboxylic acid methyl ester To a mixture of palladium(II)acetate (17.9 mg, 79.8 µmol), butyladamantylphosphine (42.9 mg, 120 µmol), potassium cyclopropyltrifluoroborate (597 mg, 4.03 mmol) and cesium carbonate (3.9 g, 12.0 mmol) under an argon atmosphere was added a solution of -bromochloro-pyridinecarboxylic acid methyl ester (CAN 12143533, 1 g, 3.99 mmol) in toluene (25.2 ml) and water (2.8 mL) under an argon atmosphere. The reaction mixture was heated to 100°C for 20 h, diluted with water (17.5 ml), poured onto 100 ml ice / brine and extracted with i-PrOAc (2 x 100 mL). The combined extracts were dried over sodium sulfate and concentrated in vacuo to give a yellow liquid. This crude material was purified by column chromatography (70 g SiO2, n-heptane / i-PrOAc 0-10% over 120 N H N O O O O F F F Cl N O O min) to give the title compound (497 mg, 59%) as yellow solid, MS (EI): m/e = 212.0 [M+H]+ . b) 5-Cyclopropyl(2,4-dichloro-phenylamino)-pyridinecarboxylic acid methyl ester A solution of palladium(II)acetate (4.24 mg, 18.9 µmol) and 2- (dicyclohexylphosphino)biphenyl (13.2 mg, 37.8 µmol) in dioxane (1.9 ml) under an argon atmosphere was stirred for 10 min at ambient temperature and subsequently added to a suspension of 6-chlorocyclopropyl-pyridinecarboxylic acid methyl ester (100 mg, 472 µmol), 2,4-dichloroaniline (76.6 mg, 472 µmol) and potassium carbonate (1.31 g, 9.45 mmol) in dioxane (3.24 ml) under an argon atmosphere. The yellow suspension was heated to reflux and stirred for 20 h. The reaction mixture was poured into 20 mL ice / brine and extracted with i-PrOAc (2 x 50 mL). The combined organic layers were washed with ice / brine (1 x 50 mL), dried over sodium sulfate and concentrated in vacuo to give a brown oil. The crude product was purified by flash chromatography (silica gel, 4 g, 0% to 10% heptane / iPrOAc) to give the title compound (62 mg, 39%) as light brown liquid, MS (EI): m/e = 337.2 [M+H]+ . c) 5-Cyclopropyl(2,4-dichloro-phenylamino)-pyridinecarboxylic acid A solution of 5-cyclopropyl(2,4-dichloro-phenylamino)-pyridinecarboxylic acid methyl ester (62 mg, 184 µmol) and lithium hydroxide hydrate (9.3 mg, 221 µmol) in THF (100µl) and water (50 µl) was stirred at ambient temperature for 20 h. The reaction mixture was poured onto 1 M HCl / ice water (1 x 20 mL) and extracted with i-PrOAc (2 x mL). The combined organic layers were dried over sodium sulfate. The solvent was HN N O O Cl Cl HN N OH O Cl Cl removed under reduced pressure to obtain the title compound (6 mg, 10%) as colorless liquid, which was sufficiently pure to be used in the next reaction step, MS (EI): m/e = 323.3 [M+H]+ . d) Methyl 2-(5-cyclopropyl(2,4-dichlorophenylamino)picolinamido) methylpropanoate The title compound was synthesized in analogy to Example 4 b, using 5-cyclopropyl (2,4-dichloro-phenylamino)-pyridinecarboxylic acid and 2-methyl-alanine methyl ester as starting materials, MS (EI): m/e 422.1 [M+H]+ .
Example 6 Methyl 2-(6-(2,4-dichlorophenylamino)methylpicolinamido)methylpropanoate a) 6-(2,4-Dichloro-phenylamino)methyl-pyridinecarboxylic acid methyl ester 6-(2,4-Dichloro-phenylamino)methyl-pyridinecarboxylic acid methyl ester was synthesized in analogy to Example 5 b, using 6-chloromethyl-pyridinecarboxylic acid methyl ester (CAN 1784212) and 2,4-dichloroaniline as starting materials, MS (EI): m/e 311.3 [M+H]+ . b) 6-(2,4-Dichloro-phenylamino)methyl-pyridinecarboxylic acid HN Cl N N H Cl O O O HN N O O Cl Cl 6-(2,4-Dichloro-phenylamino)methyl-pyridinecarboxylic acid was synthesized in analogy to Example 5 c, using 6-(2,4-dichloro-phenylamino)methyl-pyridine carboxylic acid methyl ester as starting material, MS (EI): m/e 297.2 [M+H]+ . c) Methyl 2-(6-(2,4-dichlorophenylamino)methylpicolinamido)methylpropanoate The title compound was synthesized in analogy to Example 4 b, using 6-(2,4-dichlorophenylamino)methyl-pyridinecarboxylic acid and 2-methyl-alanine methyl ester as starting materials, MS (EI): m/e 396.0 [M+H]+ .
Example 7 2-[(6-Cyclohexyl-pyridinecarbonyl)-amino]methyl-propionic acid methyl ester a) 6-Cyclohexenyl-pyridinecarboxylic acid Under an atmosphere of nitrogen, a solution of 6-bromo-pyridinecarboxylic acid (CAN 11904, 3 g, 6.4 mol), cyclohexenylboronic acid (CAN 211904, 0.89 g, 7.1 mmol), 1,1'-bis(diphenyl-phosphino)ferrocene-palladium(II)dichloride methylene chloride complex (CAN 954644, 8 mg, 0.13 mmol), potassium carbonate (1.78 g, 12.9 mmol) in H2O (30 mL) was heated to 100°C overnight. The reaction mixture was extracted with ethyl acetate (50 mL). The pH of the aqueous layer was adjusted to 5 by addition of 1 N hydrochloric acid and the resulting mixture was extracted with ethyl acetate (3×50 mL).
HN N OH O Cl Cl N H N O HN O O Cl Cl N OH O The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by prep-HPLC to yield the title compound (0.8 g, 3.94 mmol, 61.2%) as yellow oil; MS (EI): m/e = 204.2 [M+H]+ . b) 6-Cyclohexyl-pyridinecarboxylic acid To a solution of 6-cyclohexenyl-pyridinecarboxylic acid (0.8 g, 3.94 mmol) in ethanol (50 mL) was added 10% palladium on carbon (20%, 0.16 g) under an atmosphere of nitrogen. The suspension was degassed under vacuum and exchanged with hydrogen several times. The mixture was stirred under hydrogen balloon at ambient temperature overnight. The reaction mixture was filtered through a pad of celite, the pad was washed with ethanol and the combined filtrates were concentrated to dryness. The crude title compound (0.62 g, green oil) was used for the next reaction step without further purification; MS (EI): m/e 206.2 [M+H]+ c) 2-[(6-Cyclohexyl-pyridinecarbonyl)-amino]methyl-propionic acid methyl ester The title compound was synthesized in analogy to Example 1, using 6-cyclohexylpyridinecarboxylic acid and 2-methyl-alanine methyl ester as starting materials, MS (LC/MS): 305.1 (M+H).
Example 8 6-(3-Chloro-phenyl)-pyridinecarboxylic acid (1-methyloxazolyl-ethyl)-amide a) 2-(Benzyloxycarbonylamino)methylpropanoic acid N OH O N O O O N H O N H O O OH To a solution of 2-methylalanine (CAN 627, 30.9 g, 0.3 mol) and sodium hydroxide (20 g, 0.5 mol) in water (500 mL) was added benzyl chloroformate (61.4 g, 0.36 mol) at ice-water bath temperature. The reaction mixture was allowed to warm to room temperature and stirred overnight. The resulting solution was washed with ethyl acetate (2 x 80 mL), then the aqueous layer was adjusted to pH = 2 with conc. hydrochloric acid and the solution was extracted with ethyl acetate (3 x 150 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude target compound (26 g, 36%) which was used directly for the next step without further purification; MS: m/e 238.0 [M+H] + b) Benzyl 1-(2,2-dimethoxyethylamino)methyloxopropanylcarbamate A mixture of 2-(benzyloxycarbonylamino)methylpropanoic acid (20 g, 0.084 mol), HATU (CAN 1488931, 41.56 g, 0.11 mol) and N-methylmorpholine (CAN 1094, .54 g, 0.253 mol) in DMF (400 mL) was stirred at room temperature for 10 min. 2, 2- Dimethoxyethanamine (CAN 224836, 9.75 g, 0.093 mol) was added and the mixture was stirred overnight. After evaporation of solvents, the residue was diluted with methylene chloride (500 mL) and saturated sodium bicarbonate solution (500 mL). After being separated, the organic layer was washed with 5 N citric acid solution (500 mL), brine (500 mL) and dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure left a yellow oil (27 g, 99%) which was used in the next reaction step without further purification. 1H NMR (300 MHz, CDCl3): δ 7.36 - 7.33 (m, 5H), 6.44 - 6.38 (b, 1H), 5.31 (s, 1H), 5.09 (s, 2H), 4.34 - 4.33 (m, 1H), 3.40 - 3.37 (m, 8H), 2.06 - 2.03 (m, 6H). c) Benzyl 2-methyloxo(2-oxoethylamino)propanylcarbamate To a solution of benzyl 1-(2,2-dimethoxyethylamino)methyloxopropan ylcarbamate (0.52 g, 1.6 mmol) in THF (20 mL) was added 5 M hydrochloric acid (10 mL) and the mixture was stirred at room temperature until TLC showed the reaction was completed. Ethyl acetate (50 mL) was added and the phases were separated. The organic layer was washed with brine (4 x 30 mL) to pH = 6~7, dried over anhydrous sodium O N H O O N H O O O N H O O N H O sulfate and concentrated to yield product (0.445 g, 100%) as yellow oil, which was used directly in the next step without purification; MS: m/e 279.1 [M+H] + . d) Benzyl 2-(oxazolyl)propanylcarbamate A solution of benzyl 2-methyloxo(2-oxoethylamino)propanylcarbamate (2.23 g, 8 mmol) in methylene chloride (50 mL) was added to a freshly prepared solution of PPh3 (3.15 g, 12 mmol), I2 (3.05 g, 12 mmol ) and Et3N (2.43g, 24 mmol) in methylene chloride (100 mL). The resulting mixture was stirred at room temperature until TLC showed the reaction was completed. Then water (150 mL) was added. The organic layer was washed with 5% sodium bisulfite (150 mL x 2), brine (150 mL) and dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure left a yellow oil which was purified by column chromatography (silica gel, 50 g, eluting with 25% ethyl acetate in petroleum ether) to yield the title compound (0.63 g, 30%) as colorless oil; MS: m/e 261.2 [M+H] + . 1H NMR (300 MHz, CDCl3): δ 7.57 (s, 1H), 7.37 - 7.33 (m, 5H), 7.05 (s, 1H), 5.06 (s, 2H), 1.74 (s, 6H). e) α,α-Dimethyloxazolemethanamine A mixture of benzyl 2-(oxazolyl)propanylcarbamate (0.63 g, 24 mmol) and palladium 10% on carbon (0.06 g) in ethanol (20 mL) was charged with hydrogen balloon and stirred at room temperature for 2 h. TLC showed the reaction was completed; it was filtered and concentrated to give a yellow oil (0.1 g, 33%); MS: m/e 127.1 [M+H] + . 1H NMR (300 MHz, CDCl3): δ 7.58 (d, 1H, J = 0.6 Hz), 7.02 (s, 1H), 2.56 (bs, 4H), 1.59 (s, 6H). f) 6-(3-Chloro-phenyl)-pyridinecarboxylic acid (1-methyloxazolyl-ethyl)-amide O N H O N O H2N N O N O N O Cl N H The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl) pyridinecarboxylic acid (CAN 8637045) and α,α-dimethyloxazolemethanamine (CAN 12115194) as starting materials, MS (LC/MS): 341.9 [M+H] + .
Example 9 2-{[6-Cyclopropylmethoxy(tetrahydro-pyranyl)-pyridinecarbonyl]-amino} methyl-propionic acid methyl ester a) 3,6-Dihydro-2H-pyranyl trifluoromethanesulfonate Under an atmosphere of nitrogen, to a solution of diisopropylamine (CAN 1809, 2.42 g, 0.024 mol) in THF (40 mL) was added n-butyl lithium (10.4 mL, 2.5 M solution in hexane, 26 mmol) at -78°C. The reaction mixture was reacted for 30 min at -50°C. Then tetrahydropyranone (CAN 299438, 2 g, 0.020 mol) in THF (10 mL) was added dropwise to the above solution at -78°C. The reaction mixture was reacted for 30 min at - 78°C. Then trifluoro-N-phenyl-N-(trifluoromethylsulfonyl) methanesulfonamide (CAN 375957, 7.85 g, 0.022 mol) in THF (50 mL) was added dropwise to the above solution at -78°C. The reaction mixture was stirred for 10 min at room temperature. The reaction mixture was quenched with a saturated solution of sodium bicarbonate (10 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with citric acid (50 mL) and sodium hydroxide solution (1 N, 50 mL), dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (silica gel, 10 g, 1% ethyl acetate in petroleum ether) to yield the title compound (0.7 g, 3 mmol, 15.1%) as yellow oil. 1H NMR (300 MHz , d 6 -DMSO): 6.05 - 6.03 (m, 1H), 4.17 (d, J = 3 Hz, 2H), 3.78 (t, J = 4.5 Hz, 2H), 2.38 (t, J = 3 Hz, 2H). b) 2-(3,6-Dihydro-2H-pyranyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane O OTf O B O O Under an atmosphere of nitrogen, a solution of 3, 6-dihydro-2H-pyranyl trifluoromethanesulfonate (0.7 g, 3.0 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(1,3,2- dioxaborolane) (CAN 31833, 0.84 g, 3.3 mmol), 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride methylene chloride complex (CAN 954644, 0.05 g, 0.06 mmol) and potassium acetate (0.89 g, 9.0 mmol) in DMSO (10 mL) was heated to 80°C overnight. Water (50 mL) was added to the reaction mixture which then was extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (silica gel, 9 g, 1% ethyl acetate in petroleum ether) to yield the title compound (0.32 g, 2 mmol, 50.5%) as colorless oil. 1 10 H NMR (300 MHz, CDCl3): δ 6.53 (s, 1H), 4.20 (t, J = 3 Hz, 2H), 3.76 (t, J = 6 Hz, 2H), 2.24 (dd, J1 = 6 Hz, J2 = 6 Hz, 2H), 1.28 (s, 12H). c) 5-Bromochloro-pyridinecarboxylic acid methyl ester A mixture of 5-bromo-pyridinecarboxylic acid methyl ester (CAN 296823, 50 g, 0.23 mol) and m-CPBA (CAN 9374, 80 g, 0.46 mol) in 400 mL dry methylene chloride was heated to 60°C for 20 h. After that, the mixture was quenched with saturated sodium sulfite solution and extracted with ethyl acetate (2 x 200 mL). The organic layer was washed with brine (2 x 200 mL) and evaporated to dryness. The residue was purified by column chromatography (silica gel, 300 g, eluting with 15% ethyl acetate in petroleum ether) to obtain a brown oil. The brown oil, 5-bromo(methoxycarbonyl)pyridine 1-oxide (30 g, 0.13 mol) was added into phosphoryl trichloride (CAN 100253, 80 mL) at 0°C over 1 h, then the mixture was heated to 95°C for 1 h. After that the mixture was evaporated to dryness, the residue was dissolved in water (50 mL), extracted with ethyl acetate (3 x 50 mL) and the organic layer was evaporated to dryness to obtain the product as a white solid (19 g, 59%); MS (EI): m/e = 249.9 [M+H]+ . d) 5-Bromocyclopropylmethoxy-pyridinecarboxylic acid Cl N Br O O N OH O O Br Sodium hydride (4.83 g, 0.12 mol) was added into cyclopropanemethanol (CAN 2516 8, 30 g) at 0°C and the mixture was stirred at 0°C for 1 h. Then to the mixture was added methyl 5-bromochloro-pyridinecarboxylic acid methyl ester (3 g, 12.75 mmol).The obtained solution was heated to 90°C for 2 h. Then the mixture was evaporated to dryness, the residue was dissolved in 40 mL of water, and adjusted to pH = 4 with hydrochloric acid (3 N), and extracted with ethyl acetate (3 x 30 mL). The combined organic layer was washed with water (2 x 30 mL) and brine (2 x 50 mL) then evaporated to dryness to obtain the product as a white solid (2.5 g, 76.7%); MS (EI): m/e = 272.0 [M+H]+ . e) 6-(Cyclopropylmethoxy)(tetrahydro-2H-pyranyl)-pyridinecarboxylic acid Under an atmosphere of nitrogen, a solution of 5-bromo(cyclopropylmethoxy)- pyridinecarboxylic acid (300 mg, 1.1 mmol), 2-(3,6-dihydro-2H-pyranyl)-4,4,5,5- tetramethyl- 1,3,2-dioxaborolane (278 mg, 1.3 mmol), 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride methylene chloride complex (CAN 954644, 45 mg, 0.06 mmol) and sodium carbonate (964 mg, 9.1 mmol) in DMF (10 mL) was heated to 100°C overnight. The reaction mixture was poured into water, extracted with ethyl acetate (30 mL), the pH of the aqueous layer was adjusted to 2 by addition of 1 N hydrochloric acid and the resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed six times with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (silica gel, 8 g, 30% ethyl acetate in petroleum ether) to yield the title compound (0.15 g, 1 mmol, 49.4 %) as white solid; MS (EI): m/e 276.0 [M+H] + . f) 6-Cyclopropylmethoxy(tetrahydro-pyranyl)-pyridinecarboxylic acid N OH O O O N OH O O O In analogy to the procedure described in example 7 b, the title compound was obtained (0.15 g, 1 mmol, 99%) as a yellow solid starting from 6-(cyclopropylmethoxy)(3,6- dihydro 2H-pyranyl)-pyridinecarboxylic acid ; MS (EI): m/e 270.8 [M+H] + g) 2-{[6-Cyclopropylmethoxy(tetrahydro-pyranyl)-pyridinecarbonyl]-amino} methyl-propionic acid methyl ester The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(tetrahydro-pyranyl)-pyridinecarboxylic acid and 2-methylalanine methyl ester as starting materials, MS (EI): m/e 377.2 [M+H] + .
Example 10 6-Cyclopropylmethoxy(tetrahydro-pyranyl)-pyridinecarboxylic acid [1- methyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(tetrahydro-pyranyl)-pyridinecarboxylic acid (Example 9 f) and α,α,5-trimethyl-1,2,4-oxadiazolemethanamine (CAN 11538310) as starting materials, MS (EI): m/e 401.1 [M+H] + .
Example 11 6-(3-Chloro-phenyl)-pyridinecarboxylic acid piperidinylamide O N O O O O N H N N N N H O O O O N N H N O Cl The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl) pyridinecarboxylic acid (CAN 8637045) and 1-piperidinamine (CAN 22136) as starting materials, MS (EI): m/e 316.0 [M+H] + .
Example 12 6-(3-Chloro-phenyl)-pyridinecarboxylic acid (1-methylthiazolyl-ethyl)-amide a) tert-Butyl 1-aminomethyloxopropanylcarbamate A mixture of 2-(tert-butoxycarbonylamino)methylpropanoic acid (CAN: 309921, g, 98 mmol), di-tert-butyl dicarbonate (CAN 244245, 27.67 g, 147 mmol) and pyridine (4.6 mL) in acetonitrile (500 mL) was stirred at room temperature for 20 min.
Ammonia (10 mL) was added dropwise for 20 min. The resulting reaction mixture was stirred for 4 h. After removal of most of the solvent under reduced pressure, the solid was filtered off and washed with acetonitrile. The solid was brought to dryness under reduced pressure to give the title compound (17.5 g, 88%) as white solid; MS(EI): m/e 225.1 [M+Na]+ 15 . b) tert-Butyl 1-aminomethylthioxopropanylcarbamate To a mixture of tert-butyl 1-aminomethyloxopropanylcarbamate (10 g, 49 mmol) in toluene (200 mL) was added Lawesson's reagent (CAN 191725, 10 g, 25 mmol).
The suspension was heated to 90°C and stirred for 6 h. After evaporation of solvents, the residue was purified by column chromatography (silica gel, 120 g) eluting with 30% ethyl acetate in petroleum ether to yield the title compound (6 g, 56%); MS: m/e 241.2 [M+Na]+ . c) α,α-Dimethylthiazolemethanamine O N H O NH2 O O N H O NH2 S S N H2N A mixture of tert-butyl 1-aminomethylthioxopropanylcarbamate (5.31 g, 24 mmol), 2-bromo-1,1-dimethoxyethane (CAN:72527, 5.11 g, 30 mmol) and TsOH (0.49 g, 3mmol) in acetic acid (50 mL) was stirred at 120°C for 4 h. After evaporation of solvents, the residue was diluted with ethyl acetate (50 mL) and water (50 mL). The water phase was washed with ethyl acetate (3 x 50 mL). Then water phase was lyophilized to give the title compound as brown solid (2.1 g, 65%); MS (LC/MS): 143.1 [M+H]+ . d) 6-(3-Chloro-phenyl)-pyridinecarboxylic acid (1-methylthiazolyl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl) pyridinecarboxylic acid (CAN 8637045) and α,α-dimethylthiazolemethanamine (CAN 10823931) as starting materials, MS (LC/MS): 358.0 [M+H]+ .
Example 13 2-{[6-Cyclopropylmethoxy(1H-pyrazolyl)-pyridinecarbonyl]-amino} methyl-propionic acid methyl ester a) 6-Cyclopropylmethoxy(1H-pyrazolyl)-pyridinecarboxylic acid Under an atmosphere of nitrogen, a solution of 5-bromo(cyclopropylmethoxy)- pyridinecarboxylic acid (Example 9 d, 0.4 g, 1.5 mmol), 1H-pyrazolylboronic acid (CAN 3765843, 0.2 g, 1.8 mmol), 1,1'-bis(diphenylphosphino)ferrocene20 palladium(II)dichloride methylene chloride complex (CAN 954644, 60 mg, 0.07 mmol) and sodium carbonate (1.3 g, 12 mmol) in DMF (10 mL) was heated to 100°C for 5 h. The reaction mixture was poured into water and extracted with ethyl acetate (30 mL).
The aqueous layer was adjusted to pH = 2 by addition of 1 N hydrochloric acid and the resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate and N N H N S O Cl O N OH O N HN evaporated. The residue was purified by column chromatography (silica gel, 15 g, eluting with 30% ethyl acetate in petroleum ether) to yield the title compound (0.23 g, 1 mmol, 60.3 %) as white solid; MS (EI): m/e 260.1 [M+H]+ . b) 2-{[6-Cyclopropylmethoxy(1H-pyrazolyl)-pyridinecarbonyl]-amino} methyl-propionic acid methyl ester The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(1H-pyrazolyl)-pyridinecarboxylic acid and 2-methyl-alanine methyl ester as starting materials, MS (LC/MS): 359.1 [M+H]+ .
Example 14 6-Cyclopropylmethoxypyrrolidinyl-pyridinecarboxylic acid ((S) hydroxymethylmethyl-butyl)-amide a) 6-Cyclopropylmethoxypyrrolidinyl-pyridinecarboxylic acid A mixture of 5-bromo(cyclopropylmethoxy)-pyridinecarboxylic acid (Example 9 d, 600 mg, 2 mmol), pyrrolidine (CAN 1231, 1.57g 22mmol), tris(dibenzylideneacetone)dipalladium (CAN 524090, 202 mg 0.2 mmol), rac-BINAP (CAN 761894, 275 mg, 0.4 mmol) and Cs2CO3 (2.88 mg 9 mmol) in toluene (50 mL) was heated to 95°C for 20 h in a nitrogen atmosphere. Then the mixture was diluted with methanol (30 mL), filtered and the filtrate was evaporated to dryness. The residue was purified by column chromatography (silica gel, 5 g, eluting with 10% ethyl acetate in petroleum ether) to obtain the product as a white solid (0.26 g 45%), MS (LC/MS): 263.1 [M+H]+ . b) 6-Cyclopropylmethoxypyrrolidinyl-pyridinecarboxylic acid ((S) hydroxymethylmethyl-butyl)-amide N N H N HN O O O O N OH O O N The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxypyrrolidinyl-pyridinecarboxylic acid and (2S)amino methylpentanol (CAN 75336) as starting materials, MS (LC/MS): 362.2 [M+H]+ .
Example 15 (6-Cyclopropylmethoxypyrrolidinyl-pyridinyl)-(1,1-dioxidotetrahydro-2Hthiopyranyl)-methanone The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxypyrrolidinyl-pyridinecarboxylic acid (Example 14 a) and 1,1- dioxide-thiomorpholine (CAN 390931) as starting materials, MS (LC/MS): 380.1 [M+H]+ .
Example 16 (6-Cyclopropylmethoxypyrrolidinyl-pyridinyl)-thiomorpholinyl15 methanone The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxypyrrolidinyl-pyridinecarboxylic acid (Example 14 a) and thiomorpholine (CAN 1230) as starting materials, MS (LC/MS): 348.1 [M+H]+ .
Example 17 N N N H O O OH Chiral S N N N O O O O S N N N O O 6-(3-Chloro-phenyl)-pyridinecarboxylic acid (1-methyl[1,3,4]oxadiazolylethyl)-amide a) Benzyl 1-(2-formylhydrazinyl)methyloxopropanylcarbamate A mixture of 2-(benzyloxycarbonylamino)methylpropanoic acid (Example 8 a, 1.9 g, 8 mmol), HATU (CAN 1488931, 3.97 g, 10 mmol) and N-methylmorpholine (CAN 1094, 2.43 g, 24 mmol) in DMF (20 mL) was stirred at room temperature for 15 min.
Then hydrazinecarboxaldehyde (CAN 6240, 0.53 g, 9 mmol) was added and the reaction mixture was stirred at room temperature overnight. After evaporation of solvents, the residue was diluted with ethyl acetate (30 mL) and water (30 mL). The organic layer was washed with saturated sodium bicarbonate solution (30 mL), hydrochloric acid (30 mL, 1 M), brine (30 mL) and dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure left the title compounds as yellow oil (2.1 g, 94%); MS: m/e 280.1 [M+H]+ . b) Benzyl 2-(1,3,4-oxadiazolyl)propanylcarbamate To a suspension of benzyl 1-(2-formylhydrazinyl)methyloxopropanylcarbamate (0.9 g, 3 mmol) and PPh3 (CAN 6030, 1.268 g, 5 mmol) in acetonitrile (20 mL) was added DIPEA (CAN 70875, 1.249 g, 10 mmol) and hexachloroethane (CAN 671, 0.991 g, 4 mmol). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 4 h. After evaporation of solvents, the residue was diluted with ethyl acetate (30 mL) and water (30 mL). The organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate and evaporated. The remaining residue was then purified by column chromatography (silica gel, 30 g, eluting with 10% ethyl acetate in petroleum ether) to give the title compound (1 g, 30% purity, 36%) as colorless oil containing OPPh3 and PPh3; MS: m/e 262.2 [M+H]+ . c) 1-Methyl[1,3,4]oxadiazolyl-ethylamine O N H O N H O N H O O N H O N N O A solution of benzyl 2-(1,3,4-oxadiazolyl)propanylcarbamate (1 g, 30% purity) and % Pd/C (0.06 g) in ethanol (30 mL) was charged with hydrogen balloon and stirred at room temperature overnight. After filtration, it was concentrated to give crude product which was directly used in the next reaction step without further purification but still contained OPPh3 and PPh3; MS: m/e 128.1 [M+H]+ . d) 6-(3-Chloro-phenyl)-pyridinecarboxylic acid (1-methyl[1,3,4]oxadiazolylethyl)-amide The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl) pyridinecarboxylic acid (CAN 8637045) and 1-methyl[1,3,4]oxadiazolylethylamine as starting materials, MS (LC/MS): 343.0 [M+H]+ .
Example 18 6-(3-Chloro-phenyl)-pyridinecarboxylic acid cyclohexylamide The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl) pyridinecarboxylic acid (CAN 8637045) and cyclohexanamine (CAN 1088) as starting materials, MS (EI) m/e : 315.1 [M+H]+ .
Example 19 6-(3-Chloro-phenyl)-pyridinecarboxylic acid phenylamide H2N N N O N N H N O N O Cl N N H O Cl The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl) pyridinecarboxylic acid (CAN 8637045) and aniline (CAN 623) as starting materials, MS (EI) m/e: 309.1 [M+H]+ .
Example 20 6-(3-Chloro-phenyl)-pyridinecarboxylic acid pyridinylamide The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl) pyridinecarboxylic acid (CAN 8637045) and 2-pyridinamine (CAN 5040) as starting materials, MS (EI) m/e: 310.0 [M+H]+ 10 .
Example 21 6-(3-Chloro-phenyl)-pyridinecarboxylic acid (tetrahydro-pyranyl)-amide The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl) pyridinecarboxylic acid (CAN 8637045) and tetrahydro-2H-pyranamine (CAN 380419) as starting materials, MS (LC/MS): 317.1 [M+H]+ .
Example 22 6-(3-Chloro-phenyl)-pyridinecarboxylic acid [1-methyl(3-methyl- [1,2,4]thiadiazolyl)-ethyl]-amide N N H O Cl N N H O Cl N N N H O Cl O a) tert-Butyl(1-(dimethylamino)ethylideneamino)methylthioxopropan ylcarbamate A mixture of tert-butyl 1-aminomethylthioxopropanylcarbamate (Example 12b, 0.218 g, 1 mmol) and 1,1-dimethoxy-N,N-dimethylethanamine (CAN 188714, 0.16 g, 1.2 mmol) in methylene chloride (10 mL) was stirred at room temperature for 24 h. Then it was concentrated to give crude product, which was used directly in the next step without further purification (0.28 g, 98%) as yellow oil; MS (EI): m/e 288.2 [M+H]+ . b) tert-Butyl 2-(3-methyl-1,2,4-thiadiazolyl)propanylcarbamate A mixture of tert-butyl 1-(1-(dimethylamino)ethylideneamino)methylthioxopropan2-ylcarbamate (2.9 g, 10 mmol), hydroxylamine-O-sulfonic acid (CAN 29508, 1.37 g, 12 mmol), pyridine (1.6 g, 20.2 mmol) and methanol (4 mL) in ethanol (20 mL) was stirred at room temperature for 2 h. After evaporation of solvents, the residue was diluted with ethyl acetate (40 mL) and water (40 mL). The organic layer was washed with brine (40 mL), dried over anhydrous sodium sulfate and concentrated to give crude product (2.5 g, 96%) as yellow oil. The product was used directly in the next step without further purification; MS (EI): m/e 258.2 [M+H]+ . c) 1-Methyl(3-methyl-[1,2,4]thiadiazolyl)-ethylamine A solution of tert-butyl 2-(3-methyl-1, 2, 4-thiadiazolyl)propanylcarbamate (0.15 g, 0.58 mmol) in saturated hydrochloride in ethyl acetate (10 mL) was stirred at room temperature for 1 h. Then water (20 mL) was added. The water phase was washed with ethyl acetate (2 x 20 mL). Then the water phase was adjusted with sodium hydroxide solution (2 M) to pH = 9~10 and extracted with ethyl acetate (3 x 20 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated to give product (0.08 g, 87%) as yellow oil; MS (EI): m/e 231.1 [M+H]+ .
O N H O N S N O N H O N S N H2N N S N d) 6-(3-Chloro-phenyl)-pyridinecarboxylic acid [1-methyl(3-methyl- [1,2,4]thiadiazolyl)-ethyl]-amide The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl) pyridinecarboxylic acid (CAN 8637045) and 1-methyl(3-methyl-[1,2,4]thiadiazol5-yl)-ethylamine as starting materials, MS (LC/MS): 373.0 (M+H).
Example 23 6-(3-Chloro-phenyl)-pyridinecarboxylic acid (1-dimethylcarbamoylethylpropyl)-amide a) 2-(tert-Butoxycarbonylamino)ethylbutanoic acid 3-aminopentanecarboxylic acid (CAN 25662, 2.0 g, 15.3 mmol) was combined with dioxane (100 mL) to give a colorless suspension. Sodium hydroxide (22.7 ml, 22.7 mmol, 1N) was added dropwise at 0°C within 10 min to give a colorless solution. Di-tert15 butyl dicarbonate (CAN 244245, 6.7 g, 30.9 mmol) was added in three portions. The reaction was stirred for 30 min to give a colorless suspension. Then dioxane (30 mL) was added (using less solvent resulted in a thick suspension) and the mixture was stirred for 17 h at ambient temperature. The reaction mixture was concentrated in vacuo to a volume of 50 mL and poured into 200 mL water. Then the mixture was washed with ethyl acetate (3 x 80 ml). The aqueous layers were combined, 2N hydrochloric acid was added to adjust the pH to 2, and the mixture was extracted with ethyl acetate (3 x 60 mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo to give product (1.0 g, 28%). b) tert-Butyl 3-(dimethylcarbamoyl)pentanylcarbamate N S N N N H O Cl OH O N H O O 2-(tert-butoxycarbonylamino)ethylbutanoic acid ((200 mg, 0.87 mmol), HATU (CAN 1488931, 660 mg, 1.74 mmol) and triethylamine (CAN 1218, 260 mg, 2.61 mmol) was added to a solution of dimethylamine hydrochloride (CAN 5062, 117 mg, 1.74 mmol) in DMF (10 mL). The mixture was stirred overnight at room temperature. The mixture was added to water (20 mL) and extracted with ethyl acetate (30 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by prep-HPLC (eluting with 30% ethyl acetate in petroleum ether) to give the product (120 mg, 53.7%); MS (EI): m/e = 259.2 [M+H]+ c) 2-Aminoethyl-N,N-dimethylbutanamide hydrogen chloride tert-Butyl 3-(dimethylcarbamoyl)pentanylcarbamate (0.12 g, 0.47 mmol) was added to a saturated solution of hydrochloride in ethyl acetate (5 mL) and the mixture was stirred overnight. The solvent was removed by reduced pressure to give the crude product (0.1 g); MS (EI): m/e = 159.2 [M+H]+ 15 . d) 6-(3-Chloro-phenyl)-pyridinecarboxylic acid (1-dimethylcarbamoylethyl-propyl)- amide The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl) pyridinecarboxylic acid (CAN 8637045) and 2-aminoethyl-N,N-dimethylbutyramide as starting materials, MS (EI): 374.2 [M+H]+ .
Example 24 6-Cyclohexyl-pyridinecarboxylic acid piperidinylamide N H O O O N H2N N O ClH N N H N O O Cl The title compound was synthesized in analogy to Example 1, using 6-cyclohexylpyridinecarboxylic acid (Example 7 b) and 1-piperidinamine (CAN 22136) as starting materials, MS (EI): 288.3 [M+H]+ .
Example 25 [5-Methyl(piperidinesulfonyl)-pyridinyl]-piperidinyl-methanone a) 5-Methylpyridinecarboxylic acid 1-oxide m-CPBA (CAN 9374, 5.0 g, 29.2 mmol) was added to a solution of 5-methyl10 pyridinecarboxylic acid (CAN 44343, 2.0 g, 14.6 mmol) in methylene chloride (50 mL) and the mixture was stirred overnight at room temperature. The solid was filtered off, quenched with a saturated solution of sodium thiosulfate (50 mL), and the mixture was extracted with methylene chloride (3 x 60 mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo to give yellow solid which was washed with ether (5 x 20 mL) to give the product (0.9 g, 40.3%); MS (EI): m/e = 154.1 [M+H]+ . b) 6-Chloromethyl-pyridinecarboxylic acid -Methylpyridinecarboxylic acid 1-oxide (0.9 g, 5.88 mmol) was added to phosphoryl trichloride (30 mL). The mixture was stirred at 105°C for 3 h. After that the mixture was cooled to room temperature, added to ice water slowly and extracted with methylene chloride (4 x 30 mL). The organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product (0.85 g, 84.3%); MS (EI): m/e = 172.0 [M+H]+ .
N N H N O N + O OH O N OH O Cl c) 5-Methylsulfo-pyridinecarboxylic acid 6-chloromethyl-pyridinecarboxylic acid (0.85 g, 4.97 mmol) and sodium sulfite (CAN 77577, 1.5 g, 11.9 mmol) were added to water (3 mL) and ethanol (3 mL). The mixture was heated to 180°C for 4 h in a sealed tube. After that the mixture was cooled to room temperature and a solid precipitated that was removed by filtration. The filtrate was concentrated and added to water (20 mL). The aqueous phase was washed with ethyl acetate (2 x 20 mL). Subsequently the aqueous phase was adjusted to pH = 2 with 2 N hydrochloric acid. Water was removed in vacuo to give the product as solid (1.2 g); MS (EI): m/e = 218.0 [M+H]+ 10 . d) 5-Methylsulfo-pyridinecarboxylic acid methyl ester To a mixture of 5-methylsulfo-pyridinecarboxylic acid (0.8 g, 3.69 mmol) in methanol (20 mL) was added 4 N hydrogen chloride in dioxane (8 mL). The mixture was stirred overnight at room temperature. Undissolved solid was filtered off, and the filtrate was concentrated to give the product as yellow solid 0.5 g; MS (EI): m/e = 232.0 [M+H]+ . e) 5-Methyl(piperidinesulfonyl)-pyridinecarboxylic acid methyl ester -Methylsulfo-pyridinecarboxylic acid methyl ester (340 mg, 1.47 mmol), thionyl chloride (CAN 77197, 1 mL) and 1 drop of DMF were added to methylene chloride (10 mL), and the mixture was stirred for 2 h at 40°C. The mixture was cooled to room temperature, and piperidine (CAN 1104, 1.0 g, 12 mmol) in methylene chloride (10 mL) was added to the above mixture. The solvent was removed in vacuo, and the crude product was purified by prep-HPLC (eluting with 50% ethyl acetate in petroleum ether) to give the product (53 mg, 12%); MS (EI): m/e = 299.1 [M+H]+ 25 .
N OH O S O O HO N O O S O O HO N O S O O O N f) 5-Methyl(piperidinesulfonyl)-pyridinecarboxylic acid -Methyl(piperidinesulfonyl)-pyridinecarboxylic acid methyl ester (53 mg, 0.178 mmol) in dioxane (2 mL) was added to a solution of lithium hydroxide monohydrate (CAN 13103, 0.1 g, 2.38 mmol) in water (2 mL) and the mixture was stirred for 2 h at room temperature. The solvent was removed in vacuo, water (10 mL) was added, and the pH was adjusted to 3 with1 N hydrochloric acid. The mixture was extracted by ethyl acetate (2 x 10 mL). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give the product (36 mg, 71%); MS (EI): m/e = 285.2 [M+H]+ 10 . g) [5-Methyl(piperidinesulfonyl)-pyridinyl]-piperidinyl-methanone The title compound was synthesized in analogy to Example 1, using 5-methyl (piperidinesulfonyl)-pyridinecarboxylic acid and piperidine (CAN 1104) as starting materials, MS (EI): 352.2 [M+H]+ 15 .
Example 26 6-(3-Chloro-phenyl)-pyridinecarboxylic acid (2-methyl-tetrahydro-pyranyl)- amide The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl) pyridinecarboxylic acid (CAN 8637045) and tetrahydromethyl-2H-pyranamine (CAN 895845) as starting materials, MS (EI): m/e = 331.1 [M+H]+ .
N OH O S O O N S N N N O O O N N H O O Cl Example 27 2-[(6-Cyclopropylmethoxypyrrolidinyl-pyridinecarbonyl)-amino]methylpropionic acid methyl ester The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxypyrrolidinyl-pyridinecarboxylic acid (Example 14 a) and 2- methyl-alanine methyl ester as starting materials, MS (LC/MS): 362.2 [M+H]+ .
Example 28 6-(3-Chloro-phenyl)-pyridinecarboxylic acid [1-methyl(3-methyl-isoxazolyl)- ethyl]-amide a) 1-Methyl(3-methyl-isoxazolyl)-ethylamine To a solution of (E)-acetaldehyde oxime (CAN 1079, 1.0 g, 16.9 mmol), 2-methylbut3-ynamine (CAN 29787, 1.4 g, 16.9 mmol) and triethylamine (CAN 1218, 0.17 g, 1.69 mmol) in methylene chloride (25 mL) at 0°C was added a 5% aqueous solution of sodium hypochlorite (5%, 42.6 g) over 3 h. The reaction was allowed to warm to 4°C and stirring continued for 5 h. The organic layer was separated, and the aqueous layer was extracted with methylene chloride (50 mL). The combined methylene chloride extracts were washed with saturated aqueous sodium chloride (60 mL) and dried over anhydrous magnesium sulfate. The solvent was removed to give a yellow oil. The crude product was purified by column chromatography (silica gel 30 g, eluting with 30% ethyl acetate in petroleum ether) to yield the product as yellow solid (0.1 g, 4.2%); MS (EI): m/e = 141.2 [M+H]+ . b) 6-(3-Chloro-phenyl)-pyridinecarboxylic acid [1-methyl(3-methyl-isoxazolyl)- ethyl]-amide N N H N O O O O N O H2N The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl) pyridinecarboxylic acid (CAN 8637045) and 1-methyl(3-methyl-isoxazolyl)- ethylamine as starting materials, MS (EI): 356.0 (M+H)+ .
Example 29 6-(3-Chloro-phenyl)-pyridinecarboxylic acid (1-ethylhydroxymethyl-propyl)- amide The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl) pyridinecarboxylic acid (CAN 8637045) and 2-aminoethylbutanol (CAN 19792- 52-0) as starting materials, MS (LC/MS): 333.1 (M+H).
Example 30 6-(3-Chloro-phenyl)-pyridinecarboxylic acid (tetrahydro-pyranyl)-amide The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl) pyridinecarboxylic acid (CAN 8637045) and tetrahydro-2H-pyranamine (CAN 1208117) as starting materials, MS (LC/MS): 317.1 (M+H).
Example 31 (6-Cyclopropylmethoxypyrrolidinyl-pyridinyl)-(2-oxaaza-spiro[3.3]hept yl)-methanone N O N N H O Cl N N H O Cl OH N N H O O Cl The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxypyrrolidinyl-pyridinecarboxylic acid (Example 14 a) and 2- oxaazaspiro[3.3]heptane (CAN 1747) as starting materials, MS (EI): m/e = 344.3 [M+H]+ 5 .
Example 32 6-Cyclopropylmethoxy(2-methyl-pyrrolidinyl)-pyridinecarboxylic acid ((S)- 1-carbamoylmethyl-butyl)-amide a) 6-Cyclopropylmethoxy(2-methyl-pyrrolidinyl)-pyridinecarboxylic acid Under an atmosphere of nitrogen, a solution of 5-bromo(cyclopropylmethoxy)- pyridinecarboxylic acid (Example 9 d, 0.4 g, 1.5 mmol), 2-methylpyrrolidine (CAN 7658, 188 mg, 2.2 mmol), R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (CAN 761894, 183 mg, 0.3 mmol), tris-(dibenzylidene-acetone)dipalladium (CAN 51364- 51-3, 135 mg, 0.15 mmol) and cesium carbonate (1.9 g, 6 mmol) in toluene (50 mL) was heated to 90°C overnight. The reaction mixture was concentrated under reduced pressure.
The residue was dissolved in water (10 mL) and extracted with ethyl acetate (30 mL), the pH of the aqueous layer was adjusted to 2 by addition of 1 N hydrochloric acid and the resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with water and brine, dried over sodium sulfate and evaporated. The residue was purified by column chromatography (silica gel, 10 g, 50% ethyl acetate in petroleum ether) to yield the title compound (0.15 g, 36.9 %) as yellow solid; MS (EI): m/e = 277.2 [M+H]+ . b) 6-Cyclopropylmethoxy(2-methyl-pyrrolidinyl)-pyridinecarboxylic acid ((S) carbamoylmethyl-butyl)-amide N N N O O O N N O OH O The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(2-methyl-pyrrolidinyl)-pyridinecarboxylic acid and (2S) aminomethyl-pentanamide (CAN 6874) as starting materials, MS (LC/MS): 389.2 [M+H]+ 5 .
Example 33 6-Cyclopropylmethoxypyrrolidinyl-pyridinecarboxylic acid [1-methyl(5- methyl-[1,2,4]oxadiazolyl)-ethyl]-amide a) tert-Butyl 2-cyanopropanylcarbamate To a solution of tert-butyl 1-aminomethyloxopropanylcarbamate (Example 12 a, 12.5 g) and triethylamine (CAN 1218, 29 g) in methylene chloride (150 mL) was added trifluoroacetic acid anhydride (CAN 4070, 27.2 g) dropwise at 0°C. The resulting mixture was allowed to warm to room temperature and stirred for 4 h. After that the mixture was washed with water, 5 N citric acid and brine, the organic phase was dried over anhydrous sodium sulfate and concentrated to give the title compound (11 g, 97%) as a yellow solid; MS: m/e = 207.1 [M+Na]+ . b) (Z)-tert-Butyl 1-amino(hydroxyimino)methylpropanylcarbamate Potassium carbonate (3.64 g) was dissolved in water (12 mL) and hydroxylammonium chloride (CAN: 54701, 1.7 g, mmol) was added. A solution of tert-butyl 2- cyanopropanylcarbamate (4.84 g, 26 mmol) in ethanol (42 mL) was added and the resulting reaction mixture was stirred for 18 h at ambient temperature. The solvent was N N N H O O O NH2 O N H O N O N H O NH2 N OH removed under reduced pressure and the residue was diluted with ethyl acetate (20 mL).
The mixture was filtered and the filtrate was concentrated to yield the crude product (5 g, 87.6%) as yellow solid. MS: m/e = 218.2 [M+H]+ . c) tert-Butyl 2-(5-methyl-1,2,4-oxadiazolyl)propanylcarbamate To a solution of acetic acid (1.8 g) in DMF (50 mL) was added N,N'-carbonyldiimidazole (CAN 5301, 4.865 g, mmol). The solution was stirred at ambient temperature for 0.5 h. (Z)-tert-butyl 1-amino(hydroxyimino)methylpropanylcarbamate (6.07 g) was added and the reaction mixture was stirred at 120°C for 10 h. Removal of the solvent under reduced pressure left a yellow oil which was purified by column chromatography (silica gel 120 g, eluting with 30% ethyl acetate in petroleum ether) to give the title compound (5.38 g, 80%) as colorless oil; MS: m/e = 264.1 [M+Na]+ . d) α,α,5-Trimethyl-1,2,4-oxadiazolemethanamine tert-Butyl(5-methyl-1,2,4-oxadiazolyl)propanylcarbamate (5.38 g) was dissolved in in ethyl acetate (30 mL) saturated with hydrochloride and stirred at room temperature for 1 h. Then water (50 mL) was added. The aqueous phase was washed with ethyl acetate (2 x 30 mL) and the pH adjusted with 1 M sodium hydroxide solution to 9~10. The solution was extracted with ethyl acetate (2 x 30 mL). The combined extracts were washed with brine and dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure left the title compound (1.7 g, 54%) as colorless oil; MS: m/e 142.2 [M+H]+ . e) 6-Cyclopropylmethoxypyrrolidinyl-pyridinecarboxylic acid [1-methyl(5- methyl-[1,2,4]oxadiazolyl)-ethyl]-amide O N H O N N O H2N N N O N N N N H O N O O The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxypyrrolidinyl-pyridinecarboxylic acid (Example 14 a) and α,α,5-trimethyl-1,2,4-oxadiazolemethanamine (CAN 11538310) as starting materials, MS (LC/MS):386.2 [M+H]+ .
Example 34 6-Cyclopropylmethoxy(tetrahydro-pyranyl)-pyridinecarboxylic acid (1- methylthiazolyl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(tetrahydro-pyranyl)-pyridinecarboxylic acid (Example 9 f) and α,α-dimethylthiazolemethanamine (CAN 10823931) as starting materials, MS (LC/MS): 402.1 [M+H]+ .
Example 35 6-Cyclopropylmethoxypyrrolidinyl-pyridinecarboxylic acid (1,1-dimethyl morpholinyl-propyl)-amide a) 3-(tert-Butoxycarbonylamino)methylbutanoic acid 3-Aminomethylbutanoic acid (CAN 6258, 2.0 g, 17 mmol) was combined with dioxane (60 mL) to give a colorless suspension. 1 N sodium hydroxide solution (17.0 mL, 17.0 mmol) was added dropwise at 0°C within 10 min. Di-tert-butyldicarbonate (4.8 g, 22.2 mmol) was added in three portions. The reaction was stirred for 30 min to give a colorless suspension. Then dioxane (30 mL) was added (using less solvent resulted in a thick suspension) and the mixture was stirred for 17 hours at ambient temperature. The reaction mixture was concentrated in vacuo to a volume of 50 mL and poured into 200 mL water. Then the mixture was washed with ethyl acetate (3 x 80 ml). The aqueous layers were combined, 2 N HCl was added and after adjusting the pH to 2 the mixture was N N H N S O O O O O N H OH O extracted with ethyl acetate (3 x 60 mL). The organic layers were combined, dried over sodium sulfate and concentrated in vacuo to give product (2.7 g, 72.9%). b) tert-Butyl 2-methylmorpholinooxobutanylcarbamate 3-(tert-Butoxycarbonylamino)methylbutanoic acid (2.7 g, 12.4 mmol), HBTU (CAN 947901, 6.1 g, 16.1 mmol) and triethylamine (CAN 1218, 2.5 g, 24.8 mmol) was added to a solution of morpholine (CAN 1108, 2.2 g, 24.8 mmol) in methylene chloride (50 mL). The mixture was stirred overnight at room temperature. Aqueous hydrochloride (1 N, 50 mL) was added, and the mixture extracted with methylene chloride.
The organic extracts were washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (silica gel, 50 g, eluting with 30% ethyl acetate in petroleum ether) to give the product (2.1 g, 59%); MS (EI): m/e 287.1 [M+H]+ . c) 3-Aminomethylmorpholinobutanone hydrochloride tert-Butyl 2-methylmorpholinooxobutanylcarbamate (0.5 g, 1.7 mmol) was dissolved in a saturated solution of hydrogen chloride in ethyl acetate (20 mL). The mixture was stirred for 3 h. The solvent was removed by reduced pressure to give crude product (0.55 g). d) 1,1-Dimethylmorpholinyl-propylamine 3-Aminomethylmorpholinobutanone (0.55 g, 2.96 mmol) and borane in THF (1 M, 6 mL, 6 mmol) were mixed together. The mixture was stirred at room temperature overnight, another portion borane in THF (6 mL) was added and the mixture stirred for another day. Methanol (5 mL) was added and the solvent was removed in vacuo. Water (20 mL) was added and the mixture was extracted with ethyl acetate (3 x 20 mL). The LCN H O O O N O ClH H2N O N O H2N N O MS showed still product in the water phase which was now extracted with methylene chloride (2 x 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate and the solvent was removed in vacuo to give the crude product (0.09 g); MS (EI): m/e = 173.2 [M+H]+ . c) 6-Cyclopropylmethoxypyrrolidinyl-pyridinecarboxylic acid (1,1-dimethyl morpholinyl-propyl)-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxypyrrolidinyl-pyridinecarboxylic acid (Example 14 a) and 1,1- dimethylmorpholinyl-propylamine as starting materials, MS(EI): 417.2 [M+H]+ 10 .
Example 36 6-Cyclopropylmethoxymethyl-pyridinecarboxylic acid (1-methyl methylcarbamoyl-ethyl)-amide a) 5-Methylpyridinecarbonitrile A solution of 2-fluoromethylpyridine (CAN: 23699, 10 g, 90 mmol) and sodium cyanide (8.8 g, 180 mmol) in DMSO (15 mL) was heated to150°C for 48 h. Then water was added, the resulting mixture was extracted with ethyl acetate (3 x 50 mL) and the combined extracts were washed with sodium hypochlorite solution and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (silica gel, 40 g, 10% ethyl acetate in petroleum ether) to yield the title compound (3.2 g, 27 mmol, 30.1%) as yellow solid; MS (EI): m/e = 119.1 [M+H]+ . b) 5-Methyloxy-pyridinecarbonitrile N N N H N O O O N N N + N O m-CPBA (CAN 9374, 0.58 g, 3.4 mmol) was added in batches to a solution of 5- methylpyridinecarbonitrile (3 g, 25 mmol) in methylene chloride (60 mL) at room temperature and the reaction mixture was heated to 60°C overnight. Then the reaction mixture was washed with sodium thiosulphate solution (3 x 50 mL) and brine (3 x 50 mL), dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (silica gel, 35 g, 50% ethyl acetate in petroleum ether) to yield the title compound (2.6 g, 19 mmol, 77.6 %) as yellow solid; MS (EI): m/e =135.1 [M+H]+ . c) 6-Chloromethylpicolinonitrile 5-Methyloxy-pyridinecarbonitrile (2.6 g, 19 mmol) was added in batches to phosphorus oxychloride (CAN 100253, 20 mL) at 0°C. The reaction mixture was heated to 90°C for 2 h. The volatiles were then removed and the remaining residue was neutralized with a saturated solution of sodium bicarbonate. This mixture was extracted with ethyl acetate (3 x 30 mL) and the combined extracts were dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (silica gel, 30 g, 10% ethyl acetate in petroleum ether) to yield the title compound (1.6 g, mmol, 54.1%) as yellow solid; MS (EI): m/e = 153.1 [M+H]+ . d) 6-Cyclopropylmethoxymethyl-pyridinecarboxylic acid Sodium hydride (CAN 76467, 1.24 g, 37 mmol) was added in batches to a solution of cyclopropanemethanol (CAN 25168, 20 mL) and the reaction mixture was reacted for min at ambient temperature. Then 6-chloromethylpicolinonitrile (1.1 g, 7.2 mmol) was added to the above reaction mixture. The reaction mixture was heated to 100°C overnight, quenched with water and evaporated. The residue was dissolved in water, extracted with ethyl acetate (50 mL). The pH of the aqueous layer was adjusted to 2 by addition of 1 N hydrochloric acid and the resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by column N N Cl O N OH O chromatography (silica gel, 25 g, 50% ethyl acetate in Petroleum ether) to yield the title compound (1 g, 5 mmol, 67%) as yellow solid; MS (EI): m/e = 208.1 [M+H]+ . e) 6-Cyclopropylmethoxymethyl-pyridinecarboxylic acid (1-methyl methylcarbamoyl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxymethyl-pyridinecarboxylic acid and 2-amino-N,2-dimethylpropanamide (CAN 1069142) as starting materials, MS (EI): m/e = 318.1 [M+H]+ .
Example 37 6-(Tetrahydro-pyranyl)-pyridinecarboxylic acid piperidinylamide a) 6-(3,6-Dihydro-2H-pyranyl)-pyridinecarboxylic acid Under an atmosphere of nitrogen, a solution of 6-bromo-pyridinecarboxylic acid (CAN: 211904, 1 g, 4.9 mmol), 2-(3,6-dihydro-2H-pyranyl)-4,4,5,5-tetramethyl15 1,3,2-dioxaborolane (Example 9-d, 1.1 g, 5.4 mmol), 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride methylene chloride complex (CAN 954644, 0.08 g, 0.1 mmol) and potassium carbonate (1.37 g, 10 mmol) in water (50 mL) was stirred for 24 h at 100°C. The reaction mixture was extracted with ethyl acetate (50 mL), the pH of the aqueous layer was adjusted to 2 by addition of 1 N hydrochloric acid and the resulting mixture was extracted with ethyl acetate (3 x 50 mL).
The combined organic extracts were washed with brine（6 x 50 mL), dried over anhydrous sodium sulfate and evaporated. The residue was purified by prep-HPLC to yield the title compound (0.3 g, 1.5 mmol, 29.5%) as white solid; MS (EI): m/e = 206.1 [M+H]+ . b) 6-(Tetrahydro-pyranyl)-pyridinecarboxylic acid N N H O O O N H N OH O O The title compound was synthesized in analogy to Example 7 b, using 6-(3,6-dihydro-2Hpyranyl)-pyridinecarboxylic acid and 10% Pd/C as starting materials, MS (EI): m/e 208.1 [M+H]+ . c) 6-(Tetrahydro-pyranyl)-pyridinecarboxylic acid piperidinylamide The title compound was synthesized in analogy to Example 1, using 6-(tetrahydro-pyran4-yl)-pyridinecarboxylic acid and 1-piperidinamine (CAN 22136) as starting materials, MS (LC/MS): 290.2 [M+H]+ .
Example 38 6-(3-Chloro-phenyl)-pyridinecarboxylic acid [(S)cyclopropyl(5-methyl1,2,4]oxadiazolyl)-ethyl]-amide a) (S)-tert-Butyl 1-aminocyclopropyloxopropanylcarbamate A mixture of (S)(tert-butoxycarbonylamino)cyclopropylpropanoic acid (CAN 894837, 10 g, 44 mmol), di-tert-butyl dicarbonate (CAN:244245, 14.28 g, 66 mmol) and pyridine (2.4 mL) in acetonitrile (200 mL) was stirred at room temperature for min. Ammonia (10 mL) was added dropwise for 20 min. The resulting reaction mixture was stirred for 4 h. During removal of most of the solvent under reduced pressure the product precipitated and the solid was filtered off and washed with acetonitrile (20 mL).
The solid was dried under reduced pressure to give the title compound (7.73 g, 78%) as white solid; MS (EI): m/e 251.2 [M+Na]+ . b) (S)-tert-Butyl 1-cyanocyclopropylethylcarbamate N OH O O N N H N O O O N H O NH2 O To a solution of (S)-tert-butyl 1-aminocyclopropyloxopropanylcarbamate (3.7 g, 16 mmol) and triethylamine (6.55 g, 65 mmol) in methylene chloride (50 mL) was added trifluoroacetic acid anhydride (6.81 g, 32 mmol) dropwise at 0°C. The resulting mixture was allowed to warm to room temperature and stirred for 4 h. The mixture was washed with water (150 mL), citric acid (150 mL, 5 M) and brine (150 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to give product (3.31 g, 97%) as a yellow solid; MS (EI): m/e 233.1 [M+Na]+ . c) (S, Z)-tert-Butyl 1-aminocyclopropyl(hydroxyimino)propanylcarbamate Potassium carbonate (2.18 g, 16 mmol) was dissolved in water (8 mL) and hydroxylamine hydrochloride (1.1 g, 16 mmol) was added. A solution of (S)-tert-butyl 1-cyano cyclopropylethylcarbamate (3.31 g, 16 mmol) in ethanol (24 mL) was added thereto and the resulting reaction mixture was stirred for 72 h. After evaporation of solvents, the residue was dissolved with ethyl acetate (20 mL) and then filtered. The filtrate was concentrated to yield crude product as yellow solid (3.61 g, 94%); MS (EI): m/e 244.2 [M+H]+ . d) (S)-tert-Butyl 2-cyclopropyl(5-methyl-1,2,4-oxadiazolyl)ethylcarbamate To a solution of acetic acid (0.224 g, 4 mmol) in DMF (5 mL) was added N,N'- carbonyldiimidazole (0.6 g, 4 mmol) and the mixture was stirred for 0.5 h at room temperature. (S,Z)-tert-butyl 1-aminocyclopropyl(hydroxyimino)propan ylcarbamate (0.84 g, 3 mmol) was added and the mixture was heated to 120°C and stirred for 4 h. After evaporation of solvents, the residue was purified by column chromatography O N H O N O N H O N NH2 OH O N H O N O N (silica gel, 20 g, eluting with 10% ethyl acetate in petroleum ether) to give the title compound (0.5 g; 54%) as yellow solid; MS (EI): m/e 290.1 [M+Na]+ . e) (S)Cyclopropyl(5-methyl-[1,2,4]oxadiazolyl)-ethylamine A solution of (S)-tert-butyl 2-cyclopropyl(5-methyl-1,2,4-oxadiazol yl)ethylcarbamate (0.5 g, 2 mmol) in sat. hydrochloric acid (10 mL) was stirred at room temperature for 1 h. Then water (20 mL) was added. The water phase was washed with ethyl acetate (2 x 20 mL) and adjusted with 2 M sodium hydroxide solution to pH = 9~10.
It was then extracted with ethyl acetate (2 x 20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated to give crude product as a white solid (0.25 g, 80%); MS (EI): m/e 168.2 [M+H]+ . f) 6-(3-Chloro-phenyl)-pyridinecarboxylic acid [(S)cyclopropyl(5-methyl1,2,4]oxadiazolyl)-ethyl]-amide The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl) pyridinecarboxylic acid (CAN 8637045) and (S)cyclopropyl(5-methyl- [1,2,4]oxadiazolyl)-ethylamine as starting materials, MS (EI): m/e 383.1 [M+H]+ .
Example 39 (5-Cyclopentylcyclopropylmethoxy-pyridinyl)-(1,1-dioxidotetrahydro-2H20 thiopyranyl)-methanone a) 5-Cyclopentenyl(cyclopropylmethoxy)-pyridinecarboxylic acid H2N N O N N N N N H O O Cl Chiral The mixture of 5-bromo(cyclopropylmethoxy)-pyridinecarboxylic acid (Example 9 d, 1.0 g, 4 mmol), 2-cyclopentenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAN 287944- -9, 0.86 g, 4 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride methylene chloride complex (CAN 954644, 150 mg 0.18 mmol) and aqueous sodium carbonate solution (2N, 16 mL) was added to DMF (10 ml). The mixture was heated to 100°C overnight; then the solution was diluted with water (15 mL), extracted with ethyl acetate (30 mL), the water layer was adjusted to pH = 3.0 by hydrochloric acid (3N) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with water (2 x 100 mL) and brine (80 mL) and evaporated to dryness. The residue was purified by column chromatography (silica gel, 8 g, eluting with 15% ethyl acetate in petroleum ether) to obtain the product (0.85 g, 89%) as a white solid; MS (LC/MS): 260.1 [M+H]+ . b) 5-Cyclopentylcyclopropylmethoxy-pyridinecarboxylic acid The mixture of 5-cyclopentenyl(cyclopropylmethoxy)-pyridinecarboxylic acid (0.95 g, 4 mmol), Pd/C (10%w/w, 0.2 g) in 30 mL of ethanol in a hydrogen atmosphere was stirred for 4 h at room temperature. The mixture was filtered and the filtrate was evaporated to dryness to obtain the product (0.76 g, 79%) as white solid. The product was directly used for the next step; MS (LC/MS): 262.1 [M+H]+ . c) (5-Cyclopentylcyclopropylmethoxy-pyridinyl)-(1,1-dioxidotetrahydro-2Hthiopyranyl)-methanone O N OH O O N OH O S N N O O O O The title compound was synthesized in analogy to Example 1, using 5-cyclopentyl cyclopropylmethoxy-pyridinecarboxylic acid and 1,1-dioxide-thiomorpholine (CAN 390931) as starting materials, MS (LC/MS): 379.2 [M+H]+ .
Example 40 5-Cyclopentylcyclopropylmethoxy-pyridinecarboxylic acid (1-methyl methylcarbamoyl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopentyl cyclopropylmethoxy-pyridinecarboxylic acid (Example 39 b) and 2-amino-N,2- dimethyl-propanamide (CAN 1069142) as starting materials, MS (LC/MS): 360.2 [M+H]+ .
Example 41 6-(3-Chloro-phenyl)-pyridinecarboxylic acid [1-methyl(5-methyl- [1,2,4]oxadiazolyl)-ethyl]-amide The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl) pyridinecarboxylic acid (CAN 8637045) and α,α,5-trimethyl-1,2,4-oxadiazole methanamine (Example 33 d, CAN 11538310) as starting materials, MS (LC/MS): 357.1 [M+H]+ .
Example 42 -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid piperidinylamide a) 5-Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid N N H O O O N H N N N N H O O Cl A mixture of 5-bromo(cyclopropylmethoxy)-pyridinecarboxylic acid (Example 9 d, 1.5 g, 5.5 mmol), cyclopropylboronic acid (CAN 4112359, 0.57 g, 7 mmol), palladium diacetate (CAN 33753, 62 mg, 0.28 mmol), tricyclohexylphosphine (CAN 26222, 154 mg, 0.1 mmol) and potassium phosphate (4.1 g, 19 mmol) in toluene/water (20/1v/v, mL) was heated to 100°C overnight. After that the mixture was evaporated to dryness, dissolved in 30 mL of water, extracted with ethyl acetate (30 mL) and the organic layer was dropped. The water layer was adjusted to pH = 3 and extracted with ethyl acetate (2 x mL), this organic layer was washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate then evaporated to dryness. The residue was purified by column chromatography (silica gel, 10 g, eluting with 15% ethyl acetate in petroleum ether) to obtain the title compound (0.96 g, 75%) as white solid; MS (LC/MS): 234.1 [M+H]+ . b) 5-Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid piperidinylamide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethoxy-pyridinecarboxylic acid and 1-piperidinamine (CAN 22136) as starting materials, MS (LC/MS): 316.2 [M+H]+ .
Example 43 -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid (1-methyl methylcarbamoyl-ethyl)-amide O N OH O N N H O N O N N H O O O N H The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethoxy-pyridinecarboxylic acid (Example 42 a) and 2-amino-N,2- dimethyl-propanamide (CAN 1069142) as starting materials, MS (LC/MS): 332.2 [M+H]+ .
Example 44 -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid (1-methylthiazol2-yl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethoxy-pyridinecarboxylic acid (Example 42 a) and α,α-dimethyl thiazolemethanamine (CAN 10823931) as starting materials, MS (LC/MS): 358.1 [M+H]+ .
Example 45 -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [1-methyl(5- methyl-[1,2,4]oxadiazolyl)-ethyl]-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethoxy-pyridinecarboxylic acid (Example 42 a) and α,α,5-trimethyl-1,2,4- oxadiazolemethanamine (CAN 11538310) as starting materials, MS (LC/MS): 357.1 [M+H]+ 20 .
Example 46 6-(4-Chloro-phenyl)-pyridinecarboxylic acid piperidinylamide N N H N O S O N N N N H O O O The title compound was synthesized in analogy to Example 1, using 6-(4-chlorophenyl) pyridinecarboxylic acid (CAN 1354328) and 1-piperidinamine (CAN 22136) as starting materials, MS (EI): m/e = 316.1 [M+H]+ .
Example 47 6-Cyclopropylmethoxymethyl-pyridinecarboxylic acid piperidinylamide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxymethyl-pyridinecarboxylic acid (Example 36 d) and 1- piperidinamine (CAN 22136) as starting materials, MS (EI): m/e 290.2 [M+H]+ 10 .
Example 48 [6-(3-Chloro-phenyl)cyclopropyl-pyridinyl]-(1,1-dioxidotetrahydro-2Hthiopyranyl)-methanone a) 5-Cyclopropyl-pyridinecarboxylic acid methyl ester -Bromo-pyridinecarboxylic acid methyl ester (CAN 296823, 2.16 g, 0.01 mol), cyclopropylboronic acid (CAN 4112359, 0.9 g, 0.01 mol), tris(dibenzylideneacetone)dipalladium (CAN 524090, 0.2 g), 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (CAN 1612658, 0.3 g) and cesium carbonate (CAN 5348, 3.3 g, 0.01 mol) was added into 1.4-dioxane (40 mL). The mixture was stirred for 12 h at 110°C under nitrogen atmosphere. Subsequently, the mixture was filtered and concentrated. The residue was poured into water (20 mL) and extracted with ethyl acetate N N H N O Cl N N H O N O N O O (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give crude product. The crude product was purified by a flash column chromatography (silica gel, 50 g, eluting with 20% ethyl acetate in petroleum ether) to give product (0.8 g, 45%); MS (EI): m/e 178.1 [M+H]+ . b) 5-Cyclopropyloxy-pyridinecarboxylic acid methyl ester -Cyclopropyl-pyridinecarboxylic acid methyl ester (0.8 g, 5 mmol) and m-CPBA (CAN 9374, 1.2 g, 7 mmol) was added into methylene chloride (15 mL). The mixture was stirred for 6 hours at 60°C. Subsequently the mixture was concentrated to the crude product. The crude product was purified by a flash column chromatography (silica gel, 20 g, eluting with ethyl acetate) to give product (0.3 g, 34%); MS (EI): m/e 194.1 [M+H]+ . c) 6-Bromocyclopropyl-pyridinecarboxylic acid methyl ester -Cyclopropyloxy-pyridinecarboxylic acid methyl ester (0.3 g, 2 mmol) was added into phosphorus oxybromide (CAN 77895, 5 g, 17 mmol). The mixture was stirred for 2 h at 80°C. Subsequently, the reaction solution was poured into water (30 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated to give crude product. The crude product was purified by a flash column chromatography (silica gel, 10 g, 20%, ethyl acetate in petroleum ether) to give product (0.1 g, 25%); MS: (EI) m/e 256.0 [M+H]+ 20 . d) 6-(3-Chloro-phenyl)cyclopropyl-pyridinecarboxylic acid methyl ester N + O O O N O O Br 6-Bromocyclopropyl-pyridinecarboxylic acid methyl ester (0.1 g, 0.4 mmol), 3- chlorophenylboronic acid (CAN 635036, 0.08 g, 0.5 mmol), 1,1'- bis(diphenylphosphino)-ferrocene-palladium(II)dichloride methylene chloride adduct (CAN 954644, 50 mg) and cesium carbonate (CAN 5348, 0.2 g, 0.6 mmol) was added into 1,4-dioxane (10 mL) under nitrogen atmosphere. The mixture was stirred for 12 h at 110°C. Subsequently, the mixture was concentrated to give crude product. The crude product was purified by a flash column chromatography (silica gel, 5 g, 20% ethyl acetate in petroleum ether) to give product (80 mg, 71%); MS: (EI) m/e 288.1 [M+H]+ . e) 6-(3-Chloro-phenyl)cyclopropyl-pyridinecarboxylic acid 6-(3-Chloro-phenyl)cyclopropyl-pyridinecarboxylic acid methyl ester (80 mg, 0.28 mmol) and sodium hydroxide (CAN 13102, 30 mg,) was added into water (10 mL).
The mixture was stirred for 2 h at ambient temperature. Subsequently the pH was adjusted to 3 with 1M hydrochloric acid, the mixture extracted with ethyl acetate (3 x 10 mL), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give product (60 mg, 78%); MS (EI): m/e 274.1 [M+H]+ . f) [6-(3-Chloro-phenyl)cyclopropyl-pyridinyl]-(1,1-dioxidotetrahydro-2H-thiopyran4-yl)-methanone N O O Cl N OH O Cl S N N O O O Cl The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)- -cyclopropyl-pyridinecarboxylic acid and 1,1-dioxide-thiomorpholine (CAN 39093- 93-1) as starting materials, MS (LC/MS): m/e 391.0 [M+H]+ .
Example 49 6-(3-Chloro-phenyl)methyl-pyridinecarboxylic acid (1-methyloxazolylethyl)-amide a) 5-Methyl-pyridinecarbonitrile 2-Fluoromethylpyridine (CAN 23699, 50 g, 90 mmol) and sodium cyanide (CAN 1439, 70 g, 1.43 mol) were dissolved in DMSO (200 mL), the mixture was stirred for 3 days at 150°C. The mixture was cooled to room temperature, ice water (200 mL) was added and the product was obtained as red solid (26.5 g, 50%) by filtration and drying; MS (EI): m/e 119.1 [M+H]+ . b) 5-Methyloxy-pyridinecarbonitrile Hydrogen peroxide (CAN 77221, 30%, 30 mL) was added to a solution of 5-methylpyridinecarbonitrile (3.0 g, 25 mmol) in acetic acid (30 mL) and the mixture was stirred at 60°C overnight. The solvent was removed by reduced pressure to give the crude product (3.0 g, 88%); MS (EI): m/e 135.1[M+H]+ . c) 6-Bromomethyl-pyridinecarbonitrile -Methyloxy-pyridinecarbonitrile (example 36 b, 1.5 g, 11 mmol) and phosphorus oxide tribromide (CAN 77895, 10 g) were mixed together. The mixture was stirred for 1 h at 100°C. Ice water was added, and the mixture extracted with ethyl acetate (10 mL).
The organic phase was dried over anhydrous sodium sulfate and concentrated to give the crude product (1.0 g, 41.6%); MS (EI): m/e 197.0 [M+H]+ .
N N N + N O N N Br d) 6-Bromomethyl-pyridinecarboxylic acid 6-Bromomethyl-pyridinecarbonitrile (1.0 g, 5.0 mmol) was added to a solution of sodium hydroxide (0.3 g, 7 mmol) in water (20 mL), the mixture was stirred at 120°C overnight. Subsequently, the mixture was adjusted to pH = 3 and extracted with ethyl acetate (2 x 15 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated to give the product (0.7 g, 63.8%); MS (EI): m/e 216.0 [M+H]+ . e) 6-(3-Chloro-phenyl)methyl-pyridinecarboxylic acid 3-Chlorophenylboronic acid (CAN 635036, 0.61 g, 3.9 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride methylene chloride complex (CAN 95464- 05-4, 53 mg, 0.065 mmol) and potassium carbonate (CAN 5847, 0.54 g, 3.9 mmol) was added to a solution of 6-bromomethyl-pyridinecarboxylic acid (0.7 g, 3.2 mmol) in water ( 30 mL). The mixture was stirred at 100°C overnight. The reaction mixture was adjusted to pH = 3 and the mixture was extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo to give product (0.55 g, 56.9%); MS (EI): m/e 248.1 [M+H]+ . f) 6-(3-Chloro-phenyl)methyl-pyridinecarboxylic acid (1-methyloxazolyl20 ethyl)-amide The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)- -methyl-pyridinecarboxylic acid and α,α-dimethyloxazolemethanamine (CAN 12115194) as starting materials, MS (EI):356.1 (M+H)+ .
Br N OH O N OH O Cl N O Cl O N N H Example 50 6-(3-Chloro-phenyl)methyl-pyridinecarboxylic acid (1-methylthiazolylethyl)-amide The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)- -methyl-pyridinecarboxylic acid (Example 49 e) and α,α-dimethyl thiazolemethanamine (CAN 10823931) as starting materials, MS (EI): 372.0 [M+H]+ .
Example 51 6-(3-Chloro-phenyl)methyl-pyridinecarboxylic acid [1-methyl(5-methyl10 [1,2,4]oxadiazolyl)-ethyl]-amide The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)- -methyl-pyridinecarboxylic acid (Example 49 e) and α,α,5-trimethyl-1,2,4-oxadiazole3-methanamine (CAN 11538310) as starting materials, MS (EI): 371.1 [M+H]+ .
Example 52 6-(3-Chloro-phenyl)methyl-pyridinecarboxylic acid piperidinyl-amide The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)- -methyl-pyridinecarboxylic acid (Example 49 e) and 1-piperidinamine (CAN 2213 6) as starting materials, MS (EI): 330.1 [M+H]+ 20 .
N O Cl S N N H N O Cl N O N N H N N H O Cl N Example 53 -Cyclopentylcyclopropylmethoxy-pyridinecarboxylic acid [(S)cyclopropyl (5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopentyl cyclopropylmethoxy-pyridinecarboxylic acid (Example 39 b) and (S)cyclopropyl (5-methyl-[1,2,4]oxadiazolyl)-ethylamine (Example 38 e) as starting materials, MS (LC/MS): 411.2 [M+H]+ .
Example 54 5-Cyclopentylcyclopropylmethoxy-pyridinecarboxylic acid [1-methyl(5- methyl-[1,2,4]oxadiazolyl)-ethyl]-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopentyl cyclopropylmethoxy-pyridinecarboxylic acid (Example 39 b) and α,α,5-trimethyl-1,2,4- oxadiazolemethanamine (CAN 11538310, Example 33 d) as starting materials, MS (LC/MS): 385.2 [M+H]+ .
Example 55 -Cyclopentylcyclopropylmethoxy-pyridinecarboxylic acid (1-methylthiazol2-yl-ethyl)-amide O N N H O N O N Chiral N O O N O N N H The title compound was synthesized in analogy to Example 1, using 5-cyclopentyl cyclopropylmethoxy-pyridinecarboxylic acid (Example 39 b) and α,α-dimethyl thiazolemethanamine (CAN 10823931) as starting materials, MS (LC/MS): 386.1 [M+H]+ 5 .
Example 56 6-(3-Chloro-phenyl)-pyridinecarboxylic acid ((S)methylthiazolyl-butyl)- amide a) (S)(tert-Butoxycarbonylamino)methylpentanoic acid To a mixture of L-leucine (CAN: 615, 8 g, 0.061 mmol) in 1,4-dioxane (200 mL) was added aqueous sodium hydroxide solution (1N, 8.5 mL) and di-tert-butyl dicarbonate (17.5 g, 80 mmol), and the mixture was stirred overnight. After evaporation of solvents, the residue was diluted with water (50 mL) and washed with ethyl acetate (2 x 50 mL).
The aqueous phase was adjusted to pH = 2~3 and then extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate and concentrated to give product (6.75 g, 48%) as a white solid; MS (EI): m/e = 232.2 [M+H]+ . b) (S)-tert-Butyl 1-aminomethyloxopentanylcarbamate A mixture of (S)(tert-butoxycarbonylamino)methylpentanoic acid (1.8 g), di-tertbutyl dicarbonate (CAN:244245, 12 mmol) and pyridine (3 mL) in CH3CN (50 mL) O N N H O N S O N H O O OH O N H O O NH2 was stirred at room temperature for 20 min. Ammonium hydroxide solution (25% - 28% NH3, 15 mL) was added dropwise during 30 min. The resulting reaction mixture was stirred overnight. During the removal of solvents, the product precipitated, was collected by filtration and dried to give the target compound as a white solid (1.55 g, 86%). MS (EI): m/e = 253.2 [M+Na]+ 5 . c) ((S)Methylthiocarbamoyl-butyl)-carbamic acid tert-butyl ester A mixture of (S)-tert-butyl 1-aminomethyloxopentanylcarbamate (1.8 g, 8 mmol) and Lawesson's reagent (1.58 g, 4 mmol) in toluene (20 mL) was stirred at 90°C for 2.5 h.
After removal of the solvent under reduced pressure, the residue was purified by column chromatography (silica gel, 30 g, ethyl acetate/MeOH, 20/1) to yield the title compound (1.38 g, 72%) as yellow solid; MS: m/e 269.2 [M+H]+ . d) (S)-α-(2-Methylpropyl)thiazolemethanamine acetate A mixture of ((S)methylthiocarbamoyl-butyl)-carbamic acid tert-butyl ester (1.38 g, 6 mmol), 2-bromo-1,1-dimethoxyethane (CAN:72527, 1.14 g, 7 mmol) and p-toluene sulfonic acid (50 mg) in acetic acid (20 mL) was stirred at 120°C for 4 . After evaporation of solvents, the residue was diluted with ethyl acetate (20 mL) and water (20 mL). The aqueous phase was washed with ethyl acetate (3 x 20 mL) and lyophilized to give a brown solid (0.6 g, 63%); MS: m/e 171.1 [M+H+ 20 ]. e) 6-(3-Chloro-phenyl)-pyridinecarboxylic acid ((S)methylthiazolyl-butyl)- amide O N H O S NH2 H2N N S Chiral CH3COOH N N H N S O Cl Chiral The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl) pyridinecarboxylic acid (CAN 8637045) and (S)-α-(2-methylpropyl) thiazolemethanamine as starting materials, MS (LC/MS): 386.1 [M+H]+ .
Example 57 6-Cyclopropylmethoxymethyl-pyridinecarboxylic acid [(S)cyclopropyl(5- methyl-[1,2,4]oxadiazolyl)-ethyl]-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxymethyl-pyridinecarboxylic acid (Example 36 d) and (S) cyclopropyl(5-methyl-[1,2,4]oxadiazolyl)-ethylamine (Example 38 e) as starting materials, MS (EI): m/e 357.2 [M+H]+ .
Example 58 -Chloro(3-chloro-phenyl)-pyridinecarboxylic acid (1-methylthiazolylethyl)-amide a) 5-Chlorooxy-pyridinecarboxylic acid A mixture of 5-chloro-pyridinecarboxylic acid (CAN 868731, 6.3 g, 0.04 mol) and m-CPBA (CAN 9374, 20.7 g, 0.12 mol) in methylene chloride (200 ml) was stirred overnight at 40oC. After evaporation of solvents, the crude product was purified by column chromatography (silica gel, 200 g, petroleum ether/ethyl acetate 4/1 firstly, then methanol/ ethyl acetate 1/1) to give the title compound (6.5 g, 94%) as yellow solid; MS (EI): m/e = 174.0 [M+H]+ . b) 6-Bromochloro-pyridinecarboxylic acid N N N N H O O O Chiral N + O Cl OH O -Chlorooxy-pyridinecarboxylic acid (3.5 g, 20mmol) was added into phosphorus oxide tribromide (CAN 77895, 30 g) at 80oC, stirred for 2 h. The mixture was poured into water (100 mL), extracted with ethyl acetate (3 x 50 mL), dried over anhydrous sodium sulfate, and solvent removed in vacuo. The crude product was purified by column chromatography (silica gel, 100 g, eluting with 50% ethyl acetate in petroleum ether) to give the title compound (1.12 g, 23%) as grey solid; MS (EI): m/e 236.0 [M+H]+ . c) 5-Chloro(3-chloro-phenyl)-pyridinecarboxylic acid Under nitrogen atmosphere, 6-bromochloro-pyridinecarboxylic acid (0.38 g, 1.6 mmol), 3-chlorophenylboronic acid (CAN 635036, 0.33 g, 2.1 mmol), 1,1'- bis(diphenylphosphino)-ferrocene-palladium(II) dichloride methylene chloride complex (CAN 954644, 30 mg) and cesium carbonate (CAN 5348, 1.6 g, 4.8 mmol) was added into DMF (30 mL). The mixture was stirred at 80oC overnight. After evaporation of solvents, the crude product was purified by column chromatography (silica gel, 12 g, petroleum ether/ethyl acetate 4/1 firstly, then methanol/ methylene chloride 1/10) to give the title compound (0.14 g, 32%) as brown solid; MS (EI): m/e = 268.0 [M+H]+ . d) 5-Chloro(3-chloro-phenyl)-pyridinecarboxylic acid (1-methylthiazolylethyl)-amide The title compound was synthesized in analogy to Example 1, using 5-chloro(3-chlorophenyl)-pyridinecarboxylic acid and α,α-dimethylthiazolemethanamine (CAN 10823931) as starting materials, MS (LC/MS): 392.0 [M+H]+ .
Br N Cl OH O N OH O Cl Cl N N H N S O Cl Cl Example 59 6-Cyclopropylmethoxy(tetrahydro-pyranyl)-pyridinecarboxylic acid ((S) cyclopropylthiazolyl-ethyl)-amide a) (S)-tert-Butyl 1-aminocyclopropylthioxopropanylcarbamate A mixture of (S)-tert-butyl 1-aminocyclopropyloxopropanylcarbamate (Example 38 a, 6.7 g, 29 mmol) and Lawesson's reagent (CAN 191725, 6.06 g, 15 mmol) in toluene (60 mL) was stirred at 90°C for 2.5 h. After removal of the solvent in vacuo, the residue was purified by column chromatography (silica gel, 100 g, eluting with 5% methanol in ethyl acetate) to yield the title compound (5.1 g, 71%) as yellow solid; MS: m/e = 267.1 [M+Na]+ b) (S)Cyclopropylthiazolyl-ethylamine acetate In analogy to the procedure described in Example 56 d, the title compound was obtained as yellow oil starting from (S)-tert-butyl 1-aminocyclopropylthioxopropan ylcarbamate (0.75 g, 31%); MS: m/e = 169.1 [M+H]+ . c) 6-Cyclopropylmethoxy(tetrahydro-pyranyl)-pyridinecarboxylic acid ((S) cyclopropylthiazolyl-ethyl)-amide O N H O S NH2 H2N S N CH3COOH N N H N O S O O Chiral The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(tetrahydro-pyranyl)-pyridinecarboxylic acid (Example 9 f) and (S)cyclopropylthiazolyl-ethylamine as starting materials, MS (LC/MS): 428.2 [M+H]+ .
Example 60 6-(3-Chloro-phenyl)-pyridinecarboxylic acid ((S)cyclopropylthiazolylethyl)-amide The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl) pyridinecarboxylic acid (CAN 8637045) and (S)cyclopropylthiazolylethylamine (Example 59 b) as starting materials, MS (LC/MS): 384.1 [M+H]+ .
Example 61 6-Cyclopropylmethoxy(2-oxo-pyrrolidinyl)-pyridinecarboxylic acid (1- methyloxazolyl-ethyl)-amide a) 4-Chlorobutanamide A solution of 4-chlorobutanoyl chloride (CAN 46350, 20 g, 140 mmol) in THF (100 mL) was added dropwise to ammonium hydroxide (100 mL) at 0°C and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into water, extracted with ethyl acetate (3 x 30 mL), the organic layers were combined, washed with brine (6 x 30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the crude product. The crude product was used directly for the next step without purification. 1H-NMR (d 6 -DMSO):  7.32 (s, 1H), 6.78 (s, 1H), 3.66 - 3.62 (m, 2H), 2.38 (t, J = 7 Hz, 1H), 2.20 (t, J = 7 Hz, 1H), 1.96 - 1.93 (m, 2H). b) Pyrrolidinone N N H N S O Cl Chiral Cl NH2 O A solution of 4-chlorobutanamide (4.4 g, 36 mmol) and potassium tert-butoxide (CAS 8654, 8.1 g, 72 mmol) in THF (50 mL) was stirred for 36 h at room temperature. The reaction mixture was filtered and the filter cake was washed with ethyl acetate. The combined filtrates were concentrated to dryness to give the crude product. The crude product was purified by flash chromatography (silica gel, 100g, 0% to 50% ethyl acetate in petroleum ether) to give the desired product (2.7 g) as a colorless oil. 1H-NMR (d 6 - DMSO):  6.64 (s, 1H) 3.38 (t, J = 6 Hz, 2H), 2.28 - 2.25 (m, 2H), 2.17 - 2.14 (m, 2H). c) 6-Cyclopropylmethoxy(2-oxo-pyrrolidinyl)-pyridinecarboxylic acid Under nitrogen atmosphere, pyrrolidinone (375 mg, 4.4 mmol), dimethylbisdiphenylphosphinoxanthene (CAS 1612658, 127 mg, 2.4 mmol), tris(dibenzylideneacetone)dipalladium (CAS 513643, 67 mg, 0.1 mmol) and cesium carbonate (CAS 5348, 1.8 g, 6 mmol) in 1,4-dioxane (100 mL) were added to a solution of 5-bromocyclopropylmethoxy-pyridinecarboxylic acid (Example 9 d, 1 g, 4 mmol) and the reaction mixture was stirred overnight at 110°C. The reaction mixture was concentrated in vacuo, dissolved in water and extracted with ethyl acetate (3 x 30 mL). The aqueous layer was adjusted to pH = 2 with aqueous solution of hydrochloride (1N), the resulting precipitate was collected by filtration and dried. The crude product was purified by column chromatography (silica gel, 20 g, eluting with 30% ethyl acetate in petroleum ether) to give the desired product (600 mg) as a yellow solid; MS (EI): m/e = 277.1 [M+H]+ . c) 6-Cyclopropylmethoxy(2-oxo-pyrrolidinyl)-pyridinecarboxylic acid (1-methyl1-oxazolyl-ethyl)-amide NH O O N OH O N O The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(2-oxo-pyrrolidinyl)-pyridinecarboxylic acid and α,αdimethyloxazolemethanamine (CAN 12115194) as starting materials, MS (EI): m/e = 358.2 [M+H]+ 5 .
Example 62 6-Cyclopropylmethoxymethyl-pyridinecarboxylic acid (1-methylthiazolylethyl)-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxymethyl-pyridinecarboxylic acid (Example 36 d) and α,αdimethylthiazolemethanamine (CAN 10823931) as starting materials, MS (EI): m/e = 332.2 [M+H]+ .
Example 63 6-Cyclopropylmethoxypyrrolidinyl-pyridinecarboxylic acid [1-(4,5-dihydrooxazolyl)methyl-ethyl]-amide a) 1-(4,5-Dihydro-oxazolyl)methyl-ethylamine A mixture of benzyl 2-(oxazolyl)propanylcarbamate (Example 8 d, 0.63 g) and palladium on carbon (10%w/w, 0.06 g) in ethanol (20 mL) was charged with hydrogen balloon and stirred at room temperature for 2 h. TLC showed the reaction was complete; it was filtered and concentrated to give the product as yellow oil (0.1 g, 33%); MS (EI): m/e = 129.1 [M+H]+ .
N N N H N O O O O N N H N S O O H2N N O b) 6-Cyclopropylmethoxypyrrolidinyl-pyridinecarboxylic acid [1-(4,5-dihydrooxazolyl)methyl-ethyl]-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxypyrrolidinyl-pyridinecarboxylic acid (Example 14 a) and 1- (4,5-dihydro-oxazolyl)methyl-ethylamine as starting materials, MS(EI): m/e = 373.2 [M+H]+ .
Example 64 6-Cyclopropylmethoxymethyl-pyridinecarboxylic acid ((S)methylthiazol10 2-yl-butyl)-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxymethyl-pyridinecarboxylic acid (Example 36 d) and (S)-α-(2- methylpropyl)thiazolemethanamine (Example 56 d) as starting materials, MS (EI): m/e = 360.2 [M+H]+ 15 .
Example 65 6-Cyclopropylmethoxymethyl-pyridinecarboxylic acid ((S)cyclopropyl thiazolyl-ethyl)-amide N N H N O N O O N N H N O S O Chiral N N H N O S O Chiral The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxymethyl-pyridinecarboxylic acid (Example 36 d) and (S) cyclopropylthiazolyl-ethylamine (Example 59 b) as starting materials, MS (LC/MS): 358.2 [M+H]+ .
Example 66 -Chloro(3-chloro-phenyl)-pyridinecarboxylic acid piperidinylamide The title compound was synthesized in analogy to Example 1, using 5-chloro(3-chlorophenyl)-pyridinecarboxylic acid (Example 58 c) and 1-piperidinamine (CAN 2213 6) as starting materials, MS (LC/MS): 350.1 [M+H]+ 10 .
Example 67 6-(3-Chloro-phenyl)cyclopropyl-pyridinecarboxylic acid (1-methyl methylcarbamoyl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)- -cyclopropyl-pyridinecarboxylic acid (Example 48 e) and 2-amino-N,2-dimethylpropanamide (CAN 1069142) as starting materials, MS (EI) m/e: 372.1 [M+H]+ .
Example 68 6-Cyclopropylmethoxy-pyridinecarboxylic acid piperidinylamide N N H N O Cl Cl N N H O O N H Cl The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy-pyridinecarboxylic acid (CAN 12480775) and 1- piperidinamine (CAN 22136) as starting materials, MS (LC/MS): 276.1 (M+H).
Example 69 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (1- methylthiazolyl-ethyl)-amide a) 6-Chloro(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid methyl ester Under a nitrogen atmosphere a mixture of methyl 5-bromochloro-pyridinecarboxylic acid methyl ester (Example 9 c, 2 g, 8 mmol), 3,3-difluoroazetidine hydrochloride (CAN 2883157, 1 g, 8 mmol), tris(dibenzylideneacetone)dipalladium (CAN 513643, 0.16 g, 0.16 mmol), (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (CAN 76189 4, 0.19 g, 0.32 mmol) and cesium carbonate (3.9 g, 12 mmol) in toluene (50 mL) was stirred at 110°C overnight. After concentration, the residue was partitioned between water (50 mL) and ethyl acetate (40 mL), the aqueous phase was extracted with ethyl acetate (2 x 40 mL). The combined organic phase was washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, 20 g, 10% ethyl acetate in petroleum ether) to give the target compound (0.44 g, 21%) as light-yellow solid; MS (EI): m/e = 263.0 [M+H]+ . b) 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid N N H N O O N O O Cl N F F Sodium hydride (0.29 g, 8.4 mmol) was added in portion to a solution of cyclopropylmethanol (CAN 25168, 0.36 g, 5 mmol) in DMF (3 mL) and the mixture was stirred at room temperature for 2 h. 6-Chloro(3,3-difluoro-azetidinyl)-pyridine5 2-carboxylic acid methyl ester (0.44 g, 1.68 mmol) was added to the mixture and the resulting solution was stirred at 110°C overnight. After concentration, water (20 mL) was added to the residue and the solution was acidified with an aqueous solution of hydrochloride (6 N), then extracted with ethyl acetate (2 x 20 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-TLC (eluting with 50% ethyl acetate in petroleum ether) to give the target compound (0.07 g, 14%); MS (EI): m/e = 285.1 [M+H]+ . c) 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (1- methylthiazolyl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid and α,αdimethylthiazolemethanamine (CAN 10823931) as starting materials, MS (EI): m/e = 409.1 [M+H]+ .
Example 70 6-(3-Chloro-phenyl)methyl-pyridinecarboxylic acid (1-ethyl methylcarbamoyl-propyl)-amide a) tert-Butyl 3-(methylcarbamoyl)pentanylcarbamate O N OH O N F F N N N H N O S O F F A mixture of 2-(tert-butoxycarbonylamino)ethylbutanoic acid (Example 23 a, 400 mg 2 mmol), HBTU (CAN 947901, 1.3 g, 3 mmol), Et3N (0.7 g, 7 mmol) in DMF (10 mL) was stirred for 30 min, then methanamine hydrochloride (CAN 5931, 260 mg, 6 mmol) was added into the mixture and the solution was stirred overnight. After that, the solution was diluted with water (20 mL) and extracted with ethyl acetate (3 x 30 mL), the combined organic layer was washed with water (3 x 50 mL) and brine (60 mL), then evaporated to dryness. The crude product (0.18 g, 45%) obtained as a light yellow solid was used for the next step directly. b) 2-Aminoethyl-N-methyl-butyramide A mixture of tert-butyl 3-(methylcarbamoyl)pentanylcarbamate (0.18 g, 0.74 mmol) in ml saturated hydrochloride in ethyl acetate was stirred for 60 min at room temperature.
Then the solution was evaporated to dryness to obtain the product (80 mg, 75%) as a light yellow solid; MS (LC/MS): 145.2 [M+H]+ 15 . c) 6-(3-Chloro-phenyl)methyl-pyridinecarboxylic acid (1-ethylmethylcarbamoylpropyl)-amide The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)- 5-methyl-pyridinecarboxylic acid (Example 49 e) and 2-aminoethyl-N-methylbutyramide as starting materials, MS (LC/MS): 374.2 [M+H]+ .
Example 71 O N H O O N H H2N O N H N N H O O N H Cl 6-(3-Chloro-phenyl)cyclopropyl-pyridinecarboxylic acid (1-ethyl methylcarbamoyl-propyl)-amide The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)- 5-cyclopropyl-pyridinecarboxylic acid (Example 48 e) and 2-aminoethyl-N-methylbutyramide (Example 70 b) as starting materials, MS (EI): m/e = 400.2 [M+H]+ .
Example 72 6-(3-Chloro-phenyl)-pyridinecarboxylic acid (1-methyl[1,2,4]oxadiazolylethyl)-amide a) tert-Butyl 2-(1,2,4-oxadiazolyl)propanylcarbamate To a solution of (Z)-tert-butyl 1-amino(hydroxyimino)methylpropanylcarbamate (Example 33 b, 2 g, 9.2 mmol) in acetonitrile (10 mL) was added triethoxymethane (CAN 1220, 4.8 mL) and trifluoroacetic acid (CAN 761, 0.1 mL). The mixture was heated to 50°C and stirred overnight. The reaction mixture was added to methanol (10 mL) and water (10 mL). After evaporation of solvents, the residue was purified by column chromatography (silica gel, 60 g, eluting with 30% to 50% ethyl acetate in petroleum ether) to give the target product (0.668 g, 32%) MS (EI): m/e = 250.1 [M+H]+ . b) 1-Methyl[1,2,4]oxadiazolyl-ethylamine hydrochloride tert-Butyl 2-(1,2,4-oxadiazolyl)propanylcarbamate (0.668 g, 2.9 mmol) was dissolved in in ethyl acetate saturated with hydrochloride (10 mL) and stirred at room N N H O O N H Cl O N H O N N O H2N N N O ClH temperature for 0.5 h. Then it was concentrated to give product (0.45 g, 94%); MS (EI): m/e = 128.2 [M+H]+ . c) 6-(3-Chloro-phenyl)-pyridinecarboxylic acid (1-methyl[1,2,4]oxadiazolylethyl)-amide The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl) pyridinecarboxylic acid (CAN 8637045) and 1-methyl[1,2,4]oxadiazolylethylamine (CAN 11537575) as starting materials, MS (EI): m/e = 343.1 [M+H]+ .
Example 73 5-Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid (1-methyl [1,2,4]oxadiazolyl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethoxy-pyridinecarboxylic acid (Example 42 a) and 1-methyl [1,2,4]oxadiazolyl-ethylamine (CAN 11537575) as starting materials, MS (LC/MS): 343.1 (M+H).
Example 74 -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid (1-ethyl methylcarbamoyl-propyl)-amide N N N H N O O Cl N N N H N O O O N N H O O O N H The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethoxy-pyridinecarboxylic acid (Example 42 a) and 2-aminoethyl-Nmethyl-butyramide (Example 70 b) as starting materials, MS (LC/MS): 360.2 (M+H).
Example 75 6-Cyclopropylmethoxy(3-hydroxy-azetidinyl)-pyridinecarboxylic acid (1- methylthiazolyl-ethyl)-amide a) 6-Cyclopropylmethoxy(3-hydroxy-azetidinyl)-pyridinecarboxylic acid To a mixture of azetidinol (CAN 453478, 200 mg, 3 mmol), (±)-2,2'- bis(diphenylphosphino)-1,1'-binaphthalene (CAS 983278, 114 mg, 0.185 mmol), tris(dibenzylideneacetone)dipalladium (CAS 513643, 85 mg, 0.1 mmol) and cesium carbonate (CAS 5348, 1.8 mg, 5.55 mmol) in toluene (8 mL) under nitrogen atmosphere, was added a solution of 5-bromocyclopropylmethoxy-pyridine carboxylic acid (Example 9 d, 500 mg, 1.85 mmol). The reaction mixture was stirred overnight at 110°C. The reaction mixture was concentrated in vacuo and the residue dissolved in water and extracted with ethyl acetate (1 x 30 mL). The aqueous layer was adjusted to pH = 2 by addition of 1 N hydrochloric acid, the resulting precipitate was collected by filtration, the solid was lyophilized. The crude product was purified by flash chromatography (silica gel, 50 g, 0% to 100% ethyl acetate in petroleum ether) to give the desired product (180 mg) as a yellow solid; MS (EI): m/e = 265.2 [M+H]+ 20 . b) 6-Cyclopropylmethoxy(3-hydroxy-azetidinyl)-pyridinecarboxylic acid (1- methylthiazolyl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3-hydroxy-azetidinyl)-pyridinecarboxylic acid and α,αO N OH O N HO N N N H N O S O HO dimethylthiazolemethanamine (CAN 10823931) as starting materials, MS (EI): m/e = 389.1 [M+H]+ .
Example 76 6-(4-Chloro-phenyl)-pyridinecarboxylic acid (1-ethylmethylcarbamoyl-propyl)- amide The title compound was synthesized in analogy to Example 1, using 6-(4-chlorophenyl) pyridinecarboxylic acid (CAN 1354328) and 2-aminoethyl-N-methyl-butyramide (Example 70 b) as starting materials, MS (EI): m/e = 360.1 [M+H]+ .
Example 77 6-(Cyclopropylmethoxy)(1,1-dioxido-isothiazolidinyl)-N-[2-(1,3-thiazol yl)propanyl]pyridinecarboxamide a) 3-Chloropropanesulfonamide Ammonia gas was bubbled through a stirred solution of 3-chloropropanesulfonyl chloride (CAN 16335, 10 g, 56 mmol) in methylene chloride (100 mL) for 30 min at 0°C. The reaction mixture was stirred for 1 h at room temperature. The ammonium chloride precipitate was removed by filtration. The solvent was removed under reduced pressure, the solid was purified by re-crystallization from methylene chloride to give the title compound (7.9 g, 0.05 mol, 88.7%) as white solid. 1H NMR (300 MHz , d 6 20 -DMSO):  6.88 (s, 2H), 3.75 (t, J = 6.5 Hz, 2H), 3.11 - 3.06 (m, 2H), 2.16 - 2.07 (m, 2H). b) Isothiazolidine 1,1-dioxide N N H O O N H Cl Cl S NH2 O O NH S O O Sodium (1.6 g, 70 mmol) was added in portions to ethanol (50 mL) at room temperature.
After complete dissolution of sodium, 3-chloropropanesulfonamide (7.9 g, 50 mmol) was added to the above solution. The reaction mixture was reacted for 2 h at 90°C. After that the reaction mixture was cooled, the precipitate was removed by filtration, the solvent was removed under reduced pressure, the product was dissolved in ethyl acetate, the precipitate was removed by filtration and the solvent was removed under reduced pressure.
The crude title compound (3.2 g, yellow oil) was used for the next reaction step without further purification. 1H NMR (300 MHz , d 6 -DMSO):  6.70 (s, 1H), 3.13 (t, J = 6.9 Hz, 2H), 2.99 - 2.94 (m, 2H), 2.28 - 2.19 (m, 2H). c) 6-Chloro(1,1-dioxido-isothiazolidinyl)-pyridinecarboxylic acid methyl ester Under a nitrogen atmosphere, a solution of 5-bromochloro- pyridinecarboxylic acid methyl ester (Example 9 c, 1g, 4 mmol), isothiazolidine 1,1-dioxide (730 mg, 06 mmol), copper(I) iodide (150 mg, 0.8 mmol), 1,3-di(pyridinyl)propane-1,3-dione (CAN 10198- 89-7, 180 mg, 0.8 mmol) and potassium carbonate (1.1 g, 8 mmol) in DMF (20 mL) was reacted for 24 h at 110°C. The reaction mixture was poured into water, and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (silica gel, 4 g, 10% ethyl acetate in petroleum ether) to yield the title compound (0.048 g, 1.6 mmol, 41.4 %) as yellow solid; MS (EI): m/e = 291.0 [M+H]+ . d) 6-Cyclopropylmethoxy(1,1-dioxido-isothiazolidinyl)-pyridinecarboxylic acid Sodium hydride (0.029 g, 0.86 mmol) was added in portions to a solution of cyclopropanemethanol (CAN 25168, 20 mL) and the reaction mixture was stirred for min at room temperature. 6-Chloro(1,1-dioxido-isothiazolidinyl)-pyridine N O O Cl N S O O N S O O O N OH O carboxylic acid methyl ester (0.050 g, 0.17 mmol) was added and the mixture was heated to 100°C overnight, quenched with water and concentrated under reduced pressure. The residue was dissolved in water, extracted with ethyl acetate (50 mL). The pH of the aqueous layer was adjusted to 2 by addition of 1 N hydrochloric acid and subsequently extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (silica gel, 4 g, 33% ethyl acetate in petroleum ether) to yield the title compound (25 mg, 0.08 mmol, 46%) as yellow solid; MS (EI): m/e = 313.1 [M+H]+ . e) 6-(Cyclopropylmethoxy)(1,1-dioxido-isothiazolidinyl)-N-[2-(1,3-thiazol yl)propanyl]pyridinecarboxamide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(1,1-dioxido-isothiazolidinyl)-pyridinecarboxylic acid and α,α-dimethylthiazolemethanamine (CAN 10823931) as starting materials, MS (EI): m/e = 437.0 [M+H]+ .
Example 78 6-Cyclopropylmethoxy(3,3-difluoro-pyrrolidinyl)-pyridinecarboxylic acid (1- ethylmethylcarbamoyl-propyl)-amide a) 6-Chloro(3,3-difluoro-pyrrolidinyl)-pyridinecarboxylic acid methyl ester Under nitrogen atmosphere, a suspension of 5-bromochloro-pyridinecarboxylic acid methyl ester (Example 9 c, 1.5 g, 6 mmol), 3,3-difluoropyrrolidine hydrochloride (CAN S N N N H N O O O S O Cl N N O O F F 1634576, 0.64 g, 6 mmol), tris(dibenzylideneacetone)dipalladium (CAN 513643, 120 mg, 0.12 mmol), (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (CAN 76189- 55-4, 150 mg, 0.24 mmol) and cesium carbonate (3.9 g, 12 mmol) in toluene (30 mL) was stirred at 110°C overnight. After concentration, the residue was partitioned between water (30 mL) and ethyl acetate (30 mL). The aqueous phase was extracted with ethyl acetate (2 x 30 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by column chromatography (silica gel, 15 g, 10% ethyl acetate in petroleum ether) to give the target compound (0.5g, 30%) as light-yellow solid; MS (EI): m/e = 277.0 [M+H]+ 10 . b) 6-Cyclopropylmethoxy(3,3-difluoro-pyrrolidinyl)-pyridinecarboxylic acid Sodium hydride (0.27 g, 8 mmol) was added in portions to cyclopropylmethanol (CAN 25168, 6 mL) and the mixture was stirred at room temperature for 2 hours. 6-Chloro15 5-(3,3-difluoro-pyrrolidinyl)-pyridinecarboxylic acid methyl ester (0.45 g, 1.6 mmol) was added to the mixture and the resulting solution was stirred in a sealed tube at 110°C overnight. After concentration under reduced pressure, water (15 mL) was added to the residue and the solution was acidified with hydrochloric acid (6 N). The aqueous solution was extracted with ethyl acetate (3 x 20 mL) and the combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the target compound which was used directly in the next step without further purification; MS (EI): m/e = 299.1 [M+H]+ . c) 6-Cyclopropylmethoxy(3,3-difluoro-pyrrolidinyl)-pyridinecarboxylic acid (1- ethylmethylcarbamoyl-propyl)-amide N O N OH O F F N N N H O O O N H F F The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3,3-difluoro-pyrrolidinyl)-pyridinecarboxylic acid and 2- aminoethyl-N-methyl-butyramide (Example 70 b) as starting materials, MS (EI): m/e = 425.3 [M+H]+ .
Example 79 [6-Cyclopropylmethoxy(3,3-difluoro-pyrrolidinyl)-pyridinyl]-(1,1- dioxidotetrahydro-2H-thiopyranyl)-methanone The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3,3-difluoro-pyrrolidinyl)-pyridinecarboxylic acid (Example 78 b) and 1,1-dioxide-thiomorpholine (CAN 390931) as starting materials, MS (EI): m/e = 416.1 [M+H]+ .
Example 80 6-Cyclopropylmethoxy(3,3-difluoro-pyrrolidinyl)-pyridinecarboxylic acid (1- methylmethylcarbamoyl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3,3-difluoro-pyrrolidinyl)-pyridinecarboxylic acid (Example 78 b) and 2-amino-N,2-dimethyl-propanamide (CAN 1069142) as starting materials, MS (EI): m/e = 397.1 [M+H]+ 20 .
Example 81 S N N N O O O O F F N N N H O O O N H F F 6-(3-Chloro-phenyl)methoxy-pyridinecarboxylic acid (1-ethyl methylcarbamoyl-propyl)-amide a) 5-Methoxyoxy-pyridinecarboxylic acid A mixture of 5-methoxy-pyridinecarboxylic acid (CAN 290826, 3 g, 20 mmol) and m-CPBA (CAN 9374, 8 g, 47 mmol) in methylene chloride (100 mL) was stirred for 12 hours at 60°C. The reaction mixture was cooled to ambient temperature, filtered, concentrated and purified by column chromatography (silica gel, 100 g, eluting with 10% methanol in methylene chloride) to give the title compound (1.2 g, 36%); MS (EI): m/e = 170.2 [M+H]+ 10 . b) 6-Bromomethoxy-pyridinecarboxylic acid -Methoxyoxy-pyridinecarboxylic acid (1.2 g, 7 mmol) was added to phosphorus oxybromide (CAN 77895, 10 g) at 80°C and stirred for 3 h. The mixture was poured into water (100 mL), extracted with ethyl acetate (3 x 50 mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (silica gel, 60 g, eluting with 10% methanol in methylene chloride) to give the title compound (1 g, 61%); MS (EI): m/e = 232.0 [M+H]+ . c) 6-(3-Chlorophenyl)methoxy-pyridinecarboxylic acid A mixture of 6-bromomethoxy-pyridinecarboxylic acid (0.3 g, 1 mmol), 3- chlorophenylboronic acid (CAN 635036, 0.23 g, 1 mmol), tris(dibenzylideneacetone)- dipalladium(0) (CAN 524090, 0.12 g), 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (CAN 1612658, 0.15 g) and potassium carbonate N + O OH O O N O OH O Br N O OH O Cl (0.21 g, 2 mmol) in 1,4-dioxane (10 mL) was stirred for 12 h at 110°C under a nitrogen atmosphere. The reaction mixture was filtered, concentrated under reduced pressure and purified by column chromatography (silica gel, 10 g, eluting with 10% methanol in methylene chloride) to give the title compound (0.1 g, 29%); MS (EI): m/e = 264.0 [M+H]+ 5 . d) 6-(3-Chloro-phenyl)methoxy-pyridinecarboxylic acid (1-ethyl methylcarbamoyl-propyl)-amide The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)- 5-methoxy-pyridinecarboxylic acid and 2-aminoethyl-N-methyl-butyramide (Example 70 b) as starting materials, MS (EI): m/e = 390.2 [M+H]+ .
Example 82 6-(3-Chloro-phenyl)methoxy-pyridinecarboxylic acid (1-methylthiazolylethyl)-amide The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)- -methoxy-pyridinecarboxylic acid and (Example 81 c) and α,α-dimethyl thiazolemethanamine (CAN 10823931) as starting materials, MS (EI): m/e = 388.0 [M+H]+ .
Example 83 -Chlorocyclopropylmethoxy-pyridinecarboxylic acid (1-methyl [1,2,4]oxadiazolyl-ethyl)-amide a) 5,6-Dichloro-pyridinecarboxylic acid N N H O O N H Cl O N N H N S O Cl O A mixture of 5-chloro-pyridinecarboxylic acid (CAN 868731, 9.8 g, 62 mmol) and m-CPBA (CAN 9374, 21.5 g, 0.124 mol) in methylene chloride (100 mL) was heated to reflux for 48 h. The reaction mixture was quenched with saturated sodium sulfite solution (70 mL), filtered and extracted with methylene chloride (50 mL). The organic layer was washed with water (2 x 100ml) and brine (100 mL) and evaporated to dryness.
The residue was purified by column chromatography (silica gel, 80 g, eluting with 15% ethyl acetate in petroleum ether) to obtain a colorless oil (3.3 g, 30%). The colorless oil, 5- chlorooxy-pyridinecarboxylic acid (1.2 g, 7 mmol) was added into POCl3 (10 g) at 0°C and the mixture was heated to 95°C for 1 h. The reaction mixture was evaporated to dryness. The residue was dissolved in 15 mL water and extracted with ethyl acetate (2 x 15 mL), the combined organic layer was washed with water (2 x 30 mL) and brine (30 mL), then evaporated to dryness to obtain the title compound (1 g, 75%) as a yellow solid, MS (EI): m/e = 191.9 [M+H]+ . b) 5-Chloro(cyclopropylmethoxy)-pyridinecarboxylic acid Sodium hydride (CAN 76467, 60% w/w, 1.05 g, 26 mmol) was added to cyclopropylmethanol (CAN 25168, 7.5 g) at 0°C and the mixture was stirred for 1 h. ,6-Dichloro-pyridinecarboxylic acid (1 g, 5 mmol) was added and the mixture was heated to 95°C for 3 h. The solvent was removed under reduced pressure. The residue was diluted with water (10 mL) and adjusted to pH = 3.0 by hydrochloric acid (3 N). The solution was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with water (3 x 30 mL) and brine (2 x 40 mL) and evaporated to dryness to give the crude product (0.35 g, 25%), which was used in the next step without further purification, MS (EI): m/e = 228.1 [M+H]+ 25 . c) 5-Chlorocyclopropylmethoxy-pyridinecarboxylic acid (1-methyl [1,2,4]oxadiazolyl-ethyl)-amide N Cl OH O Cl N Cl OH O O The title compound was synthesized in analogy to Example 1, using 5-chloro cyclopropylmethoxy-pyridinecarboxylic acid and 1-methyl[1,2,4]oxadiazolyl ethylamine (CAN 11537575) as starting materials, MS (LC/MS): m/e = 337.1 [M+H]+ 5 .
Example 84 6-Cyclohexyl-pyridinecarboxylic acid (2-hydroxy-cyclohexyl)-amide The title compound was synthesized in analogy to Example 1, using 6-cyclohexyl10 pyridinecarboxylic acid (Example 7 b) and 2-aminocyclohexanol (CAN 68500) as starting materials, MS (EI): m/e = 303.2 [M+H]+ .
Example 85 6-Cyclopropylmethoxy(tetrahydro-pyranyl)-pyridinecarboxylic acid (1-ethyl1-methylcarbamoyl-propyl)-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(tetrahydro-pyranyl)-pyridinecarboxylic acid (Example 9 f) and 2-aminoethyl-N-methyl-butyramide (Example 70 b) as starting materials, MS (EI): m/e = 404.2 [M+H]+ .
Example 86 N N N H N O O O Cl N N H O OH N N H O O O O N H 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (1- ethylmethylcarbamoyl-propyl)-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example 69 b) and 2-aminoethyl-N-methyl-butyramide (Example 70 b) as starting materials, MS (EI): m/e = 411.1 [M+H]+ .
Example 87 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (1- methylmethylcarbamoyl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example 69 b) and 2-amino-N,2-dimethyl-propanamide (CAN 1069142) as starting materials, MS (EI): m/e = 383.1 [M+H]+ 15 .
Example 88 -Chloro(3-chloro-phenyl)-pyridinecarboxylic acid (1-methyl [1,2,4]oxadiazolyl-ethyl)-amide N N N H O O O F F N H N N N H O O O F F N H N N N H N O O Cl Cl The title compound was synthesized in analogy to Example 1, using 5-chloro(3-chlorophenyl)-pyridinecarboxylic acid (Example 58 c) and 1-methyl[1,2,4]oxadiazolyl ethylamine (CAN 11537575) as starting materials, MS (EI): m/e = 377.0 [M+H]+ .
Example 89 6-(3-Chloro-phenyl)methoxy-pyridinecarboxylic acid [1-methyl(5-methyl- [1,2,4]oxadiazolyl)-ethyl]-amide The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)- -methoxy-pyridinecarboxylic acid (Example 81 c) and α,α,5-trimethyl-1,2,4- oxadiazolemethanamine (CAN 11538310) as starting materials, MS (EI): m/e = 387.0 [M+H]+ .
Example 90 6-(3-Chloro-phenyl)methoxy-pyridinecarboxylic acid (1-methyloxazolylethyl)-amide The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)- -methoxy-pyridinecarboxylic acid (Example 81 c) and α,α-dimethyl oxazolemethanamine (CAN 12115194) as starting materials, MS (EI): m/e = 372.1 [M+H]+ .
Example 91 -Chloro(3-chloro-phenyl)-pyridinecarboxylic acid (1-ethyl methylcarbamoyl-propyl)-amide N N N N H O O Cl O N N H N O O Cl O The title compound was synthesized in analogy to Example 1, using 5-chloro(3-chlorophenyl)-pyridinecarboxylic acid (Example 58 c) and 2-aminoethyl-N-methylbutyramide (Example 70 b) as starting materials, MS (EI): m/e = 394.1 [M+H]+ .
Example 92 2-[(6-Cyclohexyl-pyridinecarbonyl)-amino]-cyclohexanecarboxylic acid methyl ester The title compound was synthesized in analogy to Example 1, using 6-cyclohexyl10 pyridinecarboxylic acid (Example 7 b) and methyl 2-aminocyclohexanecarboxylate (CAN 400151) as starting materials, MS (EI): m/e = 345.2 [M+H]+ .
Example 93 6-Cyclopropylmethoxy(tetrahydro-pyranyl)-pyridinecarboxylic acid (1- methyloxazolyl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(tetrahydro-pyranyl)-pyridinecarboxylic acid (Example 9 f) and α,α-dimethyloxazolemethanamine (CAN 12115194) as starting materials, MS (EI): m/e = 386.2 [M+H]+ .
N N H O O N H Cl Cl N N H O O O N N H N O O O O Example 94 6-Cyclopentyl-pyridinecarboxylic acid piperidinylamide a) 6-Cyclopentenyl-pyridinecarboxylic acid A mixture of 6-bromo-pyridinecarboxylic acid (CAN 211904, 0.375 g, 1.86 mmol), 2-cyclopentenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAN 2879449, 0.3 g, 1.6 mmol), Pd(dppf)Cl2 (CAN 954644, 0.06 g, 0.08 mmol) and K2CO3 (0.642 g, 4.7 mmol) in DMF (10 mL) and water (1 mL) was heated to 100°C overnight. After filtration, the filtrate was concentrated and the residue was purified by column chromatography (silica gel, 15 g, eluting with 10% ethyl acetate in petroleum ether) to give the title compound (0.08 g, 23%) as white solid; MS (EI): m/e = 190.1 [M+H]+ . b) 6-Cyclopentyl-pyridinecarboxylic acid A mixture of 6-cyclopentenyl-pyridinecarboxylic acid (0.08 g, 0.42 mmol) and palladium on carbon (10% w/w, 0.04 g, 0.3 mmol) in ethanol (10 mL) was charged with a hydrogen balloon and stirred at room temperature overnight. The reaction mixture was filtered and the filtrate was concentrated to obtain the crude product as white solid (0.08 g, 99%) which was used directly in the next step without further purification; MS (EI): m/e = 192.2 [M+H]+ . c) 6-Cyclopentyl-pyridinecarboxylic acid piperidinylamide The title compound was synthesized in analogy to Example 1, using 6-cyclopentylpyridinecarboxylic acid and 1-piperidinamine (CAN 22136) as starting materials, MS (EI): m/e = 274.1 [M+H]+ .
N OH O N OH O N N H N O Example 95 6-(3-Chloro-phenyl)cyclopropyl-pyridinecarboxylic acid (1-methyloxazol yl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)- -cyclopropyl-pyridinecarboxylic acid (Example 48 e) and α,α-dimethyl oxazolemethanamine (CAN 12115194) as starting materials, MS (EI): m/e = 382.1 [M+H]+ .
Example 96 6-(3-Chloro-phenyl)cyclopropyl-pyridinecarboxylic acid [1-methyl(5-methyl- [1,2,4]oxadiazolyl)-ethyl]-amide The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)- -cyclopropyl-pyridinecarboxylic acid (Example 48 e) and α,α,5-trimethyl-1,2,4- oxadiazolemethanamine (CAN 11538310) as starting materials, MS (EI): m/e = 397.1 [M+H]+ .
Example 97 6-(3-Chloro-phenyl)cyclopropyl-pyridinecarboxylic acid ((S)carbamoyl cyclopropyl-ethyl)-amide a) (S)Aminocyclopropylpropanamide hydrochloride N N H N O O Cl N N N N H O O Cl (S)(tert-butoxycarbonylamino)cyclopropylpropanoic acid (CAN 894837, 1.2 g, mmol) was dissolved in ethyl acetate saturated with hydrochloride (30 mL) and stirred for 30 min. The solvent was removed under reduced pressure to give the title compound; MS (EI): m/e = 129.1 [M+H]+ 5 . b) 6-(3-Chloro-phenyl)cyclopropyl-pyridinecarboxylic acid ((S)carbamoyl cyclopropyl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)- 5-cyclopropyl-pyridinecarboxylic acid (Example 48 e) and (S)aminocyclopropylpropanamide hydrochloride as starting materials, MS (EI): m/e = 384.2 [M+H]+ .
Example 98 -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid ((S)carbamoyl cyclopropyl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethoxy-pyridinecarboxylic acid (Example 42 a) and (S)amino cyclopropyl-propanamide (CAN 1560779) as starting materials, MS (LC/MS): m/e = 344.3 [M+H]+ .
H2N O NH2 ClH N N H O O NH2 Cl Chiral N N H O O O NH2 Chiral Example 99 -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid ((S)cyclopropyl1-thiazolyl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethoxy-pyridinecarboxylic acid (Example 42 a) and (S)cyclopropyl thiazolyl-ethylamine (Example 59 b) as starting materials, MS (LC/MS): m/e = 384.3 [M+H]+ .
Example 100 5-Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid ((S)carbamoyl methyl-butyl)-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethoxy-pyridinecarboxylic acid (Example 42 a) and (2S)amino methyl-pentanamide (CAN 6874) as starting materials, MS (LC/MS): m/e = 346.2 [M+H]+ .
Example 101 6-(3-Chloro-phenyl)(tetrahydro-furanyl)-pyridinecarboxylic acid (1-methyl1-thiazolyl-ethyl)-amide a) 5-(2,5-Dihydrofuranyl)-pyridinecarboxylic acid methyl ester (a1) and 5-(4,5- dihydrofuranyl)-pyridinecarboxylic acid methyl ester (a2) N N H N O S O Chiral N N H O O O NH2 Chiral A mixture of 5-bromo-pyridinecarboxylic acid methyl ester (CAN 296823, 15 g, 69 mmol), 2,5-dihydrofuran (CAN 366205, 48 g, 0.69 mol), palladium diacetate (CAN 33753, 0.8 g, 3.6 mmol), sodium acetate (6.9 g, 84 mmol) and tri-tert-butylphosphine (CAN 137166, 10%, 14 g, 7 mmol) in DMF (50 ml) was stirred at 120°C in a sealed tube for 2.5 h. After cooling to room temperature, the reaction mixture was concentrated.
The crude product was purified by column chromatography (silica gel, 200 g, eluting with % ethyl acetate in petroleum ether) to give 5-(2,5-dihydrofuranyl) -pyridine carboxylic acid methyl ester (a1) and 5-(4,5-dihydrofuranyl) -pyridinecarboxylic acid methyl ester (a2) (mixture, a1/a2 = 1/0.94 at UV 254 nm , 10.8 g, 76%) as colorless oil; MS (EI): m/e = 206.1 [M+H]+ . b) 5-(Tetrahydrofuranyl)-pyridinecarboxylic acid methyl ester (b1) and 5- (tetrahydrofuranyl)-pyridinecarboxylic acid methyl ester (b2) To a solution of 5-(2,5-dihydrofuranyl)-pyridinecarboxylic acid methyl ester (a1) and 5-(4,5-dihydrofuranyl)-pyridinecarboxylic acid methyl ester (a2) (mixture from Example 101 a, 8 g, 39 mmol) in methanol (200 ml) was added palladium on carbon (10% w/w, 0.8 g). The mixture was stirred under hydrogen balloon overnight at room temperature. After concentration, the crude product was purified by column chromatography (silica gel, 100 g, eluting with 30% ethyl acetate in petroleum ether) to give 5-(tetrahydrofuranyl)-pyridinecarboxylic acid methyl ester (b1) and 5- (tetrahydrofuranyl)-pyridinecarboxylic acid methyl ester (b2) (mixture, b1/b2 = 1/0.85 at UV 254 nm , 7.8 g, 97%) as colorless oil; MS (EI): m/e = 208.1 [M+H]+ .
N O O O N O O O a1 a2 N O O O N O O O b1 b2 c) 1-Oxy(tetrahydro-furanyl)-pyridinecarboxylic acid methyl ester (c1) and 1- Oxy(tetrahydro-furanyl)-pyridinecarboxylic acid methyl ester (c2) A mixture of 5-(tetrahydrofuranyl)-pyridinecarboxylic acid methyl ester (b1) and 5- (tetrahydrofuranyl)-pyridinecarboxylic acid methyl ester (b2) (mixture from Example 101 b, 8 g, 39 mmol) and m-CPBA (CAN 9374, 13.3 g, 77 mmol) in methylene chloride (100 ml) was stirred at 40°C overnight. After concentration, the crude product was purified by column chromatography (silica gel, 100 g, eluting with 25% ethyl acetate in petroleum ether firstly, then 50% methanol in ethyl acetate) to give 1-oxy (tetrahydro-furanyl)-pyridinecarboxylic acid methyl ester (c1) and 1-oxy (tetrahydro-furanyl)-pyridinecarboxylic acid methyl ester (c2) (mixture, c1/c2 = 1/0.67 at UV 254 nm, 8 g, 93%) as yellow oil; MS (EI): m/e = 224.1 [M+H]+ . d) 6-Bromo(tetrahydrofuranyl)-pyridinecarboxylic acid methyl ester (d1) and 6- bromo(tetrahydrofuranyl)-pyridinecarboxylic acid methyl ester (d2) Phosphorus oxide bromide (CAN 77895, 11 g, 38 mmol) was added to a solution of 1- oxy(tetrahydro-furanyl)-pyridinecarboxylic acid methyl ester (c1) and 1-oxy (tetrahydro-furanyl)-pyridinecarboxylic acid methyl ester (c2) (mixture from Example 101 c, 2.86 g, 13 mmol) in methylene chloride. The reaction mixture was stirred at room temperature overnight and poured into 100 ml methanol. After removal of the solvents by evaporation, the mixture was diluted with ethyl acetate, and washed with H2O (2 x 100 mL). The organic layer was evaporated to dryness. The crude product was N + O O O O N + O O O O c1 c2 N O O O Br N O O O Br d1 d2 purified by column chromatography (silica gel, 40 g, petroleum ether/ethyl acetate 3/1) to give 6-bromo(tetrahydrofuranyl)-pyridinecarboxylic acid methyl ester (d1) (185 g, 5%) as yellow solid, MS (EI): m/e = 286.0 and also 6-bromo(tetrahydrofuranyl)- pyridinecarboxylic acid methyl ester (d2) (0.138 g, 4%) as yellow solid; MS (EI): m/e = 286.0 [M+H]+ 5 . e) 6-(3-Chlorophenyl)(tetrahydrofuranyl)-pyridinecarboxylic acid methyl ester A solution of methyl 6-bromo(tetrahydrofuranyl)-pyridinecarboxylic acid methyl ester (0.185 g, 0.65 mmol), 3-chlorophenylboronic acid (CAN 635036, 0.15 g, 0.96 mmol), 1,1'-bis(diphenylphosphino)-ferrocene-palladium(II) dichloride methylene chloride complex (CAN 954644, 20 mg) and cesium carbonate (CAN 5348, 0.63 g, 2 mmol) in DMF (10 mL) was stirred overnight at 80°C under a nitrogen atmosphere. After filtration, the reaction mixture was poured into water (20 mL) and washed with ethyl acetate (2 x 20 mL). The organic layer was concentrated in vacuo to provide the title compound (0.75 g, 73%) as black oil which was used in the next step without further purification; MS (EI): m/e = 318.1 [M+H]+ . f) 6-(3-Chloro-phenyl)(tetrahydro-furanyl)-pyridinecarboxylic acid A mixture of 6-(3-chlorophenyl)(tetrahydrofuranyl)-pyridinecarboxylic acid methyl ester (0.15 g, 0.5 mmol) and lithium hydroxide monohydrate (CAN 13103, 88 mg, 2.1 mmol) in THF/H2O 1/1 (20 mL)) was stirred at room temperature for 1 h. After removal of the organic solvent under reduced pressure, the aqueous phase was washed with ethyl acetate (10 mL) and acidified with 1 N HCl to pH=3. The resulting solution was N O O O Cl N OH O O Cl extracted with ethyl acetate (2 x 20 mL). The combined organic layer was concentrated under reduced pressure to provide the title compound (0.12 g, 81%) as black oil which was used in the next step without further purification; MS (EI): m/e = 304.1 [M+H]+ . g) 6-(3-Chloro-phenyl)(tetrahydro-furanyl)-pyridinecarboxylic acid (1-methyl thiazolyl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)- -(tetrahydro-furanyl)-pyridinecarboxylic acid and α,α-dimethyl thiazolemethanamine (CAN 10823931) as starting materials, MS (EI): m/e = 428.1 [M+H]+ 10 .
Example 102 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid [1- methyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example 69 b) and α,α,5-trimethyl-1,2,4-oxadiazolemethanamine (CAN 11538310) as starting materials, MS (EI): m/e = 408.1 [M+H]+ .
Example 103 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid ((S)- 1-carbamoylcyclopropyl-ethyl)-amide N N H N S O O Cl N N N N N H O O O F F The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example 69 b) and (S)aminocyclopropyl-propionamide (CAN 1560779) as starting materials, MS (EI): m/e = 395.2 [M+H]+ 5 .
Example 104 -Chloro(3-chloro-phenyl)-pyridinecarboxylic acid (1-methyloxazolylethyl)-amide The title compound was synthesized in analogy to Example 1, using 5-chloro(3-chlorophenyl)-pyridinecarboxylic acid (Example 58 c) and α,α-dimethyl oxazolemethanamine (CAN 12115194) as starting materials, MS (EI): m/e = 376.0 [M+H]+ .
Example 105 5-Chloro(3-chloro-phenyl)-pyridinecarboxylic acid ((S)carbamoylmethylbutyl)-amide N N N H O O O F F NH2 Chiral N N H N O O Cl Cl N N H O O NH2 Cl Cl Chiral The title compound was synthesized in analogy to Example 1, using 5-chloro(3-chlorophenyl)-pyridinecarboxylic acid (Example 58 c) and (2S)aminomethylpentanamide (CAN 6874) as starting materials, MS (EI): m/e = 380.0 [M+H]+ .
Example 106 6-(3-Chloro-phenyl)cyclopentyl-pyridinecarboxylic acid [1-methyl(5-methyl- [1,2,4]oxadiazolyl)-ethyl]-amide a) 5-Cyclopentenyl-pyridinecarboxylic acid -Bromo-pyridinecarboxylic acid (CAN 307661, 3.4 g, 17 mmol), 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride methylene chloride complex (CAN 954644, 530 mg, 0.65 mmol) and Cs2CO3 (6.3 g, 19 mmol) were added to a solution of 2-cyclopentenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAN 2879449, 2.5 g, 13 mmol) in DMF (50 mL) and water (10 mL). The mixture was stirred at 150°C overnight and concentrated in vacuo. Water (50 mL) was added and the mixture was extracted with ethyl acetate (3 x 40 mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated to give the title compound (1.0 g, 31%); MS (EI): m/e = 190.1 [M+H]+ . b) 5-Cyclopentyl-pyridinecarboxylic acid A suspension of 5-cyclopentenyl-pyridinecarboxylic acid (2.0 g, 11 mmol) and palladium on carbon (10% w/w, 0.5 g) in methanol (20 mL) under a hydrogen atmosphere was stirred at ambient temperature overnight. The mixture was filtered and the filtrate concentrated in vacuo to give the title compound which was used in the next step without further purification (1.4 g, 72%); MS (EI): m/e = 192.1 [M+H]+ . c) 5-Cyclopentyloxy-pyridinecarboxylic acid N OH O N OH O m-CPBA (CAN 9374, 4.5 g, 22 mmol) was added to a solution of 5-cyclopentylpyridinecarboxylic acid (1.4 g, 7.3 mmol) in methylene chloride (20 mL).. The mixture was stirred overnight at room temperature. The solid was filtered off, a saturated solution of sodium thiosulfate (50 mL) was added, and the mixture was extracted with methylene chloride (3 x 60 mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude product. The crude product was purified by column chromatography (silica gel, 200 g, eluting with 10% ethyl acetate in petroleum ether) to give the title compound (0.3 g, 66%); MS (EI): m/e = 208.1 [M+H]+ . d) 6-Bromocyclopentyl-pyridinecarboxylic acid methyl ester -Cyclopentyloxy-pyridinecarboxylic acid (1.0 g, 4.8 mmol) was added to POBr3 (15 g) and the mixture was stirred for 2 h at 80°C. Ice water was added and the mixture was extracted with methylene chloride (3 x 50 mL). The combined organic layer was dried over sodium sulfate and concentrated to give the crude product. The crude product was purified by column chromatography (silica gel, 30 g, eluting with 50% ethyl acetate in petroleum ether) to give the title compound (0.6 g, 46%); MS (EI): m/e = 270.1 [M+H]+ . e) 6-(3-Chloro-phenyl)cyclopentyl-pyridinecarboxylic acid 6-Bromocyclopentyl-pyridinecarboxylic acid methyl ester (0.6 g, 2.1 mmol), bis(diphenylphosphino)ferrocene-palladium(II)dichloride methylene chloride complex (CAN 954644, 90 mg, 0.11 mmol) and potassium carbonate (0.37 g, 2.68 mmol) were N + OH O O N OH O Br N OH O Cl added to a solution of 3-chlorophenylboronic acid (CAN 635036, 0.42 g, 2.69 mmol) in water (20 mL) and DMF (2 mL). The mixture was stirred for 48 h at 100°C. Its pH was adjusted to pH = 3 with diluted hydrochloric acid. The mixture was extracted with methylene chloride (3 x 20 mL). The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to give the title compound (130 mg, 20%) which was used in the next step without further purification; MS (EI): m/e = 302.0 [M+H]+ . f) 6-(3-Chloro-phenyl)cyclopentyl-pyridinecarboxylic acid [1-methyl(5-methyl- [1,2,4]oxadiazolyl)-ethyl]-amide The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)- -cyclopentyl-pyridinecarboxylic acid and α,α,5-trimethyl-1,2,4-oxadiazole methanamine (CAN 11538310) as starting materials, MS (EI): m/e = 425.2 [M+H]+ .
Example 107 5-Cyclopentylcyclopropylmethoxy-pyridinecarboxylic acid ((S)carbamoyl cyclopropyl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopentyl cyclopropylmethoxy-pyridinecarboxylic acid (Example 39 b) and (S)amino cyclopropyl-propionamide (CAN 1560779) as starting materials, MS (EI): m/e = 372.3 [M+H]+ .
Example 108 N N N N H O O Cl N N H O O O NH2 Chiral -Chlorocyclopropylmethoxy-pyridinecarboxylic acid [1-methyl(5-methyl- [1,2,4]oxadiazolyl)-ethyl]-amide The title compound was synthesized in analogy to Example 1, using 5-chloro cyclopropylmethoxy-pyridinecarboxylic acid (Example 83 b) and α,α,5-trimethyl-1,2,4- oxadiazolemethanamine (CAN 11538310) as starting materials, MS (EI): m/e = 351.1 [M+H]+ .
Example 109 -Chlorocyclopropylmethoxy-pyridinecarboxylic acid (1-ethyl methylcarbamoyl-propyl)-amide The title compound was synthesized in analogy to Example 1, using 5-chloro cyclopropylmethoxy-pyridinecarboxylic acid (Example 83 b) and 2-aminoethyl-Nmethyl-butyramide (Example 70 b) as starting materials, MS (EI): m/e = 354.2 [M+H]+ .
Example 110 -Bromocyclopropylmethoxy-pyridinecarboxylic acid ((S)carbamoyl cyclopropyl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using 5-bromo cyclopropylmethoxy-pyridinecarboxylic acid (Example 9 d) and (S)amino N N N N H O O O Cl N N H O O O N H Cl N N H O O O NH2 Br Chiral cyclopropyl-propionamide (CAN 1560779) as starting materials, MS (EI): m/e = 382.0 [M+H]+ .
Example 111 -Cyclopentylcyclopropylmethoxy-pyridinecarboxylic acid (1-ethyl methylcarbamoyl-propyl)-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopentyl cyclopropylmethoxy-pyridinecarboxylic acid (Example 39 b) and 2-aminoethyl-Nmethyl-butyramide (Example 70 b) as starting materials, MS (EI): m/e = 388.2 [M+H]+ .
Example 112 6-Cyclopropylmethoxy(3,3-difluoro-pyrrolidinyl)-pyridinecarboxylic acid ((S)carbamoylcyclopropyl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3,3-difluoro-pyrrolidinyl)-pyridinecarboxylic acid (Example 78 b) and (S)aminocyclopropyl-propionamide (CAN 1560779) as starting materials, MS (EI): m/e = 409.3 [M+H]+ .
Example 113 6-Cyclopropylmethoxytrifluoromethyl-pyridinecarboxylic acid ((S) carbamoylcyclopropyl-ethyl)-amide N N H O O O N H N N N H O O O NH2 F F Chiral a) 5-(Trifluoromethyl)-pyridinecarboxylic acid methyl ester A solution of 5-(trifluoromethyl)-pyridinecarboxylic acid (CAN 801940, 3 g, 15.7 mmol) and sulfurous dichloride (0.1 mL) in methanol (30 mL) was stirred under reflux conditions overnight. Removal of the solvent provided the crude title compound which was purified by column chromatography (silica gel, 20 g, 10% ethyl acetate in petroleum ether) to obtain the title compound (2.7 g, 84%) as white solid; MS (EI): m/e = 206.1 [M+H]+ . b) 1-Oxytrifluoromethyl-pyridinecarboxylic acid methyl ester A mixture of 5-(trifluoromethyl)-pyridinecarboxylic acid methyl ester (2.7 g, 13 mmol) and m-CPBA (CAN 9374, 6.7 g, 39 mmol) in dry methylene chloride (30 mL) was stirred under reflux conditions overnight. Removal of the solvent in vacuo and purification of the obtained residue by column chromatography (silica gel, 15 g, 20% ethyl acetate in petroleum ether) provided the title compound (2.2 g, 76%) as light-yellow solid; MS (EI): m/e = 222.1 [M+H]+ . c) 6-Chloro(trifluoromethyl)-pyridinecarboxylic acid methyl ester 1-Oxytrifluoromethyl-pyridinecarboxylic acid methyl ester (2.2 g, 10 mmol) was added in portions to phosphoryl trichloride (CAN 100253, 10 mL) at 0°C and the N O O F F F N + O O F O F F N O O F F F Cl resulting mixture was stirred at 50°C overnight. Removal of the solvent in vacuo gave a brown oil which was dissolved in ethyl acetate (30 mL) and carefully neutralized with a aqueous solution of sodium carbonate. The mixture was extracted with ethyl acetate (2 x mL) and the combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a light-brown solid. The solid was purified by column chromatography (silica gel, 15 g, 3% ethyl acetate in petroleum ether) to give the target compound (1.5 g, 63%) as white solid; MS (EI): m/e = 240.0 [M+H]+ . d) 6-Cyclopropylmethoxytrifluoromethyl-pyridinecarboxylic acid Sodium hydride (1.1 g, 31.4 mmol) was added in portions to cyclopropylmethanol (20 mL) and the mixture was stirred at room temperature for 0.5 hours. 6-Chloro (trifluoromethyl)-pyridinecarboxylic acid methyl ester (1.5 g, 6.3 mmol) was added and the resulting solution was stirred at 80°C for 1 h. Water (20 mL) was added; the solution was acidified with 6 N hydrochloric acid and then concentrated to give a residue which was partitioned between water (30 mL) and ethyl acetate (20 mL). The aqueous solution was extracted with ethyl acetate (2 x 20 mL) and the combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude target compound. The crude target compound was purified by column chromatography (silica gel, 10 g, 15% ethyl acetate in petroleum ether) to give the title compound (1.4 g, 85%) as white solid; MS (EI): m/e = 262.0 [M+H]+ . e) 6-Cyclopropylmethoxytrifluoromethyl-pyridinecarboxylic acid ((S)carbamoyl2-cyclopropyl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxytrifluoromethyl-pyridinecarboxylic acid and (S)amino N OH O O F F F N N H O O F O F F NH2 Chiral cyclopropyl-propionamide (CAN 1560779) as starting materials, MS (EI): m/e = 372.1 [M+H]+ .
Example 114 6-Cyclopropylmethoxy(tetrahydro-furanyl)-pyridinecarboxylic acid ((S) carbamoylmethyl-butyl)-amide a) 5-Bromo(cyclopropylmethoxy)-pyridinecarboxylic acid methyl ester A solution of 5-bromo(cyclopropylmethoxy)-pyridinecarboxylic acid (Example 9 d, 0.4 g, 1.5 mmol), iodomethane (CAN 165195, 0.42 g, 3 mmol), sodium carbonate (0.16 g, 1.5 mmol) in DMF (10 mL) was stirred overnight at room temperature. Water was poured into the reaction solution and the resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (silica gel, 20 g, 5% ethyl acetate in petroleum ether) to yield the title compound (0.2 g, 0.7 mmol, 48%) as white solid; MS (EI): m/e = 286.0 [M+H]+ 15 . b) 6-(Cyclopropylmethoxy)(2,5-dihydrofuranyl)-pyridinecarboxylic acid methyl ester (b1) and 6-(cyclopropylmethoxy)(4,5-dihydrofuranyl)-pyridinecarboxylic acid methyl ester (b2) A mixture of 5-bromo(cyclopropylmethoxy)-pyridinecarboxylic acid methyl ester (0.5 g, 1.7 mmol), 2,5-dihydrofuran (CAN 17088, 1.2 g, 17 mmol), palladium(II) N O O O Br N O O O O N O O O O b1 b2 acetate (CAN 33753, 0.02 g, 0.09 mmol), sodium acetate (0.17 g, 2 mmol) and tri-tertbutylphosphine (CAN 137166, 0.037 g, 0.2 mmol) in DMF(10 mL) was stirred at 120°C for 2.5 h under a nitrogen atmosphere. Water was poured into the reaction mixture and the resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (silica gel, 10 g, eluting with 5% ethyl acetate in petroleum ether) to yield 6-(cyclopropylmethoxy)(2,5- dihydrofuranyl)-pyridinecarboxylic acid methyl ester (b1) and 6- (cyclopropylmethoxy)(4,5-dihydrofuranyl)-pyridinecarboxylic acid methyl ester (b2) (mixture b1: b2 = 3:2, 0.38 g, 1.4 mmol, 79%) as yellow oil; MS (EI): m/e = 376.1 [M+H]+ . c) 6-(Cyclopropylmethoxy)(tetrahydrofuranyl)-pyridinecarboxylic acid methyl ester (c1) and 6-(cyclopropylmethoxy)(tetrahydrofuranyl)-pyridinecarboxylic acid methyl ester (c2) To a solution of 6-(cyclopropylmethoxy)(2,5-dihydrofuranyl)-pyridinecarboxylic acid methyl ester (b1) and 6-(cyclopropylmethoxy)(4,5-dihydrofuranyl)-pyridine carboxylic acid methyl ester (b2) (mixture from Example 114 b, 0.38 g, 1.38 mmol) in EtOH (50 mL) was added Pd/C (20%, 0.08 g) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 balloon at room temperature overnight. The reaction mixture was filtered through a pad of celite, the pad was washed with EtOH and the combined filtrates were concentrated to dryness.
The crude product 6-(cyclopropylmethoxy)(tetrahydrofuranyl)-pyridinecarboxylic acid methyl ester (c1) and 6-(cyclopropylmethoxy)(tetrahydrofuranyl)-pyridine carboxylic acid methyl ester (c2) (mixture, c1: c2 = 3:2, 0.36 g) was used for next step without further purification; MS (EI): m/e = 278.1 [M+H]+ , Rt = 1.71 min. d) 6-(Cyclopropylmethoxy)(tetrahydrofuranyl)-pyridinecarboxylic acid (d1) and 6-(Cyclopropylmethoxy)(tetrahydrofuranyl)-pyridinecarboxylic acid (d2) N O O O O N O O O O c1 c2 A solution of 6-(cyclopropylmethoxy)(tetrahydrofuranyl)-pyridinecarboxylic acid methyl ester (c1) and 6-(cyclopropylmethoxy)(tetrahydrofuranyl)-pyridine carboxylic acid methyl ester (c2) (mixture from Example 114 c, 0.35 g, 1.3 mmol) and sodium hydroxide (55 mg, 1.4 mmol) in ethanol (50 mL) was heated to 90°C for 2 h. The reaction mixture was evaporated, dissolved in water and extracted with ethyl acetate (30 mL). The pH of the aqueous layer was adjusted to 2 by addition of 1 N hydrochloric acid and the resulting precipitate was collected by filtration and dried in vacuo to give 6- (cyclopropylmethoxy)(tetrahydrofuranyl)-pyridinecarboxylic acid (d1) and 6- (cyclopropylmethoxy)(tetrahydrofuranyl)-pyridinecarboxylic acid (d2) (mixture, d1: d2 = 3:2, 0.33 g, 1.3 mmol, 100%) as yellow solid; MS (EI): m/e = 264.2 [M+H]+ . e) 6-Cyclopropylmethoxy(tetrahydro-furanyl)-pyridinecarboxylic acid ((S) carbamoylmethyl-butyl)-amide The title compound was synthesized in analogy to Example 1, using the mixture of 6- (cyclopropylmethoxy)(tetrahydrofuranyl)-pyridinecarboxylic acid and 6- (cyclopropylmethoxy)(tetrahydrofuranyl)-pyridinecarboxylic acid (mixture from Example 114 d), and (2S)aminomethyl-pentanamide (CAN 6874) as starting materials, MS (EI): m/e = 376.2 [M+H]+ .
Example 115 6-Cyclopropylmethoxy(tetrahydro-furanyl)-pyridinecarboxylic acid ((S) carbamoylmethyl-butyl)-amide O O N OH O O O N OH O d1 d2 N N H O O O O NH2 The title compound was synthesized in analogy to Example 1, using the mixture of 6- (cyclopropylmethoxy)(tetrahydrofuranyl)-pyridinecarboxylic acid and 6- (cyclopropylmethoxy)(tetrahydrofuranyl)-pyridinecarboxylic acid (mixture from Example 114 d), and (2S)aminomethyl-pentanamide (CAN 6874) as starting materials, MS (EI): m/e = 376.2 [M+H]+ .
Example 116 6-(3-Chloro-phenyl)cyclopropyl-pyridinecarboxylic acid (1-methylthiazol yl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)- -cyclopropyl-pyridinecarboxylic acid (Example 48 e) and α,α-dimethyl thiazolemethanamine (CAN 10823931) as starting materials, MS (EI): m/e = 398.1 [M+H]+ .
Example 117 -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [2-(2-methoxyethoxy)-1,1-dimethyl-ethyl]-amide N N H O O O O NH2 N N H N S O Cl N N H O O O O The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethoxy-pyridinecarboxylic acid (Example 42 a) and 2-(2-methoxyethoxy)-1,1-dimethyl-ethylamine (CAN 9477237) as starting materials, MS (EI): m/e = 363.2 [M+H]+ .
Example 118 6-Cyclopropylmethoxytrifluoromethyl-pyridinecarboxylic acid ((S) carbamoylmethyl-butyl)-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxytrifluoromethyl-pyridinecarboxylic acid (Example 113 d) and (2S)aminomethyl-pentanamide (CAN 6874) as starting materials, MS (EI): m/e = 374.1 [M+H]+ .
Example 119 6-Cyclopropylmethoxytrifluoromethyl-pyridinecarboxylic acid (1-methyl [1,2,4]oxadiazolyl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxytrifluoromethyl-pyridinecarboxylic acid (Example 113 d) and 1- methyl[1,2,4]oxadiazolyl ethylamine (CAN 11537575) as starting materials, MS (EI): m/e = 371.2 [M+H]+ 20 .
Example 120 6-Cyclopropylmethoxytrifluoromethyl-pyridinecarboxylic acid [1-methyl(5- methyl-[1,2,4]oxadiazolyl)-ethyl]-amide N N H O O O F F F NH2 Chiral N N N H N O O O F F F The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxytrifluoromethyl-pyridinecarboxylic acid (Example 113 d) and α,α,5-trimethyl-1,2,4-oxadiazolemethanamine (CAN 11538310) as starting materials, MS (EI): m/e = 385.1 [M+H]+ 5 .
Example 121 6-Cyclopropylmethoxytrifluoromethyl-pyridinecarboxylic acid (1-methyl thiazolyl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxytrifluoromethyl-pyridinecarboxylic acid (Example 113 d) and α,α-dimethylthiazolemethanamine (CAN 10823931) as starting materials, MS (EI): m/e = 386.0 [M+H]+ .
Example 122 6-Cyclohexyl-pyridinecarboxylic acid (2-hydroxymethyl-cyclohexyl)-amide The title compound was synthesized in analogy to Example 1, using 6-cyclohexylpyridinecarboxylic acid (Example 7 b) and 2-amino-cyclohexanemethanol (CAN 898542) as starting materials, MS (EI): m/e = 317.2 [M+H]+ .
Example 123 N N N N H O O O F F F N N H N S O O F F F N N H O OH 6-Cyclopropylmethoxy(tetrahydro-furanyl)-pyridinecarboxylic acid [1- methyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide The title compound was synthesized in analogy to Example 1, using the mixture of 6- (cyclopropylmethoxy)(tetrahydrofuranyl)-pyridinecarboxylic acid and 6- (cyclopropylmethoxy)(tetrahydrofuranyl)-pyridinecarboxylic acid (mixture from Example 114 d) and α,α,5-trimethyl-1,2,4-oxadiazolemethanamine (CAN 1153831 0) as starting materials, MS (EI): m/e = 387.2 [M+H]+ .
Example 124 6-Cyclopropylmethoxy(tetrahydro-furanyl)-pyridinecarboxylic acid [1- methyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide The title compound was synthesized in analogy to Example 1, using the mixture of 6- (cyclopropylmethoxy)(tetrahydrofuranyl)-pyridinecarboxylic acid and 6- (cyclopropylmethoxy)(tetrahydrofuranyl)-pyridinecarboxylic acid (mixture from Example 114 d), and α,α,5-trimethyl-1,2,4-oxadiazolemethanamine (CAN 1153831 0) as starting materials, MS (EI): m/e = 387.2 [M+H]+ .
Example 125 6-(3-Chloro-phenyl)(tetrahydro-furanyl)-pyridinecarboxylic acid [1-methyl20 1-(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide a) 6-(3-Chlorophenyl)(tetrahydrofuranyl)-pyridinecarboxylic acid methyl ester N N N N H O O O O N N N N H O O O O A solution of 6-bromo(tetrahydrofuranyl)-pyridinecarboxylic acid methyl ester (mixture of example 101 d, 0.296g, 1 mmol), 3-chlorophenylboronic acid (CAN 63503- 60-6, 0.24 g, 1.5 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride methylene chloride complex (CAN 954644, 34 mg) and cesium carbonate (CAN 534- 17-8, 1 g, 3 mmol) in DMF (10 mL) was stirred overnight at 80°C under a nitrogen atmosphere. After filtration, the reaction mixture was poured into 20 mL H2O and washed with ethyl acetate (2 x 20 mL). The organic layer was concentrated under reduced pressure to provide the title compound (0.3 g, 91%) as black oil which was used in the next step without further purification; MS (EI): m/e = 318.1 [M+H]+ 10 . b) 6-(3-Chloro-phenyl)(tetrahydro-furanyl)-pyridinecarboxylic acid A mixture of 6-(3-chlorophenyl)(tetrahydrofuranyl)-pyridinecarboxylic acid methyl ester (0.3 g, 1 mmol) and lithium hydroxide monohydrate (CAN 13103, 130 mg, 3 mmol) in THF/H2O 1/1 (20 mL) was stirred at room temperature for 1 h. After removal of the organic solvent under reduced pressure the aqueous phase was washed with ethyl acetate (10 mL) and acidified with 1 N HCl to pH = 3. The resulting solution was extracted with ethyl acetate (2 x 20 mL). The organic layer was concentrated under reduced pressure to give the title compound (0.28 g, 98%) as black oil which was used in the next step without further purification; MS (EI): m/e = 304.0 [M+H]+ 20 . c) 6-(3-Chloro-phenyl)(tetrahydro-furanyl)-pyridinecarboxylic acid [1-methyl (5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide N O O Cl O N OH O Cl O The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)- -(tetrahydro-furanyl)-pyridinecarboxylic acid and α,α,5-trimethyl-1,2,4-oxadiazole3-methanamine (CAN 11538310) as starting materials, MS (EI): m/e = 427.1 [M+H]+ .
Example 126 6-(3-Chloro-phenyl)(tetrahydro-furanyl)-pyridinecarboxylic acid (1-methyl1-oxazolyl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)- 5-(tetrahydro-furanyl)-pyridinecarboxylic acid (Example 125 b) and α,α-dimethyl oxazolemethanamine (CAN 12115194) as starting materials, MS (EI): m/e = 412.1 [M+H]+ .
Example 127 6-(3-Chloro-phenyl)(tetrahydro-furanyl)-pyridinecarboxylic acid (1-methyl15 1-thiazolyl-ethyl)-amide N N N N H O O O Cl N N H N O O O Cl N N H N S O O Cl The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)- -(tetrahydro-furanyl)-pyridinecarboxylic acid (Example 125 b) and α,α-dimethyl thiazolemethanamine (CAN 10823931) as starting materials, MS (EI): m/e = 428.1 [M+H]+ .
Example 128 6-(3-Chloro-phenyl)cyclopentyl-pyridinecarboxylic acid (1-methylthiazol yl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)- 5-cyclopentyl-pyridinecarboxylic acid (Example 106 e) and α,α-dimethyl thiazolemethanamine (CAN 10823931) as starting materials, MS (EI): m/e = 426.1 [M+H]+ .
Example 129 6-Cyclopropylmethoxytrifluoromethyl-pyridinecarboxylic acid (1-methyl oxazolyl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxytrifluoromethyl-pyridinecarboxylic acid (Example 113 d) and α,α-dimethyloxazolemethanamine (CAN 12115194) as starting materials, MS (EI): m/e = 370.1 [M+H]+ 20 .
Example 130 6-Cyclopropylmethoxymethyl-pyridinecarboxylic acid ((S)carbamoyl cyclopropyl-ethyl)-amide N N H N S O Cl N N H N O O O F F F The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxymethyl-pyridinecarboxylic acid (Example 36 d) and (S) aminocyclopropyl-propionamide (CAN 1560779) as starting materials, MS (EI): m/e = 318.2 [M+H]+ 5 .
Example 131 6-Cyclopropylmethoxy(3-hydroxy-azetidinyl)-pyridinecarboxylic acid ((S) carbamoylmethyl-butyl)-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3-hydroxy-azetidinyl)-pyridinecarboxylic acid (Example 75 a) and (2S)aminomethyl-pentanamide (CAN 6874) as starting materials, MS (EI): m/e = 377.2 [M+H]+ .
Example 132 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid ((S)- 1-carbamoylmethyl-butyl)-amide N N H O O O NH2 Chiral N N N H O O O NH2 HO Chiral N N N H O O O F F NH2 Chiral The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example 69 b) and (2S)aminomethyl-pentanamide (CAN 6874) as starting materials, MS (EI): m/e = 397.2 [M+H]+ .
Example 133 -Cyclopropylaminocyclopropylmethoxy-pyridinecarboxylic acid ((S) carbamoylcyclopropyl-ethyl)-amide a) 5-(Cyclopropylamino)(cyclopropylmethoxy)-pyridinecarboxylic acid methyl ester Cyclopropanamine (CAS 7650, 158 mg, 2.8 mmol), bis(diphenylphosphino)-1,1'- binaphthalene (CAS 983278, 115 mg, 0.19 mmol), tris(dibenzylideneacetone)dipalladium (CAS 513643, 84 mg, 0.093 mmol) and cesium carbonate (CAS 5348, 1.8 g, 6.6 mmol) were added to solution of 5-bromo (cyclopropylmethoxy)-pyridinecarboxylic acid methyl ester (Example 114 a, 530 mg, 1.85 mmol) in toluene (20 mL) under a nitrogen atmosphere. The reaction mixture was stirred overnight at 110°C and concentrated in vacuo. The residue was dissolved in water and extracted with ethyl acetate (30 mL). The pH of the aqueous layer was adjusted to 2 by addition of 1 N HCl, the resulting precipitate was collected by filtration, dried in vacuo and purified by column chromatography (silica gel, 50 g, 50% ethyl acetate in petroleum ether) to yield the title compound (400 mg, 82%) as a yellow solid; MS (EI): m/e = 263.1 [M+H]+ . b) 5-Cyclopropylaminocyclopropylmethoxy-pyridinecarboxylic acid A solution of 5-(cyclopropylamino)(cyclopropylmethoxy)-pyridinecarboxylic acid methyl ester (400 mg, 1.53 mmol), sodium hydroxide (244 mg, 6.1 mmol) in THF/H2O 1/1 (10 mL) was stirred for 1 h at room temperature. The reaction mixture was concentrated N O O O N H HN O N OH O under reduced pressure. Water was added and the pH was adjusted to 2 by addition of 1 N HCl. Extraction with ethyl acetate (30 mL) was followed by washing with brine (6 x 30 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 50 g, 50% ethyl acetate in petroleum ether) to yield the title compound (350 mg, 92%) as yellow solid; MS (EI): m/e =249.3 [M+H]+ . c) 5-Cyclopropylaminocyclopropylmethoxy-pyridinecarboxylic acid ((S) carbamoylcyclopropyl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropylamino6-cyclopropylmethoxy-pyridinecarboxylic acid and (S)aminocyclopropylpropionamide (CAN 1560779) as starting materials, MS (EI): m/e = 359.2 [M+H]+ .
Example 134 -Cyclopropylaminocyclopropylmethoxy-pyridinecarboxylic acid ((S) carbamoylmethyl-butyl)-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropylamino6-cyclopropylmethoxy-pyridinecarboxylic acid (Example 133 b) and (2S)amino methyl-pentanamide (CAN 6874) as starting materials, MS (EI): m/e = 361.3 [M+H]+ .
Example 135 N N H HN O O O NH2 Chiral N N H HN O O O NH2 Chiral 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid ((S)- 1-cyclopropylmethylhydroxymethyl-propyl)-amide a) (S)-Methyl 2-(tert-butoxycarbonylamino)cyclopropylpropanoate To a mixture of (S)(tert-butoxycarbonylamino)cyclopropylpropanoic acid (CAN 894837, 6.792 g, 30 mmol) and K2CO3 (8.173 g, 59 mmol) in DMF (100 mL) was added MeI (10.37 g, 73 mmol). The reaction mixture was stirred overnight at room temperature. After filtration, the filtrate was concentrated to give the title compound as yellow oil (6.44 g, 89%); MS (EI): m/e = 266.2 [M+Na]+ . b) (S)-tert-Butyl 1-cyclopropylhydroxymethylbutanylcarbamate To a solution of (S)-methyl 2-(tert-butoxycarbonylamino)cyclopropylpropanoate (0.972 g, 4 mmol) in THF (20 mL) was added a solution of MeMgBr in diethyl ether (3 M, 3.34 mL, 10 mmol) at 0°C. The resulting mixture was stirred at 0°C for 3 h. Then it was quenched with water. The mixture was diluted with ethyl acetate (20 mL) and brine (20 mL). The organic layer was washed with brine (20 mL) again, dried over anhydrous sodium sulfate and concentrated to give the title compound as white solid (0.8 g, 82%); MS (EI): m/e = 266.2 [M+Na]+ . c) (S)Aminocyclopropylmethyl-butanol A solution of (S)-tert-butyl 1-cyclopropylhydroxymethylbutanylcarbamate (0.8 g, 3 mmol) in ethyl acetate was saturated with hydrochloride (10 mL) and stirred for 1 h at room temperature. After diluting with water (20 mL), the layers were separated and the N H O O O O N H OH O O H2N OH water phase was washed with ethyl acetate (20 mL). Then it was adjusted with 1 N NaOH to pH = 8~9 and extracted with methylene chloride (3 x 20 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated to give the title compound as yellow oil (0.3 g, 64%); MS (EI): m/e = 144.2 [M+Na]+ . d) 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid ((S) cyclopropylmethylhydroxymethyl-propyl)-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example 69 b) and (S)aminocyclopropylmethyl-butanol as starting materials, MS (EI): m/e = 410.2 [M+H]+ .
Example 136 6-Cyclopropylmethoxy(tetrahydro-furanyl)-pyridinecarboxylic acid ((S) carbamoylcyclopropyl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using the mixture of 6- (cyclopropylmethoxy)(tetrahydrofuranyl)-pyridinecarboxylic acid and 6- (cyclopropylmethoxy)(tetrahydrofuranyl)-pyridinecarboxylic acid (mixture from Example 114 d), and (S)aminocyclopropyl-propionamide (CAN 1560779) as starting materials, MS (EI): m/e = 374.2 [M+H]+ 20 .
Example 137 N N N H O O F F OH Chiral N N H O O O O NH2 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (2- hydroxy-cyclohexyl)-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example 69 b) and 2-amino-cyclohexanol (CAN 68500) as starting materials, MS (EI): m/e = 382.2 [M+H]+ .
Example 138 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid [(S)- 2-cyclopropyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example 69 b) and (S)cyclopropyl(5-methyl-[1,2,4]oxadiazolyl)-ethylamine (Example 38 e) as starting materials, MS (EI): m/e = 434.2 [M+H]+ 15 .
Example 139 -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid ((S) cyclopropylmethylhydroxymethyl-propyl)-amide N N N H O O F F OH N N N N N H O O O F F Chiral The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethoxy-pyridinecarboxylic acid (Example 42 a) and (S)amino cyclopropylmethyl-butanol (Example 135 c) as starting materials, MS (EI): m/e = 359.2 [M+H]+ 5 .
Example 140 6-(3-Chloro-phenyl)(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid ((S) carbamoylmethyl-butyl)-amide a) 6-(3-Chloro-phenyl)(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid 6-Chloro(3,3-difluoroazetidinyl)-pyridinecarboxylic acid methyl ester (Example 69 a, 0.3 g, 1.15 mmol), 1,1’-bis(diphenylphosphino)ferrocene-palladium(II)dichloride methylene chloride complex (CAN 722874, 47 mg, 0.058 mmol) and cesium carbonate (CAN 5348, 0.56 g, 1.72 mmol) were added to a solution of 3- chlorophenylboronic acid (CAN 635036, 0.27 g, 1.72 mmol) in water (20 mL) and DMF (10 mL). The mixture was stirred for 48 h at 100°C. The reaction mixture was adjusted to pH = 3 and extracted with methylene chloride (3 x 20 mL). The organic layers were combined, dried over sodium sulfate and concentrated to give the crude product (110 mg, 30%); MS (EI): 325.0 [M+H]+ . b) 6-(3-Chloro-phenyl)(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid ((S) carbamoylmethyl-butyl)-amide N N H O O OH Chiral N N OH O F F Cl The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)- -(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid and (2S)aminomethylpentanamide (CAN 6874) as starting materials, MS (EI): m/e = 437.2 [M+H]+ .
Example 141 6-Cyclopropylmethoxy(tetrahydro-furanyl)-pyridinecarboxylic acid (2- hydroxy-1,1-dimethyl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using the mixture of 6- (cyclopropylmethoxy)(tetrahydrofuranyl)-pyridinecarboxylic acid and 6- (cyclopropylmethoxy)(tetrahydrofuranyl)-pyridinecarboxylic acid (mixture from Example 114 d), and 2-aminomethylpropanol (CAN 1245) as starting materials, MS (EI): m/e = 335.1 [M+H]+ .
Example 142 5-Cyclopropyl(2-methoxy-ethoxy)-pyridinecarboxylic acid ((S)carbamoyl methyl-butyl)-amide a) 5-Bromo(2-methoxyethoxy)-pyridinecarboxylic acid NaH (2.26 g, 66 mmol) was added in portions to a solution of 2-methoxyethanol (30 mL).
The mixture was stirred for 30 min at room temperature. Then 5-bromochloro-pyridineN N N H O O F F NH2 Cl Chiral N N H O O O OH N OH O O Br O 2-carboxylic acid methyl ester (Example 9 c, 3 g, 12 mmol) was added and the reaction mixture was heated to 100°C overnight. The mixture was poured into water and extracted with ethyl acetate (30 mL). The pH of the aqueous layer was adjusted to 2 by addition of 1 N hydrochloric acid and the resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed three times with brine, dried (sodium sulfate) and evaporated. The crude title compound (2.48 g, yellow solid) was used for the next reaction step without further purification; MS (EI): m/e 276.0 [M+H]+ . b) 5-Bromo(2-methoxyethoxy)-pyridinecarboxylic acid methyl ester A solution of 5-bromo(2-methoxyethoxy)-pyridinecarboxylic acid (2.48 g, 9 mmol), iodomethane (2.55 g, 18 mmol) and sodium carbonate (0.106 g, 9 mmol) in DMF (30 mL) was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed three times with brine, dried (sodium sulfate) and evaporated. The residue was purified by column chromatography (silica gel, 50 g, 30% ethyl acetate in petroleum ether) to yield the title compound (1.7 g, 6 mmol, 65 %) as yellow solid; MS (EI): m/e 290.0 [M+H]+ . c) 5-Cyclopropyl(2-methoxyethoxy)-pyridinecarboxylic acid methyl ester Under an atmosphere of nitrogen, a solution of 5-bromo(2-methoxyethoxy)-pyridine carboxylic acid methyl ester (0.2 g, 0.7 mmol), cyclopropylboronic acid (CAN 411235 9, 81 mg, 0.9 mmol), palladium acetate (CAN 33753, 8 mg, 0.037 mmol), tricyclohexylphosphine (CAN 26222, 0.021 g, 0.07 mmol) and potassium phosphate (0.54 g, 0.20 mmol) in toluene (20 mL) and water (1 mL) was heated to 110°C for 48 h.
N O O Br O O N O O O O The reaction mixture was concentrated under reduced pressure, dissolved in water, extracted with ethyl acetate (3 x 30 mL), washed with brine, dried (sodium sulfate) and evaporated to dryness. The residue was purified by column chromatography (silica gel, 10 g, 5% ethyl acetate in petroleum ether) to yield the title compound (0.16 g, 1 mmol, 93%) as yellow oil; MS (EI): m/e 252.2 [M+H]+ 5 . d) 5-Cyclopropyl(2-methoxyethoxy)-pyridinecarboxylic acid A solution of 5-cyclopropyl(2-methoxyethoxy)-pyridinecarboxylic acid methyl ester (0.16 g, 0.6 mmol) and sodium hydroxide (31 mg, 0.7 mmol) in ethanol (40 mL) was heated to 90°C for 2 h. The reaction mixture was evaporated, dissolved in water and extracted with ethyl acetate (30 mL). The pH of the aqueous layer was adjusted to 2 by addition of 1 N hydrochloric acid, the resulting precipitate was collected by filtration and dried in vacuo to give the title compound (0.11 g, 0.5 mmol; 73%) as yellow oil; MS: m/e = 238.1 [M+H]+ . e) 5-Cyclopropyl(2-methoxy-ethoxy)-pyridinecarboxylic acid ((S)carbamoyl methyl-butyl)-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl(2- methoxy-ethoxy)-pyridinecarboxylic acid and (2S)aminomethyl-pentanamide (CAN 6874) as starting materials, MS (EI): m/e = 350.2 [M+H]+ .
Example 143 7,7-Dimethyl-5,6,7,8-tetrahydro-quinolinecarboxylic acid ((R)cyclopropyl hydroxy-propyl)-amide N OH O O O N N H O O O NH2 O Chiral a) 7,7-Dimethyl-5,6,7,8-tetrahydro-1H-quinolinone A solution of 3,3-dimethylcyclohexanone (10 g, 71.3 mmol) and methyl propiolate (11.5 g, 136 mmol) in ammonia (390 ml, 2.73 mol) was heated and stirred in an autoclave at 140°C for 16 h. The autoclave was cooled to ambient temperature, and the reaction mixture was transferred into a 1 L round-bottomed flask and was evaporated in vacuo to give a solid residue which was purified by gradient chromatography on silica with ethyl acetate in heptane to give 7.0 g (55%) of the title compound as colorless oil; LC-MS (UV peak area/EIC) 85%, 178.1228 (M+H)+ . b) Trifluoro-methanesulfonic acid 7,7-dimethyl-5,6,7,8-tetrahydro-quinolinyl ester 7,7-Dimethyl-5,6,7,8-tetrahydro-1H-quinolinone (2.0 g, 11.3 mmol) was dissolved in CH2Cl2 (50 ml). After addition of triethylamine (1.37 g, 1.89 mL, 13.5 mmol) the mixture was cooled to -45°C with stirring. Trifluoromethanesulfonic anhydride (4.78 g, 2.86 mL, 16.9 mmol) was added slowly over a period of 10 min at -50 to -45°C. The mixture was stirred for 15 min at this temperature. The cooling-bath was removed and the reaction mixture was stirred for 1h at room temperature; poured onto ice (50 mL) and stirred for 5 min after adding 20 mL 15% NaOH solution. Phases were separated and the aqueous phase was extracted with CH2Cl2 (2 x 30 mL). The org. layers were combined, washed with 15%-NaOH (2 x 20mL), dried with Na2SO4, and concentrated in vacuo. The resulting light brown oil was purified by gradient chromatography on silica with ethyl acetate in heptane to give 3.3 g (94%) of the title compound as colorless oil; LC-MS (UV peak area/EIC) 100%, 310.0722 (M+H)+ . c) 7,7-Dimethyl-5,6,7,8-tetrahydro-quinolinecarboxylic acid methyl ester N H O N O S O O F F F N O O Trifluoro-methanesulfonic acid 7,7-dimethyl-5,6,7,8-tetrahydro-quinolinyl ester (3.1 g, .0 mmol) was dissolved in methanol (45 mL) and ethyl acetate (45 mL). PdCl2(dppf)- CH2Cl2 adduct (311 mg, 381 µmol) and triethylamine (1.52 g, 2.1 mL, 15.0 mmol) were added and the mixture was stirred in an autoclave at 110°C with a CO pressure of 70 bar for 24 h. The solvents were evaporated to give a red-brown oily residue that was purified by gradient chromatography on silica with ethyl acetate in heptane. The chromatography yielded 1.9 g (86%) of the title compound as white solid; LC-MS (UV peak area/EIC) 100%, 220.1335 (M+H)+ . d) 7,7-Dimethyl-5,6,7,8-tetrahydro-quinolinecarboxylic acid 7,7-Dimethyl-5,6,7,8-tetrahydro-quinolinecarboxylic acid methyl ester (1.88 g, 8.57 mmol) was dissolved in THF (30 mL) and water (10 mL). Lithium hydroxide monohydrate (616 mg, 25.7 mmol) was added with stirring at room temperature and the reaction mixture was stirred at reflux temperature for 1h. The mixture was cooled, acidified with 2 N HCl to pH = 5 and extracted with ethyl acetate. The organic phases were combined, dried with Na2SO4, and concentrated in vacuo. The residue was stirred with ethyl acetate (5 mL) at 40°C; n-heptane (10 mL) was added and stirring at room temperature continued for 30 min. The precipitate was filtered and dried to give 1.7 g (96%) of the title compound as white solid; MS (ISP): m/e 206.1 [M+H]+ . e) 7,7-Dimethyl-5,6,7,8-tetrahydro-quinolinecarboxylic acid ((R)cyclopropyl hydroxy-propyl)-amide The title compound was synthesized in analogy to Example 1, using 7,7-dimethyl-5,6,7,8- tetrahydro-quinolinecarboxylic acid and (αR)-α-(aminomethyl)-α-methyl-cyclo25 propanemethanol (CAN 9124549) as starting materials, LC-MS (UV peak area/EIC) 99.3%, 303.2078 (M+H)+ .
Example 144 7,7-dimethyl-N-(2-(5-methyl-1,2,4-oxadiazolyl)propanyl)-5,6,7,8- tetrahydroquinolinecarboxamide N OH O N N H O OH The title compound was synthesized in analogy to Example 1, using 7,7-dimethyl-5,6,7,8- tetrahydro-quinolinecarboxylic acid (Example 143 d) and α,α,5-trimethyl-1,2,4- oxadiazolemethanamine (CAN 11538310) as starting materials, LC-MS (UV peak area/EIC) 100%, 329.1977 (M+H)+ 5 .
Example 145 N-(1-hydroxymethylpropanyl)-7,7-dimethyl-5,6,7,8-tetrahydroquinoline carboxamide The title compound was synthesized in analogy to Example 1, using 7,7-dimethyl-5,6,7,8- tetrahydro-quinolinecarboxylic acid (Example 143 d) and 2-aminomethylpropanol (CAN 1245) as starting materials, LC-MS (UV peak area/EIC) 99.7%, 277.1910 (M+H)+ .
Example 146 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid ((S)- 2-cyclopropylthiazolyl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example 69 b) and (S)cyclopropylthiazolyl-ethylamine (Example 59 b) as starting materials, MS (EI): m/e = 435.1 [M+H]+ .
N N H O N O N N N H O OH N O N N H O F F N S Example 147 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (pyridinylmethyl)-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example 69 b) and pyridinyl-methylamine (CAN 37319) as starting materials, MS (EI): m/e = 375.2 [M+H]+ .
Example 148 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (2- hydroxy-1,1-dimethyl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example 69 b) and 2-aminomethylpropanol (CAN 1245) as starting materials, MS (EI): m/e = 356.2 [M+H]+ .
Example 149 [6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinyl]-((S) hydroxymethyl-pyrrolidinyl)-methanone N N N H O N O F F N N N H O O F F OH The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example 69 b) and (S)pyrrolidinyl-methanol (CAN 233569) as starting materials, MS (EI): m/e = 368.2 [M+H]+ 5 .
Example 150 6-Cyclopropylmethoxy(3-hydroxy-oxetanyl)-pyridinecarboxylic acid ((S) carbamoylmethyl-butyl)-amide a) 6-Cyclopropylmethoxy(3-hydroxy-oxetanyl)-pyridinecarboxylic acid Under a nitrogen atmosphere, n-BuLi (3.23 mL, 5.6 mmol) was added dropwise to a solution of 5-bromocyclopropylmethoxy-pyridinecarboxylic acid (Example 9 d, 1.1g, 4.0 mmol) in THF (50 mL) at -78°C and stirred for 1 h at this temperature. Then a solution of oxetanone (CAN 67040, 0.73 g, 10 mmol) in THF (5 mL) was added at -78°C. The reaction mixture was stirred for 1 h at room temperature and quenched with aq.
NH4Cl solution. The pH was adjusted to 2 with conc. HCl. The mixture was extracted with ethyl acetate (3 x 50 mL), the organic layers were combined, washed with brine (2 x 50 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by chromatography over silica gel using petroleum ether/ethyl acetate = 1/1 to give the title compound (0.13 g, 30.8%) as a yellow solid; MS (EI): m/e = 266.1 [M+H]+ . b) 6-Cyclopropylmethoxy(3-hydroxy-oxetanyl)-pyridinecarboxylic acid ((S) carbamoylmethyl-butyl)-amide N N O N O F F OH Chiral O N OH O O OH The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3-hydroxy-oxetanyl)-pyridinecarboxylic acid and (2S) aminomethyl-pentanamide (CAN 6874) as starting materials, MS (EI): m/e = 378.2 [M+H]+ 5 .
Example 151 6-(3-Chloro-phenyl)(tetrahydro-furanyl)-pyridinecarboxylic acid [1-methyl1-(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)- -(tetrahydro-furanyl)-pyridinecarboxylic acid (Example 101 f) and α,α,5-trimethyl1,2,4-oxadiazolemethanamine (CAN 11538310) as starting materials, MS (EI): m/e = 427.1 [M+H]+ .
Example 152 6-(3-Chloro-phenyl)(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid [2-(2- methoxy-ethoxy)-1,1-dimethyl-ethyl]-amide N N H O O O O NH2 OH Chiral N N N N H O O O Cl The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)- -(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example 140 a) and 2-(2- methoxy-ethoxy)-1,1-dimethyl-ethylamine (CAN 9477237) as starting materials, MS (EI): m/e = 454.1 [M+H]+ 5 .
Example 153 -Cyclopropyl(2-methoxy-ethoxy)-pyridinecarboxylic acid [1-methyl(5- methyl-[1,2,4]oxadiazolyl)-ethyl]-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl(2- methoxyethoxy)-pyridinecarboxylic acid (Example 142 d) and α,α,5-trimethyl-1,2,4- oxadiazolemethanamine (CAN 11538310) as starting materials, MS (EI): m/e = 361.1 [M+H]+ .
Example 154 5-Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid (1,1-dimethyl morpholinyl-propyl)-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethoxy-pyridinecarboxylic acid (Example 42 a) and 1,1-dimethyl N N N H O F F Cl O O N N N N H O O O O N N H N O O O morpholinyl-propylamine (Example 35 d) as starting materials, MS (EI): m/e = 388.3 [M+H]+ .
Example 155 -Cyclopropyl(4-fluoro-benzyl)-pyridinecarboxylic acid ((S)carbamoyl methyl-butyl)-amide a) 5-Bromomethyl-pyridinecarbonitrile NaCN (4 g, 82 mmol) was added to a solution of 3-bromofluoromethyl-pyridine (4 g, 21 mmol) in DMSO (100 mL) The mixture was stirred for 2 h at 100°C, poured into H2O (100 mL) and extracted with ethyl acetate (2 x 100mL). The organic layers were dried over Na2SO4, concentrated and purified by flash column chromatography (silica gel, g, eluting with 10% ethyl acetate in petroleum ether) to give the title compound (0.6 g, %) as white solid; MS (EI): m/e = 197.0 [M+H]+ . b) 5-Cyclopropylmethyl-pyridinecarbonitrile -Bromomethyl-pyridinecarbonitrile (0.5 g, 2.5 mmol), cyclopropylboronic acid (CAN:4112359,0.36 g, 4 mmol), Pd2(dba)3 (CAN:4112359,0.1 g, 0.2mmol), xantphos (CAN:1612658,0.15 g, 0.26mmol) and Cs2CO3 (1.1 g, 3 mmol) were suspended in 1,4-dioxane (30 mL) under a nitrogen atmosphere. The mixture was stirred for 12 h at 110°C, filtered, concentrated under reduced pressure and purified by column chromatography (silica gel, 5 g, eluting with 10% ethyl acetate in petroleum ether) to give the title compound (0.3 g, 75%) as yellow solid; MS (EI): m/e = 159.2 [M+H]+ . c) 5-Cyclopropylmethyloxy-pyridinecarbonitrile N Br CN N CN A mixture of 5-cyclopropylmethyl-pyridinecarbonitrile (0.2 g, 1.3 mmol) and mCPBA (0.5 g, 3 mmol) in CH2Cl2 (10 mL) was stirred for 12 hours at 60°C. After cooling to ambient temperature, the mixture was filtered, concentrated under reduced pressure and purified by column chromatography (silica gel, 3 g, eluting with 50% ethyl acetate in petroleum ether) to give the title compound (0.2 g, 91%) as yellow solid; MS (EI): m/e = 175.0 [M+H]+ . d) 5-Cyclopropylhydroxymethyl-pyridinecarbonitrile Trifluoroacetic acid anhydride (CAN 4570, 1 mL) was added to a solution of 5- cyclopropylmethyloxy-pyridinecarbonitrile (0.2 g, 1.1 mmol) in CH2Cl2 (10 mL).
The reaction mixture was stirred for 12 h at ambient temperature and then partitioned between 6 N NaOH aq. (10 mL) and CH2Cl2 (10 mL). The aqueous phase was washed several times with CH2Cl2 and the combined organic fractions were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 3 g, eluting with 1% methanol in methylene chloride) to give the title compound (0.1 g, 50%) as yellow oil; MS (EI): m/e = 175.2 [M+H]+ . e) 6-Bromomethylcyclopropyl-pyridinecarbonitrile A solution of 5-cyclopropylhydroxymethyl-pyridinecarbonitrile (0.1 g, 0.6 mmol), CBr4 (0.8 g, 1.2 mmol), PPh3 (0.3 g, 1.2 mmol) in THF (10 mL) was stirred for 12 h at 40°C. The solvent was removed under reduced pressure and the crude product purified by flash column chromatography (silica gel, 3 g, eluting with 25% ethyl acetate in petroleum ether) to give the title compound (0.1 g, 74%) as yellow solid; MS (EI): m/e = 236.9 [M+H]+ 25 .
N + CN O N HO N N CN Br f) 5-Cyclopropyl(4-fluoro-benzyl)-pyridinecarbonitrile A mixture of 6-bromomethylcyclopropyl-pyridinecarbonitrile (0.1 g, 0.4 mmol), 4- fluoro-benzylboronic acid (CAN 17651, 0.1 g, 0.7 mmol), Pd(dppf)Cl2 (CAN 95464- 05-4, 50 mg, 0.068 mmol), Cs2CO3 (0.2 g, 0.6 mmol) in 1.4-dioxane (10 mL) was stirred for 12 h at 110°C under a nitrogen atmosphere. The mixture was filtered, concentrated and purified by flash column chromatography (silica gel, 3 g, eluting with 25% ethyl acetate in petroleum ether) to give the title compound (80 mg, 75%) as yellow solid; MS (EI): m/e = 253.2 [M+H]+ . g) 5-Cyclopropyl(4-fluoro-benzyl)-pyridinecarboxylic acid A solution of 5-cyclopropyl(4-fluoro-benzyl)-pyridinecarbonitrile (0.08 g, 0.3 mmol) and NaOH (0.05 g, 1.2 mmol) in H2O (10 mL) was stirred for 2 hours at 90°C. The pH was adjusted to 3 with 1 M HCl. The mixture was extracted with ethyl acetate (3 x 10 mL), dried over Na2SO4, concentrated under reduced pressure and purified by column chromatography to give the title compound (0.06 g, 70%) as yellow solid; MS (EI): m/e = 272.1 [M+H]+ . h) 5-Cyclopropyl(4-fluoro-benzyl)-pyridinecarboxylic acid ((S)carbamoyl methyl-butyl)-amide N CN F N F COOH The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl(4- fluoro-benzyl)-pyridinecarboxylic acid and (2S)aminomethyl-pentanamide (CAN 6874) as starting materials, MS (EI): m/e = 384.2 [M+H]+ .
Example 156 6-(3-Chloro-phenyl)(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (1- methylthiazolyl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)- 5-(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example 140 a) and α,αdimethylthiazolemethanamine (CAN 10823931) as starting materials, MS (EI): m/e = 449.1 [M+H]+ .
Example 157 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid [(S)- 2-cyclopropyl(2-methoxy-ethoxymethyl)-ethyl]-amide a) (S)-tert-Butyl 1-cyclopropylhydroxypropanylcarbamate N N H O O NH2 F Chiral N N N H N S O F F Cl N H OH O O NaBH4 (1.5 g, 39 mmol) was added in portions to a solution of (S)-methyl 2-(tertbutoxycarbonylamino)cyclopropylpropanoate (Example 135 a, 3.15 g, 13 mmol) in MeOH (30 mL) at room temperature. The mixture was stirred at room temperature for 2 h.
H2O (50 mL) was added and a white precipitate formed. The precipitate was collected by filtration and dried to give the title product (1.84 g, 66%) as white solid which was used in the next step without further purification; MS (EI): m/e = 238.1 [M+Na]+ . b) (S)-tert-Butyl 1-cyclopropyl(2-methoxyethoxy)propanylcarbamate NaH (70%，0.504 g, 15 mmol) was added in portions to a solution of (S)-tert-butyl 1- cyclopropylhydroxypropanylcarbamate (1.6 g, 7.5 mmol) in THF (30 mL) at room temperature. The mixture was stirred at room temperature for 20 min. 1-Bromo methoxyethane (2.07 g, 15 mmol) was added and stirring was continued for 2 h. The reaction was quenched by careful addition of H2O (5 mL). After evaporation of solvent the residue was diluted with ethyl acetate (20 mL) and H2O (20 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, and concentrated to give the title product as yellow oil (1.01 g, 50%); MS (EI): m/e = 296.2 [M+Na]+ . c) (S)Cyclopropyl(2-methoxyethoxy)propanamine (S)-tert-Butyl 1-cyclopropyl(2-methoxyethoxy)propanylcarbamate (1.01 g, 4 mmol) was dissolved in HCl / ethyl acetate (10 mL) and stirred at room temperature for 30 min.
Then the reaction mixture was concentrated to give a residue, which was dissolved in H2O (10 mL) and then washed with ethyl acetate (2 x 10 mL). The pH of the aqueous layer was adjusted to 9~10 with 5 N NaOH solution. After extraction with ethyl acetate (3 x 20 mL) the combined organic layers were washed with brine (50 mL), dried over Na2SO4 and concentrated to give the title product (0.072 g, 11%) as yellow oil; MS (EI): m/e = 174.2 [M+Na]+ . d) 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid [(S) cyclopropyl(2-methoxy-ethoxymethyl)-ethyl]-amide N H O O O O H2N O O The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example 69 b) and (S)cyclopropyl(2-methoxy-ethoxymethyl)-ethylamine as starting materials, MS (EI): m/e = 440.1 [M+H]+ 5 .
Example 158 -(3,3-Difluoro-azetidinyl)(2-methoxy-ethoxy)-pyridinecarboxylic acid ((S) carbamoylmethyl-butyl)-amide a) 5-(3,3-Difluoroazetidinyl)(2-methoxyethoxy)-pyridinecarboxylic acid methyl ester Under a nitrogen atmosphere a mixture of 5-bromo(2-methoxyethoxy)-pyridine carboxylic acid methyl ester (Example 142 b, 0.42 g, 1.45 mmol), 3,3-difluoroazetidine hydrochloride (0.22 g, 1.74 mmol), tris(dibenzylideneacetone)dipalladium (CAN 51364- 51-3, 27 mg, 0.03 mmol), (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (CAN 761894, 36 mg, 0.06 mmol) and cesium carbonate (1.4 g, 4.35 mmol) in toluene (50 mL) was stirred at 110°C overnight. After evaporation of solvents the residue was partitioned between water (30 mL) and ethyl acetate (30 mL) and the aqueous phase was extracted with ethyl acetate (2 x 30 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue which was purified by column chromatography (silica gel, 8 g, 15% ethyl acetate in petroleum ether) to give the title compound (0.3 g, 68%) as white solid; MS (EI): m/e = 303.1 [M+H]+ .
N N N H O O F F O O Chiral O N N O O F F O b) 5-(3,3-Difluoro-azetidinyl)(2-methoxy-ethoxy)-pyridinecarboxylic acid A solution of 5-(3,3-difluoroazetidinyl)(2-methoxyethoxy)-pyridinecarboxylic acid methyl ester (0.3 g, 1 mmol) and lithium hydroxide monohydrate (0.25 g, 6 mmol) in THF / H2O (30 mL) was stirred at room temperature for 3 h. After removal of the organic solvent, the aqueous phase was extracted with ethyl acetate (20 mL) and then acidified with 6 N hydrochloric acid to pH 2 to form a precipitate which was collected by filtration and dried under reduced pressure to give the target compound (0.24 g, 84%) as off-white solid which was used directly in the next step without further purification; MS (EI): m/e = 289.1 [M+H]+ 10 . c) 5-(3,3-Difluoro-azetidinyl)(2-methoxy-ethoxy)-pyridinecarboxylic acid ((S) carbamoylmethyl-butyl)-amide The title compound was synthesized in analogy to Example 1, using 5-(3,3-difluoro15 azetidinyl)(2-methoxy-ethoxy)-pyridinecarboxylic acid and (2S)amino methyl-pentanamide (CAN 6874) as starting materials, MS (EI): m/e = 401.1 [M+H]+ .
Example 159 -Cyclopropylaminocyclopropylmethoxy-pyridinecarboxylic acid (2-hydroxy1,1-dimethyl-ethyl)-amide N N OH O F F O O N N N H O O F F O NH2 O Chiral The title compound was synthesized in analogy to Example 1, using 5-cyclopropylamino6-cyclopropylmethoxy-pyridinecarboxylic acid (Example 133 b) and 2-amino methylpropanol (CAN 1245) as starting materials, MS (EI): m/e = 401.1 [M+H]+ .
Example 160 6-Cyclopropylmethoxy(1-hydroxy-cyclobutyl)-pyridinecarboxylic acid [1- methyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide a) 6-Cyclopropylmethoxy(1-hydroxy-cyclobutyl)-pyridinecarboxylic acid Under nitrogen atmosphere, BuLi (0.58 mL, 0.89 mmol) was added dropwise to a solution of 5-bromocyclopropylmethoxy-pyridinecarboxylic acid (Example 9 d, 0.2g, 0.74 mmol) in THF (20 mL) at -78°C. The reaction mixture was stirred for 1 h at -78°C then cyclobutanone (CAN 11913, 1.11 mL, 1.47 mmol) in THF (3 mL) was added to the above solution at -78°C. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. The reaction mixture was then quenched with NH4Cl and the pH was adjusted to 2 by addition of 1 N HCl. The mixture was extracted with ethyl acetate (3 x 10 mL); the organic layers were combined, washed with brine (2 x 10 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was used for the next step without further purification; MS (EI): m/e = 264.1 [M+H]+ 20 . b) 6-Cyclopropylmethoxy(1-hydroxy-cyclobutyl)-pyridinecarboxylic acid [1-methyl1-(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide N N H HN O O OH N OH O O OH The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(1-hydroxy-cyclobutyl)-pyridinecarboxylic acid and α,α,5- trimethyl-1,2,4-oxadiazolemethanamine (CAN 11538310) as starting materials, MS (EI): m/e = 387.2 [M+H]+ 5 .
Example 161 -Cyclopropyl(2-methoxy-ethoxy)-pyridinecarboxylic acid ((S)carbamoyl cyclopropyl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl(2- methoxyethoxy)-pyridinecarboxylic acid (Example 142 d) and (S)amino cyclopropyl-propionamide (CAN 1560779) as starting materials, MS (EI): m/e = 348.1 [M+H]+ .
Example 162 5-[Bis-(2,2,2-trifluoro-ethyl)-amino]cyclopropylmethoxy-pyridinecarboxylic acid ((S)carbamoylcyclopropyl-ethyl)-amide a) 5-(Bis(2,2,2-trifluoroethyl)amino)(cyclopropylmethoxy)-pyridinecarboxylic acid methyl ester N N N N H O O O OH N N H O O O NH2 O Chiral Under a nitrogen atmosphere, a solution of 5-bromo(cyclopropylmethoxy)-pyridine carboxylic acid methyl ester (Example 114 a, 1 g, 3.5 mmol), bis(2,2,2- trifluoroethyl)amine (1.90 g, 10 mmol), (±)-2,2'-bis(diphenylphosphino)-1,1'- binaphthalene (CAN 983278, 0.435 g, 1 mmol), tris(dibenzylideneacetone)dipalladium (CAN 513643, 0.32 g, 0.35 mmol) and cesium carbonate (CAN 5348, 3.4 g, 10 mmol) in toluene (50 mL) was reacted overnight at 110°C. The reaction mixture was concentrated under reduced pressure, dissolved in water, extracted with ethyl acetate (50 mL), the aqueous layer was adjusted to pH 2 with conc.
HCl, then extracted with ethyl acetate (3 x 50 mL), washed with brine (2 x 50 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 10 g, 20% ethyl acetate in petroleum ether) to yield the title compound (0.5 g, 29.7%) as a yellow oil; MS: m/e = 387.1 [M+H]+ . b) 5-[Bis-(2,2,2-trifluoro-ethyl)-amino]cyclopropylmethoxy-pyridinecarboxylic acid A solution of 5-(bis(2,2,2-trifluoroethyl)amino)(cyclopropylmethoxy)-pyridine carboxylic acid methyl ester (60 mg, 0.16 mmol) and sodium hydroxide (9 mg, 0.23 mmol) in ethanol (20 mL) was reacted for 2 h at 90°C. The reaction mixture was concentrated under reduced pressure, dissolved in water and extracted with ethyl acetate (10 mL). The pH of the aqueous layer was adjusted to 2 by addition of 1 N hydrochloric acid; the aqueous layer was extracted with ethyl acetate (3 x 10 mL), washed with brine (2 x 10 mL), dried over Na2SO4 and evaporated to dryness (0.03 g, crude). The crude product was used for next step without further purification; MS: m/e = 373.1 [M+H]+ .
N O O O N F F F F F F N N OH O O F F F F F F c) 5-[Bis-(2,2,2-trifluoro-ethyl)-amino]cyclopropylmethoxy-pyridinecarboxylic acid ((S)carbamoylcyclopropyl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using 5-[bis-(2,2,2-trifluoro5 ethyl)-amino]cyclopropylmethoxy-pyridinecarboxylic acid and (S)amino cyclopropyl-propionamide (CAN 1560779) as starting materials, MS (EI): m/e = 483.1 [M+H]+ .
Example 163 -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [(S)cyclopropyl10 1-(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethoxy-pyridinecarboxylic acid (Example 42 a) and (S)cyclopropyl (5-methyl-[1,2,4]oxadiazolyl)-ethylamine (Example 38 e) as starting materials, MS (EI): m/e = 383.2 [M+H]+ 15 .
Example 164 6-(3-Chloro-phenyl)(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid [(S) cyclopropyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide N N N H O O F O F F F F F NH2 Chiral N N N N H O O O Chiral The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)- -(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example 140 a) and (S) cyclopropyl(5-methyl-[1,2,4]oxadiazolyl)-ethylamine (Example 38 e) as starting materials, MS (EI): m/e = 474.1 [M+H]+ 5 .
Example 165 -[Bis-(2,2,2-trifluoro-ethyl)-amino]cyclopropylmethoxy-pyridinecarboxylic acid (1-ethylmethylcarbamoyl-propyl)-amide The title compound was synthesized in analogy to Example 1, using 5-[bis-(2,2,2-trifluoroethyl)-amino]cyclopropylmethoxy-pyridinecarboxylic acid (Example 162 b) and 2- aminoethyl-N-methyl-butyramide (Example 70 b) as starting materials, MS (EI): m/e = 499.2 [M+H]+ .
Example 166 5-Cyclopropyl(tetrahydro-furanylmethoxy)-pyridinecarboxylic acid [1- methyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide N N N N N H O O F F Cl Chiral N N N H O O O N H F F F F F F a) 5-Bromo(tetrahydro-furanylmethoxy)-pyridinecarboxylic acid 5-Bromochloropicolinic acid (200 mg, 846 µmol; CAN 9599589) and powdered potassium hydroxide (190 mg, 3.38 mmol) were combined with DMSO (1.93 mL) to give a colorless solution which was stirred for 15 min at ambient temperature before tetrahydro2-furanmethanol (130 mg, 123 µl, 1.27 mmol, CAN 974) was added, and stirring continued for 1 day at ambient temperature. The reaction mixture was poured into a mixture of ice-water and 1 M NaOH, and extracted with t-butylmethyl ether (2x 25 mL) and washed with ice-water/brine. The water phases were combined acidified with ice/1 N HCl and extracted with isopropyl acetate (2 x 30 mL). The organic layers were washed with ice-water/brine (2 x 30 mL), dried with Na2SO4 and concentrated in vacuo to give the title compound (254 mg, 99%) as light brown oil; MS (ESI): 301.8 [M-H]- . b) 5-Cyclopropyl(tetrahydro-furanylmethoxy)-pyridinecarboxylic acid Palladium(II)acetate (1.19 mg, 5.3 µmol), butylbis(tricyclo[3.3.1.13,7]decyl)-phosphine (2.85 mg, 7.94 µmol, CAN 3219215), potassium cyclopropyltrifluoroborate (39.6 mg, 267 µmol) and cesium carbonate (259 mg, 794 µmol) were combined to give a white solid.
To this solid a degassed solution of 5-bromo(tetrahydro-furanylmethoxy)-pyridine N O N N H O N O O OH O N O Br O O N O OH O carboxylic acid (80 mg, 265 µmol) in toluene (2.02 mL) / water (224 µL) was added through a septum cap. The reaction mixture was heated to 120°C and stirred for 20 h. After cooling to ambient temperature the reaction mixture was diluted with water (2 mL), poured onto 20 mL ice water/brine/1 N HCl, extracted with isopropyl acetate (2 x 40 mL), and washed with 20 mL ice water/brine. The organic layers were dried with Na2SO4 and concentrated in vacuo to give a light brown oily residue which was purified by preparative TLC (silica gel, 2.0 mm, DCM/MeOH, 49:1). The title compound (25 mg, 36%) was isolated as light yellow liquid; MS (ESI): 262.0 [M-H]- . b) 5-Cyclopropyl(tetrahydro-furanylmethoxy)-pyridinecarboxylic acid [1-methyl10 1-(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl (tetrahydro-furanylmethoxy)-pyridinecarboxylic acid (Example 166 b) and α,α,5- trimethyl-1,2,4-oxadiazolemethanamine (CAN 11538310) as starting materials, MS (EI): m/e = 387.0 [M+H]+ .
Example 167 N-(2-Cyanopropanyl)cyclopropyl(cyclopropylmethoxy)picolinamide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethoxy-pyridinecarboxylic acid (Example 42 a) and 2-aminomethylpropanenitrile, (CAN 193552) as starting materials, LC-MS (UV peak area/ESI) 89%, 300.1702 (M+H)+ .
Example 168 (S)Cyclopropyl(cyclopropylmethoxy)-N-(3,3-dimethyl(methylamino) oxobutanyl)picolinamide O N N H O N The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethoxy-pyridinecarboxylic acid (Example 42 a) and (2S)amino-N,3,3- trimethyl-butanamide, (CAN 892260) as starting materials, LC-MS (UV peak area/ESI) 96%, 360.2272 (M+H)+ 5 .
Example 169 N-(1-Amino-2,3-dimethyloxobutanyl)cyclopropyl(cyclopropylmethoxy) picolinamide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethoxy-pyridinecarboxylic acid (Example 42 a) and 2-amino-2,3- dimethyl-butanamide (CAN 409632) as starting materials, LC-MS (UV peak area/ESI) 96%, 346.2136 (M+H)+ .
Example 170 N-(1-Aminomethyloxobutanyl)cyclopropyl(cyclopropylmethoxy) picolinamide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethoxy-pyridinecarboxylic acid (Example 42 a) and 2-aminomethylO N N H O O N H Chiral O N N H O O NH2 O N N H O O NH2 butanamide (CAN 592094) as starting materials, LC-MS (UV peak area/ESI) 96%, 332.1982 (M+H)+ .
Example 171 -Cyclopropyl(cyclopropylmethoxy)-N-(1-(5-methyl-1,2,4-oxadiazolyl) cyclobutyl)picolinamide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethoxy-pyridinecarboxylic acid (Example 42 a) and 1-(5-methyl-1,2,4- oxadiazolyl)-cyclobutanamine hydrochloride (1:1) (CAN 11708975) as starting materials, LC-MS (UV peak area/ESI) 97.8%, 369.1914 (M+H)+ .
Example 172 (S)-N-(2-Aminooxophenylethyl)cyclopropyl(cyclopropylmethoxy) picolinamide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethoxy-pyridinecarboxylic acid (Example 42 a) and (αS)-α-aminobenzeneacetamide hydrochloride (1:1) (CAN 600798) as starting materials, LC-MS (UV peak area/ESI) 98%, 366.1814 (M+H)+ 20 .
Example 173 O N N H O N O N O N N H O NH2 O Chiral (R)-N-(2-Aminooxophenylethyl)cyclopropyl(cyclopropylmethoxy) picolinamide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethoxy-pyridinecarboxylic acid (Example 42 a) and (αR)-α-aminobenzeneacetamide hydrochloride (1:1) (CAN 632914) as starting materials, LC-MS (UV peak area/ESI) 100%, 366.1808 (M+H)+ .
Example 174 (R)Cyclopropyl(cyclopropylmethoxy)-N-(1-hydroxymethylpentan yl)picolinamide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethoxy-pyridinecarboxylic acid (Example 42 a) and (2R)amino methylpentanol (CAN 534482) as starting materials, LC-MS (UV peak area/ESI) 100%, 333.2165 (M+H)+ 15 .
Example 175 -Cyclopropyl(cyclopropylmethoxy)-N-(1-(hydroxymethyl)cyclopentyl) picolinamide O N N H O NH2 O Chiral O N N H O OH Chiral The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethoxy-pyridinecarboxylic acid (Example 42 a) and 1-aminocyclopentanemethanol (CAN 103167) as starting materials, LC-MS (UV peak area/ESI) 100%, 331.2014 (M+H)+ 5 .
Example 176 -Cyclopropyl(cyclopropylmethoxy)-N-(2-(3-methyl-1,2,4-oxadiazolyl)propan2-yl)picolinamideinamide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethoxy-pyridinecarboxylic acid (Example 42 a) and α,α,3-trimethyl-1,2,4- oxadiazolemethanamine (CAN 12482895) as starting materials, LC-MS (UV peak area/ESI) 100%, 357.1921 (M+H)+ .
Example 177 5-Bromo(4-fluoro-phenoxy)-pyridinecarboxylic acid ((S)carbamoyl methyl-butyl)-amide a) 5-Bromochloro-pyridinecarboxylic acid ((S)carbamoylmethyl-butyl)-amide O N N H O OH O N N H O O N N O N Br O N H O NH2 F The title compound was synthesized in analogy to Example 1, using 5-bromo chloropicolinic acid (CAN 9599589) and (2S)aminomethyl-pentanamide (CAN 6874) as starting materials, MS (EI): m/e = 350.0 [M+H]+ . b) 5-Bromo(4-fluoro-phenoxy)-pyridinecarboxylic acid ((S)carbamoylmethylbutyl)-amide -Bromochloro-pyridinecarboxylic acid ((S)carbamoylmethyl-butyl)-amide (50mg, 143 µmol) was dissolved in DMF (0.5 mL) to give a colorless solution. 4- Fluorophenol (19.3 mg, 172 µmol) and sodium carbonate (45.6 mg, 430 µmol) were added successively to give a yellow solution. The reaction mixture was stirred at 120°C over the weekend, cooled to ambient temperature and poured into 40 mL water. The mixture was extracted with isopropyl acetate (2 x 40 mL), organic phases were combined, dried with Na2SO4 and concentrated in vacuo. The residue was purified by preparative TLC (silica gel, 2.0 mm, isopropyl acetate) to give the title compound (23 mg, 38%) as colorless oil, MS (ESI): m/e = 421.9 [M-H]- 15 .
Example 178 N-(1-Amino-2,4-dimethyloxopentanyl)cyclopropyl(cyclopropylmethoxy) picolinamide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethoxy-pyridinecarboxylic acid (Example 42 a) and 2-amino-2,4- dimethyl-pentanamide (CAN 1135097) as starting materials, LC-MS (UV peak area/ESI) 100%, 360.2287 (M+H)+ .
Example 179 Cl N Br O N H O NH2 O N N H O NH2 O N-(1-Amino-3,3-dimethyloxobutanyl)cyclopropyl(cyclopropylmethoxy) picolinamide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethoxy-pyridinecarboxylic acid (Example 42 a) and 2-amino-3,3- dimethyl-butanamide hydrochloride (1:1) (CAN 3598441) as starting materials, LCMS (UV peak area/ESI) 100%, 346.2113 (M+H)+ .
Example 180 -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid (4-carbamoyl10 tetrahydro-pyranyl)-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethoxy-pyridinecarboxylic acid (Example 42 a) and 4-aminotetrahydro2H-pyrancarboxamide (CAN 11833787) as starting materials, MS (EI): m/e = 360.1 [M+H]+ 15 .
Example 181 (S)cyclopropyl(cyclopropylmethoxy)-N-(4-methyl(methylamino) oxopentanyl)picolinamide O N N H O NH2 O O HN NH2 O O N O The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethoxy-pyridinecarboxylic acid (Example 42 a) and (2S)amino-N,4- dimethyl-pentanamide monohydrochloride (CAN 991458) as starting materials, MS (EI): m/e = 360.1 [M+H]+ 5 .
Example 182 (S)Cyclopropyl(cyclopropylmethoxy)-N-(4,4-dimethyl(methylamino) oxopentanyl)picolinamide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethoxy-pyridinecarboxylic acid (Example 42 a) and (2S)amino-N,4,4- trimethyl-pentanamide (CAN 11601615) as starting materials, MS (EI): m/e = 374.1 [M+H]+ .
Example 183 5-Cyclopropyl-N-((S)-3,3-dimethyl(methylamino)oxobutanyl) ((tetrahydrofuranyl)methoxy)picolinamide N H O HN O N O Chiral N H O HN O N O Chiral O NH O N N H O O Chiral The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl (tetrahydro-furanylmethoxy)-pyridinecarboxylic acid (Example 166 b) and (2S) amino-N,3,3-trimethyl-butanamide, (CAN 892260) as starting materials, MS (EI): m/e = 390.4 [M+H]+ .
Example 184 -Cyclopropyl-N-((S)methyl(methylamino)oxopentanyl) ((tetrahydrofuranyl)methoxy)picolinamide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl (tetrahydro-furanylmethoxy)-pyridinecarboxylic acid (Example 166 b) and (2S) amino-N,4-dimethyl-pentanamide monohydrochloride (CAN 991458) as starting materials, MS (EI): m/e = 390.0 [M+H]+ .
Example 185 -Cyclopropyl-N-((S)-4,4-dimethyl(methylamino)oxopentanyl) ((tetrahydrofuranyl)methoxy)picolinamide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl (tetrahydro-furanylmethoxy)-pyridinecarboxylic acid (Example 166 b) and (2S) amino-N,4,4-trimethyl-pentanamide (CAN 11601615) as starting materials, MS (EI): m/e = 404.1 [M+H]+ 20 .
Example 186 O NH O N N H O O Chiral O NH O N N H O O Chiral N-((S)Aminomethyloxopentanyl)cyclopropyl((tetrahydrofuran yl)methoxy)picolinamide a) 5-Bromo(tetrahydro-furanylmethoxy)-pyridinecarboxylic acid ((S) carbamoylmethyl-butyl)-amide The title compound was synthesized in analogy to Example 1, using 5-bromo (tetrahydro-furanylmethoxy)-pyridinecarboxylic acid (Example 166 a) and (2S) aminomethyl-pentanamide (CAN 6874) as starting materials, MS (EI): m/e = 416.0 [M+H]+ 10 . b) N-((S)aminomethyloxopentanyl)cyclopropyl((tetrahydrofuran yl)methoxy)picolinamide The title compound was synthesized in analogy to Example 166 b, using 5-bromo (tetrahydro-furanylmethoxy)-pyridinecarboxylic acid ((S)carbamoylmethyl15 butyl)-amide (Example 186 a) and potassium cyclopropyltrifluoroborate as starting materials, MS (EI): m/e = 376.2 [M+H]+ .
Example 187 -Cyclopropyl(4-fluoro-phenoxy)-pyridinecarboxylic acid ((S)carbamoyl methyl-butyl)-amide N H N O O O NH2 O Chiral O N Br O N H O O NH2 The title compound was synthesized in analogy to Example 166 b, using 5-bromo(4- fluoro-phenoxy)-pyridinecarboxylic acid ((S)carbamoylmethyl-butyl)-amide (Example 177 b) and potassium cyclopropyltrifluoroborate as starting materials, MS (EI): m/e = 386.0 [M+H]+ 5 .
Example 188 -Bromo(tetrahydro-furanylmethoxy)-pyridinecarboxylic acid ((S)-2,2- dimethylmethylcarbamoyl-propyl)-amide The title compound was synthesized in analogy to Example 1, using 5-bromo (tetrahydro-furanylmethoxy)-pyridinecarboxylic acid (Example 166 a) and (2S) amino-N,3,3-trimethyl-butanamide, (CAN 892260) as starting materials, MS (EI): m/e = 428.0 [M+H]+ .
Example 189 5-Cyclopropyl-N-(1-(5-methyl-1,2,4-oxadiazolyl)cyclobutyl)(pyridin ylmethoxy)picolinamide a) 5-Bromo(pyridinylmethoxy)-pyridinecarboxylic acid O NH2 N O O F HN Chiral O N Br O N H O NH O N Br O OH N O The title compound was synthesized in analogy to Example 9 d, using 5-bromochloropyridinecarboxylic acid and 2-pyridinemethanol (CAN 5861) as starting materials, LC-MS (UV peak area/ESI) 100%, 308.9876 (M+H)+ . b) 5-Cyclopropyl(pyridinylmethoxy)-pyridinecarboxylic acid The title compound was synthesized in analogy to Example 42 a, using 5-bromo (pyridinylmethoxy)-pyridinecarboxylic acid and cyclopropylboronic acid (CAN 4112359) as starting materials, LC-MS (UV peak area/ESI) 100%, 271.1081 (M+H)+ . c) 5-Cyclopropyl-N-(1-(5-methyl-1,2,4-oxadiazolyl)cyclobutyl)(pyridin ylmethoxy)picolinamide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl (pyridinylmethoxy)-pyridinecarboxylic acid and 1-(5-methyl-1,2,4-oxadiazolyl)- cyclobutanamine hydrochloride (1:1) (CAN 11708975) as starting materials, MS (EI): m/e = 406.2 [M+H]+ 15 .
Example 190 -Cyclopropyl-N-(cyclopropyl(5-methyl-1,2,4-oxadiazolyl)methyl) (cyclopropylmethoxy)picolinamide O N OH N O O N N O N O N N H The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethoxy-pyridinecarboxylic acid (Example 42 a) and cyclopropyl-(5- methyl-[1,2,4]oxadiazolyl)-methylamine (which can e.g. be prepared in a similar manner than (S)cyclopropyl(5-methyl-[1,2,4]oxadiazolyl)-ethylamine (Example 38 e)) as starting materials, MS (EI): m/e = 369.2 [M+H]+ .
Example 191 -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid ((R) hydroxymethyl-1,2-dimethyl-propyl)-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethoxy-pyridinecarboxylic acid (Example 42 a) and (R)amino-2,3- dimethyl-butanol [CAN 1551581] as starting materials, MS (EI): m/e = 333.2 [M+H]+ .
Example 192 (S)(3-Chlorophenyl)-N-(3,3-dimethyl(methylamino)oxobutan yl)picolinamide O N NH O N O N O N NH O OH Chiral O NH N N H O Cl Chiral The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl) pyridinecarboxylic acid (CAN 8637045) and (2S)amino-N,3,3-trimethylbutanamide (CAN 892260) as starting materials, MS (EI): m/e = 360.0 [M+H]+ .
Example 193 (S)(3-Chlorophenyl)-N-(4,4-dimethyl(methylamino)oxopentan yl)picolinamide The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl) pyridinecarboxylic acid (CAN 8637045) and (2S)amino-N,4,4-trimethylpentanamide (CAN 11601615) as starting materials, MS (EI): m/e = 374.1 [M+H]+ 10 .
Example 194 -Cyclopropyl(cyclopropylmethoxy)-N-(4-hydroxymethylbutan yl)picolinamide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethoxy-pyridinecarboxylic acid (Example 42 a) and 3-aminomethylbutanol (CAN 425141) as starting materials, LC-MS (UV peak area/ESI) 100%, 319.1 (M+H)+ .
Example 195 (S)Cyclopropyl-N-(3,3-dimethyl(methylamino)oxobutanyl)((tetrahydro2H-pyranyl)methoxy)picolinamide O NH N N H O Cl Chiral O N NH O OH The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl (tetrahydro-pyranylmethoxy)-pyridinecarboxylic acid (which can e.g. be prepared in a similar manner than 5-cyclopropyl(tetrahydro-furanylmethoxy)-pyridine carboxylic acid (Example 166 b)) and (2S)amino-N,3,3-trimethyl-butanamide (CAN 892260) as starting materials, MS (EI): m/e = 404.3 [M+H]+ .
Example 196 (S)Cyclopropyl-N-(4,4-dimethyl(methylamino)oxopentanyl) ((tetrahydro-2H-pyranyl)methoxy)picolinamide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl (tetrahydro-pyranylmethoxy)-pyridinecarboxylic acid (which can e.g. be prepared in a similar manner than 5-cyclopropyl(tetrahydro-furanylmethoxy)-pyridine carboxylic acid (Example 166 b)) and (2S)amino-N,4,4-trimethyl-pentanamide (CAN 11601615) as starting materials, MS (EI): m/e = 418.3 [M+H]+ 15 .
Example 197 (-)Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [cyclopropyl-(5- methyl-[1,2,4]oxadiazolyl)-methyl]-amide N H O N O N H O O Chiral O NH N H O N O O Chiral The title compound can be obtained by chiral chromatography from 5-cyclopropyl-N- (cyclopropyl(5-methyl-1,2,4-oxadiazolyl)methyl)(cyclopropylmethoxy)picolinamide (Example 190), MS (EI): m/e = 369.2 [M+H]+ .
Example 198 (+)Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [cyclopropyl-(5- methyl-[1,2,4]oxadiazolyl)-methyl]-amide The title compound can be obtained by chiral chromatography from 5-cyclopropyl-N10 (cyclopropyl(5-methyl-1,2,4-oxadiazolyl)methyl)(cyclopropylmethoxy)picolinamide (Example 190), MS (EI): m/e = 369.2 [M+H]+ .
Example 199 -Cyclopropyl-N-(2-(5-methyl-1,2,4-oxadiazolyl)propanyl)(pyridin ylmethoxy)picolinamide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl (pyridinylmethoxy)-pyridinecarboxylic acid (Example 189 b) and α,α,5-trimethylO N NH O N O N Chiral O N NH O N O N Chiral O N O N N H N O N 1,2,4-oxadiazolemethanamine (CAN 11538310) as starting materials, MS (EI): m/e = 394.2 [M+H]+ .
Example 200 (S)-N-(1-Aminomethyloxopentanyl)cyclopropyl(pyridin ylmethoxy)picolinamide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl (pyridinylmethoxy)-pyridinecarboxylic acid (Example 189 b) and (2S)amino methyl-pentanamide (CAN 6874) as starting materials, MS (EI): m/e = 383.2 [M+H]+ .
Example 201 (S)Cyclopropyl-N-(3,3-dimethyl(methylamino)oxobutanyl)(pyridin ylmethoxy)picolinamide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl (pyridinylmethoxy)-pyridinecarboxylic acid (Example 189 b) and (2S)aminoN,3,3-trimethyl-butanamide (CAN 892260) as starting materials, MS (EI): m/e = 397.2 [M+H]+ .
Example 202 -Cyclopropyl-N-(2-(5-methyl-1,2,4-oxadiazolyl)propanyl)((tetrahydro-2H20 pyranyl)methoxy)picolinamide O N O N N H NH2 O Chiral O N O N N H N H O Chiral The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl (tetrahydro-pyranylmethoxy)-pyridinecarboxylic acid (which can e.g. be prepared in a similar manner than 5-cyclopropyl(tetrahydro-furanylmethoxy)-pyridine carboxylic acid (Example 166 b)) and α,α,5-trimethyl-1,2,4-oxadiazolemethanamine (CAN 11538310) as starting materials, MS (EI): m/e = 401.2 [M+H]+ .
Example 203 (S)Cyclopropyl-N-(4-methyl(methylamino)oxopentanyl)((tetrahydro2H-pyranyl)methoxy)picolinamide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl (tetrahydro-pyranylmethoxy)-pyridinecarboxylic acid (which can e.g. be prepared in a similar manner than 5-cyclopropyl(tetrahydro-furanylmethoxy)-pyridine carboxylic acid (Example 166 b)) and (2S)aminomethyl-pentanamide (CAN 687 4) as starting materials, MS (EI): m/e = 404.2 [M+H]+ 15 .
Example 204 (S)-N-(3,3-Dimethyl(methylamino)oxobutanyl)phenylpicolinamide N N O N O N H O O O NH N H O N O O Chiral N N H O N H O Chiral The title compound can be prepared in analogy to Example 1, using 6-phenyl-pyridine carboxylic acid (CAN 397742) and (2S)amino-N,3,3-trimethyl-butanamide (CAN 892260) as starting materials, MS (EI): m/e = 326.2 [M+H]+ .
Example 205 (S)-N-(4-Methyl(methylamino)oxopentanyl)phenylpicolinamide The title compound can be prepared in analogy to Example 1, using 6-phenyl-pyridine carboxylic acid (CAN 397742) and (2S)aminomethyl-pentanamide (CAN 687- 51-4) as starting materials, MS (EI): m/e = 326.2 [M+H]+ .
Example 206 -(3,3-Difluoroazetidinyl)-N-((S)-3,3-dimethyl(methylamino)oxobutanyl)- 6-((tetrahydrofuranyl)methoxy)picolinamide The title compound was synthesized by addition of 3,3-difluoroazetidine hydrochloride (CAN 2883157) to 5-bromo(tetrahydro-furanylmethoxy)-pyridinecarboxylic acid ((S)-2,2-dimethylmethylcarbamoyl-propyl)-amide (Example 188) in analogy to the procedure described in Example 69 a, MS (EI): m/e = 441.0 [M+H]+ .
Example 207 2-(6-(Cyclopropylmethoxy)(3,3-difluoroazetidinyl)picolinamido) ethylbutanoic acid N N H O N H O Chiral O NH O N N H O O N F F Chiral The title compound can e.g. be synthesized by: i) coupling of 6-cyclopropylmethoxy (3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example 69 b) with 2-amino ethyl-butyric acid methyl ester (CAN 709744) in analogy to Example 1; and ii) saponification of the ester group in analogy to the conditions described in Example 48 e), MS (EI): m/e = 396.1 [M-H]- .
Example 208 (S)(Cyclopropylmethoxy)(3,3-difluoroazetidinyl)-N-(3,3-dimethyl (methylamino)oxobutanyl)picolinamide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example 69 b) and (2S)amino-N,3,3-trimethyl-butanamide (CAN 892260) as starting materials, MS (EI): m/e = 411.4 [M+H]+ .
Example 209 (S)(Cyclopropylmethoxy)(3,3-difluoroazetidinyl)-N-(4,4-dimethyl (methylamino)oxopentanyl)picolinamide N H OH O O N O N F F O NH N N N H O O F F Chiral The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example 69 b) and (2S)amino-N,4,4-trimethyl-pentanamide (CAN 11601615) as starting materials, MS (EI): m/e = 425.0 [M+H]+ 5 .
Example 210 (S)(3-Fluorophenyl)-N-(4-methyl(methylamino)oxopentanyl)picolinamide The title compound can be prepared in analogy to Example 1, using 6-(3-fluoro-phenyl)- pyridinecarboxylic acid (CAN 8879823) and (2S)aminomethyl-pentanamide (CAN 6874) as starting materials, LC-MS (UV peak area/ESI) 100%, 344.1768 (M+H)+ .
Example 211 (S)-N-(4-Methyl(methylamino)oxopentanyl)(3-(trifluoromethyl)phenyl) picolinamide O NH N N N H O O F F Chiral N H O N H N F O Chiral N H O N H N F F F O Chiral The title compound can be prepared in analogy to Example 1, using 6-(3-trifluoromethylphenyl)-pyridinecarboxylic acid (CAN 8879821) and (2S)aminomethylpentanamide (CAN 6874) as starting materials, LC-MS (UV peak area/ESI) 99.5%, 394.1734 (M+H)+ .
Example 212 (S)(3-Chlorofluorophenyl)-N-(4-methyl(methylamino)oxopentan yl)picolinamide The title compound can be prepared in analogy to Example 1, using 6-(3-chlorofluoro10 phenyl)-pyridinecarboxylic acid (CAN 12619225) and (2S)aminomethylpentanamide (CAN 6874) as starting materials, LC-MS (UV peak area/ESI) 97.8%, 378.1376 (M+H)+ .
Example 213 (S)-N-(3,3-Dimethyl(methylamino)oxobutanyl)(3- fluorophenyl)picolinamide The title compound can be prepared in analogy to Example 1, using 6-(3-fluoro-phenyl)- pyridinecarboxylic acid (CAN 8879823) and (2S)amino-N,3,3-trimethylbutanamide (CAN 892260) as starting materials, LC-MS (UV peak area/ESI) 99.1%, 344.1774 (M+H)+ 20 .
Example 214 (S)-N-(3,3-Dimethyl(methylamino)oxobutanyl)(3-(trifluoromethyl)phenyl)- picolinamide N H O N H N Cl F O Chiral N H O N H N F O Chiral The title compound can be prepared in analogy to Example 1, using 6-(3-trifluoromethylphenyl)-pyridinecarboxylic acid (CAN 8879821) and (2S)amino-N,3,3- trimethyl-butanamide (CAN 892260) as starting materials, LC-MS (UV peak area/ESI) 99.0%, 394.1735 (M+H)+ 5 .
Example 215 (S)-N-(3,3-Dimethyl(methylamino)oxobutanyl)(3-methoxyphenyl) picolinamide The title compound can be prepared in analogy to Example 1, using 6-(3-methoxyphenyl)-pyridinecarboxylic acid (CAN 8879828) and (2S)amino-N,3,3- trimethyl-butanamide (CAN 892260) as starting materials, LC-MS (UV peak area/ESI) 99.1%, 356.1961 (M+H)+ .
Example 216 (S)(3-Chlorofluorophenyl)-N-(3,3-dimethyl(methylamino)oxobutan yl)picolinamide N H O N H N F F F O Chiral N H O N H N O O Chiral N H O N H N Cl F O Chiral The title compound can be prepared in analogy to Example 1, using 6-(3-chlorofluorophenyl)-pyridinecarboxylic acid (CAN 12619225) and (2S)amino-N,3,3- trimethyl-butanamide (CAN 892260) as starting materials, LC-MS (UV peak area/ESI) 98.4%, 378.1372 (M+H)+ .
Example 217 (S)Cyclopropyl(cyclopropylmethoxy)-N-(2,2,2-trifluoro(pyridinyl)ethyl)- picolinamide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethoxy-pyridinecarboxylic acid (Example 42 a) and (S)-2,2,2-trifluoro pyridinyl-ethylamine (CAN 3361055) as starting materials, MS (EI): m/e = 392.2 [M+H]+ .
Example 218 (R)Cyclopropyl(cyclopropylmethoxy)-N-(2,2,2-trifluoro(pyridinyl)ethyl)- picolinamide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethoxy-pyridinecarboxylic acid (Example 42 a) and (R)-2,2,2-trifluoro pyridinyl-ethylamine (CAN 12128133) as starting materials, MS (EI): m/e = 392.2 [M+H]+ 20 .
Example 219 -Cyclopropyl(tetrahydro-pyranylmethoxy)-pyridinecarboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazolyl)-methyl]-amide O N N H O F F F N Chiral O N N H O F F F N Chiral The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl (tetrahydro-pyranylmethoxy)-pyridinecarboxylic acid (which can e.g. be prepared in a similar manner than 5-cyclopropyl(tetrahydro-furanylmethoxy)-pyridine carboxylic acid (Example 166 b)) and cyclopropyl-(5-methyl-[1,2,4]oxadiazolyl)- methylamine (which can e.g. be prepared in a similar manner than (S)cyclopropyl(5- methyl-[1,2,4]oxadiazolyl)-ethylamine (Example 38 e)) as starting materials, MS (EI): m/e = 413.1 [M+H]+ .
Example 220 2-({5-[Bis-(2,2,2-trifluoro-ethyl)-amino]cyclopropylmethoxy-pyridinecarbonyl}- amino)ethyl-butyric acid methyl ester The title compound was synthesized in analogy to Example 1, using 5-[bis-(2,2,2-trifluoroethyl)-amino]cyclopropylmethoxy-pyridinecarboxylic acid (Example 162 b) and methyl 2-aminoethylbutanoate hydrochloride (CAN 923984) as starting materials, MS (EI): m/e = 500.1 [M+H]+ .
Example 221 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazolyl)-methyl]-amide N H O O O N O N F F F F F F N H N O O N N O N F F The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example 69 b) and cyclopropyl-(5-methyl-[1,2,4]oxadiazolyl)-methylamine (which can e.g. be prepared in a similar manner than (S)cyclopropyl(5-methyl-[1,2,4]oxadiazolyl)- ethylamine (Example 38 e)) as starting materials, MS (EI): m/e = 420.0 [M+H]+ 5 .
Example 222 -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid ((S)cyclopropyl1-dimethylcarbamoyl-ethyl)-amide a) (S)-tert-Butyl 3-cyclopropyl(dimethylamino)oxopropanylcarbamate The title compound was synthesized in analogy to Example 1, using (S)(tertbutoxycarbonylamino)cyclopropylpropanoic acid (CAN 894837) and dimethylamine hydrochloride as starting materials. MS (EI): m/e = 256.3 [M]+ . b) (S)Aminocyclopropyl-N,N-dimethylpropanamide hydrochloride A 4M solution of HCl in dioxane (4.68 mL, 18.7 mmol) was added to a solution of (S)- tert-butyl 3-cyclopropyl(dimethylamino)oxopropanylcarbamate (1.2 g, 4.68 mmol) in ethanol (10 mL). After 16 h stirring at ambient temperature the solvent was removed under reduced pressure. The remaining solid was digerated with diethyl ether (10 mL), filtered off, washed with diethyl ether (3 x 5 mL) and dried for 3 h in vacuo at 40°C to give the title compound as off-white solid (820 mg, 91%). MS (EI): m/e = 157.1 [M+H]+ .
O N N H O N O Chiral O N H O N O H2N N O Chiral ClH c) 5-Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid ((S)cyclopropyl dimethylcarbamoyl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethyloxy-pyridinecarboxylic acid (Example 42a) and (S)amino cyclopropyl-N,N-dimethylpropanamide hydrochloride as starting materials, LC-MS (UV peak area/ESI) 100%, 372.2278 (M+H)+ .
Example 223 -Cyclopropyl(tetrahydro-pyranylmethoxy)-pyridinecarboxylic acid (2,2,2- trifluoropyridinyl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl (tetrahydro-pyranylmethoxy)-pyridinecarboxylic acid (which can e.g. be prepared in a similar manner than 5-cyclopropyl(tetrahydro-furanylmethoxy)-pyridine carboxylic acid (Example 166 b)) and 2,2,2-trifluoro(pyridinyl)ethanamine (CAN 5031736) as starting materials, MS (EI): m/e = 436.1 [M+H]+ 15 .
Example 224 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (2,2,2-trifluoropyridinyl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example 69 b) and 2,2,2-trifluoro(pyridinyl)ethanamine (CAN 5031736) as starting materials, MS (EI): m/e = 443.1 [M+H]+ .
Example 225 N H O N O O F F F N N H O N O N F F N F F F -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid ((-)- methylcarbamoyl-phenyl-methyl)-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethyloxy-pyridinecarboxylic acid (Example 42a) and (αR)-α-amino-Nmethyl-benzeneacetamide hydrochloride (1:1) (CAN 975495) as starting materials.
Racemization occurred during the synthesis and the product was isolated by chiral chromatography on Chiralpak AD using heptane/20% ethanol as eluent. The (-)- enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 380.1968 (M+H)+ , ( )  6.0 10  D MeOH .
Example 226 -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid ((+)- dimethylcarbamoyl-phenyl-methyl)-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethyloxy-pyridinecarboxylic acid (Example 42a) and (αR)-α-amino-N,Ndimethyl-benzeneacetamide hydrochloride (1:1) (CAN 1291575) as starting materials.
Racemization occurred during the synthesis and the product was isolated by chiral chromatography on Reprosil Chiral NR using heptane/20% ethanol as eluent. The (+)- enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 394.2120 (M+H)+ 20 , ( )  44.4  D MeOH .
Example 227 -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid ((-)- dimethylcarbamoyl-phenyl-methyl)-amide O N N H O N H O Chiral O N N H O N O Chiral The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethyloxy-pyridinecarboxylic acid (Example 42a) and (αR)-α-amino-N,Ndimethyl-benzeneacetamide hydrochloride (1:1) (CAN 1291575) as starting materials.
Racemization occurred during the synthesis and the product was isolated by chiral chromatography on Reprosil Chiral NR using heptane/20% ethanol as eluent. The (-)- enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 394.2126 (M+H)+ , ( )  44.9  D MeOH .
Example 228 6-Cyclopropylmethoxytrifluoromethyl-pyridinecarboxylic acid ((S)-3,3- dimethylmethylcarbamoyl-butyl)-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxytrifluoromethyl-pyridinecarboxylic acid (Example 113 d) and (2S)amino-N,4,4-trimethyl-pentanamide (CAN 11601615) as starting materials, MS (EI): m/e = 402.1 [M+H]+ .
Example 229 6-Cyclopropylmethoxytrifluoromethyl-pyridinecarboxylic acid [cyclopropyl-(5- methyl-[1,2,4]oxadiazolyl)-methyl]-amide O N N H O N O Chiral O NH N N H O O F F F Chiral N N H O O F F F N O N The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxytrifluoromethyl-pyridinecarboxylic acid (Example 113 d) and cyclopropyl-(5-methyl-[1,2,4]oxadiazolyl)-methylamine (which can e.g. be prepared in a similar manner than (S)cyclopropyl(5-methyl-[1,2,4]oxadiazolyl)-ethylamine (Example 38 e)) as starting materials, MS (EI): m/e = 397.0 [M+H]+ 5 .
Example 230 6-(Tetrahydro-pyranylmethoxy)trifluoromethyl-pyridinecarboxylic acid ((S)- 3,3-dimethylmethylcarbamoyl-butyl)-amide a) 6-Chloro(trifluoromethyl)picolinic acid N OH O Cl F F F The title compound was synthesized in analogy to the procedure described in Example 125 b), using methyl 6-chloro(trifluoromethyl)picolinate (Example 113 c) as starting material. MS (EI): m/e = 223.9 [M-H]- . b) 6-((Tetrahydro-2H-pyranyl)methoxy)(trifluoromethyl)picolinic acid N OH O O O F F F 6-Chloro(trifluoromethyl)picolinic acid (330 mg, 1.46 mmol) and powdered potassium hydroxide (328 mg, 5.85 mmol) were dissolved in DMSO (9 mL). The solution was stirred for 15 min. at ambient temperature. (Tetrahydro-2H-pyranyl)methanol (170 mg, 170 µL, 1.46 mmol; CAN 147749) was added. The mixture was stirred for 1 d at ambient temp., poured onto ice water/brine/1N HCl (75 mL) and extracted with EtOAc (2 x 150 N N H O O F F F O O NH Chiral mL). The combined extracts were washed with ice water/brine (75 mL), dried over Na2SO4. The solvent was removed under reduced pressure to give the title compound as a grey solid (385 mg, 86%) which was used in the next step without further purification.
MS: 304.0 [M-H]- . c) 6-(Tetrahydro-pyranylmethoxy)trifluoromethyl-pyridinecarboxylic acid ((S)- 3,3-dimethylmethylcarbamoyl-butyl)-amide The title compound was synthesized in analogy to Example 1, using 6-((tetrahydro-2Hpyranyl)methoxy)(trifluoromethyl)picolinic acid and (2S)amino-N,4,4-trimethylpentanamide (CAN 11601615) as starting materials, MS (EI): m/e = 446.4 [M+H]+ .
Example 231 -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid ((S) dimethylcarbamoylmethyl-butyl)-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethyloxy-pyridinecarboxylic acid (Example 42a) and (2S)aminoN,N,4-trimethyl-pentanamide hydrochloride (1:1) (CAN 2075951) as starting materials, LC-MS (UV peak area/ESI) 100%, 374.2240 (M+H)+ .
Example 232 6-(3-Chlorofluoro-phenyl)-pyridinecarboxylic acid [cyclopropyl-(5-methyl20 [1,2,4]oxadiazolyl)-methyl]-amide a) 6-Bromo-pyridinecarboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazolyl)- methyl]-amide O N N H O N O Chiral N O N N H N Cl F O The title compound can be prepared in analogy to Example 1, using 6-bromo pyridinecarboxylic acid (CAN 211904) and cyclopropyl-(5-methyl-[1,2,4]oxadiazol yl)-methylamine (which can e.g. be prepared in a similar manner than (S)cyclopropyl5 1-(5-methyl-[1,2,4]oxadiazolyl)-ethylamine (Example 38e) as starting materials, LCMS (UV peak area/ESI) 97%, 337.0289 (M+H)+ . b) 6-(3-Chlorofluoro-phenyl)-pyridinecarboxylic acid [cyclopropyl-(5-methyl- [1,2,4]oxadiazolyl)-methyl]-amide The title compound can be prepared in analogy to Example 177b, using 6-Bromo-pyridine10 2-carboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazolyl)-methyl]-amide (Example 232a) and B-(3-chlorofluorophenyl)-boronic acid (CAN 1444329) as starting materials, MS (EI): m/e = 387.1 [M+H]+ .
Example 233 2-{[5-Cyclopropyl(tetrahydro-furanylmethoxy)-pyridinecarbonyl]-amino} ethyl-butyric acid methyl ester The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl (tetrahydro-furanylmethoxy)-pyridinecarboxylic acid (Example 166 b) and methyl 2- aminoethylbutanoate hydrochloride (CAN 923984) as starting materials, MS (EI): m/e = 391.3 [M+H]+ 20 .
Example 234 6-Cyclopropylmethoxy(6-oxaaza-spiro[3.3]heptyl)-pyridinecarboxylic acid ((S)-3,3-dimethylmethylcarbamoyl-butyl)-amide N O Br N H N O N N H N O O O O O a) 6-Cyclopropylmethoxy(6-oxaaza-spiro[3.3]heptyl)-pyridinecarboxylic acid methyl ester N N O O O O The title compound was synthesized in analogy to the procedure described in Example 32 a), using 5-bromo(cyclopropylmethoxy)-pyridinecarboxylic acid methyl ester (Example 9 d) and 6-oxaazaspiro[3.3]heptane, oxalate salt (CAN 13596558) as starting materials. MS (EI): m/e = 305.0 [M+H]+ . b) 6-Cyclopropylmethoxy(6-oxaaza-spiro[3.3]heptyl)-pyridinecarboxylic acid N N OH O O O 10 The title compound was synthesized in analogy to the procedure described in Example 125 b), using 6-cyclopropylmethoxy(6-oxaaza-spiro[3.3]heptyl)-pyridinecarboxylic acid methyl ester as starting material. MS (EI): m/e = 289.0 [M-H]- . c) 6-Cyclopropylmethoxy(6-oxaaza-spiro[3.3]heptyl)-pyridinecarboxylic acid ((S)-3,3-dimethylmethylcarbamoyl-butyl)-amide The title compound was synthesized in analogy to Example 1, using 6- (cyclopropylmethoxy)(6-oxaazaspiro[3.3]heptanyl)picolinic acid and (2S) O N N H O O N N H O Chiral amino-N,4,4-trimethyl-pentanamide (CAN 11601615) as starting materials. MS (EI): m/e = 431.1 [M+H]+ .
Example 235 6-Cyclopropylmethoxy(6-oxaaza-spiro[3.3]heptyl)-pyridinecarboxylic acid [1-methyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide The title compound was synthesized in analogy to Example 1, using 6- (cyclopropylmethoxy)(6-oxaazaspiro[3.3]heptanyl)picolinic acid (Example 234 b) and α,α,5-trimethyl-1,2,4-oxadiazolemethanamine (CAN 11538310) as starting materials. MS (EI): m/e = 414.1 [M+H]+ 10 .
Example 236 6-Cyclopropylmethoxy(6-oxaaza-spiro[3.3]heptyl)-pyridinecarboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazolyl)-methyl]-amide The title compound was synthesized in analogy to Example 1, using 6- (cyclopropylmethoxy)(6-oxaazaspiro[3.3]heptanyl)picolinic acid (Example 234 b) and cyclopropyl-(5-methyl-[1,2,4]oxadiazolyl)-methylamine (which can e.g. be prepared in a similar manner than (S)cyclopropyl(5-methyl-[1,2,4]oxadiazolyl)- ethylamine (Example 38 e) as starting materials. MS (EI): m/e = 426.0 [M+H]+ .
Example 237 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid ((R)- 2,2,2-trifluoropyridinyl-ethyl)-amide O N H N O O N N O N N N H O O N O N N O The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example 69 b) and (R)-2,2,2-trifluoropyridinyl-ethylamine (CAN 12128133) as starting materials. MS (EI): m/e = 443.1 [M+H]+ 5 .
Example 238 2-Ethyl{[6-(tetrahydro-pyranylmethoxy)trifluoromethyl-pyridine carbonyl]-amino}-butyric acid methyl ester The title compound was synthesized in analogy to Example 1, using 6-((tetrahydro-2Hpyranyl)methoxy)(trifluoromethyl)picolinic acid (Example 230 b) and methyl 2- aminoethylbutanoate hydrochloride (CAN 923984) as starting materials, MS (EI): m/e = 433.5 [M+H]+ .
Example 239 (S)[(5-Cyclopropylcyclopropylmethoxy-pyridinecarbonyl)-amino]-3,3- dimethyl-butyric acid methyl ester The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethyloxy-pyridinecarboxylic acid (Example 42a) and 3-methyl-L-valine methyl ester hydrochloride (1:1) (CAN 630387) as starting materials, MS (ESI) 361.3 (M+H)+ .
N H O N O N F F N F F F Chiral N H O O O N O O F F F O N N H O O O Chiral Example 240 -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid ((-)-2,2,2-trifluoro1-pyridinyl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethyloxy-pyridinecarboxylic acid (Example 42a) and α-(trifluoromethyl)- 2-pyridinemethanamine (CAN 5031736) as starting materials. The product was isolated by chiral chromatography on Reprosil Chiral NR using heptane/20% ethanol as eluent. The (S)-(-)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 392.1950 (M+H)+ ; ( )  91.1  D MeOH .
Example 241 -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [(-)(5-methyl- [1,2,4]oxadiazolyl)-ethyl]-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethyloxy-pyridinecarboxylic acid (Example 42a) and α,5-dimethyl-1,2,4- oxadiazolemethanamine (CAN 11538342) as starting materials. The product was isolated by chiral chromatography on Chiralpak AD using heptane/20% ethanol as eluent.
The (-)-enantiomer was isolated. LC-MS (UV peak area/ESI) 98.1%, 343.1767 (M+H)+ , ( )  28.2 20  D MeOH .
Example 242 -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [(+)methyl(5- methyl-[1,2,4]oxadiazolyl)-butyl]-amide O N N H N F F F O Chiral O N N H O N O N Chiral The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethyloxy-pyridinecarboxylic acid (Example 42a) and 5-methyl-α-(2- methylpropyl)-1,2,4-oxadiazolemethanamine (CAN 11555389) as starting materials. The product was isolated by chiral chromatography on Chiralpak AD using heptane/8% ethanol as eluent. The (+)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 385.2234 (M+H)+ , ( )  22.5  D MeOH .
Example 243 -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [(-)methyl(5- methyl-[1,2,4]oxadiazolyl)-butyl]-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethyloxy-pyridinecarboxylic acid (Example 42a) and 5-methyl-α-(2- methylpropyl)-1,2,4-oxadiazolemethanamine (CAN 11555389) as starting materials. The product was isolated by chiral chromatography on Chiralpak AD using heptane/8% ethanol as eluent. The (-)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 385.2234 (M+H)+ , ( )  24.8  D MeOH .
Example 244 -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [(+)(5-methyl20 [1,2,4]oxadiazolyl)-propyl]-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethyloxy-pyridinecarboxylic acid (Example 42a) and α-ethylmethylO N N H O N O N Chiral O N N H O N O N Chiral O N N H O N O N Chiral 1,2,4-oxadiazolemethanamine hydrochloride (1:1) (CAN 1119973) as starting materials. The product was isolated by chiral chromatography on Chiralpak AD using heptane/8% ethanol as eluent. The (+)-enantiomer was isolated. LC-MS (UV peak area/ESI) 98.5%, 357.1925 (M+H)+ , ( )  36.7  D MeOH .
Example 245 -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [(-)(5-methyl- [1,2,4]oxadiazolyl)-propyl]-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethyloxy-pyridinecarboxylic acid (Example 42a) and α-ethylmethyl1,2,4-oxadiazolemethanamine hydrochloride (1:1) (CAN 1119973) as starting materials. The product was isolated by chiral chromatography on Chiralpak AD using heptane/8% ethanol as eluent. The (-)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 357.1913 (M+H)+ , ( )  35.1  D MeOH .
Example 246 -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid ((-)-cyano-methylmethyl)-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethyloxy-pyridinecarboxylic acid (Example 42a) and 2-aminopropanenitrile monohydrochloride (CAN 21347) as starting materials. The product was isolated by chiral chromatography on Reprosil Chiral NR using heptane/15% ethanol as eluent. The (-)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 286.1552 (M+H)+ , ( )  9.6  D MeOH .
Example 247 -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid ((-)cyano methyl-butyl)-amide O N N H O N O N Chiral O N N H O N Chiral The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethyloxy-pyridinecarboxylic acid (Example 42a) and 2-aminomethylpentanenitrile (CAN 654519) as starting materials. The product was isolated by chiral chromatography on Reprosil Chiral NR using heptane/15% ethanol as eluent. The (-)- enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 328.2026 (M+H)+ , ( )  8.0  D MeOH .
Example 248 -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid ((+)-cyano10 cyclopropyl-methyl)-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethyloxy-pyridinecarboxylic acid (Example 42a) and α-aminocyclopropaneacetonitrile (CAN 1493576) as starting materials. The product was isolated by chiral chromatography on Reprosil Chiral NR using heptane/20% ethanol as eluent. The (+)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 312.1706 (M+H)+ , ( )  9.0  D MeOH .
Example 249 2-[(6-Cyclopropylmethoxytrifluoromethyl-pyridinecarbonyl)-amino]ethyl20 butyric acid methyl ester O N N H O N Chiral O N N H O N Chiral N H O O O N O F F F The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxytrifluoromethyl-pyridinecarboxylic acid (Example 113 d) and methyl 2-aminoethylbutanoate hydrochloride (CAN 923984) as starting materials.
MS (EI): m/e = 389.0 [M+H]+ .
Example 250 -Cyclopropyl(tetrahydro-furanylmethoxy)-pyridinecarboxylic acid (1-ethyl1-methylcarbamoyl-propyl)-amide a) 2-(5-Cyclopropyl((tetrahydrofuranyl)methoxy)picolinamido)ethylbutanoic acid N H N O O O OH O Methyl 2-(5-cyclopropyl((tetrahydrofuranyl)methoxy)picolinamido) ethylbutanoate (60 mg, 154 µmol, Example 233) and lithium hydroxide hydrate (7.74 mg, 184 µmol) were dissolved in a mixture of THF (600 µL) and water (150 µL). The reaction mixture was stirred for 48 h at ambient temp. Additional sodium hydroxide (24.6 mg, 614 µmol) was added and stirring was continued at 70°C for additional 3d. The mixture was poured onto ice water/brine/1N HCl (25 mL) and extracted with EtOAc (2 x 30 mL). The combined extracts were washed with ice water/brine (25 mL) and dried over Na2SO4.
Concentration in vacuo afforded the title compound (49 mg, 85 %) as a light yellow waxy solid. MS: 375.3 [M-H]- . b) 5-Cyclopropyl(tetrahydro-furanylmethoxy)-pyridinecarboxylic acid (1-ethyl methylcarbamoyl-propyl)-amide The title compound was synthesized in analogy to Example 1, using 2-(5-cyclopropyl ((tetrahydrofuranyl)methoxy)picolinamido)ethylbutanoic acid and methanamine hydrochloride as starting materials, MS (EI): m/e = 390.3 [M+H]+ .
N H N O O O N H O Example 251 2-[(5-Cyclopropylcyclopropylmethoxy-pyridinecarbonyl)-amino]ethylbutyric acid methyl ester The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethyloxy-pyridinecarboxylic acid (Example 42a) and 2-aminoethylbutanoic acid ethyl ester hydrochloride (1:1) (CAN 709744) as starting materials, LCMS (UV peak area/ESI) 100%, 361.2120 (M+H)+ .
Example 252 2-[(6-Cyclopropylmethoxytrifluoromethyl-pyridinecarbonyl)-amino]ethylbutyric acid a) Ethyl 2-(6-(cyclopropylmethoxy)(trifluoromethyl)picolinamido)ethylbutanoate N O HN O F F F O O The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxytrifluoromethyl-pyridinecarboxylic acid (Example 113 d) and ethyl 2-aminoethylbutanoate hydrochloride (CAN 11352192) as starting materials, MS (EI): m/e = 403.4 [M+H]+ .
O N N H O O O N H OH O O N O F F F b) 2-[(6-Cyclopropylmethoxytrifluoromethyl-pyridinecarbonyl)-amino]ethylbutyric acid Ethyl 2-(6-(cyclopropylmethoxy)(trifluoromethyl)picolinamido)ethylbutanoate (62 mg, 154 µmol) was dissolved in a mixture of 1 M aqueous sodium hydroxide solution (616 µL, 616 µmol), THF (600 µL) and MeOH (600 µL). The mixture was stirred at 60°C for 3 d, poured onto ice water/brine/1N HCl (20 mL) and extracted with EtOAc (2 x 30 mL).
The combined extracts were washed with ice water/brine (20 mL) and dried over Na2SO4.
The solvent was removed in vacuo to give the title compound (58 mg, quant.) as a light yellow solid. MS: 373.1 [M-H]- .
Example 253 6-(Tetrahydro-pyranylmethoxy)trifluoromethyl-pyridinecarboxylic acid (1- ethylmethylcarbamoyl-propyl)-amide a) 2-Ethyl(6-((tetrahydro-2H-pyranyl)methoxy) (trifluoromethyl)picolinamido)butanoic acid N H OH O O N O F F F O The title compound was synthesized in analogy to the procedure described in Example 252 b), using methyl 2-ethyl(6-((tetrahydro-2H-pyranyl)methoxy) (trifluoromethyl)picolinamido)butanoate (Example 238) as starting material. MS (EI): m/e = 417.0 [M-H]- 20 . b) 6-(Tetrahydro-pyranylmethoxy)trifluoromethyl-pyridinecarboxylic acid (1- ethylmethylcarbamoyl-propyl)-amide N H N H O O N O F F F O The title compound was synthesized in analogy to Example 1, using 2-ethyl(6- ((tetrahydro-2H-pyranyl)methoxy)(trifluoromethyl)picolinamido)butanoic acid and methanamine hydrochloride as starting materials. MS (EI): m/e = 432.3 [M+H]+ .
Example 254 2-Ethyl{[6-(tetrahydro-furanylmethoxy)trifluoromethyl-pyridine carbonyl]-amino}-butyric acid ethyl ester a) 6-((Tetrahydrofuranyl)methoxy)(trifluoromethyl)picolinic acid OH O N O F F F O The title compound was prepared in analogy to the procedure described in Example 230 b), using 6-chloro(trifluoromethyl)picolinic acid and (tetrahydrofuranyl)methanol (CAN 974) as starting materials. MS: 290.0 [M-H]- . b) 2-Ethyl{[6-(tetrahydro-furanylmethoxy)trifluoromethyl-pyridinecarbonyl]- amino}-butyric acid ethyl ester The title compound was synthesized in analogy to Example 1, using 6-((tetrahydrofuran yl)methoxy)(trifluoromethyl)picolinic acid and ethyl 2-aminoethylbutanoate hydrochloride (CAN 11352192) as starting materials. MS (EI): m/e = 433.4 [M+H]+ .
Example 255 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (dimethylcarbamoyl-phenyl-methyl)-amide N H O O O N O F F F O The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example 69 b) and 2-amino-N,N-dimethylphenylacetamide hydrochloride (CAN 12140367) as starting materials. MS (EI): m/e = 445.1 [M+H]+ 5 .
Example 256 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid ((S)- 2-cyclopropyldimethylcarbamoyl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example 69 b) and (S)aminocyclopropyl-N,N-dimethylpropanamide hydrochloride (Example 222 b) as starting materials. MS (EI): m/e = 423.0 [M+H]+ .
Example 257 2-[(5-Cyclopropylcyclopropylmethoxy-pyridinecarbonyl)-amino]ethylbutyric acid ethyl ester The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethyloxy-pyridinecarboxylic acid (Example 42 a) and ethyl 2-amino N H O N O N O N F F N H O N O N O N F F Chiral N H O O O N O ethylbutanoate hydrochloride (CAN 11352192) as starting materials. MS (EI): m/e = 375.0 [M+H]+ .
Example 258 (S)Cyclopropyl[(5-cyclopropylcyclopropylmethoxy-pyridinecarbonyl)- amino]-propionic acid methyl ester The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethyloxy-pyridinecarboxylic acid (Example 42a) and (αS)-α-aminocyclopropanepropanoic acid methyl ester hydrochloride (1:1) (CAN 2064385) as starting materials, LC-MS (UV peak area/ESI) 100%, 359.153 (M+H)+ 10 .
Example 259 6-Cyclopropylmethoxytrifluoromethyl-pyridinecarboxylic acid (1-ethyl methylcarbamoyl-propyl)-amide a) 2-(6-(Cyclopropylmethoxy)(trifluoromethyl)picolinamido)ethylbutanoic acid N H N O O OH F O F F The title compound was synthesized in analogy to the procedure described in Example 252 b), using methyl 2-(6-(cyclopropylmethoxy)(trifluoromethyl)picolinamido) ethylbutanoate (Example 249) as starting material. MS (EI): m/e = 373.1 [M-H]- .
O N N H O O O Chiral N H N O O N H F O F F b) 6-Cyclopropylmethoxytrifluoromethyl-pyridinecarboxylic acid (1-ethyl methylcarbamoyl-propyl)-amide The title compound was synthesized in analogy to Example 1, using 2-(6- (cyclopropylmethoxy)(trifluoromethyl)picolinamido)ethylbutanoic acid and methanamine hydrochloride as starting materials. MS (EI): m/e = 388.0 [M+H]+ 5 .
Example 260 6-(3-Chlorofluoro-phenyl)-pyridinecarboxylic acid [(-)-cyclopropyl-(5-methyl- [1,2,4]oxadiazolyl)-methyl]-amide The title compound was isolated by chiral chromatography of the racemate (Example 232) on Reprosil Chiral NR using heptane/30% 2-propanol as eluent. The (-)-enantiomer was isolated; MS (EI) 387.4 (M+H)+ .
Example 261 6-(3-Chlorofluoro-phenyl)-pyridinecarboxylic acid [(+)-cyclopropyl-(5-methyl15 [1,2,4]oxadiazolyl)-methyl]-amide The title compound was isolated by chiral chromatography of the racemate (Example 232) on Reprosil Chiral NR using heptane/30% 2-propanol as eluent. The (-)-enantiomer was isolated; MS (EI) 387.3 (M+H)+ .
Example 262 6-(Tetrahydro-pyranylmethoxy)trifluoromethyl-pyridinecarboxylic acid (1- dimethylcarbamoylethyl-propyl)-amide N N H O N O N Cl F Chiral N N H O N O N Cl F Chiral The title compound was synthesized in analogy to Example 1, using 2-ethyl(6- ((tetrahydro-2H-pyranyl)methoxy)(trifluoromethyl)picolinamido)butanoic acid (Example 253 a) and dimethylamine hydrochloride as starting materials. MS (EI): m/e = 463.4 [M+NH4] + 5 .
Example 263 2-{[6-Cyclopropylmethoxy(6-oxaaza-spiro[3.3]heptyl)-pyridinecarbonyl]- amino}ethyl-butyric acid ethyl ester The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(6-oxaaza-spiro[3.3]heptyl)-pyridinecarboxylic acid (Example 234 b) and ethyl 2-aminoethylbutanoate hydrochloride (CAN 11352192) as starting materials. MS (EI): m/e = 432.3 [M+H]+ .
Example 264 6-(Tetrahydro-furanylmethoxy)trifluoromethyl-pyridinecarboxylic acid (1- dimethylcarbamoylethyl-propyl)-amide The title compound was synthesized in analogy to Example 1, using 2-ethyl(6- ((tetrahydro-2H-pyranyl)methoxy)(trifluoromethyl)picolinamido)butanoic acid N H N O O N O F F F O O N H O O O N O N N H N O O N O F F F O (Example 253 a) and dimethylamine hydrochloride as starting materials. MS (EI): m/e = 432.1 [M+H]+ .
Example 265 2-[(5-Bromocyclopropylmethoxy-pyridinecarbonyl)-amino]ethyl-butyric acid ethyl ester The title compound was synthesized in analogy to Example 1, using 5-bromo (cyclopropylmethoxy)-pyridinecarboxylic acid (Example 9 d) and ethyl 2-amino ethylbutanoate hydrochloride (CAN 11352192) as starting materials. MS (EI): m/e = 415.0 [M+H]+ 10 .
Example 266 2-{[6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarbonyl]- amino}ethyl-butyric acid ethyl ester The title compound was synthesized in analogy to the procedure described in Example 69 a, using ethyl 2-(5-bromo(cyclopropylmethoxy)picolinamido)ethylbutanoate (Example 265) and 3,3-difluoroazetidine hydrochloride (CAN 2883157) as starting materials. MS (EI): m/e = 426.0 [M+H]+ .
Example 267 6-(4-Chlorofluoro-phenyl)-pyridinecarboxylic acid [1-methyl(5-methyl- [1,2,4]oxadiazolyl)-ethyl]-amide N H O O O N O Br N N N H O O F F O O a) 6-Bromo-pyridinecarboxylic acid [1-methyl(5-methyl-[1,2,4]oxadiazolyl)- ethyl]-amide The title compound can be prepared in analogy to Example 1, using 6-bromo pyridinecarboxylic acid (CAN 211904) and α,α,5-trimethyl-1,2,4-oxadiazole methanamine hydrochloride (1:1) (CAN 12405265) as starting materials, LC-MS (UV peak area/ESI) 85%, 325.0293 (M+H)+ . b) 6-(4-Chlorofluoro-phenyl)-pyridinecarboxylic acid [1-methyl(5-methyl10 [1,2,4]oxadiazolyl)-ethyl]-amide The title compound can be prepared in analogy to Example 177b, using 6-bromo-pyridine2-carboxylic acid [1-methyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide (Example 267a) and B-(4-chlorofluorophenyl)-boronic acid (CAN 1375040) as starting materials, LC-MS (UV peak area/ESI) 100%, 375.1017 (M+H)+ .
Example 268 6-(3-Chlorofluoro-phenyl)-pyridinecarboxylic acid [1-methyl(5-methyl- [1,2,4]oxadiazolyl)-ethyl]-amide The title compound was synthesized in analogy to Example 267b, 6-bromo-pyridine carboxylic acid [1-methyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide (Example 267a) and B-(3-chlorofluorophenyl)-boronic acid (CAN 1444329) as starting materials, LC-MS (UV peak area/ESI) 91%, 375.1018 (M+H)+ .
Example 269 N N H O N O N F Cl Br N N H O N O N N N H O N O N Cl F 2-{[6-Cyclopropylmethoxy(3,3-difluorooxo-azetidinyl)-pyridinecarbonyl]- amino}ethyl-butyric acid methyl ester The title compound was isolated in less than 1% yield in a reaction combining 6- cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example 69 b) and methyl 2-aminoethylbutanoate hydrochloride (CAN 923984) as starting materials in analogy to the procedure described in Example 1. We believe 6- cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid was contaminated with a small amount of 6-cyclopropylmethoxy(3,3-difluorooxoazetidinyl)-pyridinecarboxylic acid; MS (EI): m/e = 426.0 [M+H]+ 10 .
Example 270 (S)[(5-Cyclopropylcyclopropylmethoxy-pyridinecarbonyl)-amino]methylpentanoic acid methyl ester The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethyloxy-pyridinecarboxylic acid (Example 42a) and L-leucine methyl ester hydrochloride (1:1) (CAN 75173) as starting materials, LC-MS (UV peak area/ESI) 100%, 361.2120 (M+H)+ .
Example 271 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (1- cyanomethyl-butyl)-amide N H O O O N O N F F O O N N H O O O Chiral The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example 69 b) and 2-aminomethylpentanenitrile hydrochloride (CAN 721773) as starting materials. MS (EI): m/e = 379.1 [M+H]+ 5 .
Example 272 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid [3- methyl(5-methyl-[1,2,4]oxadiazolyl)-butyl]-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example 69 b) and 5-methyl-α-(2-methylpropyl)-1,2,4-oxadiazolemethanamine (CAN 1155538- 06-9) as starting materials. MS (EI): m/e = 436.0 [M+H]+ .
Example 273 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (1- hydroxymethyl-1,3-dimethyl-butyl)-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example N H N O N O N F F O N O N F F N H N O N O N O N F F N H OH 69 b) and 2-amino-2,4-dimethylpentanol (CAN 138935) as starting materials. MS (EI): m/e = 398.1 [M+H]+ .
Example 274 -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [1-(azetidine carbonyl)ethyl-propyl]-amide a) 2-(5-Cyclopropyl(cyclopropylmethoxy)picolinamido)ethylbutanoic acid O N OH N H O O The title compound was synthesized in analogy to the procedure described in Example 252 b), using ethyl 2-(5-cyclopropyl(cyclopropylmethoxy)picolinamido)ethylbutanoate (example 257) as the starting material. MS (EI): m/e = 347.1 [M+H]+ . b) 5-Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [1-(azetidine carbonyl)ethyl-propyl]-amide The title compound was synthesized in analogy to Example 1, using 2-(5-cyclopropyl (cyclopropylmethoxy)picolinamido)ethylbutanoic acid and azetidine (CAN 5037) as starting materials. MS (EI): m/e = 386.0 [M+H]+ .
Example 275 -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [1-ethyl(2- methoxy-ethylcarbamoyl)-propyl]-amide O N N N H O O N H O O N N H O O The title compound was synthesized in analogy to Example 1, using 2-(5-cyclopropyl (cyclopropylmethoxy)picolinamido)ethylbutanoic acid (Example 274 a) and 2- methoxyethanamine (CAN 1093) as starting materials. MS (EI): m/e = 404.4 [M+H]+ .
Example 276 5-Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [1-ethyl(ethylmethyl-carbamoyl)-propyl]-amide The title compound was synthesized in analogy to Example 1, using 2-(5-cyclopropyl (cyclopropylmethoxy)picolinamido)ethylbutanoic acid (Example 274 a) and Nmethylethanamine (CAN 6242) as starting materials. MS (EI): m/e = 388.0 [M+H]+ 10 .
Example 277 6-(4-Fluoro-benzyl)-pyridinecarboxylic acid ((S)carbamoylmethyl-butyl)- amide a) 6-(4-Fluorobenzyl)picolinic acid OH F N O 6-(4-Fluorobenzyl)picolinonitrile (24 mg, 113 µmol; CAN 12374311) and powdered sodium hydroxide (18.1 mg, 452 µmol) were dissolved in water (3 mL). The reaction mixture was heated to 90°C for 2.5 h. Additional powdered sodium hydroxide (18.1 mg, 452 µmol) was added and heating was continued for another 2.5 h. The reaction mixture was poured onto 25 mL ice/0.1N HCl and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with ice water/brine (25 mL), dried over Na2SO4 and concentrated in vacuo to give the title compound (21 mg, 80%) as light yellow oil which was used in the next step without further purification. MS (EI): m/e = 230.1 [M-H]- .
O N N N H O O O NH2 N H F N O Chiral b) 6-(4-Fluoro-benzyl)-pyridinecarboxylic acid ((S)carbamoylmethyl-butyl)- amide The title compound was synthesized in analogy to Example 1, using 6-(4- fluorobenzyl)picolinic acid and (2S)aminomethyl-pentanamide (CAN 6874) as starting materials. MS (EI): m/e = 344.0 [M+H]+ 5 .
Example 278 6-(4-Fluoro-benzyl)-pyridinecarboxylic acid ((R)-2,2,2-trifluoropyridinylethyl)-amide The title compound was synthesized in analogy to Example 1, using 6-(4- fluorobenzyl)picolinic acid (Example 277 a) and (R)-2,2,2-trifluoro(pyridin yl)ethanamine hydrochloride (CAN 12285654) as starting materials. MS (EI): m/e = 390.1 [M+H]+ .
Example 279 5-Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid ((S) hydroxymethyl-1,2-dimethyl-propyl)-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethyloxy-pyridinecarboxylic acid (Example 42a) and (2S)amino-2,3- dimethylbutanol (CAN 9561020) as starting materials, LC-MS (UV peak area/ESI) 100%, 333.2175 (M+H)+ .
Example 280 -Bromo(3-methyl-oxetanylmethoxy)-pyridinecarboxylic acid (1-methyl thiazolyl-ethyl)-amide N H F F F F N O N Chiral O N N H O OH Chiral a) 5-Bromochloropicolinic acid N O OH Cl Br In a 500ml two-necked-round-bottom flask, 3-bromochloromethylpyridine (CAN 1850175) (4.0 g, 19.4 mmol) was suspended in H2O (160 ml) to give a colorless suspension. Under stirring, sodium dodecyl sulfate (64 mg, 222 µmol) and KMnO4 (9.19 g, 58.1 mmol) were added. The reaction mixture was stirred at 100°C for 18h. The reaction was then cooled to RT and 100ml NaHSO3-solution (40%) was added dropwise under ice bath-cooling (decolorization). A white precipitate formed and the mixture was stirred a further 30min. The reaction mixture was acidified with 120ml 2N-HCl followed by extraction with ethyl acetate (2x200ml). The combined organic layer was dried over Na2SO4, filtered off and concentrated in vacuo to give a white solid containing a mixture of starting material and the product. The solid was dissolved in 50ml TBME/THF 9:1 and under stirring was added 15ml 2N-NaOH which formed a suspension. The suspension was then extracted with 100ml water. The water-layer was washed with 50ml TBME. The water-layer was acidified with 20ml 2N-HCl which was then extracted with a mixture TBME/THF 9:1 (2x 50ml). The combined organic layers were dried over Na2SO4, filtered off and concentrated in vacuo to dryness to give the title compound (1.8g, 39%) as a white solid ; MS (LC/MS): 235.9[M-H]+ . b) 5-Bromo(3-methyl-oxetanylmethoxy)-pyridinecarboxylic acid N O OH O Br O To a solution of 5-bromochloropicolinic acid (Example 280a) (0.75 g, 3.17 mmol) in dry DMF (18 ml) under argon was added (3-methyloxetanyl)-methanol (389 mg, 3.81 mmol) and NaH (279 mg, 6.98 mmol) was added by portions. The reaction mixture was stirred at room temperature for 20 min until gas release ceased. The reaction mixture was then stirred at 110°C for 16h. The reaction mixture was diluted with ethyl acetate, and the solution was poured into a separatory funnel with 10ml aq. solution 1.0M HCl. After N O N H N S O O Br extraction, the organic phase was collected and the aqueous phase was back extracted with ethylacetate. The organic phases were combined, dried over Na2SO4 and evaporated down in vacuo. The residue was purified by preparative HPLC to give the title compound (260mg, 27%), MS (EI): m/e = 302.0 [M+H]+ . c) 5-Bromo(3-methyl-oxetanylmethoxy)-pyridinecarboxylic acid (1-methyl thiazolyl-ethyl)-amide To a solution of 5-bromo(3-methyl-oxetanylmethoxy)-pyridinecarboxylic acid (Example 280b) (30mg, 100 µmol) in dry DMF (1 ml) was added 4-(4,6-dimethoxy-1,3,5- triazinyl)methylmorpholinium chloride (29.1 mg, 105 µmol) and Hunig's base (52.4uL, 300umol). The reaction was stirred at r.t for 30 min, followed by addition of α,αDimethylthiazolemethanamine (Example 12c) (14.2mg, 100 µmol). The reactions was stirred at room temperature overnight and monitored by LC-MS. When the reaction was complete, purification was directly done by preparative HPLC without any work-up procedure to give the title compound (9.8mg, 23%). MS (EI): m/e = 425.9 [M+H]+ .
Example 281 -Bromo(3-methyl-oxetanylmethoxy)-pyridinecarboxylic acid (3-thiazolyloxetanyl)-amide a) 2-Methyl-propanesulfinic acid (3-thiazolyl-oxetanyl)-amide O N H S O N S A solution of n-butyllithium in hexanes (1.6 M, 2.5 mL, 3.99 mmol) was added dropwise to a solution of thiazole (364 mg, 4.23 mmol) in tetrahydrofuran (30 mL) at -78°C. The resulting mixture was stirred for 30 min at -78°C before a solution of 2-methyl-n-(oxetan3-ylidene)propanesulfinamide (CAN 11580987) (500 mg, 2.85 mmol) in tetrahydrofuran (3.5 mL) was added dropwise at -78°C. The reaction solution was stirred for an additional 30 min at -78°C before being warmed to 22°C, and then was quenched N O N H O S N O O Br with saturated aqueous ammonium chloride solution. The crude reaction mixture was then partitioned between water and ethyl acetate. The aqueous layer was further extracted with ethyl acetate and the organic layers were combined. The combined layers were washed with saturated aqueous sodium chloride solution, and the washed solution was dried with anhydrous sodium sulfate and evaporated down to dryness. The crude product was purified by flash-column chromatography (40% ethyl acetate-hexanes, grading to 100% ethyl acetate, then flushing with 10% methanol-dichloromethane) to give the title compound (495mg, 67%). MS (EI): m/e = 261.0 [M+H]+ . b) 3-(Thiazolyl)oxetanamine hydrochloride O H2N N S ClH A 4.0 M solution of hydrochloric acid (117 μL, 467 μmol) in dioxane was added to a solution of 2-methyl-propanesulfinic acid (3-thiazolyl-oxetanyl)-amide (Example 281a) (81 mg, 311 μmol) in methanol (0.5 mL) at 0°C. The mixture was stirred at 0°C for min before the solvents were removed under reduced pressure. The resulting white solid was triturated with diethyl ether and filtered off. The solid was further washed with diethyl ether and dried under high vacuum to yield the title compound (42mg, 70%) as a white solid., MS (EI): m/e = 157.1 [M+H]+ . c) 5-Bromo(3-methyl-oxetanylmethoxy)-pyridinecarboxylic acid (3-thiazolyloxetanyl)-amide The title compound was synthesized in analogy to Example 280c, using 5-bromo(3- methyl-oxetanylmethoxy)-pyridinecarboxylic acid (Example 280b) and 3-(thiazol yl)oxetanamine hydrochloride (Example 281b) as starting materials, MS (EI): m/e = 440.4 [M+H]+ .
Example 282 5-Bromo(2,2,2-trifluoro-ethoxy)-pyridinecarboxylic acid (3-thiazolyl-oxetan3-yl)-amide N O N H O S N O F F F Br a) 5-Bromo(2,2,2-trifluoro-ethoxy)-pyridinecarboxylic acid N O OH O Br F F F In a 25 mL round-bottomed flask, 5-bromochloropicolinic acid (433 mg, 1.83 mmol) and powdered potassium hydroxide (411 mg, 7.32 mmol) were combined with DMSO (1.9 ml) to give a colorless solution which was stirred at room temperature for 15min. 2,2,2- trifluoroethanol (275 mg, 198 µl, 2.75 mmol, Eq: 1.5) was added. The reaction mixture was stirred for 24 h at ambient temperature. Since the reaction was complete, 0.75 extra equivalents of 2,2,2-trifluoroethanol was added and the reaction was stirred 48h at ambient temperature. The reaction mixture was poured onto 1 M HCl/ice water (1 x 20 mL), extracted with iPrOAc (2 x 25 mL). The organic layers were dried over Na2SO4 and filtered, removed under reduced pressure to give the title compound as a white solid after recrystallization from CH2Cl2 and heptane (409 mg, 1.36 mmol, 74.4 % yield), MS (EI): m/e = 299.9 [M+H]+ . b) 5-Bromo(2,2,2-trifluoro-ethoxy)-pyridinecarboxylic acid (3-thiazolyl-oxetan yl)-amide The title compound was synthesized in analogy to Example 280c, using 5-bromo(2,2,2- trifluoro-ethoxy)-pyridinecarboxylic acid (Example 282a) and 3-(thiazolyl)oxetan amine hydrochloride (Example 281b) as starting materials, MS (EI): m/e = 438.0 [M+H]+ .
Example 283 5-Bromo(3-methyl-oxetanylmethoxy)-pyridinecarboxylic acid (2,2,2- trifluoropyridinyl-ethyl)-amide The title compound was synthesized in analogy to Example 280c, using 5-bromo(2,2,2- trifluoro-ethoxy)-pyridinecarboxylic acid (Example 282a) and 2,2,2-trifluoro (pyridinyl)ethanamine (CAN 352722) as starting materials, MS (EI): m/e = 460.4 [M+H]+ .
Example 284 N O N H F F F O N O Br -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [1- (cyclopropylmethyl-carbamoyl)ethyl-propyl]-amide The title compound was synthesized in analogy to Example 1, using 2-(5-cyclopropyl (cyclopropylmethoxy)picolinamido)ethylbutanoic acid (Example 274 a) and cyclopropylmethanamine (CAN 25164) as starting materials. MS (EI): m/e = 400.1 [M+H]+ .
Example 285 -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid (1-methyl pyridinyl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethyloxy-pyridinecarboxylic acid (Example 42a) and α,α-dimethyl pyridinemethanamine (CAN 525682) as starting materials, LC-MS (UV peak area/ESI) 100%, 352.2021 (M+H)+ 15 .
Example 286 6-(4-Fluoro-benzyl)-pyridinecarboxylic acid ((S)-3,3-dimethylmethylcarbamoylbutyl)-amide The title compound was synthesized in analogy to Example 1, using 6-(4- fluorobenzyl)picolinic acid (Example 277 a) and (2S)amino-N,4,4-trimethylpentanamide (CAN 11601615) as starting materials. MS (EI): m/e = 372.0 [M+H]+ .
N H O N N H O O O N N H O N N F N H O O NH Chiral Example 287 -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [1-(3,3-difluoroazetidinecarbonyl)ethyl-propyl]-amide The title compound was synthesized in analogy to Example 1, using 2-(5-cyclopropyl (cyclopropylmethoxy)picolinamido)ethylbutanoic acid (Example 274 a) and 3,3- difluoroazetidine hydrochloride (CAN 2883157) as starting materials. MS (EI): m/e = 422.0 [M+H]+ .
Example 288 5-(3,3-Difluoro-azetidinyl)(2,2,2-trifluoro-ethoxy)-pyridinecarboxylic acid (1- methylthiazolyl-ethyl)-amide a) 5-Bromo(2,2,2-trifluoro-ethoxy)-pyridinecarboxylic acid (1-methylthiazol yl-ethyl)-amide N O N H O Br N S F F F The title compound was synthesized in analogy to Example 280c, using 5-bromo(2,2,2- trifluoro-ethoxy)-pyridinecarboxylic acid (Example 282a) and α,α-dimethyl thiazolemethanamine (Example 12c) as starting materials, MS (EI): m/e = 424.3 [M+H]+ . b) 5-(3,3-Difluoro-azetidinyl)(2,2,2-trifluoro-ethoxy)-pyridinecarboxylic acid (1- methylthiazolyl-ethyl)-amide To a solution of 5-bromo(2,2,2-trifluoro-ethoxy)-pyridinecarboxylic acid (1-methyl1-thiazolyl-ethyl)-amide (Example 288a) (63.6mg, 150 µmol) in dry toluene (1 ml) was N F F O N N H O O N O N F F F O N H N S F F added 3,3-difluoroazetidine hydrochloride (21.4 mg, 165 µmol), BINAP (9.34 mg, 15.0 µmol), Pd(OAc)2 (3.37 mg, 15.0 µmol) and Cs2CO3 (122 mg, 375 µmol).The reaction was stirred at 120°C overnight and controlled by LC-MS. Evaporation of the volatiles, residue was redissolved in DMF and directly purified by preparative HPLC to give the title compound (21mg, 48umol , 32%), MS (EI): m/e = 437.4 [M+H]+ 5 .
Example 289 2-[(6-Cyclopropylmethoxypyrrolidinyl-pyridinecarbonyl)-amino]ethylbutyric acid ethyl ester The title compound was synthesized in analogy to the procedure described in Example 32 a, using 2-[(5-bromocyclopropylmethoxy-pyridinecarbonyl)-amino]ethyl-butyric acid ethyl ester (Example 265) and pyrrolidine (CAN 1231) as starting materials. MS (EI): m/e = 404.4 [M+H]+ .
Example 290 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (1- methyloxo-pyrrolidinyl)-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example 69 b) and 4-aminomethylpyrrolidinone hydrochloride (CAN 12288380) as starting materials. MS (EI): m/e = 381.3 [M+H]+ .
Example 291 2-[(6-Cyclopropylmethoxypyrrolidinyl-pyridinecarbonyl)-amino]ethylbutyric acid N H O O O N O N N N H O O N F F N O In analogy to the procedure described in Example 252 b, 2-[(6-cyclopropylmethoxy pyrrolidinyl-pyridinecarbonyl)-amino]ethyl-butyric acid ethyl ester (Example 289) was treated with sodium hydroxide to give the title compound as colorless oil. MS: 376.3 [M+H]+ 5 .
Example 292 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (1,1- dioxo-tetrahydro-1λ6 -thiophenyl)-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example 69 b) and 1,1-dioxidotetrahydrothienylamine (CAN 63381) as starting materials.
MS (EI): m/e = 402.1 [M+H]+ .
Example 293 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid N'- (1,1-dioxo-tetrahydro-1λ6 -thiophenyl)-hydrazide 6-(Cyclopropylmethoxy)(3,3-difluoroazetidinyl)picolinic acid (10 mg, 35.2 µmol, Example 69 b), 3-sulfanyl hydrazine hydrochloride (6.34 mg, 42.2 µmol; CAN 1004 5), 1-hydroxybenzotriazole hydrate (10.8 mg, 70.4 µmol), 1-(3-dimethylaminopropyl) N N N H O O O OH N H S O O O N O N F F N H S O O N H O N O N F F ethylcarbodiimide hydrochloride (12.1 mg, 70.4 µmol) and N-ethyl-N-isopropylpropan amine (18.2 mg, 24.6 µL, 141 µmol) were dissolved in DMF (100 µL). The reaction mixture was stirred for 1 d at ambient temperature, poured onto 1 M HCl/icewater (20 mL) and extracted with EtOAc (2 x 25 mL). The combined extracts were washed with icewater (2 x 25 mL), dried over Na2SO4 and the solvent was removed under reduced pressure to give 23 mg of crude product which was purified by preparative TLC (silica gel, 1.0 mm, heptane/EtOAc 2:1, elution with EtOAc) to give the title compound (5 mg, 34%) as colorless oil. MS (EI): m/e = 417.3 [M+H]+ .
Example 294 5-Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [1-methyl(4- methyl-thiazolyl)-ethyl]-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethyloxy-pyridinecarboxylic acid (Example 42a) and α,α,5-trimethyl thiazolemethanamine (CAN 11555308) as starting materials, LC-MS (UV peak area/ESI) 97%, 372.1742 (M+H)+ .
Example 295 -(3,3-Difluoro-azetidinyl)(3-methyl-oxetanylmethoxy)-pyridinecarboxylic acid (1-methylthiazolyl-ethyl)-amide The title compound was synthesized in analogy to Example 288b, using 5-bromo(3- methyl-oxetanylmethoxy)-pyridinecarboxylic acid (1-methylthiazolyl-ethyl)- amide (Example 281c) and 3,3-difluoroazetidine hydrochloride as starting materials, MS (EI): m/e = 439.3 [M+H]+ .
Example 296 O N N H O N S O N O N F F O N H N S -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [1-(5-amino- [1,2,4]oxadiazolyl)methyl-ethyl]-amide a) [1-(5-Amino-[1,2,4]oxadiazolyl)methyl-ethyl]-carbamic acid tert-butyl ester To a colorless solution of [1-(N-hydroxycarbamidoyl)methyl-ethyl]-carbamic acid tertbutyl ester (CAN 12514302, 5.9 g, 27.2 mmol) in DMF (11.8 mL) and in an inert gas atmosphere was added 1-piperidinecarbonitrile (CAN 15306) with stirring (3.29 g, 3.46 mL, 29.9 mmol). The reaction mixture was heated and stirred for 2.5 hours at 130°C.
After cooling to room temperature ice-water (400 mL) was added and the mixture was extracted with ethyl acetate (3x200 mL), organic phases were washed with ice water (200 mL), combined, dried with Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel with mixtures of ethyl acetate / n-heptane as eluent to give the title compound as white solid (5.0 g, 76%); LC-MS (UV peak area/ESI) 83%, 243.1453 (M+H)+ 15 . b) 3-(1-Aminomethyl-ethyl)-[1,2,4]oxadiazolylamine hydrochloride (1:1) To a solution of [1-(5-amino-[1,2,4]oxadiazolyl)methyl-ethyl]-carbamic acid tertbutyl ester (1.6 g, 6.6 mmol) in ethanol (30 mL) was added HCl in dioxane (4 M, 6.6 ml, 26.4 mmol) and the reaction mixture was stirred 16 hours at room temperature. The reaction mixture was concentrated in vacuo and dried by applying high vacuum at 40°C for 4 hours to give the title compound as off-white solid (1.2 g, quant.); LC-MS (UV peak area/ESI) 99.9%, 143.0927 (M+H)+ . c) 5-Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [1-(5-amino25 [1,2,4]oxadiazolyl)methyl-ethyl]-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethyloxy-pyridinecarboxylic acid (Example 42a) and 3-(1-amino O N N H O N O N NH2 N O N N O H O NH2 N O N H2N NH2 ClH methyl-ethyl)-[1,2,4]oxadiazolylamine hydrochloride (1:1) (Example 296b) as starting materials, LC-MS (UV peak area/ESI) 98%, 358.1879 (M+H)+ .
Example 297 6-(2,2,3,3,3-Pentafluoro-propoxy)-pyridinecarboxylic acid (1-ethyl methylcarbamoyl-propyl)-amide a) 5-Bromo(2,2,3,3,3-pentafluoro-propoxy)-pyridinecarboxylic acid -Bromochloropyridinecarboxylic acid (CAN 9599589; 0.6 g, 2.54 mmol) and potassium tert-butoxide (712 mg, 6.34 mmol) were combined with DMF (30 mL) and THF (10 mL) to give a yellow suspension. To this suspension was added 2,2,3,3,3- pentafluoropropanol (CAN 4229; 3.01 g, 2 ml, 20.1 mmol) and the mixture was heated to 140°C for 20 hours. After cooling the mixture was poured was poured into ethyl acetate (75 mL) and the combined mixture was washed with cold 1 M HCl (1 x 10 mL).
The aqueous layer was extracted with ethyl acetate (50 mL). The organic layers were combined, dried with Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (silica gel, 20 g, 0% to 100% ethyl acetate in heptane) and further purified by preparative HPLC to give the title compound (0.176 g 20%) as off white solid; MS (EI) 350.1 (M+H)+ . b) 6-(2,2,3,3,3-Pentafluoro-propoxy)-pyridinecarboxylic acid and 5-cyclopropyl (2,2,3,3,3-pentafluoro-propoxy)-pyridinecarboxylic acid O N N H F O F F F F O N H O N OH F O F F F F Br O N F F F F F OH O O N F F F F F OH O + Palladium(II)acetate (2.44 mg, 10.9 µmol), butylbis(tricyclo[3.3.1.13,7]decyl)- phosphine, (5.8 mg, 16.3 µmol), (T-4)-cyclopropyltrifluoro-borate(1-) potassium (1:1) (80 mg, 543 µmol) and cesium carbonate (531 mg, 1.63 mmol) were combined to give a white solid. To this solid a solution of 5-bromo(2,2,3,3,3-pentafluoro-propoxy)-pyridine carboxylic acid (190 mg, 543 µmol) in toluene (4.8 mL) and water (532 µl) (evacuated and flushed with argon) was added through a septum cap. The reaction mixture was heated to 120°C and stirred for 20 hours. After cooling to ambient temperature the reaction mixture was diluted with water (20 mL), poured onto a mixture of ice-water/brine/1 N HCl (200 mL) and extracted with ethyl acetate (2 x 200 mL). The organic phases were washed with 200 mL icewater/brine, combined, dried with Na2SO4 and concentrated in vacuo to give a yellow oil. The crude material was purified by flash chromatography (silica gel, 20g, ethyl acetate) to get 195 mg of a mixture 1 / 1 of both products as yellow solid which was used without further purification. c) 6-(2,2,3,3,3-Pentafluoro-propoxy)-pyridinecarboxylic acid (1-ethyl methylcarbamoyl-propyl)-amide The title compound was synthesized in analogy to Example 1, using the mixture of 6- (2,2,3,3,3-pentafluoro-propoxy)-pyridinecarboxylic acid and 5-cyclopropyl (2,2,3,3,3-pentafluoro-propoxy)-pyridinecarboxylic acid (Example 297b) and 2-amino2-ethyl-N-methyl-butyramide (Example 70b) as starting materials, the product was isolated by preparative HPLC; LC-MS (UV peak area/ESI) 100%, 398.1488 (M+H)+ 20 .
Example 298 -Cyclopropyl(2,2,3,3,3-pentafluoro-propoxy)-pyridinecarboxylic acid (1-ethyl1-methylcarbamoyl-propyl)-amide The title compound was synthesized in analogy to Example 1, using the mixture of 6- (2,2,3,3,3-pentafluoro-propoxy)-pyridinecarboxylic acid and 5-cyclopropyl (2,2,3,3,3-pentafluoro-propoxy)-pyridinecarboxylic acid (Example 297b) and 2-amino2-ethyl-N-methyl-butyramide (Example 70b) as starting materials, the product was isolated by preparative HPLC; LC-MS (UV peak area/ESI) 97%, 438.1810 (M+H)+ .
O N N H F O F F F F O N H Example 299 -Cyclopropyl(2,2,3,3,3-pentafluoro-propoxy)-pyridinecarboxylic acid ((S)-3,3- dimethylmethylcarbamoyl-butyl)-amide The title compound was synthesized in analogy to Example 1, using the mixture of 6- (2,2,3,3,3-pentafluoro-propoxy)-pyridinecarboxylic acid and 5-cyclopropyl (2,2,3,3,3-pentafluoro-propoxy)-pyridinecarboxylic acid (Example 297b) and (2S) amino-N,4,4-trimethyl-pentanamide (CAN 11601615) as starting materials, the product was isolated by preparative HPLC; LC-MS (UV peak area/ESI) 100%, 452.1962 (M+H)+ 10 .
Example 300 -Cyclopropyl(2,2,3,3,3-pentafluoro-propoxy)-pyridinecarboxylic acid [(S) cyclopropyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide The title compound was synthesized in analogy to Example 1, using the mixture of 6- (2,2,3,3,3-pentafluoro-propoxy)-pyridinecarboxylic acid and 5-cyclopropyl (2,2,3,3,3-pentafluoro-propoxy)-pyridinecarboxylic acid (Example 297b) and (S) cyclopropyl5-methyl-[1,2,4]oxadiazolyl)-ethylamine (Example 38e) as starting materials, the product was isolated by preparative HPLC; LC-MS (UV peak area/ESI) 100%, 461.1607 (M+H)+ 20 .
Example 301 -Cyclopropyl(2,2,2-trifluoro-ethoxy)-pyridinecarboxylic acid ((S)-carbamoylphenyl-methyl)-amide O N N H F O F F F F O N H Chiral O N N H F O F F F F N N O Chiral a) 5-Cyclopropyl(2,2,2-trifluoro-ethoxy)-pyridinecarboxylic acid N O OH O F F F In a 150 ml round-bottom-flask, Pd(OAc)2 (15.7 mg, 70.0 µmol), butyl adamantylphosphin (37.6 mg, 105 µmol), potassium cyclopropyltrifluoroborate (523 mg, 3.53 mmol), cesium carbonate (3.42 g, 10.5 mmol) and 5-bromo(2,2,2- trifluoroethoxy)picolinic acid (Example 282a) (1.05 g, 3.5 mmol) were combined. The flask was evacuated in vacuo and flushed with argon three times, followed by addition of a mixture toluene (25 ml) / H2O (3 ml) through a septum cap. The reaction mixture was heated to 120°C, stirred for 20 h and then cooled to ambient temperature. Evaporation of volatiles in vacuo and the residue was redissolved in ethyl acetate and extracted with 1M HCl (12.5ml). The aqueous phase was back-extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated in vacuo The crude material was purified by flash chromatography (silica gel, 50g, 0% to 5% MeOH in DCM) to give the title compound (530mg, 58%). MS (EI): m/e = 262.2[M+H]+ 15 . b) 5-Cyclopropyl(2,2,2-trifluoro-ethoxy)-pyridinecarboxylic acid ((S)-carbamoylphenyl-methyl)-amide The title compound was synthesized in analogy to Example 280c, using 5-cyclopropyl (2,2,2-trifluoro-ethoxy)-pyridinecarboxylic acid (Example 301a) and (S)amino phenyl-acetamide hydrochloride (CAN 600798) as starting materials, MS (EI): m/e = 394.1 [M+H]+ .
Example 302 -Cyclopropyl(2,2,2-trifluoro-ethoxy)-pyridinecarboxylic acid (2,2,2-trifluoro pyridinyl-ethyl)-amide O N F F F O N H NH2 O Chiral The title compound was synthesized in analogy to Example 280c, using 5-cyclopropyl (2,2,2-trifluoro-ethoxy)-pyridinecarboxylic acid (Example 301a) and 2,2,2-trifluoro (pyridinyl)ethanamine (CAN 352722) as starting materials, MS (EI): m/e = 420.1 [M+H]+ 5 .
Example 303 -Cyclopropyl(2,2,2-trifluoro-ethoxy)-pyridinecarboxylic acid ((S) hydroxymethylmethyl-butyl)-amide The title compound was synthesized in analogy to Example 280c, using 5-cyclopropyl (2,2,2-trifluoro-ethoxy)-pyridinecarboxylic acid (Example 301a) and L-leucinol (CAN 170164) as starting materials, MS (EI): m/e = 361.3 [M+H]+ .
Example 304 -Cyclopropyl(2,2,2-trifluoro-ethoxy)-pyridinecarboxylic acid (3-thiazolyl15 oxetanyl)-amide The title compound was synthesized in analogy to Example 280c, using 5-cyclopropyl (2,2,2-trifluoro-ethoxy)-pyridinecarboxylic acid (Example 301a) and 3-(thiazol yl)oxetanamine hydrochloride (Example 281b) as starting materials, MS (EI): m/e = 400.1 [M+H]+ 20 .
Example 305 O N F F F O N H N F F F O N F F F O N H OH Chiral O O N F F F O N H N S -Cyclopropyl(2,2,2-trifluoro-ethoxy)-pyridinecarboxylic acid (1-methyl thiazolyl-ethyl)-amide The title compound was synthesized in analogy to Example 280c, using 5-cyclopropyl (2,2,2-trifluoro-ethoxy)-pyridinecarboxylic acid (Example 301a) and α,α-dimethyl thiazolemethanamine (Example 12c) as starting materials, MS (EI): m/e = 386.3 [M+H]+ .
Example 306 -Cyclopropyl(2,2,2-trifluoro-ethoxy)-pyridinecarboxylic acid (2,2-dimethyl thiazolyl-propyl)-amide a) (E)-N-(2,2-Dimethylpropylidene)methylpropanesulfinamide N S O To a solution of pivalaldehyde (2 g, 2.56 ml, 23.2 mmol) in dry dichloromethane (150mL) under argon atmosphere was added 2-methylpropanesulfinamide (3.38 g, 27.9 mmol) and titanium (IV) ethoxide (6.36 g, 5.84 ml, 27.9 mmol) to give a colorless solution. The reaction mixture was stirred at r.t overnight and quenched by slow addition of water while the reaction still stirring until a precipitate formed. The reaction mixture was then filtered through a pad of celite. The filtrate was extracted with water, the organic phase was collected, dried over Na2SO4 and evaporated down in vacuo to give the title compound (3.6gr, 82%) as crude oil. The crude was used without any further purification for the next step, MS (EI): m/e = 190.3 [M+H]+ . b) N-(2,2-Dimethyl(thiazolyl)propyl)methylpropanesulfinamide O N F F F O N H N S O N F F F O N H N S N H S O S N To a solution of thiazole (247 mg, 206 µl, 2.91 mmol) in 10 mL dry THF under argon at - 73°C was slowly added a 1.6M solution of BuLi in hexane (1.82 ml, 2.91 mmol). The resulting reaction mixture was stirred at -75°C for 30min and a solution of (E)-N-(2,2- dimethylpropylidene)methylpropanesulfinamide (Example 306a) (500mg, 2.64 mmol) in 5mL dry THF was added. The reaction mixture was stirred at -75°C for 30min, then cooling bath was removed and reaction stirred at r.t for 1h. The reaction was quenched by the addition of few drops of water, the reaction mixture poured into ethyl acetate, and the solution was then extracted with aqueous NaHCO3 1M. The organic phase was collected, dried over Na2SO4 and evaporated down to dryness to give the title compound (666mg, 92%) as crude dark orange oil. The crude was used without any further purification, MS (EI): m/e = 275.2 [M+H]+ . c) 5-Cyclopropyl(2,2,2-trifluoro-ethoxy)-pyridinecarboxylic acid (2,2-dimethyl thiazolyl-propyl)-amide To a solution of N-(2,2-dimethyl(thiazolyl)propyl)methylpropanesulfinamide (Example 306c) (666 mg, 2.43 mmol) in methanol (15 ml) was added a solution 4.0M HCl in dioxane (3.03 ml, 12.1 mmol) to give a light red solution. The reaction mixture was stirred at r.t for 1h and reaction was then evaporated down to dryness. The crude solid was triturated in diethyl ether, filtered off and dried under high vacuum to give the title compound (346mg, 69%) as an off-white solid which was used to synthesize the title compound in analogy to Example 280c, using 5-cyclopropyl(2,2,2-trifluoro-ethoxy)- pyridinecarboxylic acid (Example 301a) as starting material, MS (EI): m/e = 414.3 [M+H]+ .
Example 307 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid [1- (3,3-difluoro-azetidinecarbonyl)ethyl-propyl]-amide N N N H O O F F O N F F a) 2-(6-(Cyclopropylmethoxy)(3,3-difluoroazetidinyl)picolinamido)ethylbutanoic acid N N N H O O F F O OH In analogy to the procedure described in Example 252 b), 2-{[6-cyclopropylmethoxy (3,3-difluoro-azetidinyl)-pyridinecarbonyl]-amino}ethyl-butyric acid ethyl ester (Example 266) was treated with sodium hydroxide to give the title compound as colorless oil. MS: 396.2 [M-H]- . b) 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid [1- (3,3-difluoro-azetidinecarbonyl)ethyl-propyl]-amide In analogy to the procedure described in Example 293, 2-(6-(cyclopropylmethoxy)(3,3- difluoroazetidinyl)picolinamido)ethylbutanoic acid and 3,3-difluoroazetidine (CAN 6794318) were condensed to the title product. MS (EI): m/e = 471.4 [M-H]- .
Example 308 6-(4-Fluoro-benzyl)-pyridinecarboxylic acid N'-(1,1-dioxo-tetrahydro-1λ6 - thiophenyl)-hydrazide In analogy to the procedure described in Example 293, 6-(4-fluorobenzyl)picolinic acid (Example 277 a) and 3-sulfanyl hydrazine hydrochloride (CAN 10045) were condensed to the title product. MS (EI): m/e = 364.1 [M+H]+ .
Example 309 -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [1-(3-amino- [1,2,4]oxadiazolyl)methyl-ethyl]-amide N H S O O N N H F O a) [1-(3-Amino-[1,2,4]oxadiazolyl)methyl-ethyl]-carbamic acid tert-butyl ester To a colorless solution of N-[(1,1-dimethylethoxy)carbonyl]methyl-alanine (CAN 309921; 1.0 g, 4.92 mmol) in DMF (24 mL) was added (benzotriazol yloxy)tripyrrolidinophosphonium hexafluorophosphate (3.07 g, 5.9 mmol) and DIEA (1.72 mL, 4.9 mmol), and the resulting pale yellow solution was stirred under argon for 30 minutes at room temperature. This mixture was added dropwise over 40 minutes to a suspension of hydroxyguanidine sulfate monohydrate (3.93 g, 14.8 mmol), DIEA (2.6 mL, 7.4 mmol), and molecular sieves (4Å, 2 g) in DMF (35 mL) under argon, the temperature not exceeding 25°C. Once addition was complete another 2 g of molecular sieves was added and the reaction mixture (pale yellow suspension) was stirred for 1.5 hours under argon at room temperature then stirred at 130°C for 20 hours. After cooling to room temperature the mixture was filtered through Celite®. The filtrate was concentrated in vacuo (HV pump) and the residue was stirred vigorously with 2-methoxymethylpropane (40 mL) and 1N NaOH (40 mL) for 20 h. Phases were separated; the aqueous phase was washed with 2-methoxymethylpropane (2x10 mL). Combined organic extracts were washed with water, then dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel, 50 g, 0% to 100% EtOAc in hexanes) to give the title compound (106 mg, 8.9%), which was used without further purification. b) 5-(1-Aminomethyl-ethyl)-[1,2,4]oxadiazolylamine hydrochloride (1:1) To a solution of [1-(3-amino-[1,2,4]oxadiazolyl)methyl-ethyl]-carbamic acid tertbutyl ester (100 mg, 0.41 mmol) in ethanol (2 mL) was added HCl in dioxane (4 M, 0.41 ml, 1.65 mmol) and the reaction mixture was stirred 16 hours at room temperature. The reaction mixture was concentrated in vacuo and dried by applying high vacuum at 40°C for 4 hours to give the title compound as white solid (75 mg, quant.); LC-MS (UV peak area/ESI) nd, 143.0928 (M+H)+ .
O N N H O O N N NH2 O N N N H NH2 O O O N N H2N NH2 ClH c) 5-Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [1-(3-amino- [1,2,4]oxadiazolyl)methyl-ethyl]-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethyloxy-pyridinecarboxylic acid (Example 42a) and 5-(1-amino methyl-ethyl)-[1,2,4]oxadiazolylamine hydrochloride (1:1) (Example 309b) as starting materials, LC-MS (UV peak area/ESI) 100%, 358.1872 (M+H)+ .
Example 310 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid [(S)- 1-(3,3-difluoro-azetidinecarbonyl)-2,2-dimethyl-propyl]-amide a) (S)-Methyl 2-(6-(cyclopropylmethoxy)(3,3-difluoroazetidinyl)picolinamido)-3,3- dimethylbutanoate O N N F F O HN O O The title compound was synthesized in analogy to Example 1, using 6- (cyclopropylmethoxy)(3,3-difluoroazetidinyl)picolinic acid (Example 69 b) and (S)- methyl 2-amino-3,3-dimethylbutanoate hydrochloride (CAN 630387) as starting materials. MS (EI): m/e = 412.3 [M+H]+ . b) (S)(6-(Cyclopropylmethoxy)(3,3-difluoroazetidinyl)picolinamido)-3,3- dimethylbutanoic acid O N N F F O HN O N F F Chiral O N N F F O HN O OH In analogy to the procedure described in Example 5 c), (S)-methyl 2-(6- (cyclopropylmethoxy)(3,3-difluoroazetidinyl)picolinamido)-3,3-dimethylbutanoate was saponified with lithium hydroxide to obtain the title compound. MS (EI): m/e = 396.1 [M-H]- 5 . c) 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid [(S) (3,3-difluoro-azetidinecarbonyl)-2,2-dimethyl-propyl]-amide The title compound was synthesized in analogy to Example 1, using (S)(6- (cyclopropylmethoxy)(3,3-difluoroazetidinyl)picolinamido)-3,3-dimethylbutanoic acid and 3,3-difluoroazetidine hydrochloride (CAN 2883157)) as starting materials.
MS (EI): m/e = 473.0 [M+H]+ .
Example 311 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid [(S)- 1-(3,3-difluoro-azetidinecarbonyl)methyl-butyl]-amide a) (S)-Ethyl 2-(6-(cyclopropylmethoxy)(3,3-difluoroazetidinyl)picolinamido) methylpentanoate O N N F F O HN O N F F Chiral O N N F F O HN O O The title compound was synthesized in analogy to Example 1, using 6- (cyclopropylmethoxy)(3,3-difluoroazetidinyl)picolinic acid (Example 69 b) and (S)- ethyl 2-aminomethylpentanoate hydrochloride (CAN 27430) as starting materials.
MS (EI): m/e = 426.3 [M+H]+ 5 . b) (S)(6-(Cyclopropylmethoxy)(3,3-difluoroazetidinyl)picolinamido) methylpentanoic acid O N N F F O HN O OH In analogy to the procedure described in Example 5 c), (S)-ethyl 2-(6- (cyclopropylmethoxy)(3,3-difluoroazetidinyl)picolinamido)methylpentanoate was saponified with lithium hydroxide to obtain the title compound. MS (EI): m/e = 396.3 [MH]- . c) 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid [(S) (3,3-difluoro-azetidinecarbonyl)-2,2-dimethyl-propyl]-amide The title compound was synthesized in analogy to Example 1, using (S)(6- (cyclopropylmethoxy)(3,3-difluoroazetidinyl)picolinamido)methylpentanoic acid and 3,3-difluoroazetidine hydrochloride (CAN 2883157) as starting materials. MS (EI): m/e = 473.3 [M+H]+ .
Example 312 2-[(6-Cyclopropylmethoxytrifluoromethyl-pyridinecarbonyl)-amino]ethylbutyric acid ethyl ester In analogy to the procedure described in Example 293, 6-cyclopropylmethoxy trifluoromethyl-pyridinecarboxylic acid (Example 113 d) and ethyl 2-amino ethylbutanoate hydrochloride (CAN 11352192) were condensed to the title product.
MS (EI): m/e = 403.4 [M+H]+ 5 .
Example 313 -Cyclopropyl((R)hydroxytrifluoromethyl-propoxy)-pyridinecarboxylic acid (1-ethylmethylcarbamoyl-propyl)-amide a) 5-Cyclopropyl((R)hydroxytrifluoromethyl-propoxy)-pyridinecarboxylic acid 6-Chlorocyclopropylpyridinecarboxylic acid (CAN 12115308; 100 mg, 506 µmol), (R)-4,4,4-trifluorobutane-1,3-diol (219 mg, 1.52 mmol) and potassium tertbutoxide (114 mg, 1.01 mmol) were combined with DMF (2 mL) to give a white suspension. The reaction mixture was heated to 140°C and stirred for 20 h. After cooling the mixture was poured into cold 1 M HCl (15 mL) and extracted with ethyl acetate (2 x 75 mL). The phases were combined, dried with Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (12 mg, 7.8%) and its regioisomer; MS (EI) 304.2 (M+H)+ .
N O HN O F F F O O O N NH O HO N H O F F F Chiral N OH O O HO F F F b) 5-Cyclopropyl((R)hydroxytrifluoromethyl-propoxy)-pyridinecarboxylic acid (1-ethylmethylcarbamoyl-propyl)-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl((R)- 3-hydroxytrifluoromethyl-propoxy)-pyridinecarboxylic acid (Example 313a) and 2- aminoethyl-N-methyl-butyramide (Example 70b) as starting materials; MS (EI) 432.4 (M+H)+ .
Example 314 -Cyclopropyl((R)-4,4,4-trifluorohydroxy-butoxy)-pyridinecarboxylic acid (1-ethylmethylcarbamoyl-propyl)-amide a) 5-Cyclopropyl((R)hydroxytrifluoromethyl-propoxy)-pyridinecarboxylic acid 6-Chlorocyclopropylpyridinecarboxylic acid (CAN 12115308; 100 mg, 506 µmol), (R)-4,4,4-trifluorobutane-1,3-diol (219 mg, 1.52 mmol) and potassium tert15 butoxide (114 mg, 1.01 mmol) were combined with DMF (2 mL) to give a white suspension. The reaction mixture was heated to 140°C and stirred for 20 h. After cooling the mixture was poured into cold 1 M HCl (15 mL) and extracted with ethyl acetate (2 x 75 mL). The phases were combined, dried with Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (8 mg, 5.2%) and its regioisomer; MS (EI) 304.2 (M+H)+ 20 . b) 5-Cyclopropyl((R)-4,4,4-trifluorohydroxy-butoxy)-pyridinecarboxylic acid (1- ethylmethylcarbamoyl-propyl)-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl((R)- 3-hydroxytrifluoromethyl-propoxy)-pyridinecarboxylic acid (Example 314a) and 2- aminoethyl-N-methyl-butyramide (Example 70b) as starting materials; MS (EI) 432.4 (M+H)+ .
O N NH O HO F F F N H O Chiral N OH O O HO F F F Example 315 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (3- methylpyridinyl-butyl)-amide In analogy to the procedure described in Example 293, 6-(cyclopropylmethoxy)(3,3- difluoroazetidinyl)picolinic acid (Example 69 b) and 3-methyl(pyridinyl)butan amine (CAN 8256476) were condensed to the title product. MS (EI): m/e = 431.4 [M+H]+ .
Example 316 6-Cyclopropylmethoxytrifluoromethyl-pyridinecarboxylic acid [1-(3,3-difluoroazetidinecarbonyl)ethyl-propyl]-amide In analogy to the procedure described in Example 293, 2-[(6-cyclopropylmethoxy trifluoromethyl-pyridinecarbonyl)-amino]ethyl-butyric acid (Example 252 b) and 3,3-difluoroazetidine hydrochloride (CAN 2883157) were condensed to the title product. MS (EI): m/e = 450.0 [M+H]+ .
Example 317 6-[(4-Fluoro-phenyl)-hydroxy-methyl]-pyridinecarboxylic acid ((S)carbamoyl3-methyl-butyl)-amide N N O F F O HN N N O HN O F F F O N F F a) Methyl 6-((4-fluorophenyl)(hydroxy)methyl)picolinate N O O OH F A suspension of (6-bromopyridinyl)(4-fluorophenyl)methanol (1 g, 3.54 mmol; CAN 8755629), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (174 mg, 0.06 eq.; CAN 954644) and triethylamine (464 mg, 639 L, 4.6 mmol) in methanol (10 mL) was shaken in an autoclave under 70 bar carbon monoxide pressure at 110°C for 18 h. The reaction mixture was filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 70 g, 20% to 60% EtOAc in heptane) to give the title compound (853 mg, 92 %) as pale yellow oil. MS (EI): m/e = 262.0 [M+H]+ . b) 6-((4-Fluorophenyl)(hydroxy)methyl)picolinic acid N O OH OH F In analogy to the procedure described in Example 5 c), methyl 6-((4- fluorophenyl)(hydroxy)methyl)picolinate was saponified with lithium hydroxide to obtain the title compound. MS (EI): m/e = 246.1 [M-H]- . c) 6-[(4-Fluoro-phenyl)-hydroxy-methyl]-pyridinecarboxylic acid ((S)carbamoyl methyl-butyl)-amide The title compound was synthesized in analogy to Example 1, using 6-((4- fluorophenyl)(hydroxy)methyl)picolinic acid and (2S)aminomethyl-pentanamide (CAN 6874) as starting materials. MS (EI): m/e = 360.1 [M+H]+ .
Example 318 6-[(4-Fluoro-phenyl)-hydroxy-methyl]-pyridinecarboxylic acid [(S)methyl(5- methyl-[1,2,4]oxadiazolyl)-butyl]-amide N O N H OH O NH2 F The title compound was synthesized in analogy to Example 1, using 6-((4- fluorophenyl)(hydroxy)methyl)picolinic acid and (S)methyl-α-(2-methylpropyl)-1,2,4- oxadiazolemethanamine hydrochloride (which was prepared from (2S)[(tert5 butoxycarbonyl)amino]methylpentanoic acid (CAN 131396) in analogy to the procedures described in Example 38 a to e) as starting materials. MS (EI): m/e = 399.2 [M+H]+ .
Example 319 -Cyclopropyl((S)hydroxytrifluoromethyl-propoxy)-pyridinecarboxylic acid (1-ethylmethylcarbamoyl-propyl)-amide a) 5-Cyclopropyl((S)hydroxytrifluoromethyl-propoxy)-pyridinecarboxylic acid 6-Chlorocyclopropylpyridinecarboxylic acid (CAN 12115308; 180 mg, 901 µmol), (S)-4,4,4-trifluorobutane-1,3-diol (394 mg, 2.73 mmol) and potassium tertbutoxide (307 mg, 2.73 mmol) were combined with DMF (3 mL) to give a white suspension. The reaction mixture was heated to 140°C and stirred for 48 h. After cooling the mixture was poured into cold 1 M HCl (15 mL) and extracted with ethyl acetate (2 x 75 mL). The phases were combined, dried with Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (15 mg, 5.4%) and its regioisomer; MS (EI) 304.2 (M+H)+ .
N OH O F N O N N H O N NH O HO N H O F F F Chiral N OH O O HO F F F b) 5-Cyclopropyl((S)hydroxytrifluoromethyl-propoxy)-pyridinecarboxylic acid (1-ethylmethylcarbamoyl-propyl)-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl((S)- 3-hydroxytrifluoromethyl-propoxy)-pyridinecarboxylic acid (Example 319a) and 2- aminoethyl-N-methyl-butyramide (Example 70b) as starting materials; MS (EI) 432.4 (M+H)+ .
Example 320 -Cyclopropyl((S)-4,4,4-trifluorohydroxy-butoxy)-pyridinecarboxylic acid (1- ethylmethylcarbamoyl-propyl)-amide a) 5-Cyclopropyl((S)hydroxytrifluoromethyl-propoxy)-pyridinecarboxylic acid 6-Chlorocyclopropylpyridinecarboxylic acid (CAN 12115308; 180 mg, 901 µmol), (S)-4,4,4-trifluorobutane-1,3-diol (394 mg, 2.73 mmol) and potassium tert15 butoxide (307 mg, 2.73 mmol) were combined with DMF (3 mL) to give a white suspension. The reaction mixture was heated to 140°C and stirred for 48 h. After cooling the mixture was poured into cold 1 M HCl (15 mL) and extracted with ethyl acetate (2 x 75 mL). The phases were combined, dried with Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (23 mg, 8.3%) and its regioisomer; MS (EI) 304.2 (M+H)+ 20 . b) 5-Cyclopropyl((S)-4,4,4-trifluorohydroxy-butoxy)-pyridinecarboxylic acid (1- ethylmethylcarbamoyl-propyl)-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl((S)- 3-hydroxytrifluoromethyl-propoxy)-pyridinecarboxylic acid (Example 320a) and 2- aminoethyl-N-methyl-butyramide (Example 70b) as starting materials; MS (EI) 432.4 (M+H)+ .
O N NH O HO F F F N H O Chiral N OH O O HO F F F Example 321 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (3- methylpyridazinyl-butyl)-amide a) 3-Methyl(pyridazinyl)butanamine H2N N N A suspension of 3-methyl(pyridazinyl)butanone (0.85 g, 5.2 mmol; CAN 138835- 88-8), sodium cyanoborohydride (1.2 g, 19.2 mmol) and ammonium acetate (1.28 g, 16.6 mmol) in methanol (11.1 mL) was heated at 70°C for 12 h. The solvent was removed under reduced pressure and the residual oil was partitioned between EtOAc and 1 M aqueous HCl solution. The aqueous layer was basified with 10% aqueous NaOH solution and extracted with EtOAc. The combined extracts were washed with brine and dried over Na2SO4. Filtration and evaporation provided the title compound (233 mg, 27 %) as brown oil which was sufficiently pure to be used in the next reaction step. MS (EI): m/e = 166.2 [M+H]+ 15 . b) 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (3- methylpyridazinyl-butyl)-amide In analogy to the procedure described in Example 293, 6-(cyclopropylmethoxy)(3,3- difluoroazetidinyl)picolinic acid (Example 69 b) and 3-methyl(pyridazinyl)butan1-amine were condensed to the title product. MS (EI): m/e = 432.4 [M+H]+ 20 .
Example 322 6-Cyclopropylmethoxy(3-oxo-azetidinyl)-pyridinecarboxylic acid [1-methyl1-(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide O N N F F O HN N N a) 5-Bromocyclopropylmethoxy-pyridinecarboxylic acid [1-methyl(5-methyl- [1,2,4]oxadiazolyl)-ethyl]-amide The title compound was synthesized in analogy to Example 1, using 5-bromo cyclopropylmethoxy-pyridinecarboxylic acid (Example 9d) and α,α,5-trimethyl-1,2,4- oxadiazolemethanamine (Example 33d) as starting materials; MS (EI) 455.1 (M+H)+ . b) 6-Cyclopropylmethoxy(3-hydroxy-azetidinyl)-pyridinecarboxylic acid [1- methyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide -Bromocyclopropylmethoxy-pyridinecarboxylic acid [1-methyl(5-methyl- [1,2,4]oxadiazolyl)-ethyl]-amide (150 mg, 380 µmol) was dissolved in toluene (6.0 mL) to give a colorless solution. This solution was degassed under an Argon stream for 5 minutes. Cesium carbonate (371 mg, 1.14 mmol), Pd2(dba)3CHCl3 (39.3 mg, 38.0 µmol), [rac]-BINAP (47.3 mg, 75.9 µmol) and 3-azetidinol hydrochloride (1:1) (CAN 18621 6; 49.9 mg, 455 µmol) were added and the mixture was heated for 18 hours in a microwave oven to 100°C. After cooling to room temperature the mixture was diluted with ethyl acetate (5 mL) and water (3 mL), filtered through Celite® and the filter pad was washed with water (10 mL) and ethyl acetate (30mL). Phases were separated and the aqueous phase was extracted with ethyl acetate (20 mL). Organic phases were combined, dried with Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel,20 g, 0% to 100% ethyl acetate in heptane) to give the title compound (80 mg, 54%) as yellow solid; NMR complies. c) 6-Cyclopropylmethoxy(3-oxo-azetidinyl)-pyridinecarboxylic acid [1-methyl (5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide N N H O N O N O N O O N Br N H O N O N N N N N N H O O O HO To a solution of oxalyl chloride (14.4 mg, 9.94 µl, 114 µmol) in dichloromethane (1 mL) was added with stirring DMSO (17.7 mg, 16.1 µl, 227 µmol) in dichloromethane (0.5 mL) at -60°C. The mixture was stirred for 15 minutes at -60°C to -50°C. A solution of 6- cyclopropylmethoxy(3-hydroxy-azetidinyl)-pyridinecarboxylic acid [1-methyl (5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide (40 mg, 103 µmol) in dichloromethane (1 mL) was added at -50°C over a period of 2 minutes. Stirring continued for 1 hour at -60°C to -50°C. Afterwards triethylamine (52.2 mg, 72.0 µl, 516 µmol) was added and the reaction mixture was allowed to warm up slowly to room temperature and stirred for another 16 hours at room temperature. Water (10 mL) was added and the mixture was extracted with dichloromethane (3x10 mL). The organic phases were combined, dried with Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 5 g, 0% to 100% ethyl acetate in heptane) to give the title compound (34 mg, 85%) as off-white solid; LC-MS (UV peak area/ESI) 92%, 386.1820 (M+H)+ .
Example 323 5-Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [(+)cyclopropyl1-(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethyloxy-pyridinecarboxylic acid (Example 42a) and α-cyclopropyl-α,5- dimethyl-1,2,4-oxadiazolemethanamine (CAN 11555363) as starting materials. The product was isolated by chiral chromatography on Lux 5u Amylose-2 using heptane/15% 2-propanol as eluent. The (+)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 383.2090 (M+H)+ , ( )  49.3  D MeOH Example 324 5-Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [(-)cyclopropyl (5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide O N N H O N O N Chiral O N N H O N O N Chiral The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethyloxy-pyridinecarboxylic acid (Example 42a) and α-cyclopropyl-α,5- dimethyl-1,2,4-oxadiazolemethanamine (CAN 11555363) as starting materials. The product was isolated by chiral chromatography on Lux 5u Amylose-2 using heptane/15% 2-propanol as eluent. The (-)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 383.2082 (M+H)+ , ( )  44.7  D MeOH Example 325 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (3- methylpyridinyl-butyl)-amide In analogy to the procedure described in Example 293, 6-(cyclopropylmethoxy)(3,3- difluoroazetidinyl)picolinic acid (Example 69 b) and 3-methyl(pyridinyl)butan amine (CAN 9384592) were condensed to the title product. MS (EI): m/e = 431.5 [M+H]+ .
Example 326 -Cyclopropyl(4-fluoro-benzyl)-pyridinecarboxylic acid ((S)carbamoyl cyclopropyl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl(4- fluoro-benzyl)-pyridinecarboxylic acid (Example 155 g) and (S)amino cyclopropylpropanamide hydrochloride (Example 97 a) as starting materials. MS (EI): m/e = 382.1 [M+H]+ .
N N O O F F HN N O NH2 N H N O F Chiral Example 327 -Cyclopropyl(4-fluoro-benzyl)-pyridinecarboxylic acid [(S)cyclopropyl(5- methyl-[1,2,4]oxadiazolyl)-ethyl]-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl(4- fluoro-benzyl)-pyridinecarboxylic acid (Example 155 g) and (S)cyclopropyl5- methyl-[1,2,4]oxadiazolyl)-ethylamine (Example 38e) as starting materials. MS (EI): m/e = 421.1 [M+H]+ .
Example 328 5-Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [(S)-carbamoyl-(4- fluoro-phenyl)-methyl]-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethyloxy-pyridinecarboxylic acid (Example 42a) and (αS)-α-amino fluoro-benzeneacetamide (CAN 7850415) as starting materials; LC-MS (UV peak area/ESI) 100%, 384.1716 (M+H)+ .
Example 329 -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [(S)-carbamoyl-(4- chloro-phenyl)-methyl]-amide N H N O F N O N Chiral O N N H O O NH2 F Chiral The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethyloxy-pyridinecarboxylic acid (Example 42a) and (αS)-α-amino chloro-benzeneacetamide (CAN 4888360) as starting materials; LC-MS (UV peak area/ESI) 95%, 400.1434 (M+H)+ 5 .
Example 330 6-(2-Methyl-propanesulfonyl)-pyridinecarboxylic acid ((S)carbamoyl methyl-butyl)-amide a) 6-(Isobutylsulfonyl)picolinonitrile O S N O N A mixture of 6-(isobutylthio)picolinonitrile (109 mg, 567 µmol; CAN 13420948) and 3-chlorobenzoperoxoic acid (293 mg, 1.7 mmol) in dichloromethane (3 mL) was stirred at ambient temperature for 24 h, quenched with aqueous Na2S2O3 solution and diluted with dichloromethane. The organic layer was washed with sat. aqueous NaHCO3 solution, dried over Na2SO4 and concentrated in vacuo to give the title compound (126 mg, 99%) as white solid which was sufficiently pure to be used in the next step. MS (EI): m/e = 225.1 [M+H]+ . b) 6-(Isobutylsulfonyl)picolinic acid O N N H O O NH2 Cl Chiral N O N H O NH2 O S O Chiral N O OH O S O A suspension of 6-(isobutylsulfonyl)picolinonitrile (126 mg, 562 µmol) and powdered sodium hydroxide (89.9 mg, 2.25 mmol) in water (15 mL) was heated to 90°C for 24 h, poured into ice water / 0.1 N aqueous HCl solution (1:1) and extracted 3 times with EtOAc. The organic layers were washed with ice water / brine (1:1), dried over Na2SO4 and concentrated in vacuo to give the title compound (116 mg, 85%) as white solid which was sufficiently pure to be used in the next reaction step. MS (EI): m/e = 241.9 [M-H]- . c) 6-(2-Methyl-propanesulfonyl)-pyridinecarboxylic acid ((S)carbamoyl methyl-butyl)-amide The title compound was synthesized in analogy to Example 1, using 6- (isobutylsulfonyl)picolinic acid and (2S)aminomethyl-pentanamide (CAN 6874) as starting materials. MS (EI): m/e = 356.2 [M+H]+ .
Example 331 6-Isobutylsulfanyl-pyridinecarboxylic acid ((S)carbamoylmethyl-butyl)- amide The title compound was synthesized in analogy to Example 1, using 6- (isobutylthio)picolinic acid (CAN 12476079) and (2S)aminomethylpentanamide (CAN 6874) as starting materials. MS (EI): m/e = 324.2 [M+H]+ .
Example 332 -Cyclopropyl(4-fluoro-benzyl)-pyridinecarboxylic acid ((S)-2,2,2-trifluoro pyridinyl-ethyl)-amide N O N H O NH2 S Chiral The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl(4- fluoro-benzyl)-pyridinecarboxylic acid (Example 155 g) and (S)-2,2,2-trifluoro (pyridinyl)ethanamine hydrochloride (CAN 3361054) as starting materials. MS (EI): m/e = 430.3 [M+H]+ 5 .
Example 333 2-{[5-Cyclopropyl(4-fluoro-benzyl)-pyridinecarbonyl]-amino}ethyl-butyric acid a) Ethyl 2-(5-cyclopropyl(4-fluorobenzyl)picolinamido)ethylbutanoate N H O O N O F The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl(4- fluoro-benzyl)-pyridinecarboxylic acid (Example 155 g) and ethyl 2-amino ethylbutanoate hydrochloride (CAN 11352192) as starting materials. MS (EI): m/e = 413.1 [M+H]+ 15 . b) 2-{[5-Cyclopropyl(4-fluoro-benzyl)-pyridinecarbonyl]-amino}ethyl-butyric acid N H N O F F F F N Chiral N H OH O N O F In analogy to the procedure described in Example 252 b), ethyl 2-(5-cyclopropyl(4- fluorobenzyl)picolinamido)ethylbutanoate was treated with sodium hydroxide to give the title compound as white solid. MS: 383.3 [M-H]- .
Example 334 6-Cyclopropylmethoxy(3-oxo-pyrrolidinyl)-pyridinecarboxylic acid [1- methyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide a) 6-Cyclopropylmethoxy((S)hydroxy-pyrrolidinyl)-pyridinecarboxylic acid [1-methyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide The title compound was synthesized in analogy to Example 322b, using 5-bromo cyclopropylmethoxy-pyridinecarboxylic acid [1-methyl(5-methyl-[1,2,4]oxadiazol3-yl)-ethyl]-amide (Example 322a) and (3S)[[(1,1-dimethylethyl)dimethylsilyl]oxy]- pyrrolidine (CAN 2071138) as starting materials. The protecting group was removed with tetrabutylammonium fluoride in THF; LC-MS (UV peak area/ESI) 100%, 402.2134 (M+H)+ . c) 6-Cyclopropylmethoxy(3-oxo-pyrrolidinyl)-pyridinecarboxylic acid [1-methyl1-(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide The title compound was synthesized in analogy to Example 322c, using 6- cyclopropylmethoxy((S)hydroxy-pyrrolidinyl)-pyridinecarboxylic acid [1- methyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide (Example 334a) as starting material; LC-MS (UV peak area/ESI) 100%, 400.1987 (M+H)+ .
Example 335 O N N H O N O N N O O N N H O N O N N HO Chiral 6-(2-Methyl-propanesulfonyl)-pyridinecarboxylic acid [(S)methyl(5- methyl-[1,2,4]oxadiazolyl)-butyl]-amide The title compound was synthesized in analogy to Example 1, using 6- (isobutylsulfonyl)picolinic acid (Example 330 b) and (S)methyl-α-(2-methylpropyl)- 1,2,4-oxadiazolemethanamine hydrochloride (which was prepared from (2S)[(tertbutoxycarbonyl)amino]methylpentanoic acid (CAN 131396) in analogy to the procedures described in Example 38 a to e) as starting materials. MS (EI): m/e = 395.2 [M+H]+ .
Example 336 (S){[5-Cyclopropyl(4-fluoro-benzyl)-pyridinecarbonyl]-amino}methylpentanoic acid a) (S)-Ethyl 2-(5-cyclopropyl(4-fluorobenzyl)picolinamido)methylpentanoate The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl(4- fluoro-benzyl)-pyridinecarboxylic acid (Example 155 g) and (S)-ethyl 2-amino methylpentanoate hydrochloride (CAN 27430) as starting materials. MS (EI): m/e = 413.2 [M+H]+ . b) (S){[5-Cyclopropyl(4-fluoro-benzyl)-pyridinecarbonyl]-amino}methyl20 pentanoic acid In analogy to the procedure described in Example 5 c), (S)-ethyl 2-(5-cyclopropyl(4- fluorobenzyl)picolinamido)methylpentanoate was saponified with lithium hydroxide to obtain the title compound. MS (EI): m/e = 385.2 [M+H]+ .
Example 337 N O S O O N H N O N Chiral OH O N O F N H Chiral 2-{[5-Cyclopropyl(tetrahydro-pyranylmethoxy)-pyridinecarbonyl]-amino} ethyl-butyric acid a) Ethyl 2-(5-cyclopropyl((tetrahydro-2H-pyranyl)methoxy)picolinamido) ethylbutanoate N H O O N O O O The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl (tetrahydro-pyranylmethoxy)-pyridinecarboxylic acid (which can e.g. be prepared in a similar manner than 5-cyclopropyl(tetrahydro-furanylmethoxy)-pyridine carboxylic acid (Example 166 b)) and ethyl 2-aminoethylbutanoate hydrochloride (CAN 11352192) as starting materials. MS (EI): m/e = 419.3 [M+H]+ . b) 2-{[5-Cyclopropyl(tetrahydro-pyranylmethoxy)-pyridinecarbonyl]-amino} ethyl-butyric acid In analogy to the procedure described in Example 252 b), ethyl 2-(5-cyclopropyl ((tetrahydro-2H-pyranyl)methoxy)picolinamido)ethylbutanoate was treated with sodium hydroxide to give the title compound as white solid. MS: 389.3 [M-H]- .
Example 338 -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [1-methyl(4- methyloxo-4,5-dihydro-[1,2,4]oxadiazolyl)-ethyl]-amide N H OH O N O O O O N N H O N O N O a) [1-Methyl(5-oxo-4,5-dihydro-[1,2,4]oxadiazolyl)-ethyl]-carbamic acid tert-butyl ester To a colorless solution of [1-(N-hydroxycarbamidoyl)methyl-ethyl]-carbamic acid tert5 butyl ester (CAN 12514302, 1.0 g, 4.6 mmol) in DMF (7.5 mL) was added pyridine (455 mg, 465 µl, 5.75 mmol). The mixture was cooled to 0°C and methyl chloroformate (478 mg, 392 µl, 5.06 mmol) was added in one portion. The mixture was allowed to warm up and stirred at room temperature for another 90 minutes. Solvents were removed in vacuo and the residue was partitioned between ethyl acetate (30 mL) and water (15 mL).
The aqueous phase was extracted with ethyl acetate (30 mL), organic phases were combined, dried with MgSO4 and concentrated in vacuo. The residue (1.2 g white solid) was combined with pyridine (5 mL) and stirred for 3 hours at reflux temperature. The pyridine was removed in vacuo to give the title compound (1.0 g, 89%) as off-white solid; LC-MS (ESI) 242.1151 (M-H)- . b) [1-Methyl(4-methyloxo-4,5-dihydro-[1,2,4]oxadiazolyl)-ethyl]-carbamic acid tert-butyl ester To a colorless solution of [1-methyl(5-oxo-4,5-dihydro-[1,2,4]oxadiazolyl)-ethyl]- carbamic acid tert-butyl ester (1.5 g, 6.17 mmol) in THF (30.0 mL) was added methanol (296 mg, 374 µl, 9.25 mmol) and triphenylphosphine (1.94 g, 7.4 mmol). The mixture was cooled to 0-5°C and diisopropyl azodicarboxylate (1.5 g, 1.46 ml, 7.4 mmol) was added slowly over a period of 20 minutes at max: 5°C. The mixture was stirred for another 30 minutes at 0-5°C and for 16 hours at room temperature. Solvents were removed in vacuo and the residue was purified by flash chromatography (silica gel, 70g, 0% to 100% ethyl acetate in heptane) to give the title compound (1.4 g, 89%) as white solid; GC-MS (EI) 98%, 257.0 (M)+ . c) 3-(1-Aminomethyl-ethyl)methyl-4H-[1,2,4]oxadiazolone hydrochloride (1:1) N H O O N O N H O N H O O N O N O H2N N O N O ClH To a solution of [1-methyl(4-methyloxo-4,5-dihydro-[1,2,4]oxadiazolyl)-ethyl]- carbamic acid tert-butyl ester (1.45 g, 5.64 mmol) in ethanol (15 mL) was added 4M-HCl in dioxane (5.64 mL, 22.5 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The solution was concentrated in vacuo to a volume of 5 mL. With stirring diethyl ether (15 mL) was added drop by drop over a period of 30 minutes and stirring was continued for another 30 minutes. The precipitate was isolated by filtration, washed with diethyl ether (3x1 mL) and dried in vacuo, to give the title compound (1.0 g, 95%) as white solid; GC-MS (EI) 157.0 (M)+ . d) 5-Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [1-methyl(4- methyloxo-4,5-dihydro-[1,2,4]oxadiazolyl)-ethyl]-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethyloxy-pyridinecarboxylic acid (Example 42a) and 3-(1-amino methyl-ethyl)methyl-4H-[1,2,4]oxadiazolone hydrochloride (1:1) (Example 338c) as starting materials; LC-MS (UV peak area/ESI) 99%, 373.1870 (M+H)+ .
Example 339 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (3- methylpyrimidinyl-butyl)-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example 69 b) and 3-methyl(pyrimidinyl)butanamine (CAN 11785006) as starting materials, MS (EI): m/e = 432.4 [M+H]+ .
Example 340 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid [1- cyclopropyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide N N H O O N F F N N The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example 69 b) and α-cyclopropyl-α,5-dimethyl-1,2,4-oxadiazolemethanamine (CAN 1155536- 64-3) as starting materials. MS (EI): m/e = 434.5 [M+H]+ 5 .
Example 341 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid [2- cyclopropylmethyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide a) 2-Aminocyclopropylmethyl-propionitrile H2N N To a solution of 1-cyclopropyl-propanone (1.0 g, 10.2 mmol; CAN 41602) and aqueous ammonia (25% in water, 15 mL) in EtOH (10 mL) was added ammonium chloride (1.63 g, 30.61 mmol). The reaction mixture was stirred at ambient temperature for 1 hour. To this was added potassium cyanide (900 mg, 15.3 mmol) portion wise and the reaction mixture was stirred at ambient temperature for 12 h. Ice water (50 mL) was added and the mixture was extracted with ethyl acetate (3x50 mL). The organic phases were washed with ice water, combined, dried with Na2SO4 and concentrated in vacuo to give the title compound (0.8 g, 63%) as yellow oil. 1H-NMR (DMSO, 400 MHz): 0.14-0.16 (d, 6.4Hz, 2H); 0.45-0.49 (d, 6.4Hz, 2H); 0.78-0.85 (m, 1H); 1.39 (s, 3H); 1.46-1.51 (m, 1H), 1.53-1.63 (m, 1H); 2.52 (br s, 2H).
N H N O N N O O N F F N H N O N N O O N F F b) (Cyano-cyclopropylmethyl-methyl-methyl)-carbamic acid tert-butyl ester N H N O O To a solution of 2-aminocyclopropylmethyl-propionitrile (0.8 g, 6.45 mmol) and diisopropyl ethyl amine (3.36 mL, 19.8 mmol) in dichloromethane (20 mL) was added di5 tert-butyl dicarbonate (2.38 mL, 9.76 mmol). The reaction mixture was stirred at ambient temperature for 12 hours. The organic phase was washed with ice water, brine, dried with Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (silica gel, 100 g, 1:9 ethyl acetate / n-hexane) to give the title compound (0.8 g, 66%) as light yellow liquid. 1H-NMR (DMSO, 400 MHz): 0.12-0.21 (m, 2H); 0.46-0.48 (m, 2H); 0.72- 0.77 (m, 1H); 1.44 (s, 9H); 1.55 (s, 3H); 1.66-1.68 (dd, 13.8Hz & 7.2 Hz, 1H); 1.82-1.87 (dd, 13.8Hz & 7.2 Hz, 1H); 7.47 (br s, 1H). c) [2-Cyclopropyl(N-hydroxycarbamimidoyl)methyl-ethyl]-carbamic acid tert-butyl ester N H NH O O NH HO Sodium bi carbonate (0.204 g, 2.9 mmol) was dissolved in EtOH (10 mL) and water (10 mL). Hydroxylamine hydrochloride (0.204 g, 2.9 mmol) was added at 25°C. A solution of (cyano-cyclopropylmethyl-methyl-methyl)-carbamic acid tert-butyl ester (3) (0.7g, 2.67 mmol) in ethanol (5 mL) was added thereto and the resulting reaction mixture was heated at 80°C for 12 hours. After evaporation of solvents, the residue was dissolved in ethyl acetate (30 mL) and then filtered. The filtrate was concentrated in vacuo. The residue was purified by chromatography (Combi-Flash, 40 g, 5:95 ethyl acetate / n-hexane) to give the title compound (0.45 g, 65%) as white solid; LC-MS (ELSD peak area, ESI) 100%, 258.2 [M+H]+ . d) [2-Cyclopropylmethyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-carbamic acid tert25 butyl ester N H N O N O O To a solution of [2-cyclopropyl(N-hydroxycarbamimidoyl)methyl-ethyl]-carbamic acid tert-butyl ester (300 mg, 1.16 mmol) in acetic anhydride (10 mL) was heated to 100°C and stirred for 5 hours. After evaporation of solvents, the residue was dissolved in H2O (20 mL) and basified by aqueous NaHCO3 solution (pH~7-8). The aqueous layer was extracted with ethyl acetate (3x50 mL).The combined organic layers were washed with water (20 mL), brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, 100-200 mesh, 20 g, eluting with 20% ethyl acetate in petroleum ether) to give the title compound (0.15 g; 46%) as colorless sticky solid. 1 10 H-NMR (DMSO, 400 MHz): 0.012-0.014 (m, 2H); 0.31-0.38 (m, 2H); 0.56- 0.58 (m, 1H); 1.32 (s, 9H); 1.55 (s, 3H); 1.69-1.98 (brs, 2H); 2.56 (s, 3H), 7.19 (br s, 1H). e) 2-Cyclopropylmethyl(5-methyl-[1,2,4]oxadiazolyl)-ethylamine hydrochloride ClH H2N N O N To a solution of [2-cyclopropylmethyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]- carbamic acid tert-butyl ester (0.4 g, 1.43 mmol) in methanol (10 mL) was added hydrochloric acid (4N in dioxane, 3.5 mL, 14.8 mmol) and the reaction mixture was stirred at ambient temperature for 4 hours. The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated to give the title product (0.25 g, 81%) as a light yellow solid. 1H-NMR (DMSO, 400 MHz): 0.010-0.02 (m, 2H); 0.38-0.42 (m, 2H); 0.61-0.63 (m, 1H); 1.67 (s, 3H); 1.78-1.91 (m, 2H); 2.66 (s, 3H); 8.89 (br s, 3H). f) 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid [2- cyclopropylmethyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example 69 b) and 2-cyclopropylmethyl(5-methyl-[1,2,4]oxadiazolyl)-ethylamine hydrochloride as starting materials. MS (EI): m/e = 448.5 [M+H]+ .
Example 342 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid ((S)- 1-carbamoylmethylsulfanyl-propyl)-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example 69 b) and (2S)amino(methylthio)-butanamide, monohydrochloride (CAN 14510 1) as starting materials.MS (EI): m/e = 415.16 [M+H]+ .
Example 343 6-(3-Chlorofluoro-phenyl)-pyridinecarboxylic acid [(S)cyclopropyl(5- methyl-[1,2,4]oxadiazolyl)-ethyl]-amide a) 6-Bromo-pyridinecarboxylic acid [(S)cyclopropyl(5-methyl-[1,2,4]oxadiazol3-yl)-ethyl]-amide The title compound can be prepared in analogy to Example 1, using 6-bromo pyridinecarboxylic acid (CAN 211904) and (S)cyclopropyl(5-methyl- [1,2,4]oxadiazolyl)-ethylamine (Example 38e) as starting materials, MS (EI) 353.0 (M+H)+ . b) 6-(3-Chlorofluoro-phenyl)-pyridinecarboxylic acid [(S)cyclopropyl(5- methyl-[1,2,4]oxadiazolyl)-ethyl]-amide N O O N F F N H O NH2 S Chiral N N H O N O N Cl F Chiral N N H O Br N O N The title compound can be prepared in analogy to Example 177b, using 6-bromo-pyridine2-carboxylic acid [(S)cyclopropyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide (Example 343a) and B-(3-chlorofluorophenyl)-boronic acid (CAN 1444329) as starting materials, LC-MS (UV peak area/ESI) 100%, 401.1179 (M+H)+ .
Example 344 6-Cyclopropylmethoxypyrrolidinyl-pyridinecarboxylic acid {(S)methyl [(7-nitro-benzo[1,2,5]oxadiazolylamino)-methyl]-butyl}-amide a) 6-Cyclopropylmethoxypyrrolidinyl-pyridinecarboxylic acid ((S) azidomethylmethyl-butyl)-amide To a colorless solution of 6-cyclopropylmethoxypyrrolidinyl-pyridinecarboxylic acid ((S)hydroxymethylmethyl-butyl)-amide (Example 14b; 231 mg, 639 µmol) in DMF (25.6 mL) and CCl4 (6.4 mL) was added sodium azide (49.9 mg, 767 µmol) and triphenylphosphine (352 mg, 1.34 mmol). The resulting reaction mixture was stirred at 90°C for 4 hours. After cooling to room temperature the solvent was removed in vacuo.
The residue was partitioned between water and ethyl acetate; the organic phases were washed with brine, combined, dried with Na2SO4, filtered and concentrated in vacuo. The residue, a brown waxy solid, was purified by flash chromatography (silica gel, 50 g, 0% to 60% ethyl acetate in heptane) to give the title compound (110 mg, 45%) as white solid; MS (ESI) 387.3 (M+H)+. b) 6-Cyclopropylmethoxypyrrolidinyl-pyridinecarboxylic acid ((S) aminomethylmethyl-butyl)-amide N O N H N H N N O N + O O N O Chiral N O N H N N O Chiral N + N 6-Cyclopropylmethoxypyrrolidinyl-pyridinecarboxylic acid ((S)azidomethyl methyl-butyl)-amide (107 mg, 277 µmol) was combined with 2-propanol (725 µl) to give an off-white suspension. To this suspension was added triethylamine (56.0 mg, 77.2 µl, 554 µmol), 1,3-propanedithiol (3.00 mg, 2.8 µl, 27.7 µmol) and sodium borohydride (15.7 mg, 415 µmol). The resulting reaction mixture was stirred at room temperature for 20 hours. Volatiles were removed in vacuo and the residue was stirred with 10% citric acid solution (5 mL) and a mixture of ethyl acetate/heptane (5 mL, 1:1). The aqueous layer was brought with 2N NaOH to pH=12 and extracted twice with ethyl acetate. The organic phases were combined, dried with Na2SO4, and concentrated in vacuo to give the title compound (32 mg, 32%) as colorless, viscous oil that was used without further purification in the next step; MS (ESI) 361.3 (M+H)+ . c) 6-Cyclopropylmethoxypyrrolidinyl-pyridinecarboxylic acid {(S)methyl [(7-nitro-benzo[1,2,5]oxadiazolylamino)-methyl]-butyl}-amide To a colorless solution of 6-cyclopropylmethoxypyrrolidinyl-pyridinecarboxylic acid ((S)aminomethylmethyl-butyl)-amide (30 mg, 83.2 µmol) in THF (555 µl) was added 7-nitro-2,1,3-benzoxadiazolamine (CAN 101994, 19.9 mg, 100 µmol). The reaction mixture was stirred at room temperature for 30 minutes, followed by stirring at reflux temperature for 2 hours. After cooling to room temperature the mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL). The organic phase was washed with brine; and the aqueous phases were extracted with ethyl acetate. The organic phases were combined, dried with Na2SO4, and concentrated in vacuo. The black, solid residue was purified by flash chromatography (basic silica gel, 10 g, 0% to 100% ethyl acetate in a 1:1 mixture of dichloromethane and heptane) to give the title compound (25 mg, 57%) as brown solid; LC-MS (UV peak area/ESI) 100%, 524.2609 (M+H)+ 25 .
Example 345 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid ((S)- 1-carbamoylmethanesulfonyl-propyl)-amide N O N H NH2 N O Chiral (S)-N-(1-amino(methylthio)oxobutanyl)(cyclopropylmethoxy)(3,3- difluoroazetidinyl)picolinamide (10 mg, 24.1 µmol; Example 342) was dissolved in dichloromethane (200 µL). The yellow solution was cooled to 0°C. 3- Chlorobenzenecarboperoxoic acid (8.33 mg, 48.3 µmol) was added. The reaction mixture was stirred for 1 d at ambient temp. poured onto icewater/sat. NaHCO3-solution (20 mL), and extracted with dichloromethane (30 mL). The extract was washed with icewater/brine (20 mL). The aqueous layer was back extracted with dichloromethane (30 mL). The organic layers were combined, dried over Na2SO4 and concentrated in vacuo to give a yellow solid which was purified by preparative tlc (silica gel, EtOAc, elution with dichloromethane/EtOAc 1:1) to give the title compound (11 mg, 37%) as a white oil. MS (EI): m/e = 447.4 [M+H]+ .
Example 346 -Cyclopropylisobutylsulfanyl-pyridinecarboxylic acid ((S)carbamoyl methyl-butyl)-amide a) 5-Bromo(isobutylthio)picolinic acid -Bromochloropicolinic acid (2 g, 8.46 mmol; CAN 9599589), 2-methylpropane thiol (915 mg, 1.1 mL, 10.2 mmol) and cesium carbonate (6.89 g, 21.1 mmol) were suspended in DMSO (100 mL). The reaction mixture was heated to 150°C and stirred for 1 d and was poured onto icewater/1N HCl (100 mL). The aqueous layer was extracted with EtOAc (2x250 mL). The combined extracts were washed with icewater/brine (100 mL), N O O N F F N H O NH2 S O O Chiral O NH2 N H S N O Chiral S N OH O Br dried over Na2SO4 and concentrated in vacuo to give the title compound (2.49 g, 51%) as an orange solid which was used in the next step without further purification. MS (EI): m/e = 288.4 [M-H]- . b) Methyl 5-bromo(isobutylthio)picolinate -Bromo(isobutylthio)picolinic acid (500 mg, 1.72 mmol) was dissolved in methanol (5 mL) to give a yellow solution. Sulfuric acid (169 mg, 92.3 µL, 1.72 mmol) was added. The reaction mixture was heated to 80°C and stirred for 1 d. The reaction mixture was cooled to 0°C and poured onto icewater/brine (25 mL). The aqueous layer was extracted with EtOAc (2x40 mL) and washed with icewater/brine (20 mL). The organic layers were combined, dried over Na2SO4 and concentrated in vacuo to give crude title compound as a yellow oil. The oil was purified by flash chromatography (silica gel, 5 g, 0% to 15% EtOAc in heptane) to give the title product (205 mg, 39%) as a colorless oil. MS (EI): m/e = 306.3 [M+H]+ . c) 5-Cyclopropyl(isobutylthio)picolinic acid OH S N O The title compound was prepared in analogy to the procedure described in Example 5 a), using methyl 5-bromo(isobutylthio)picolinate as starting material. MS (EI): m/e = 252.4 [M+H]+ . d) 5-Cyclopropylisobutylsulfanyl-pyridinecarboxylic acid ((S)carbamoyl methyl-butyl)-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl (isobutylthio)picolinic acid and (2S)aminomethyl-pentanamide (CAN 6874) as starting materials. MS (EI): m/e = 364.5 [M+H]+ .
Example 347 S N O O Br 6-(3-Fluoro-phenyl)-pyridinecarboxylic acid [(S)cyclopropyl(5-methyl- [1,2,4]oxadiazolyl)-ethyl]-amide The title compound can be prepared in analogy to Example 177b, using 6-bromo-pyridine5 2-carboxylic acid [(S)cyclopropyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide (Example 343a) and B-(3-fluorophenyl)-boronic acid (CAN 7684) as starting materials, LC-MS (UV peak area/ESI) 99%, 367.1571 (M+H)+ .
Example 348 6-(4-Fluorotrifluoromethyl-phenyl)-pyridinecarboxylic acid [(S)cyclopropyl10 1-(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide The title compound can be prepared in analogy to Example 177b, using 6-bromo-pyridine2-carboxylic acid [(S)cyclopropyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide (Example 343a) and B-(4-fluoro(trifluoromethyl)-phenyl)-boronic acid (CAN 182344- 23-6) as starting materials, LC-MS (UV peak area/ESI) 100%, 435.1442 (M+H)+ 15 .
Example 349 -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid (3-methanesulfonyl1,1-dimethyl-propyl)-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethyloxy-pyridinecarboxylic acid (Example 42a) and 2-methyl (methylsulfonyl)butanamine (CAN 12505152) as starting materials; LC-MS (UV peak area/ESI) 95%, 381.1843 (M+H)+ .
N N H O N O N F Chiral N N H O N O N F F F F Chiral O N N H O S O O Example 350 -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [1-methyl(5- methyl-thiazolyl)-ethyl]-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethyloxy-pyridinecarboxylic acid (Example 42a) and α,α,5-trimethyl thiazolemethanamine (CAN 11555308) as starting materials; LC-MS (UV peak area/ESI) 94%, 372.1743 (M+H)+ .
Example 351 5-Cyclopropyl(2-methyl-propanesulfonyl)-pyridinecarboxylic acid ((S) carbamoylmethyl-butyl)-amide a) Methyl 5-bromo(isobutylsulfonyl)picolinate Methyl 5-bromo(isobutylthio)picolinate (30 mg, 98.6 µmol, Example 346 b) was dissolved in dichloromethane (1 mL). The solution was cooled to 0°C. 3- Chlorobenzoperoxoic acid (34.0 mg, 197 µmol) was added. The reaction mixture was stirred for 1 d at ambient temp., poured onto icewater (20 mL) and extracted with dichloromethane (2 x 30 mL). The extract was washed with a 10% aqueous Na2O3S2- solution (15 mL). The aqueous layer was back-extracted with dichloromethane (30 mL).
The combined organic layers were washed with an aqueous 10% sodium hydrogen carbonate solution, dried over Na2SO4 and concentrated in vacuo to give the crude product as a white solid. Filtration through silica gel (3 g, heptane/EtOAc 1:1) provided the title compound (19 mg, 70%) as a white oil. MS (EI): m/e = 338.3 [M+H]+ .
O N N H O N S O NH2 N H S N O O O Chiral S N O O Br O O b) 5-Cyclopropyl(isobutylsulfonyl)picolinic acid The title compound was prepared in analogy to the procedure described in Example 5 a), using methyl 5-bromo(isobutylsulfonyl)picolinate as starting material. MS (EI): m/e = 284.3 [M+H]+ 5 . c) 5-Cyclopropyl(2-methyl-propanesulfonyl)-pyridinecarboxylic acid ((S) carbamoylmethyl-butyl)-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl (isobutylsulfonyl)picolinic acid and (S)aminomethylpentanamide hydrochloride (CAN 6874) as starting materials. MS (EI): m/e = 395.5 [M+H]+ 10 .
Example 352 -Cyclopropyl(2-methyl-propanesulfonyl)-pyridinecarboxylic acid [(S) cyclopropyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide N H N O N S N O O O The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl(2- methyl-propanesulfonyl)-pyridinecarboxylic acid (Example 351 b) and (S) cyclopropyl5-methyl-[1,2,4]oxadiazolyl)-ethylamine (Example 38e) as starting materials. MS (EI): m/e = 433.2 [M+H]+ .
Example 353 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid [1- methyl(5-methyl-thiazolyl)-ethyl]-amide S N OH O O O The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethyloxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example 69b) and α,α,5-trimethylthiazolemethanamine (CAN 11555308) as starting materials; LC-MS (UV peak area/ESI) 100%, 422.4588 (M+H)+ 5 .
Example 354 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid ((R)- 3-methylpyridazinyl-butyl)-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example 69 b) and 3-methyl(pyridazinyl)butanamine (Example 321 a) as starting materials.
The product was isolated by chiral chromatography on Reprosil Chiral NR using a mixture of heptane, ethanol and 2-propanol as eluent. The (+)-enantiomer was isolated. MS (EI): m/e = 432.5 [M+H]+ 15 .
Example 355 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid ((S)- 3-methylpyridazinyl-butyl)-amide O N N H O N N S F F N H O N O N F F N N Chiral N H O N O N F F N N Chiral The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example 69 b) and 3-methyl(pyridazinyl)butanamine (Example 321 a) as starting materials.
The product was isolated by chiral chromatography on Reprosil Chiral NR using a mixture of heptane, ethanol and 2-propanol as eluent. The (-)-enantiomer was isolated. MS (EI): m/e = 432.5 [M+H]+ .
Example 356 -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [1-ethyl(2- hydroxy-ethylcarbamoyl)-propyl]-amide The title compound was synthesized in analogy to Example 1, using 2-(5-cyclopropyl (cyclopropylmethoxy)picolinamido)ethylbutanoic acid (Example 274 a) and 2- (trimethylsilyloxy)ethanamine (CAN 58042)-as starting materials. MS (EI): m/e = 390.5 [M+H]+ .
Example 357 -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [(+)cyclopropyl1-methyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide a) 2-Aminocyclopropylmethyl-propionitrile To a solution of 1-cyclopropyl-propanone (CAN 41602; 1.0 g, 10.2 mmol) and aqueous ammonia (25% in water, 10 mL) in ethanol (10 mL) was added ammonium N H O O N O N H OH O N N H O N O N Chiral NH2 N chloride ( 1.63 g, 30.6 mmol). The reaction mixture was stirred at ambient temperature for 1 hour. To this was added potassium cyanide (1 g, 15.30 mmol) portion wise, and the reaction mixture was stirred at ambient temperature for 12 h. Ice water (50 mL) was added and extracted with ethyl acetate (3x50 mL). The organic phases were washed with ice5 water, combined, dried with Na2SO4 and concentrated in vacuo to give the title compound (0.8 g, 62.99%) as yellow oil; NMR (400 MHz, DMSO)  = 2.52 (bds, 2H); 1.6-1.5 (m, 1H); 1.49-1.4 (m, 1H); 1.39 (S, 3H); 0.85-0.75 (m, 1H); 0.49-0.44 (m, 2H); 0.16-0.14 (m, 2H). b) (1-Cyanocyclopropylmethyl-ethyl)-carbamic acid tert-butyl ester To a solution of 2-aminocyclopropylmethyl-propionitrile (1.0 g, 6.4 mmol) and triethyl amine (3.36 mL, 19.8 mmol) in dichloromethane (20 mL) was added di-tert-butyl dicarbonate (CAN 244245, 2.38 mL, 9.47 mmol). The reaction mixture was stirred at ambient temperature for 12 hours. The organic phase was washed with ice water, brine, dried with Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (silica gel, 50 g, 1:9 ethyl acetate / n-hexane) to give the title compound (1.2 g, 66%) as light yellow liquid; LC-MS (UV peak area, ESI) 83%, 225.14 (M+H). c) [2-Cyclopropyl(N-hydroxycarbamimidoyl)methyl-ethyl]-carbamic acid tert-butyl ester Sodium bicarbonate (247.52 mg, 2.94 mmol) was dissolved in water (2 mL) and hydroxylamine hydrochloride (204.747 mg, 2.94 mmol) was added. A solution of (1- cyanocyclopropylmethyl-ethyl)-carbamic acid tert-butyl ester (600 mg, 2.69 mmol) in ethanol (10 mL) was added thereto and the resulting reaction mixture was heated at 80°C for 12 hours. After evaporation of solvents, the residue was dissolved with ethyl NH N O O NH NH O O HN OH acetate (20 mL) and then filtered. The filtrate was concentrated in vacuo. The residue was purified by chromatography (silica gel, 25 g, 3:7 ethyl acetate / n-hexane) to give the title compound (450 mg, 66%) as white solid; LC-MS (UV peak area, ESI) 100%, 258.4 (M+H). d) 2-Cyclopropylmethyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-carbamic acid tertbutyl ester A solution of [2-cyclopropyl(N-hydroxycarbamimidoyl)methyl-ethyl]-carbamic acid tert-butyl ester (300 mg, 1.16 mmol) in acetic anhydride (10 mL) was heated to 120°C and stirred for 4 hours. After evaporation of solvents, the residue was purified by column chromatography (silica gel, 20 g, eluting with 20% ethyl acetate in petroleum ether) to give the title compound (0.2 g; 61%) as colorless sticky liquid; LC-MS (UV peak area, ESI) 90%, 282.2 (M+H). e) 2-Cyclopropylmethyl(5-methyl-[1,2,4]oxadiazolyl)-ethylamine To a solution of 2-cyclopropylmethyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]- carbamic acid tert-butyl ester (0.2 g, 0.7 mmol) in methanol (5 mL) was added hydrochloric acid (4N in dioxane, 0.87 mL, 3.5 mmol) and the reaction mixture was stirred at ambient temperature for 4 hours. Then water (20 mL) was added. The water phase was washed with ethyl acetate (2 x 20 mL) and adjusted with 2 M sodium hydroxide solution to pH = 9~10. It was then extracted with ethyl acetate (2 x 20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated to give crude product as a white solid (0.1 g, 78%); LC-MS (UV peak area, ESI) 80%, 182.0 (M+H). f) 5-Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [(+)cyclopropyl methyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethyloxy-pyridinecarboxylic acid (Example 42a) and 2-cyclopropyl N H O O N O N H2N N O N methyl(5-methyl-[1,2,4]oxadiazolyl)-ethylamine (Example 357e) as starting materials. The product was isolated by chiral chromatography on Reprosil Chiral NR using heptane/10% 2-propanol as eluent. The (+)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 397.2230 (M+H)+ , ( )  25.7  D MeOH .
Example 358 -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [(-)cyclopropyl methyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethyloxy-pyridinecarboxylic acid (Example 42a) and 2-cyclopropyl methyl(5-methyl-[1,2,4]oxadiazolyl)-ethylamine (Example 357e) as starting materials. The product was isolated by chiral chromatography on Reprosil Chiral NR using heptane/10% 2-propanol as eluent. The (-)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 397.2244 (M+H)+ , ( )  22.3  D MeOH .
Example 359 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid tertbutylamide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example 69 b) and tert-butylamine (CAN 759) as starting materials. MS (EI): m/e = 340.5 [M+H]+ .
Example 360 O N N H O N O N Chiral O N O N N H F F 2-{[5-Cyclopropyl(2-methyl-propanesulfonyl)-pyridinecarbonyl]-amino} ethyl-butyric acid ethyl ester The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl (isobutylsulfonyl)picolinic acid (Example 351 b) and 2-aminoethyl-butanoic acid ethyl ester (CAN 1896317) as starting materials. MS (EI): m/e = 425.4 [M+H]+ .
Example 361 -Cyclopropyl(2-methyl-propanesulfonyl)-pyridinecarboxylic acid ((S)-3,3- dimethylmethylcarbamoyl-butyl)-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl (isobutylsulfonyl)picolinic acid (Example 351 b) and (2S)amino-N,4,4-trimethylpentanamide (CAN 11601615) as starting materials. MS (EI): m/e = 424.6 [M+H]+ .
Example 362 5-Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid ((S)oxotetrahydro-furanyl)-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethyloxy-pyridinecarboxylic acid (Example 42a) and (3S) aminodihydro-2(3H)-furanone (CAN 21856) as starting materials; LC-MS (UV peak area/ESI) 100%, 317.1500 (M+H)+ .
Example 363 N H O O S N O O O O NH S N N H O O O Chiral N N H O O O O Chiral N'-(5-Cyclopropylcyclopropylmethoxy-pyridinecarbonyl)-N-cyclopropylmethylhydrazinecarboxylic acid tert-butyl ester The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethyloxy-pyridinecarboxylic acid (Example 42a) and 1- (cyclopropylmethyl)-hydrazinecarboxylic acid 1,1-dimethylethyl ester (CAN 1314973 1) as starting materials; LC-MS (UV peak area/ESI) 100%, 402.2375 (M+H)+ .
Example 364 -Cyclopropyl(2-methyl-propanesulfonyl)-pyridinecarboxylic acid ((S)-2,2- dimethylmethylcarbamoyl-propyl)-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl (isobutylsulfonyl)picolinic acid (Example 351 b) and (2S)amino-N,3,3-trimethylbutanamide (CAN 892260) as starting materials. MS (EI): m/e = 410.6 [M+H]+ .
Example 365 -Cyclopropyl(2-methyl-propanesulfonyl)-pyridinecarboxylic acid ((S)-2,2,2- trifluoropyridinyl-ethyl)-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl (isobutylsulfonyl)picolinic acid (Example 351 b) and (S)-2,2,2-trifluoro(pyridin N N H O O N O O S N N H O O O O N H Chiral S N N H O O O F F F N Chiral yl)ethanamine hydrochloride (CAN 3361055) as starting materials. MS (EI): m/e = 442.4 [M+H]+ .
Example 366 (S)[(5-Cyclopropylcyclopropylmethoxy-pyridinecarbonyl)-amino]methyl5 pentanoic acid tert-butyl ester The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethyloxy-pyridinecarboxylic acid (Example 42a) and L-leucine 1,1- dimethylethyl ester hydrochloride (1:1) (CAN 27489) as starting materials; LC-MS (UV peak area/ESI) 98.7%, 403.2599 (M+H)+ 10 .
Example 367 -Cyclopropyl(2-methyl-propanesulfonyl)-pyridinecarboxylic acid (1-ethyl methylcarbamoyl-propyl)-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl (isobutylsulfonyl)picolinic acid (Example 351 b) and 2-aminoethyl-N-methylbutyramide (Example 70 b) as starting materials. MS (EI): m/e = 410.21 [M+H]+ .
Example 368 -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid tert-butylamide N N H O O O O Chiral N H N H O S N O O O O N N H O The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethyloxy-pyridinecarboxylic acid (Example 42 a) and tert-butylamine (CAN 759) as starting materials. MS (EI): m/e = 289.4 [M+H]+ .
Example 369 5-Cyclopropyl(tetrahydro-furanylmethoxy)-pyridinecarboxylic acid tertbutylamide The title compound was synthesized in analogy to Example 1, using 2-(5-cyclopropyl ((tetrahydrofuranyl)methoxy)picolinamido)ethylbutanoic acid (Example 166 b) and tert-butylamine (CAN 759) as starting materials. MS (EI): m/e = 319.4 [M+H]+ 10 .
Example 370 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (3- methyl-oxetanyl)-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example 69 b) and (3-methyloxetanyl)-amine (CAN 8744730) as starting materials.
Example 371 -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid (2-oxo20 [1,3]oxazinanyl)-amide O N N H O O O O N N H O N F F The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethyloxy-pyridinecarboxylic acid (Example 42a) and 3-aminotetrahydro2H-1,3-oxazinone (CAN 549249) as starting materials; LC-MS (UV peak area/ESI) 98.7%, 332.1612 (M+H)+ 5 .
Example 372 -Cyclopropyl(2,2,2-trifluoromethyl-ethoxy)-pyridinecarboxylic acid ((S) carbamoylmethyl-butyl)-amide a) 5-Bromo(1,1,1-trifluoropropanyloxy)picolinic acid OH N Br O F F F O -Bromochloropicolinic acid (5 g, 21.1 mmol; CAN 9599589 ) was dissolved in DMSO (100 mL) to give a colorless solution. To this solution potassium hydroxide (4.75 g, 84.6 mmol) was added. The reaction mixture turned into a white suspension which was stirred for 15 min. Then 1,1,1-trifluoropropanol (2.41 g, 1.92 mL, 21.1 mmol) was added. The mixture was stirred for 1 d at ambient temp., poured onto icewater/1N HCl (200 mL) and extracted with EtOAc (2 x 400 mL). The organic layers were washed with icewater/brine (200 mL), combined and dried over Na2SO4 and concentrated in vacuo to give the title compound (6.9 g, quant.) as orange solid. MS (EI): m/e = 312.3 [M-H]- . b) 5-Cyclopropyl(1,1,1-trifluoropropanyloxy)picolinic acid N N H O O N O O N H O O N NH2 F F F O Chiral OH O N F F F O -Bromo(1,1,1-trifluoropropanyloxy)picolinic acid (2 g, 6.37 mmol), potassium cyclopropyltrifluoroborate (952 mg, 6.43 mmol), cesium carbonate (6.22 g, 19.1 mmol) and palladium(II)acetate (28.6 mg, 127 µmol) were suspended in toluene (55 mL) and water (6.11 mL) under an argon atmosphere. Butyladamantylphosphin (68.5 mg, 191 µmol) was added, the reaction mixture was heated to 120°C for 1 d, poured onto icewater/1N HCl (150 mL) and extracted with EtOAc (2 x 300 mL). The combined organic layers were washed with icewater/brine (150 mL), dried over Na2SO4 and concentrated in vacuo to give the title compound (1.38 g, 79%) as a yellow solid. MS (EI): m/e = 276.2 [M+H]+ 10 . c) 5-Cyclopropyl(2,2,2-trifluoromethyl-ethoxy)-pyridinecarboxylic acid ((S) carbamoylmethyl-butyl)-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl (1,1,1-trifluoropropanyloxy)picolinic acid and (2S)aminomethyl-pentanamide (CAN 6874) as starting materials. MS (EI): m/e = 388.4 [M+H]+ 15 .
Example 373 -Cyclopropyl(2,2,2-trifluoromethyl-ethoxy)-pyridinecarboxylic acid [1- methyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl (1,1,1-trifluoropropanyloxy)picolinic acid (Example 372 b) and α,α,5-trimethyl-1,2,4- oxadiazolemethanamine (CAN 11538310) as starting materials. MS (EI): m/e = 399.5 [M+H]+ .
Example 374 N O N N H O N F F F O -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid ((+)-carbamoylcyclopropyl-methyl)-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethyloxy-pyridinecarboxylic acid (Example 42a) and α-aminocyclopropaneacetamide (CAN 11007494) as starting materials. The product was isolated by chiral chromatography on Chiralpak AD using heptane/20% 2-propanol as eluent. The (+)-enantiomer was isolated. LC-MS (UV peak area/ESI) 97.7%, 330.1804 (M+H)+ , ( )  43.3  D MeOH .
Example 375 -Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid ((-)-carbamoylcyclopropyl-methyl)-amide The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl cyclopropylmethyloxy-pyridinecarboxylic acid (Example 42a) and α-aminocyclopropaneacetamide (CAN 11007494) as starting materials. The product was isolated by chiral chromatography on Chiralpak AD using heptane/20% 2-propanol as eluent. The (-)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 330.1806 (M+H)+ ; ( )  40.1  D MeOH .
Example 376 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid ((+)- carbamoyl-cyclopropyl-methyl)-amide O N N H O NH2 O Chiral O N N H O NH2 O Chiral The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethyloxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example 69b) and α-amino-cyclopropaneacetamide (CAN 11007494) as starting materials. The product was isolated by chiral chromatography on Chiralpak AD using heptane/40% ethanol as eluent. The (+)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 381.1739 (M+H)+ , ( )  35.0  D MeOH .
Example 377 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid ((-)- carbamoyl-cyclopropyl-methyl)-amide The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethyloxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example 69b) and α-amino-cyclopropaneacetamide (CAN 11007494) as starting materials. The product was isolated by chiral chromatography on Chiralpak AD using heptane/40% ethanol as eluent. The (-)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 381.1734 (M+H)+ , ( )  23.5  D MeOH .
Example 378 6-Cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (1- trifluoromethyl-cyclopropyl)-amide N H F F F O N O N F F O N N N H O NH2 O F F Chiral O N N N H O NH2 O F F Chiral The title compound was synthesized in analogy to Example 1, using 6- cyclopropylmethoxy(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (Example 69 b) and 1-(trifluoromethyl)cyclopropanamine (CAN 1127388) as starting materials.
MS (EI): m/e = 392.4 [M+H]+ .
Example 379 (+)Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [(S) cyclopropyl(3-hydroxy-pyrrolidinylcarbamoyl)-ethyl]-amide a) (S)Cyclopropyl[(5-cyclopropylcyclopropylmethoxy-pyridinecarbonyl)- amino]-propionic acid (S)Cyclopropyl[(5-cyclopropylcyclopropylmethoxy-pyridinecarbonyl)-amino]- propionic acid methyl ester (Example 258, 42 mg, 117 µmol) was dissolved in THF (2 mL). After addition of water (0.66 mL) and lithium hydroxide monohydrate (14.8 mg, 352 µmol) the mixture was heated and stirred for 3 hours at reflux temperature. The mixture was cooled to room temperature, water (7 mL) was added and the mixture was acidified with 1 N HCl. The mixture was then extracted with ethyl acetate (14 and 7 mL), organic layers were washed with brine (10 mL), combined, dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound (36 mg, quant) as white solid; LC-MS (UV peak area/ESI) 100%, 345.1814 (M+H)+ 20 . b) 5-Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [(S)cyclopropyl ((RS)hydroxy-pyrrolidinylcarbamoyl)-ethyl]-amide N N H O O N H O N OH Chiral O N N H O OH O Chiral To a solution of (S)cyclopropyl[(5-cyclopropylcyclopropylmethoxy-pyridine carbonyl)-amino]-propionic acid (100 mg, 0.29 mmol) in DMF (3 mL), was added TBTU (103 mg, 0.319 mmol), DIEA (249 μL, 1.45 mmol) and finally 1-aminopyrrolidinol (CAN 8875918, 30 mg, 0.29 mmol). The reaction mixture was stirred for 16 h at room temperature, concentrated in vacuo and purified by flash chromatography (silica gel, 10 g, 0% to 20% methanol in dichloromethane) to give the title compound, an epimeric mixture of products, (90 mg, 72%) as white foam; LC-MS (UV peak area/ESI) 96%, 429.2493 (M+H)+ . c) (+)Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [(S) cyclopropyl(3-hydroxy-pyrrolidinylcarbamoyl)-ethyl]-amide The title compound was isolated by chiral chromatography of Example 379 b on Chiralpak AD using heptane/20% ethanol as eluent. The (+)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 429.2495 (M+H)+ , ( )  54.4  D MeOH .
Example 380 (-)Cyclopropylcyclopropylmethoxy-pyridinecarboxylic acid [(S) cyclopropyl(3-hydroxy-pyrrolidinylcarbamoyl)-ethyl]-amide The title compound was isolated by chiral chromatography of Example 379 b on Chiralpak AD using heptane/20% ethanol as eluent. The (-)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 429.2503 (M+H)+ , ( )  50.2  D MeOH .
Example 381 (+)Cyclopropyl(2-methyl-propanesulfonyl)-pyridinecarboxylic acid [1- cyclopropyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide N N H O O N H O N OH N N H O O N H O N OH Chiral N H N O N N O S O O Chiral a) 5-Cyclopropyl(2-methyl-propanesulfonyl)-pyridinecarboxylic acid [(R,S) cyclopropyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide N H N O N N O S O O The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl (isobutylsulfonyl)picolinic acid (Example 351 b) and α-cyclopropyl-α,5-dimethyl-1,2,4- oxadiazolemethanamine (CAN 11555363) as starting materials. MS (EI): m/e = 433.4 [M+H]+ . b) (+)Cyclopropyl(2-methyl-propanesulfonyl)-pyridinecarboxylic acid [1- cyclopropyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide The title compound was isolated by chiral chromatography of Example 381 a). The (+)- enantiomer was isolated. MS (EI): m/e = 433.4 [M+H]+ .
Example 382 (-)Cyclopropyl(2-methyl-propanesulfonyl)-pyridinecarboxylic acid [1- cyclopropyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide N H N O N N O S O O Chiral The title compound was isolated by chiral chromatography of Example 381 a). The (-)- enantiomer was isolated. MS (EI): m/e = 433.4 [M+H]+ .
Example 383 Pharmacological tests The following tests were carried out in order to determine the activity of the compounds of formula I: Radioligand binding assay 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 1h at 30°C shaking. The reaction was terminated by rapid filtration through microfiltration plates coated with 0.5% polyethylenimine (UniFilter GF/B filter plate; Packard). Bound radioactivity was analyzed for Ki using nonlinear regression analysis (Activity Base, ID Business Solution, Limited), with the Kd values for [3H]CP55,940 determined from saturation experiments. The compounds of formula (I) show an excellent affinity for the CB2 receptor.
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. cAMP Assay 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), 1x HT supplement, with 10 % fetal calf serum and incubated at 5% CO2 and 37°C in a humidified incubator. The growth medium was exchanged with Krebs Ringer Bicarbonate buffer with 1 mM IBMX and incubated at °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% NaN3) and 50 µl detection solutions (20 µM mAb Alexa700- cAMP 1:1, and 48 µM RutheniumAHA-cAMP) and shaken for 2h 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 10s 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.
EC50 values were determined using Activity Base analysis (ID Business Solution, Limited). The EC50 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.
In the foregoing assay, the compounds according to the invention have a human CB2 EC50 which is between 0.5 nM and 10 µM. Particular compounds according to the invention have a human CB2 EC50 between 0.5 nM and 1 µM. Further particular compounds according to the invention have a human CB2 EC50 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.
Results obtained for representative compounds of the invention are given in the following table.
Example human CB2 EC50 [µM] human CB1 EC50 [µM] 1 0.0685 -- 2 0.0577 -- 3 0.3408 >10 4 0.0772 -- 0.4345 -- 6 0.376 -- 7 0.0321 -- 8 0.0996 >10 9 0.0558 >10 0.0883 >10 11 0.0636 >10 12 0.1051 >10 13 0.4265 >10 14 0.003 >10 0.0959 >10 16 0.0166 >10 17 0.5662 >10 18 0.097 >10 19 0.4146 >10 0.2616 >10 21 0.2202 >10 22 0.6349 >10 Example human CB2 EC50 [µM] human CB1 EC50 [µM] 23 0.0482 >10 24 0.0156 >10 0.2913 >10 26 0.6908 >10 27 0.0046 >10 28 0.5637 >10 29 0.3239 >10 0.6577 >10 31 0.4232 >10 32 0.00155 1.3911 33 0.0231 >10 34 0.0537 >10 0.0071 >10 36 0.9735 >10 37 0.6249 >10 38 0.0997 >10 39 0.3033 >10 40 0.0308 >10 41 0.0999 >10 42 1.4776 >10 43 0.2749 >10 44 0.0135 1.6148 45 0.0871 1.0649 46 0.2904 >10 47 0.1384 >10 48 0.4768 >10 49 0.3078 >10 50 0.1329 1.4886 51 0.1273 >10 52 0.3215 >10 53 0.0457 >10 54 0.0114 2.1582 55 0.0317 1.3873 56 0.1733 >10 57 0.3192 >10 58 0.1038 1.1053 59 0.0325 >10 60 0.0622 >10 61 1.4785 >10 62 0.0115 0.5608 63 0.1123 >10 64 0.0189 1.4641 65 0.0338 >10 66 0.2158 >10 67 0.7971 >10 68 0.4287 >10 69 0.006 0.3797 70 0.0574 >10 71 0.0612 >10 72 0.0328 >10 73 0.0407 1.3184 74 0.0089 >10 75 0.0152 >10 76 0.1847 >10 Example human CB2 EC50 [µM] human CB1 EC50 [µM] 77 1.4028 >10 78 0.0046 >10 79 2.0386 >10 80 0.1338 0.0058 81 0.4167 >10 82 0.1403 2.2935 83 0.347 >10 84 0.2918 >10 85 0.1862 >10 86 0.0331 >10 87 0.4763 >10 88 0.3558 >10 89 0.1187 1.362 90 0.2173 >10 91 0.632 >10 92 0.3203 >10 93 0.1201 >10 94 0.1294 >10 95 0.0839 >10 96 0.0958 1.441 97 0.5079 >10 98 0.0276 >10 99 0.0597 >10 100 0.0012 0.8013 101 0.1023 >10 102 0.0627 >10 103 0.007 >10 104 0.5166 >10 105 0.2079 >10 106 0.215 >10 107 0.0107 1.4572 108 0.1903 >10 109 0.178 >10 110 0.2243 >10 111 0.0069 >10 112 0.0154 >10 113 0.1995 >10 114 0.0057 0.7032 115 0.0066 0.9529 116 0.0859 1.4461 117 0.3501 >10 118 0.0134 1.5526 119 0.2271 >10 120 0.2594 >10 121 0.111 1.3529 122 0.1576 >10 123 0.02 >10 124 0.0792 >10 125 0.2088 >10 126 0.2396 >10 127 0.2237 >10 128 0.2401 >10 129 0.1841 >10 130 0.05 >10 Example human CB2 EC50 [µM] human CB1 EC50 [µM] 131 0.0784 >10 132 0.0008 1.1323 133 0.0377 >10 134 0.0051 0.1507 135 0.0382 >10 136 0.0654 >10 137 0.211 >10 138 0.0267 >10 139 0.1131 >10 140 0.3046 >10 141 0.4591 >10 142 0.0144 >10 143 0.41 >10 144 0.0228 0.7392 145 0.2894 >10 146 0.0366 >10 147 0.9219 >10 148 0.0841 >10 149 0.1745 >10 150 0.1568 >10 151 0.3509 >10 152 0.442 >10 153 0.2929 >10 154 0.1498 >10 155 0.0007 0.1226 156 0.334 >10 157 0.0274 >10 158 0.0229 >10 159 0.7805 >10 160 0.1238 >10 161 0.1241 >10 162 0.0544 0.6741 163 0.0145 >10 164 0.2488 >10 165 0.0072 1.2015 166 0.0305 >10 167 0.2055 >10 168 0.0006 0.3126 169 0.1825 >10 170 0.1939 >10 171 0.0468 >10 172 0.0101 >10 173 0.0231 >10 174 0.032 >10 175 0.0478 >10 176 0.1142 >10 177 0.1958 >10 178 0.0422 >10 179 0.0038 0.5142 180 0.4226 >10 181 0.0013 0.2306 182 0.0017 >10 183 0.004 0.1021 184 0.0039 >10 Example human CB2 EC50 [µM] human CB1 EC50 [µM] 185 0.0075 >10 186 0.0011 1.488 187 0.0522 >10 188 0.005 0.3752 189 0.3807 >10 190 0.0204 >10 191 0.0577 >10 192 0.0642 1.5353 193 0.0994 >10 194 0.0991 >10 195 0.0014 0.2059 196 0.0103 >10 197 0.0332 >10 198 0.0068 >10 199 0.151 >10 200 0.0233 >10 201 0.0267 >10 202 0.0236 0.6151 203 0.0027 0.0749 204 0.0132 0.7372 205 0.0578 >10 206 0.025 >10 207 0.0144 >10 208 0.0089 >10 209 0.0025 >10 210 0.062 >10 211 0.0571 >10 212 0.0134 >10 213 0.0128 0.3611 214 0.0537 1.6276 215 0.1254 >10 216 0.0027 0.1156 217 0.0411 >10 218 0.0241 >10 219 0.0108 2.1419 220 0.0016 0.1287 221 0.0128 10 222 0.0032 >10 223 0.0109 0.655 224 0.0222 0.6475 225 0.0484 >10 226 0.0199 >10 227 0.0408 >10 228 0.0168 >10 229 0.0524 >10 230 0.0294 1.5912 231 0.0014 0.6781 232 0.015 1.6326 233 0.0001 0.071 234 0.0083 >10 235 0.0413 >10 236 0.0365 >10 237 0.0975 >10 238 0.0004 0.1462 Example human CB2 EC50 [µM] human CB1 EC50 [µM] 239 0.0011 0.0919 240 0.0661 >10 241 0.0491 >10 242 0.0012 >10 243 0.0221 0.8302 244 0.0141 >10 245 0.0205 >10 246 0.215 2.4723 247 0.0056 >10 248 0.051 >10 249 0.0022 >10 250 0.0095 >10 251 0.0014 0.0906 252 0.5521 >10 253 0.0143 >10 254 0.0023 0.5184 255 0.0613 >10 256 0.0093 >10 257 0.0023 0.3469 258 0.0071 >10 259 0.0051 >10 260 0.0249 >10 261 0.0101 0.26 262 0.0748 >10 263 0.0045 >10 264 0.0027 0.6019 265 0.0028 >10 266 0.002 1.2977 267 0.0264 >10 268 0.0087 0.3369 269 0.0473 >10 270 0.0013 0.0914 271 0.0079 >10 272 0.0043 >10 273 0.0054 1.2462 274 0.0016 0.3514 275 0.0518 >10 276 0.0246 >10 277 0.0166 1.6984 278 0.0202 0.3571 279 0.023 >10 280 0.1178 1.4926 281 0.4473 >10 282 0.3679 >10 283 0.1086 >10 284 0.027 >10 285 0.0316 0.7034 286 0.0082 1.8658 287 0.0036 >10 288 0.1633 >10 289 0.0014 0.2343 290 0.846 >10 291 0.4134 >10 292 0.8739 >10 Example human CB2 EC50 [µM] human CB1 EC50 [µM] 293 0.7905 >10 294 0.1121 >10 295 0.2593 >10 296 0.0608 >10 297 0.9624 >10 298 0.0142 >10 299 0.0276 0.6032 300 0.0318 >10 301 0.1297 >10 302 0.5874 >10 303 0.038 >10 304 0.1354 >10 305 0.0503 >10 306 0.1383 >10 307 0.0047 >10 308 0.5798 >10 309 0.1764 >10 310 0.0147 >10 311 0.0084 >10 312 0.0024 >10 313 0.9812 >10 314 0.0161 1.2573 315 0.1906 2.3204 316 0.0031 >10 317 0.0242 >10 318 0.0251 >10 319 0.3444 >10 320 0.0044 0.3227 321 0.0189 >10 322 0.4242 >10 323 0.0009 0.181 324 0.0041 >10 325 0.0175 >10 326 0.0002 0.059 327 0.0011 0.0136 328 0.0039 >10 329 0.0211 >10 330 0.8692 >10 331 0.0166 >10 332 0.0045 0.091 333 0.008 0.081 334 0.1082 >10 335 0.9622 >10 336 0.239 >10 337 0.0345 0.475 338 0.5343 >10 339 0.0649 >10 340 0.0057 >10 341 0.0084 >10 342 0.0028 >10 343 0.0035 >10 344 0.0256 >10 345 0.2952 >10 346 0.011 >10 Example human CB2 EC50 [µM] human CB1 EC50 [µM] 347 0.05 >10 348 0.0246 >10 349 0.4766 >10 350 0.0036 >10 351 0.0399 >10 352 0.1891 >10 353 0.0049 >10 354 0.0149 >10 355 0.0801 >10 356 0.0052 >10 357 0.0015 0.1994 358 0.0049 0.4889 359 0.0069 >10 360 0.0024 0.0885 361 0.0425 >10 362 0.4412 >10 363 0.038 >10 364 0.0129 >10 365 0.0139 >10 366 0.0264 >10 367 0.1954 >10 368 0.0263 >10 369 0.012 >10 370 0.0964 >10 371 0.4362 >10 372 0.0534 >10 373 0.1267 >10 374 0.0281 >10 375 0.3577 >10 376 0.0595 >10 377 0.1777 >10 378 0.0064 >10 379 0.0264 >10 380 0.5841 >10 381 0.0114 0.2403 382 0.0508 >10 β-Arrestin translocation assay–PathHunter™ (DiscoveRx) PathHunter™ β-arrestin CHO-K1 CNR1 cell line (catalog number #93-0200C2) and the βarrestin CHO-K1 CNR2 cell line (catalog number #93-0706C2) were purchased from DiscoveRx Corporation. The cell line was engineered to express the β-galactosidase EA fragment fused to β-arrestin and the ProLink complementary peptide fused to the target receptor. The PathHunter™ protein complementation assay (DiscoveRx Corporation #93- 0001) was performed according to the manufacturer’s protocol. Assay plates were seeded containing 7500 (CNR1) and 10000 (CNR2) cells in 384 well plates (Corning Costar #3707, white, clear bottom) in 20µL cell plating reagent 2 (Discoverx #93-0563R2A).
After incubation at 37°C (5% CO2, 95% relative humidity) overnight, 5 μl of test compound was added (1% final DMSO concentration) and the incubation continued at °C for 90 min. Detection reagent (12 μl) was then added and the incubation continued at room temperature for 60 min. Plates were then analyzed for a chemiluminescent signal using a Victor 3 5 V reader (Perkin Elmer).
Example A Film coated tablets containing the following ingredients can be manufactured in a conventional manner: 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 The active ingredient is sieved and mixed with microcrystalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidone in water. The granulate is then mixed with sodium starch glycolate and magnesium stearate and compressed to yield kernels of 120 or 350 mg respectively. The kernels are lacquered with an aq. solution / suspension of the above mentioned film coat.
Example B Capsules containing the following ingredients can be manufactured in a conventional manner: Ingredients Per capsule Compound of formula (I) 25.0 mg Lactose 150.0 mg Maize starch 20.0 mg Talc 5.0 mg The components are sieved and mixed and filled into capsules of size 2.
Example C Injection solutions can have the following composition: 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 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.

Claims (7)

Claims
1. A compound selected from Methyl 2-(6-(3-chlorophenyl)picolinamido)methylpropanoate; Methyl 2-(6-(2-chlorophenyl)picolinamido)methylpropanoate; 5 6-(4-Chloro-phenyl)-pyridinecarboxylic acid [1-methyl(5-methyl- [1,2,4]oxadiazolyl)-ethyl]-amide; Methyl 2-(5-cyclopropyl(2,4-dichlorophenylamino)picolinamido) methylpropanoate; Methyl 2-(6-(2,4-dichlorophenylamino)methylpicolinamido) 10 methylpropanoate; 6-(3-Chloro-phenyl)-pyridinecarboxylic acid (1-methyloxazolyl-ethyl)- amide; 6-(3-Chloro-phenyl)-pyridinecarboxylic acid piperidinylamide; 6-(3-Chloro-phenyl)-pyridinecarboxylic acid (1-methylthiazolyl-ethyl)- 15 amide; 6-(3-Chloro-phenyl)-pyridinecarboxylic acid (1-methyl[1,3,4]oxadiazolylethyl)-amide; 6-(3-Chloro-phenyl)-pyridinecarboxylic acid cyclohexylamide; 6-(3-Chloro-phenyl)-pyridinecarboxylic acid phenylamide; 20 6-(3-Chloro-phenyl)-pyridinecarboxylic acid pyridinylamide; 6-(3-Chloro-phenyl)-pyridinecarboxylic acid (tetrahydro-pyranyl)-amide; 6-(3-Chloro-phenyl)-pyridinecarboxylic acid [1-methyl(3-methyl- [1,2,4]thiadiazolyl)-ethyl]-amide; 6-(3-Chloro-phenyl)-pyridinecarboxylic acid (1-dimethylcarbamoylethyl25 propyl)-amide; 6-(3-Chloro-phenyl)-pyridinecarboxylic acid (2-methyl-tetrahydro-pyranyl)- amide; 6-(3-Chloro-phenyl)-pyridinecarboxylic acid [1-methyl(3-methyl-isoxazol yl)-ethyl]-amide; 6-(3-Chloro-phenyl)-pyridinecarboxylic acid (1-ethylhydroxymethyl-propyl)- amide; 5 6-(3-Chloro-phenyl)-pyridinecarboxylic acid (tetrahydro-pyranyl)-amide; 6-(3-Chloro-phenyl)-pyridinecarboxylic acid [(S)cyclopropyl(5-methyl- [1,2,4]oxadiazolyl)-ethyl]-amide; 6-(3-Chloro-phenyl)-pyridinecarboxylic acid [1-methyl(5-methyl- [1,2,4]oxadiazolyl)-ethyl]-amide; 10 6-(4-Chloro-phenyl)-pyridinecarboxylic acid piperidinylamide; [6-(3-Chloro-phenyl)cyclopropyl-pyridinyl]-(1,1-dioxidotetrahydro-2Hthiopyranyl)-methanone; 6-(3-Chloro-phenyl)methyl-pyridinecarboxylic acid (1-methyloxazolylethyl)-amide; 15 6-(3-Chloro-phenyl)methyl-pyridinecarboxylic acid (1-methylthiazolylethyl)-amide; 6-(3-Chloro-phenyl)methyl-pyridinecarboxylic acid [1-methyl(5-methyl- [1,2,4]oxadiazolyl)-ethyl]-amide; 6-(3-Chloro-phenyl)methyl-pyridinecarboxylic acid piperidinylamide; 20 6-(3-Chloro-phenyl)-pyridinecarboxylic acid ((S)methylthiazolyl-butyl)- amide; 5-Chloro(3-chloro-phenyl)-pyridinecarboxylic acid (1-methylthiazolylethyl)-amide; 6-(3-Chloro-phenyl)-pyridinecarboxylic acid ((S)cyclopropylthiazolyl25 ethyl)-amide; 5-Chloro(3-chloro-phenyl)-pyridinecarboxylic acid piperidinylamide; 6-(3-Chloro-phenyl)cyclopropyl-pyridinecarboxylic acid (1-methyl methylcarbamoyl-ethyl)-amide; 6-(3-Chloro-phenyl)methyl-pyridinecarboxylic acid (1-ethyl methylcarbamoyl-propyl)-amide; 6-(3-Chloro-phenyl)cyclopropyl-pyridinecarboxylic acid (1-ethyl methylcarbamoyl-propyl)-amide; 5 6-(3-Chloro-phenyl)-pyridinecarboxylic acid (1-methyl[1,2,4]oxadiazolylethyl)-amide; 6-(4-Chloro-phenyl)-pyridinecarboxylic acid (1-ethylmethylcarbamoylpropyl)-amide; 6-(3-Chloro-phenyl)methoxy-pyridinecarboxylic acid (1-ethyl 10 methylcarbamoyl-propyl)-amide; 6-(3-Chloro-phenyl)methoxy-pyridinecarboxylic acid (1-methylthiazol yl-ethyl)-amide; 5-Chloro(3-chloro-phenyl)-pyridinecarboxylic acid (1-methyl [1,2,4]oxadiazolyl-ethyl)-amide; 15 6-(3-Chloro-phenyl)methoxy-pyridinecarboxylic acid [1-methyl(5-methyl- [1,2,4]oxadiazolyl)-ethyl]-amide; 6-(3-Chloro-phenyl)methoxy-pyridinecarboxylic acid (1-methyloxazolylethyl)-amide; 5-Chloro(3-chloro-phenyl)-pyridinecarboxylic acid (1-ethyl 20 methylcarbamoyl-propyl)-amide; 6-(3-Chloro-phenyl)cyclopropyl-pyridinecarboxylic acid (1-methyloxazol2-yl-ethyl)-amide; 6-(3-Chloro-phenyl)cyclopropyl-pyridinecarboxylic acid [1-methyl(5- methyl-[1,2,4]oxadiazolyl)-ethyl]-amide; 25 6-(3-Chloro-phenyl)cyclopropyl-pyridinecarboxylic acid ((S)carbamoyl cyclopropyl-ethyl)-amide; 6-(3-Chloro-phenyl)(tetrahydro-furanyl)-pyridinecarboxylic acid (1-methyl1-thiazolyl-ethyl)-amide; 5-Chloro(3-chloro-phenyl)-pyridinecarboxylic acid (1-methyloxazolylethyl)-amide; 5-Chloro(3-chloro-phenyl)-pyridinecarboxylic acid ((S)carbamoyl methyl-butyl)-amide; 5 6-(3-Chloro-phenyl)cyclopentyl-pyridinecarboxylic acid [1-methyl(5- methyl-[1,2,4]oxadiazolyl)-ethyl]-amide; 6-(3-Chloro-phenyl)cyclopropyl-pyridinecarboxylic acid (1-methylthiazol2-yl-ethyl)-amide; 6-(3-Chloro-phenyl)(tetrahydro-furanyl)-pyridinecarboxylic acid [1-methyl10 1-(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide; 6-(3-Chloro-phenyl)(tetrahydro-furanyl)-pyridinecarboxylic acid (1-methyl1-oxazolyl-ethyl)-amide; 6-(3-Chloro-phenyl)(tetrahydro-furanyl)-pyridinecarboxylic acid (1-methyl1-thiazolyl-ethyl)-amide; 15 6-(3-Chloro-phenyl)cyclopentyl-pyridinecarboxylic acid (1-methylthiazol2-yl-ethyl)-amide; 6-(3-Chloro-phenyl)(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid ((S)- 1-carbamoylmethyl-butyl)-amide; 6-(3-Chloro-phenyl)(tetrahydro-furanyl)-pyridinecarboxylic acid [1-methyl20 1-(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide; 6-(3-Chloro-phenyl)(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid [2-(2- methoxy-ethoxy)-1,1-dimethyl-ethyl]-amide; 6-(3-Chloro-phenyl)(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid (1- methylthiazolyl-ethyl)-amide; 25 6-(3-Chloro-phenyl)(3,3-difluoro-azetidinyl)-pyridinecarboxylic acid [(S)- 2-cyclopropyl(5-methyl-[1,2,4]oxadiazolyl)-ethyl]-amide; (S)(3-chlorophenyl)-N-(3,3-dimethyl(methylamino)oxobutan yl)picolinamide; (S)(3-chlorophenyl)-N-(4,4-dimethyl(methylamino)oxopentan yl)picolinamide; (S)-N-(3,3-Dimethyl(methylamino)oxobutanyl)phenylpicolinamide; (S)-N-(4-Methyl(methylamino)oxopentanyl)phenylpicolinamide; 5 (S)(3-Fluorophenyl)-N-(4-methyl(methylamino)oxopentanyl) picolinamide; (S)(3-Chlorofluorophenyl)-N-(4-methyl(methylamino)oxopentan yl)picolinamide; (S)-N-(3,3-Dimethyl(methylamino)oxobutanyl)(3-fluorophenyl) 10 picolinamide; (S)-N-(3,3-Dimethyl(methylamino)oxobutanyl)(3-methoxyphenyl) picolinamide; (S)(3-Chlorofluorophenyl)-N-(3,3-dimethyl(methylamino)oxobutan yl)picolinamide; 15 6-(3-Chlorofluoro-phenyl)-pyridinecarboxylic acid [cyclopropyl-(5-methyl- [1,2,4]oxadiazolyl)-methyl]-amide; 6-(3-Chlorofluoro-phenyl)-pyridinecarboxylic acid [(-)-cyclopropyl-(5-methyl- [1,2,4]oxadiazolyl)-methyl]-amide; 6-(3-Chlorofluoro-phenyl)-pyridinecarboxylic acid [(+)-cyclopropyl-(5- 20 methyl-[1,2,4]oxadiazolyl)-methyl]-amide; 6-(4-Chlorofluoro-phenyl)-pyridinecarboxylic acid [1-methyl(5-methyl- [1,2,4]oxadiazolyl)-ethyl]-amide; 6-(3-Chlorofluoro-phenyl)-pyridinecarboxylic acid [1-methyl(5-methyl- [1,2,4]oxadiazolyl)-ethyl]-amide; 25 6-(3-Chlorofluoro-phenyl)-pyridinecarboxylic acid [(S)cyclopropyl(5- methyl-[1,2,4]oxadiazolyl)-ethyl]-amide; and 6-(3-Fluoro-phenyl)-pyridinecarboxylic acid [(S)cyclopropyl(5-methyl- [1,2,4]oxadiazolyl)-ethyl]-amide.
2. A compound according to claim 1 selected from 6-(3-Chloro-phenyl)-pyridinecarboxylic acid piperidinylamide; (S)(3-Chlorofluorophenyl)-N-(3,3-dimethyl(methylamino)oxobutan 5 yl)picolinamide; 6-(3-Chlorofluoro-phenyl)-pyridinecarboxylic acid [cyclopropyl-(5-methyl- [1,2,4]oxadiazolyl)-methyl]-amide; 6-(3-Chlorofluoro-phenyl)-pyridinecarboxylic acid [1-methyl(5-methyl- [1,2,4]oxadiazolyl)-ethyl]-amide; and 10 6-(3-Chlorofluoro-phenyl)-pyridinecarboxylic acid [(S)cyclopropyl(5- methyl-[1,2,4]oxadiazolyl)-ethyl]-amide.
3. A compound according to claim 1 or 2 for use as therapeutically active substance.
4. A pharmaceutical composition comprising a compound in accordance with claim 1 or claim 2 and a therapeutically inert carrier. 15
5. The use of a compound according to claim 1 or claim 2 for the preparation of a medicament for the treatment or prophylaxis of pain, atherosclerosis, regulation of bone mass, inflammation, ischemia, reperfusion injury, systemic fibrosis, liver fibrosis, lung fibrosis, kidney fibrosis, chronic allograft nephropathy, congestive heart failure, myocardial infarction, systemic sclerosis, glomerulonephropathy, 20 thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors.
6. A pharmaceutical composition according to claim 4 substantially as herein described with reference to any example thereof.
7. A use according to claim 5 substantially as herein described with reference to any 25 example thereof.
NZ715284A 2011-06-10 2012-06-07 Pyridin-2-amides useful as cb2 agonists NZ715284B2 (en)

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