HK1231465B - Pyridin- 2 -amides useful as cb2 agonists - Google Patents

Description

Pyridine-2-amides as CB2 agonists

This application is a divisional application of an application with a PCT international application date of June 7, 2012, PCT international application number PCT/EP2012/060785, Chinese national application number 201280028511.3, and invention name “Pyridine-2-amides useful as CB2 agonists”.

The present invention relates to organic compounds useful for treatment and/or prevention in mammals, and in particular to compounds that are preferred agonists of cannabinoid receptor 2. The compounds of formula (I) are particularly useful for the treatment or prevention of, for example, pain, in particular chronic pain, atherosclerosis, bone regulation, inflammation, ischemia, reperfusion injury, systemic fibrosis, liver fibrosis, pulmonary fibrosis, renal fibrosis, chronic allograft nephropathy, congestive heart failure, myocardial infarction, systemic sclerosis, glomerulonephropathy, thermal injury, burns, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors.

The present invention particularly relates to compounds of formula (I)

in

^R 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]thiazin-4-yl, piperidin-2-onyl, tetrahydrofuranylalkoxy, pyridinylalkoxy, alkyloxetanylalkoxy, hydroxyhaloalkyloxy, halophenylhydroxyalkyl, alkylsulfonyl, alkylsulfanyl or (halo)(haloalkyl)phenyl;

^R is hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, hydroxycycloalkyl, alkoxy, haloalkoxy, alkylamino, haloalkylamino, tetrahydropyranyl, 1H-pyrazolyl, pyrrolidinyl, alkylpyrrolidinyl, halopyrrolidinyl, oxopyrrolidinyl, haloazetidinyl, hydroxyazetidinyl, 1,1-dioxo-2-isothiazolidinyl, tetrahydrofuranyl, cycloalkylamino, hydroxyoxetanyl, alkylsulfonyl, oxetanyl, 6-oxa-1-aza-spiro[3.3]heptyl, 3,3-difluoro-2-oxo-azetidinyl, oxo-azetidinyl or oxo-pyrrolidinyl;

or R ¹ and R ² together with the ring to which they are attached form a tetrahydroquinolinyl or alkyltetrahydroquinolinyl group;

One of R ³ and R ⁴ is hydrogen and the other is -(CR ⁵ R ⁶ ) _m (CR ⁷ R ⁸ ) _n -R ⁹ ;

or R ³ and R ⁴ together with the nitrogen atom to which they are attached form piperidinyl, 1,1-dioxotetrahydro-2H-thiopyranyl, thiomorpholinyl, 2-oxa-6-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 R ⁵ and R ⁶ together with the carbon atoms to which they are attached form a cycloalkyl group, a tetrahydropyranyl group or an oxetanyl group;

^R7 and ^R8 are independently selected from hydrogen, alkyl and cycloalkyl;

^R is alkyl, hydroxy, cyano, carboxyl, alkoxycarbonyl, alkyl[1,2,4]oxadiazolyl, oxazolyl, thiazolyl, [1,3,4]oxadiazolyl, cycloalkyl, phenyl, pyridyl, 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, alkoxypyridyl, piperidyl, hydroxypiperidyl, hydroxyalkylpiperidyl, isoxazolyl, azetidine-carbonyl, alkoxyalkylaminocarbonyl, Cycloalkyl-alkylaminocarbonyl, haloazetidinylcarbonyl, alkyloxopyrrolidinyl, 1,1-dioxo-tetrahydro-1λ6-thienyl, 1,1-dioxo-tetrahydro-1λ6-thienylamino, amino[1,2,4]oxadiazolyl, 4-alkyl-5-oxo-4,5-dihydro-[1,2,4]oxadiazolyl, nitro-benzo[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.

Cannabinoid receptors are a class of cell membrane receptors that belong to the G protein-coupled receptor superfamily. There are currently two known subtypes, called cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2). CB1 receptors are primarily expressed in the central nervous system (i.e., amygdala, cerebellum, hippocampus) and are expressed in smaller amounts in the periphery. CB2, encoded by the CNR2 gene, is primarily expressed 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). CB2 receptors are also widely distributed in the brain, where they are primarily found on microglia rather than neurons (Cabral, G.A. et al. Br J Pharmacol 2008, 153(2): 240-51).

Interest in CB2 receptor agonists has steadily increased over the past decade (currently 30-40 patent applications/year) due to the fact that several of the early compounds have shown beneficial effects in preclinical models of 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), bone regulation (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, 34(1), 1192-12), and inflammatory bowel disease (Bab et al. J Neuroendocrinol 2008, 34(1), 1192-12). 2008, 153(2), 252-62), systemic fibrosis (Akhmetshina, A. et al. Arthritis Rheum 2009, 60(4), 1129-36; Garcia-Gonzalez, E. et al. Rheumatology (Oxford) 2009, 48(9), 1050-6), hepatic 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 main cause of tissue damage in conditions such as stroke, myocardial infarction, cardiopulmonary bypass and other vascular surgeries, and organ transplantation, and is the primary mechanism of end-organ damage that complicates the circulatory shock process of various etiologies. All of these conditions are characterized by the interruption of normal blood supply, resulting in insufficient tissue oxygenation. Reoxygenation, such as reperfusion, is the ultimate treatment for restoring normal tissue oxygenation. However, the lack of oxygen and nutrition from the blood produces conditions in which restoration of circulation leads to further tissue damage. The cause of reperfusion injury is, in part, an inflammatory response to the damaged tissue. Leukocytes transported to the area by newly returned blood release a large amount of inflammatory factors such as interleukins and free radicals in response to tissue damage. The restored blood flow reintroduces intracellular oxygen, which damages cellular proteins, DNA, and plasma membranes.

Remote ischemic preconditioning (RIPC) represents a strategy that exploits the body's endogenous protective abilities to counteract the damage caused by ischemia and reperfusion. It describes the intriguing phenomenon that temporary non-lethal ischemia and reperfusion of one organ or tissue confers resistance to subsequent events of "lethal" ischemia-reperfusion injury in a distant organ or tissue. Although several hypotheses have been proposed, the actual mechanism by which temporary ischemia and reperfusion of an organ or tissue confers protection is currently unknown.

The humoral hypothesis proposes that endogenous substances produced in remote organs or tissues (such as adenosine, bradykinin, opioids, CGRP, endocannabinoids, angiotensin I, or some other as yet unidentified humoral factors) enter the bloodstream and activate their respective receptors in target tissues and thereby restore the various intracellular pathways involved in ischemic preconditioning cardioprotection.

Recent data suggest that endocannabinoids and their receptors, particularly CB2, may be involved in preconditioning and contribute to the prevention of reperfusion injury by downregulating the inflammatory response (Pacher, P. et al. Br J Pharmacol 2008, 153(2), 252-62). Specifically, recent studies using CB2 tool agonists have shown the efficacy of this concept for reducing I/R injury in the heart (Defer, N. et al. Faseb J 2009, 23(7), 2120-30), brain (Zhang, M. et al. J Cereb Blood Flow Metab 2007, 27(7), 1387-96), liver (Batkai, S. et al. Faseb J 2007, 21(8), 1788-800) and kidney (Feizi, A. et al. Exp Toxicol Pathol 2008, 60(4-5), 405-10).

In addition, over the past few years, a growing body of literature has shown that CB2 may also be of interest in subchronic and chronic conditions. Specific upregulation of CB1 and CB2 has been shown 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) and is associated with CB2-related expression in myofibroblasts, the cells responsible for the fibrotic process.

Activation of CB2 receptors by selective CB2 agonists has indeed been shown to produce antifibrotic effects in diffuse systemic sclerosis (Garcia-Gonzalez, E. et al. Rheumatology (Oxford) 2009, 48(9), 1050-6) and CB2 receptors have emerged as key targets in experimental dermal fibrosis (Akhmetshina, A. et al. Arthritis Rheum 2009, 60(4), 1129-36) and in liver pathophysiology, including fibrogenesis associated with chronic liver disease (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 present invention bind to and modulate CB2 receptors and have lower CB1 receptor activity.

In the present specification, the term "alkyl", alone or in combination with other groups, means a straight-chain or branched alkyl group having 1 to 8 carbon atoms, in particular a straight-chain or branched alkyl group having 1 to 6 carbon atoms, more in particular a straight-chain or branched alkyl group having 1 to 4 carbon atoms. Examples of straight-chain and branched _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 octyl groups, in particular methyl, ethyl, propyl, butyl and pentyl, more in particular methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl and isopentyl.

The term "cycloalkyl", alone or in combination with other groups, means a cycloalkyl ring having 3 to 8 carbon atoms, and in particular a cycloalkyl ring having 3 to 6 carbon atoms. Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, cycloheptyl and cyclooctyl. Particular cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cyclopropyl, cyclobutyl and cyclopentyl are particular examples.

The term "alkoxy", alone or in combination with other groups, denotes a radical of the formula alkyl-O-, wherein the term "alkyl" has the meaning given previously, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy, in particular methoxy and ethoxy.

The term "cycloalkyloxy" or "cycloalkoxy", alone or in combination with other groups, denotes a radical of formula cycloalkyl-O-, wherein the term "cycloalkyl" has the meaning given previously, such as cyclobutyloxy, cyclopentyloxy or cyclohexyloxy.

The term "phenyloxy", alone or in combination with other groups, represents a phenyl-O- group.

The term "oxy", alone or in combination with other groups, means an -O- group.

The term "halogen" or "halo", alone or in combination with other groups, means fluorine, chlorine, bromine or iodine, and in particular fluorine, chlorine or bromine, more in particular fluorine and chlorine. The term "halo", in combination with another group, means that the group is substituted by at least one halogen, in particular by one to five halogens, especially by one to three halogens.

The terms "haloalkyl", "halocycloalkyl" and "haloalkoxy", alone or in combination with other groups, each refer to an alkyl, cycloalkyl and alkoxy group substituted with at least one halogen, particularly one to five halogens, especially one to three halogens. Particular "haloalkyl" groups are trifluoromethyl, trifluoroethyl and trifluoropropyl. Particular "haloalkoxy" groups are trifluoroethoxy.

The terms "halophenyl", "halopyrrolidinyl", "halopyridinyl" and "haloazetidinyl", alone or in combination with other groups, each refer to phenyl, pyrrolidinyl, pyridinyl and azetidinyl, which are substituted with at least one halogen, in particular with one to three halogens. Particular "halophenyl" are chlorophenyl, fluorophenyl, dichlorophenyl and chlorofluorophenyl. Particular "halopyrrolidinyl" is difluoropyrrolidinyl. Particular "haloazetidinyl" is difluoroazetidinyl.

The term "hydroxyl" or "hydroxy", alone or in combination with other groups, means an -OH group.

The term "carbonyl", alone or in combination with other groups, means a -C(O)- group.

The term "carboxy" or "carboxyl", alone or in combination with other groups, refers to a -COOH group.

The term "amino", alone or in combination with other groups, means a primary amino group ( _-NH2 ), a secondary amino group (-NH-) or a tertiary amino group (-N-).

The term "sulfonyl", alone or in combination, signifies a -SO ₂ - group.

The term "sulfanyl", alone or in combination, signifies a -SO- group.

The term "pharmaceutical salt" refers to those salts that keep the biological effectiveness and property of free alkali or free acid, and they are not biologically or otherwise unsuitable. Said salt is 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-acetylcysteine. In addition, these salts can be prepared by adding inorganic bases or organic bases to free acid. The salts deriving from inorganic bases include, but are not limited to, 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 exist in the form of zwitterions. Particularly preferred pharmaceutically acceptable salts of the compound of formula (I) are salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and methanesulfonic acid.

If one of the starting materials or the compound of formula (I) contains one or more functional groups that are unstable or reactive under the reaction conditions of one or more reaction steps, then suitable protecting groups can be introduced before the key steps using methods well known in the art (as described in, for example, T.W.Greene and P.G.M.Wutts in "Protective Groups in Organic Chemistry," 3rd edition, 1999, Wiley, New York). 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-butyloxycarbonyl (Boc), 9-fluorenylmethyl carbamate (Fmoc), 2-trimethylsilylethyl carbamate (Teoc), benzyloxycarbonyl (Cbz) and p-methoxybenzyloxycarbonyl (Moz).

The compounds of formula (I) may contain several asymmetric centers and may exist as optically pure enantiomers, mixtures of enantiomers, such as, for example, racemates, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates.

The term "asymmetric carbon atom" refers to a carbon atom having four different substituents. According to the Cahn-Ingold-Prelog Convention, an asymmetric carbon atom can be in the "R" or "S" configuration.

The present invention particularly relates to compounds of formula (I), wherein:

^R 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]thiazin-4-yl, piperidin-2-onyl, tetrahydrofuranylalkoxy or pyridinylalkoxy;

^R is hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, hydroxycycloalkyl, alkoxy, haloalkoxy, alkylamino, haloalkylamino, tetrahydropyranyl, 1H-pyrazolyl, pyrrolidinyl, alkylpyrrolidinyl, halopyrrolidinyl, oxopyrrolidinyl, haloazetidinyl, hydroxyazetidinyl, 1,1-dioxo-2-isothiazolidinyl, tetrahydrofuranyl, cycloalkylamino, hydroxyoxetanyl, alkylsulfonyl, or oxetanyl;

or R ¹ and R ² together with the ring to which they are attached form a tetrahydroquinolinyl or alkyltetrahydroquinolinyl group;

One of R ³ and R ⁴ is hydrogen and the other is -(CR ⁵ R ⁶ ) _m (CR ⁷ R ⁸ ) _n -R ⁹ ;

or R ³ and R ⁴ together with the nitrogen atom to which they are attached form piperidinyl, 1,1-dioxotetrahydro-2H-thiopyranyl, thiomorpholinyl, 2-oxa-6-aza-spiro[3.3]heptyl or 1-hydroxyalkylpyrrolidinyl;

^R5 and ^R6 are independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl and phenyl;

or R ⁵ and R ⁶ together with the carbon atoms to which they are attached form a cycloalkyl or tetrahydropyranyl group;

^R7 and ^R8 are independently selected from hydrogen, alkyl and cycloalkyl;

^R is alkyl, hydroxy, cyano, carboxyl, alkoxycarbonyl, alkyl[1,2,4]oxadiazolyl, oxazolyl, thiazolyl, [1,3,4]oxadiazolyl, cycloalkyl, phenyl, pyridyl, 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, alkoxypyridyl, piperidyl, hydroxypiperidyl, hydroxyalkylpiperidyl, isoxazolyl or piperidyl;

m is 0 or 1; and

n is 0, 1, or 2;

or a pharmaceutically acceptable salt or ester thereof.

A particular embodiment of the present invention are compounds of formula (I), wherein R ¹ is cycloalkyl, cycloalkylalkoxy, haloalkoxy, alkoxyalkoxy, phenyl, halophenyl, haloalkylphenyl, halophenylalkyl, halophenyloxy, piperidinylsulfonyl, tetrahydropyranyl, tetrahydropyranylalkoxy, tetrahydrofuranylalkoxy or pyridinylalkoxy.

Another particular embodiment of the present invention are compounds of formula (I), wherein R ¹ is cycloalkyl, cycloalkylalkoxy, haloalkoxy, alkoxyalkoxy, halophenyl, halophenylalkyl, alkoxyphenyl, halophenyloxy, piperidinylsulfonyl, tetrahydropyranyl, tetrahydropyranylalkoxy or tetrahydrofuranylalkoxy.

Yet another particular embodiment of the present invention are compounds of formula (I), wherein R ¹ is cycloalkylalkoxy, halophenyl, halophenylalkyl, tetrahydropyranylmethoxy or tetrahydrofuranylalkoxy.

Another particular embodiment of the invention are compounds of formula (I), wherein R ¹ is cyclopropylmethoxy, chlorophenyl, fluorophenylmethyl, fluorochlorophenyl or tetrahydrofurylalkoxy.

Of particular interest are compounds of formula (I) in which ^R2 is hydrogen, halogen, alkyl, haloalkyl, cycloalkyl, hydroxycycloalkyl, alkoxy, haloalkylamino, tetrahydropyranyl, 1H-pyrazolyl, pyrrolidinyl, alkylpyrrolidinyl, halopyrrolidinyl, oxopyrrolidinyl, haloazetidinyl, hydroxyazetidinyl, 1,1-dioxo-2-isothiazolidinyl, tetrahydrofuranyl, cycloalkylamino or hydroxyoxetanyl.

Of more particular interest are compounds of formula (I) wherein R ² is hydrogen, alkyl, haloalkyl, cycloalkyl, haloalkylamino, tetrahydropyranyl, pyrrolidinyl, alkylpyrrolidinyl, halopyrrolidinyl, haloazetidinyl, tetrahydrofuranyl or cycloalkylamino.

A particular embodiment of the invention are compounds of formula (I), wherein R ² is hydrogen, methyl, trifluoromethyl, cyclopropyl, cyclopentyl, bis(trifluoroethyl)amino, tetrahydropyranyl, pyrrolidinyl, methylpyrrolidinyl, difluoropyrrolidinyl, difluoroazetidinyl, tetrahydrofuranyl or cyclopropylamino.

Another particular embodiment of the present invention are compounds of formula (I), wherein R ¹ and R ² together with the ring to which they are attached form dimethyltetrahydroquinolinyl.

The present invention particularly relates to compounds of formula (I), wherein R ⁵ and R ⁶ are independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, trifluoromethyl, cyclopropyl, cyclopropylmethyl and phenyl, or R ⁵ and R ⁶ together with the carbon atoms to which they are attached form cyclobutyl or tetrahydropyranyl.

The present invention also particularly relates to compounds of formula (I), wherein R ⁷ and R ⁸ are independently selected from hydrogen and methyl.

The present invention further relates in particular to compounds of formula (I), wherein R ⁹ is hydroxy, cyano, carboxyl, alkoxycarbonyl, alkyl[1,2,4]oxadiazolyl, oxazolyl, thiazolyl, [1,3,4]oxadiazolyl, cycloalkyl, phenyl, pyridyl, tetrahydropyranyl, alkyl[1,2,4]thiadiazolyl, alkylaminocarbonyl, alkyltetrahydropyranyl, alkylisoxazolyl, aminocarbonyl, morpholinyl, alkylaminocarbonyl, dihydro-oxazolyl, [1,2,4]oxadiazolyl, hydroxycycloalkyl, alkoxycarbonylcycloalkyl, alkoxyalkoxy, hydroxyalkylcycloalkyl or piperidinyl.

A particular embodiment of the invention are compounds of formula (I), wherein R ^<9> is hydroxy, carboxyl, alkyl[1,2,4]oxadiazolyl, thiazolyl, alkylaminocarbonyl, aminocarbonyl, morpholinyl, alkoxyalkoxy or piperidinyl.

Another particular embodiment of the invention are compounds of formula (I), wherein R ^<9> is hydroxy, methyl[1,2,4]oxadiazolyl, thiazolyl, methylaminocarbonyl, aminocarbonyl, morpholinyl, methoxymethoxy or piperidinyl.

Particular compounds of the present invention are selected from:

Methyl 2-(6-(3-chlorophenyl)picolinamido)-2-methylpropanoate;

Methyl 2-(6-(2-chlorophenyl)picolinamido)-2-methylpropanoate;

6-(4-Chloro-phenyl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

Methyl 2-methyl-2-(5-methyl-6-(2,2,2-trifluoroethoxy)picolinamido)propanoate;

Methyl 2-(5-cyclopropyl-6-(2,4-dichlorophenylamino)picolinamido)-2-methylpropanoate;

Methyl 2-(6-(2,4-dichlorophenylamino)-5-methylpicolinamido)-2-methylpropanoate;

2-[(6-Cyclohexyl-pyridine-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester;

6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid (1-methyl-1-oxazol-2-yl-ethyl)-amide;

2-{[6-Cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester;

6-Cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid piperidin-1-ylamide;

6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;

2-{[6-Cyclopropylmethoxy-5-(1H-pyrazol-3-yl)-pyridine-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester;

6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide;

(6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridin-2-yl)-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)-methanone;

(6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridin-2-yl)-thiomorpholin-4-yl-methanone;

6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid (1-methyl-1-[1,3,4]oxadiazol-2-yl-ethyl)-amide;

6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid cyclohexylamide;

6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid phenylamide;

6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid pyridin-2-ylamide;

6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid (tetrahydro-pyran-4-yl)-amide;

6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid [1-methyl-1-(3-methyl-[1,2,4]thiadiazol-5-yl)-ethyl]-amide;

6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid (1-dimethylcarbamoyl-1-ethyl-propyl)-amide;

6-Cyclohexyl-pyridine-2-carboxylic acid piperidin-1-ylamide;

[5-Methyl-6-(piperidin-1-sulfonyl)-pyridin-2-yl]-piperidin-1-yl-methanone;

6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid (2-methyl-tetrahydro-pyran-4-yl)-amide;

2-[(6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester;

6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid [1-methyl-1-(3-methyl-isoxazol-5-yl)-ethyl]-amide;

6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid (1-ethyl-1-hydroxymethyl-propyl)-amide;

6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid (tetrahydro-pyran-3-yl)-amide;

(6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridin-2-yl)-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-methanone;

6-Cyclopropylmethoxy-5-(2-methyl-pyrrolidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;

6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

6-Cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;

6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid (1,1-dimethyl-3-morpholin-4-yl-propyl)-amide;

6-Cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid (1-methyl-1-methylcarbamoyl-ethyl)-amide;

6-(Tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid piperidin-1-ylamide;

6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

(5-Cyclopentyl-6-cyclopropylmethoxy-pyridin-2-yl)-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)-methanone;

5-Cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-methyl-1-methylcarbamoyl-ethyl)-amide;

6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid piperidin-1-ylamide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-methyl-1-methylcarbamoyl-ethyl)-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

6-(4-Chloro-phenyl)-pyridine-2-carboxylic acid piperidin-1-ylamide;

6-Cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid piperidin-1-ylamide;

[6-(3-Chloro-phenyl)-5-cyclopropyl-pyridin-2-yl]-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)-methanone;

6-(3-Chloro-phenyl)-5-methyl-pyridine-2-carboxylic acid (1-methyl-1-oxazol-2-yl-ethyl)-amide;

6-(3-Chloro-phenyl)-5-methyl-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;

6-(3-Chloro-phenyl)-5-methyl-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

6-(3-Chloro-phenyl)-5-methyl-pyridine-2-carboxylic acid piperidin-1-ylamide;

5-Cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

5-Cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

5-Cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;

6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid ((S)-3-methyl-1-thiazol-2-yl-butyl)-amide;

6-Cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

5-Chloro-6-(3-chloro-phenyl)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;

6-Cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid ((S)-2-cyclopropyl-1-thiazol-2-yl-ethyl)-amide;

6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid ((S)-2-cyclopropyl-1-thiazol-2-yl-ethyl)-amide;

6-Cyclopropylmethoxy-5-(2-oxo-pyrrolidin-1-yl)-pyridine-2-carboxylic acid (1-methyl-1-oxazol-2-yl-ethyl)-amide;

6-Cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;

6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid [1-(4,5-dihydro-oxazol-2-yl)-1-methyl-ethyl]-amide;

6-Cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid ((S)-3-methyl-1-thiazol-2-yl-butyl)-amide;

6-Cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid ((S)-2-cyclopropyl-1-thiazol-2-yl-ethyl)-amide;

5-Chloro-6-(3-chloro-phenyl)-pyridine-2-carboxylic acid piperidin-1-ylamide;

6-(3-Chloro-phenyl)-5-cyclopropyl-pyridine-2-carboxylic acid (1-methyl-1-methylcarbamoyl-ethyl)-amide;

6-Cyclopropylmethoxy-pyridine-2-carboxylic acid piperidin-1-ylamide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;

6-(3-Chloro-phenyl)-5-methyl-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;

6-(3-Chloro-phenyl)-5-cyclopropyl-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;

6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid (1-methyl-1-[1,2,4]oxadiazol-3-yl-ethyl)-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-methyl-1-[1,2,4]oxadiazol-3-yl-ethyl)-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;

6-Cyclopropylmethoxy-5-(3-hydroxy-azetidin-1-yl)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;

6-(4-Chloro-phenyl)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;

6-(cyclopropylmethoxy)-5-(1,1-dioxo-1,2-isothiazolidin-2-yl)-N-[2-(1,3-thiazol-2-yl)propan-2-yl]pyridine-2-carboxamide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-pyrrolidin-1-yl)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;

[6-Cyclopropylmethoxy-5-(3,3-difluoro-pyrrolidin-1-yl)-pyridin-2-yl]-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)-methanone;

6-Cyclopropylmethoxy-5-(3,3-difluoro-pyrrolidin-1-yl)-pyridine-2-carboxylic acid (1-methyl-1-methylcarbamoyl-ethyl)-amide;

6-(3-Chloro-phenyl)-5-methoxy-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;

6-(3-Chloro-phenyl)-5-methoxy-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;

5-Chloro-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-methyl-1-[1,2,4]oxadiazol-3-yl-ethyl)-amide;

6-Cyclohexyl-pyridine-2-carboxylic acid (2-hydroxy-cyclohexyl)-amide;

6-Cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1-methyl-1-methylcarbamoyl-ethyl)-amide;

5-Chloro-6-(3-chloro-phenyl)-pyridine-2-carboxylic acid (1-methyl-1-[1,2,4]oxadiazol-3-yl-ethyl)-amide;

6-(3-Chloro-phenyl)-5-methoxy-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

6-(3-Chloro-phenyl)-5-methoxy-pyridine-2-carboxylic acid (1-methyl-1-oxazol-2-yl-ethyl)-amide;

5-Chloro-6-(3-chloro-phenyl)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;

2-[(6-Cyclohexyl-pyridine-2-carbonyl)-amino]-cyclohexanecarboxylic acid methyl ester;

6-Cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid (1-methyl-1-oxazol-2-yl-ethyl)-amide;

6-Cyclopentyl-pyridine-2-carboxylic acid piperidin-1-ylamide;

6-(3-Chloro-phenyl)-5-cyclopropyl-pyridine-2-carboxylic acid (1-methyl-1-oxazol-2-yl-ethyl)-amide;

6-(3-Chloro-phenyl)-5-cyclopropyl-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

6-(3-Chloro-phenyl)-5-cyclopropyl-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-2-cyclopropyl-1-thiazol-2-yl-ethyl)-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;

6-(3-Chloro-phenyl)-5-(tetrahydro-furan-3-yl)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;

5-Chloro-6-(3-chloro-phenyl)-pyridine-2-carboxylic acid (1-methyl-1-oxazol-2-yl-ethyl)-amide;

5-Chloro-6-(3-chloro-phenyl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;

6-(3-Chloro-phenyl)-5-cyclopentyl-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

5-Cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;

5-Chloro-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

5-Chloro-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;

5-Bromo-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;

5-Cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-pyrrolidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;

6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;

6-Cyclopropylmethoxy-5-(tetrahydro-furan-3-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;

6-Cyclopropylmethoxy-5-(tetrahydro-furan-2-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;

6-(3-Chloro-phenyl)-5-cyclopropyl-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-amide;

6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;

6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (1-methyl-1-[1,2,4]oxadiazol-3-yl-ethyl)-amide;

6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;

6-Cyclohexyl-pyridine-2-carboxylic acid (2-hydroxymethyl-cyclohexyl)-amide;

6-Cyclopropylmethoxy-5-(tetrahydro-furan-2-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

6-Cyclopropylmethoxy-5-(tetrahydro-furan-3-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

6-(3-Chloro-phenyl)-5-(tetrahydro-furan-2-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

6-(3-Chloro-phenyl)-5-(tetrahydro-furan-2-yl)-pyridine-2-carboxylic acid (1-methyl-1-oxazol-2-yl-ethyl)-amide;

6-(3-Chloro-phenyl)-5-(tetrahydro-furan-2-yl)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;

6-(3-Chloro-phenyl)-5-cyclopentyl-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;

6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (1-methyl-1-oxazol-2-yl-ethyl)-amide;

6-Cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;

6-Cyclopropylmethoxy-5-(3-hydroxy-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;

5-Cyclopropylamino-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;

5-Cyclopropylamino-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-cyclopropylmethyl-2-hydroxy-2-methyl-propyl)-amide;

6-Cyclopropylmethoxy-5-(tetrahydro-furan-3-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (2-hydroxy-cyclohexyl)-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-cyclopropylmethyl-2-hydroxy-2-methyl-propyl)-amide;

6-(3-Chloro-phenyl)-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;

6-Cyclopropylmethoxy-5-(tetrahydro-furan-3-yl)-pyridine-2-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide;

5-Cyclopropyl-6-(2-methoxy-ethoxy)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;

7,7-Dimethyl-5,6,7,8-tetrahydro-quinoline-2-carboxylic acid ((R)-2-cyclopropyl-2-hydroxy-propyl)-amide;

7,7-Dimethyl-N-(2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-yl)-5,6,7,8-tetrahydroquinoline-2-carboxamide;

N-(1-hydroxy-2-methylpropan-2-yl)-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-2-carboxamide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-2-cyclopropyl-1-thiazol-2-yl-ethyl)-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (pyridin-2-ylmethyl)-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide;

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-methanone;

6-Cyclopropylmethoxy-5-(3-hydroxy-oxetan-3-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;

6-(3-Chloro-phenyl)-5-(tetrahydro-furan-3-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

6-(3-Chloro-phenyl)-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-amide;

5-Cyclopropyl-6-(2-methoxy-ethoxy)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1,1-dimethyl-3-morpholin-4-yl-propyl)-amide;

5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;

6-(3-Chloro-phenyl)-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(2-methoxy-ethoxymethyl)-ethyl]-amide;

5-(3,3-Difluoro-azetidin-1-yl)-6-(2-methoxy-ethoxy)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;

5-Cyclopropylamino-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide;

6-Cyclopropylmethoxy-5-(1-hydroxy-cyclobutyl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

5-Cyclopropyl-6-(2-methoxy-ethoxy)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;

5-[Bis-(2,2,2-trifluoro-ethyl)-amino]-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

6-(3-Chloro-phenyl)-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

5-[Bis-(2,2,2-trifluoro-ethyl)-amino]-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;

5-Cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

N-(2-cyanoprop-2-yl)-5-cyclopropyl-6-(cyclopropylmethoxy)picolinamide;

(S)-5-cyclopropyl-6-(cyclopropylmethoxy)-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)picolinamide;

N-(1-amino-2,3-dimethyl-1-oxobutan-2-yl)-5-cyclopropyl-6-(cyclopropylmethoxy)picolinamide;

N-(1-amino-2-methyl-1-oxobutan-2-yl)-5-cyclopropyl-6-(cyclopropylmethoxy)picolinamide;

5-cyclopropyl-6-(cyclopropylmethoxy)-N-(1-(5-methyl-1,2,4-oxadiazol-3-yl)cyclobutyl)picolinamide;

(S)-N-(2-amino-2-oxo-1-phenylethyl)-5-cyclopropyl-6-(cyclopropylmethoxy)picolinamide;

(R)-N-(2-amino-2-oxo-1-phenylethyl)-5-cyclopropyl-6-(cyclopropylmethoxy)picolinamide;

(R)-5-cyclopropyl-6-(cyclopropylmethoxy)-N-(1-hydroxy-4-methylpentan-2-yl)picolinamide;

5-cyclopropyl-6-(cyclopropylmethoxy)-N-(1-(hydroxymethyl)cyclopentyl)picolinamide;

5-cyclopropyl-6-(cyclopropylmethoxy)-N-(2-(3-methyl-1,2,4-oxadiazol-5-yl)propan-2-yl)picolinamide;

5-Bromo-6-(4-fluoro-phenoxy)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;

N-(1-amino-2,4-dimethyl-1-oxopentan-2-yl)-5-cyclopropyl-6-(cyclopropylmethoxy)picolinamide;

N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-5-cyclopropyl-6-(cyclopropylmethoxy)picolinamide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (4-carbamoyl-tetrahydro-pyran-4-yl)-amide;

(S)-5-cyclopropyl-6-(cyclopropylmethoxy)-N-(4-methyl-1-(methylamino)-1-oxopentan-2-yl)picolinamide;

(S)-5-cyclopropyl-6-(cyclopropylmethoxy)-N-(4,4-dimethyl-1-(methylamino)-1-oxopentan-2-yl)picolinamide;

5-cyclopropyl-N-((S)-3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-6-((tetrahydrofuran-2-yl)methoxy)picolinamide;

5-cyclopropyl-N-((S)-4-methyl-1-(methylamino)-1-oxopentan-2-yl)-6-((tetrahydrofuran-2-yl)methoxy)picolinamide;

5-cyclopropyl-N-((S)-4,4-dimethyl-1-(methylamino)-1-oxopentan-2-yl)-6-((tetrahydrofuran-2-yl)methoxy)picolinamide;

N-((S)-1-amino-4-methyl-1-oxopentan-2-yl)-5-cyclopropyl-6-((tetrahydrofuran-2-yl)methoxy)picolinamide;

5-Cyclopropyl-6-(4-fluoro-phenoxy)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;

5-Bromo-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid ((S)-2,2-dimethyl-1-methylcarbamoyl-propyl)-amide;

5-cyclopropyl-N-(1-(5-methyl-1,2,4-oxadiazol-3-yl)cyclobutyl)-6-(pyridin-2-ylmethoxy)picolinamide;

5-cyclopropyl-N-(cyclopropyl(5-methyl-1,2,4-oxadiazol-3-yl)methyl)-6-(cyclopropylmethoxy)picolinamide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((R)-1-hydroxymethyl-1,2-dimethyl-propyl)-amide;

(S)-6-(3-chlorophenyl)-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)picolinamide;

(S)-6-(3-chlorophenyl)-N-(4,4-dimethyl-1-(methylamino)-1-oxopentan-2-yl)picolinamide;

5-cyclopropyl-6-(cyclopropylmethoxy)-N-(4-hydroxy-2-methylbutan-2-yl)picolinamide;

(S)-5-cyclopropyl-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-6-((tetrahydro-2H-pyran-4-yl)methoxy)picolinamide;

(S)-5-cyclopropyl-N-(4,4-dimethyl-1-(methylamino)-1-oxopentan-2-yl)-6-((tetrahydro-2H-pyran-4-yl)methoxy)picolinamide;

(-)-5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide;

(+)-5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide;

5-cyclopropyl-N-(2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-yl)-6-(pyridin-2-ylmethoxy)picolinamide;

(S)-N-(1-amino-4-methyl-1-oxopentan-2-yl)-5-cyclopropyl-6-(pyridin-2-ylmethoxy)picolinamide;

(S)-5-cyclopropyl-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-6-(pyridin-2-ylmethoxy)picolinamide;

5-cyclopropyl-N-(2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-yl)-6-((tetrahydro-2H-pyran-4-yl)methoxy)picolinamide;

(S)-5-cyclopropyl-N-(4-methyl-1-(methylamino)-1-oxopentan-2-yl)-6-((tetrahydro-2H-pyran-4-yl)methoxy)picolinamide;

(S)-N-(3,3-Dimethyl-1-(methylamino)-1-oxobutan-2-yl)-6-phenylpicolinamide;

(S)-N-(4-methyl-1-(methylamino)-1-oxopentan-2-yl)-6-phenylpicolinamide;

5-(3,3-difluoroazetidin-1-yl)-N-((S)-3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-6-((tetrahydrofuran-2-yl)methoxy)picolinamide;

2-(6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinamido)-2-ethylbutanoic acid;

(S)-6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)picolinamide;

(S)-6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-N-(4,4-dimethyl-1-(methylamino)-1-oxopentan-2-yl)picolinamide;

(S)-6-(3-Fluorophenyl)-N-(4-methyl-1-(methylamino)-1-oxopentan-2-yl)picolinamide;

(S)-N-(4-methyl-1-(methylamino)-1-oxopentan-2-yl)-6-(3-(trifluoromethyl)phenyl)picolinamide;

(S)-6-(3-chloro-4-fluorophenyl)-N-(4-methyl-1-(methylamino)-1-oxopentan-2-yl)picolinamide;

(S)-N-(3,3-Dimethyl-1-(methylamino)-1-oxobutan-2-yl)-6-(3-fluorophenyl)picolinamide;

(S)-N-(3,3-Dimethyl-1-(methylamino)-1-oxobutan-2-yl)-6-(3-(trifluoromethyl)phenyl)picolinamide;

(S)-N-(3,3-Dimethyl-1-(methylamino)-1-oxobutan-2-yl)-6-(3-methoxyphenyl)picolinamide;

(S)-6-(3-chloro-4-fluorophenyl)-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)picolinamide;

(S)-5-cyclopropyl-6-(cyclopropylmethoxy)-N-(2,2,2-trifluoro-1-(pyridin-3-yl)ethyl)picolinamide; and

(R)-5-cyclopropyl-6-(cyclopropylmethoxy)-N-(2,2,2-trifluoro-1-(pyridin-3-yl)ethyl)picolinamide;

More particular compounds of formula (I) are selected from:

6-Cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid piperidin-1-ylamide;

6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide;

6-Cyclopropylmethoxy-5-(2-methyl-pyrrolidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;

6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid (1,1-dimethyl-3-morpholin-4-yl-propyl)-amide;

5-Cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-methyl-1-methylcarbamoyl-ethyl)-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;

5-Cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

6-Cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid ((S)-3-methyl-1-thiazol-2-yl-butyl)-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-pyrrolidin-1-yl)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-pyrrolidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;

6-Cyclopropylmethoxy-5-(tetrahydro-furan-3-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;

6-Cyclopropylmethoxy-5-(tetrahydro-furan-2-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;

6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;

6-Cyclopropylmethoxy-5-(tetrahydro-furan-2-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;

5-Cyclopropylamino-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-cyclopropylmethyl-2-hydroxy-2-methyl-propyl)-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-2-cyclopropyl-1-thiazol-2-yl-ethyl)-amide;

5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(2-methoxy-ethoxymethyl)-ethyl]-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

5-[Bis-(2,2,2-trifluoro-ethyl)-amino]-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;

(S)-5-cyclopropyl-6-(cyclopropylmethoxy)-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)picolinamide;

(S)-N-(2-amino-2-oxo-1-phenylethyl)-5-cyclopropyl-6-(cyclopropylmethoxy)picolinamide;

N-((S)-1-amino-4-methyl-1-oxopentan-2-yl)-5-cyclopropyl-6-((tetrahydrofuran-2-yl)methoxy)picolinamide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((R)-1-hydroxymethyl-1,2-dimethyl-propyl)-amide;

(S)-5-cyclopropyl-N-(4,4-dimethyl-1-(methylamino)-1-oxopentan-2-yl)-6-((tetrahydro-2H-pyran-4-yl)methoxy)picolinamide;

(+)-5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(SR)-cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide;

2-(6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinamido)-2-ethylbutanoic acid; and

(S)-6-(3-chloro-4-fluorophenyl)-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)picolinamide.

The present invention more particularly relates to:

A compound of formula (I), wherein R ¹ 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 R ¹ is cycloalkyl, cycloalkylalkoxy, haloalkoxy, alkoxyalkoxy, halophenyl, halophenylalkyl, alkoxyphenyl, halophenyloxy, piperidinylsulfonyl, tetrahydropyranyl, tetrahydropyranylalkoxy, tetrahydrofuranylalkoxy, hydroxyhaloalkyloxy, halophenylhydroxyalkyl, alkylsulfanyl or alkylsulfonyl;

A compound of formula (I) wherein R ¹ is cycloalkylalkoxy, halophenyl, halophenylalkyl, tetrahydropyranylalkoxy, tetrahydrofuranylalkoxy, haloalkoxy, hydroxyhaloalkyloxy, halophenylhydroxyalkyl, alkylsulfanyl or alkylsulfonyl;

A compound of formula (I) wherein R ¹ is cyclopropylmethoxy, chlorophenyl, fluorophenylmethyl, fluorochlorophenyl, tetrahydropyranylmethoxy, tetrahydrofuranylmethoxy, pentafluoropropoxy, trifluorohydroxybutyloxy, fluorophenylhydroxymethyl, butylsulfanyl or butylsulfonyl;

A compound of formula (I) wherein ^R is hydrogen, halogen, alkyl, haloalkyl, cycloalkyl, hydroxycycloalkyl, alkoxy, haloalkylamino, tetrahydropyranyl, 1H-pyrazolyl, pyrrolidinyl, alkylpyrrolidinyl, halopyrrolidinyl, oxopyrrolidinyl, haloazetidinyl, hydroxyazetidinyl, 1,1-dioxo-2-isothiazolidinyl, tetrahydrofuranyl, cycloalkylamino, hydroxyoxetanyl or 6-oxa-1-aza-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-oxa-1-aza-spiro[3.3]heptyl;

A compound of formula (I) wherein R ² is hydrogen, methyl, trifluoromethyl, cyclopropyl, cyclopentyl, bis(trifluoroethyl)amino, tetrahydropyranyl, pyrrolidinyl, methylpyrrolidinyl, difluoropyrrolidinyl, difluoroazetidinyl, tetrahydrofuranyl or cyclopropylamino or 6-oxa-1-aza-spiro[3.3]heptyl;

A compound of formula (I) wherein R ⁵ and R ⁶ are independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, trifluoromethyl, cyclopropyl, cyclopropylmethyl, phenyl, fluorophenyl and pyridazinyl, or R ⁵ and R ⁶ together with the carbon atom to which they are attached form cyclobutyl, tetrahydropyranyl or cyclopropyl;

A compound of formula (I) wherein ^R is hydroxy, 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, nitro-benzo[1,2,5]oxadiazolyl or alkyl;

A compound of formula (I) wherein R ⁹ is hydroxy, carboxyl, alkyl[1,2,4]oxadiazolyl, thiazolyl, alkylaminocarbonyl, aminocarbonyl, morpholinyl, alkoxyalkoxy, piperidinyl, cyano, pyridinyl, haloazetidinylcarbonyl, nitro-benzo[1,2,5]oxadiazolyl, alkoxycarbonyl or alkyl;

A compound of formula (I) wherein ^R is hydroxy, 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.

The present invention further relates to compounds of formula (I) selected from:

5-Cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide;

2-({5-[Bis-(2,2,2-trifluoro-ethyl)-amino]-6-cyclopropylmethoxy-pyridine-2-carbonyl}-amino)-2-ethyl-butyric acid methyl ester;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-2-cyclopropyl-1-dimethylcarbamoyl-ethyl)-amide;

5-Cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carboxylic acid (2,2,2-trifluoro-1-pyridin-2-yl-ethyl)-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (2,2,2-trifluoro-1-pyridin-2-yl-ethyl)-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((-)-methylcarbamoyl-phenyl-methyl)-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((+)-dimethylcarbamoyl-phenyl-methyl)-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((-)-dimethylcarbamoyl-phenyl-methyl)-amide;

6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3-dimethyl-1-methylcarbamoyl-butyl)-amide;

6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide;

6-(Tetrahydro-pyran-4-ylmethoxy)-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3-dimethyl-1-methylcarbamoyl-butyl)-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-dimethylcarbamoyl-3-methyl-butyl)-amide;

6-(3-Chloro-4-fluoro-phenyl)-pyridine-2-carboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide;

2-{[5-Cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carbonyl]-amino}-2-ethyl-butyric acid methyl ester;

6-Cyclopropylmethoxy-5-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-pyridine-2-carboxylic acid ((S)-3,3-dimethyl-1-methylcarbamoyl-butyl)-amide;

6-Cyclopropylmethoxy-5-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

6-Cyclopropylmethoxy-5-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-pyridine-2-carboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((R)-2,2,2-trifluoro-1-pyridin-3-yl-ethyl)-amide;

2-Ethyl-2-{[6-(tetrahydro-pyran-4-ylmethoxy)-5-trifluoromethyl-pyridine-2-carbonyl]-amino}-butyric acid methyl ester;

(S)-2-[(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-amino]-3,3-dimethyl-butyric acid methyl ester;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-2,2,2-trifluoro-1-pyridin-2-yl-ethyl)-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(-)-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(+)-3-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-butyl]-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(-)-3-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-butyl]-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(+)-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-propyl]-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(-)-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-propyl]-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((-)-cyano-methyl-methyl)-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((-)-1-cyano-3-methyl-butyl)-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((+)-cyano-cyclopropyl-methyl)-amide;

2-[(6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carbonyl)-amino]-2-ethyl-butyric acid methyl ester;

5-Cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;

2-[(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-amino]-2-ethyl-butyric acid methyl ester;

2-[(6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carbonyl)-amino]-2-ethyl-butyric acid;

6-(Tetrahydro-pyran-4-ylmethoxy)-5-trifluoromethyl-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;

2-Ethyl-2-{[6-(tetrahydro-furan-2-ylmethoxy)-5-trifluoromethyl-pyridine-2-carbonyl]-amino}-butyric acid ethyl ester;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (dimethylcarbamoyl-phenyl-methyl)-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-2-cyclopropyl-1-dimethylcarbamoyl-ethyl)-amide;

2-[(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-amino]-2-ethyl-butyric acid ethyl ester;

(S)-3-Cyclopropyl-2-[(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-amino]-propionic acid methyl ester;

6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;

6-(3-Chloro-4-fluoro-phenyl)-pyridine-2-carboxylic acid [(-)-cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide;

6-(3-Chloro-4-fluoro-phenyl)-pyridine-2-carboxylic acid [(+)-cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide;

6-(Tetrahydro-pyran-4-ylmethoxy)-5-trifluoromethyl-pyridine-2-carboxylic acid (1-dimethylcarbamoyl-1-ethyl-propyl)-amide;

2-{[6-Cyclopropylmethoxy-5-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-pyridine-2-carbonyl]-amino}-2-ethyl-butyric acid ethyl ester;

6-(Tetrahydro-furan-2-ylmethoxy)-5-trifluoromethyl-pyridine-2-carboxylic acid (1-dimethylcarbamoyl-1-ethyl-propyl)-amide;

2-[(5-Bromo-6-cyclopropylmethoxy-pyridine-2-carbonyl)-amino]-2-ethyl-butyric acid ethyl ester;

2-{[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-amino}-2-ethyl-butyric acid ethyl ester;

6-(4-Chloro-3-fluoro-phenyl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

6-(3-Chloro-4-fluoro-phenyl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

2-{[6-Cyclopropylmethoxy-5-(3,3-difluoro-2-oxo-azetidin-1-yl)-pyridine-2-carbonyl]-amino}-2-ethyl-butyric acid methyl ester;

(S)-2-[(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-amino]-4-methyl-pentanoic acid methyl ester;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1-cyano-3-methyl-butyl)-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [3-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-butyl]-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1-hydroxymethyl-1,3-dimethyl-butyl)-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-(azetidine-1-carbonyl)-1-ethyl-propyl]-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-ethyl-1-(2-methoxy-ethylcarbamoyl)-propyl]-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-ethyl-1-(ethyl-methyl-carbamoyl)-propyl]-amide;

6-(4-Fluoro-benzyl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;

6-(4-Fluoro-benzyl)-pyridine-2-carboxylic acid ((R)-2,2,2-trifluoro-1-pyridin-2-yl-ethyl)-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-hydroxymethyl-1,2-dimethyl-propyl)-amide;

5-Bromo-6-(3-methyl-oxetan-3-ylmethoxy)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;

5-Bromo-6-(3-methyl-oxetan-3-ylmethoxy)-pyridine-2-carboxylic acid (3-thiazol-2-yl-oxetan-3-yl)-amide;

5-Bromo-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (3-thiazol-2-yl-oxetan-3-yl)-amide;

5-Bromo-6-(3-methyl-oxetan-3-ylmethoxy)-pyridine-2-carboxylic acid (2,2,2-trifluoro-1-pyridin-2-yl-ethyl)-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-(cyclopropylmethyl-carbamoyl)-1-ethyl-propyl]-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-methyl-1-pyridin-2-yl-ethyl)-amide;

6-(4-Fluoro-benzyl)-pyridine-2-carboxylic acid ((S)-3,3-dimethyl-1-methylcarbamoyl-butyl)-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-(3,3-difluoro-azetidine-1-carbonyl)-1-ethyl-propyl]-amide;

5-(3,3-Difluoro-azetidin-1-yl)-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;

2-[(6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carbonyl)-amino]-2-ethyl-butyric acid ethyl ester;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1-methyl-5-oxo-pyrrolidin-3-yl)-amide;

2-[(6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carbonyl)-amino]-2-ethyl-butyric acid;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1,1-dioxo-tetrahydro-1λ ⁶ -thiophen-3-yl)-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid N′-(1,1-dioxo-tetrahydro-1λ ⁶ -thiophen-3-yl)-hydrazide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-methyl-1-(4-methyl-thiazol-2-yl)-ethyl]-amide;

5-(3,3-Difluoro-azetidin-1-yl)-6-(3-methyl-oxetan-3-ylmethoxy)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-(5-amino-[1,2,4]oxadiazol-3-yl)-1-methyl-ethyl]-amide;

6-(2,2,3,3,3-Pentafluoro-propoxy)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;

5-Cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;

5-Cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid ((S)-3,3-dimethyl-1-methylcarbamoyl-butyl)-amide;

5-Cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

5-Cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid ((S)-carbamoyl-phenyl-methyl)-amide;

5-Cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (2,2,2-trifluoro-1-pyridin-2-yl-ethyl)-amide;

5-Cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide;

5-Cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (3-thiazol-2-yl-oxetan-3-yl)-amide;

5-Cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;

5-Cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (2,2-dimethyl-1-thiazol-2-yl-propyl)-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [1-(3,3-difluoro-azetidine-1-carbonyl)-1-ethyl-propyl]-amide;

6-(4-Fluoro-benzyl)-pyridine-2-carboxylic acid N′-(1,1-dioxo-tetrahydro-1λ ⁶ -thiophen-3-yl)-hydrazide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-(3-amino-[1,2,4]oxadiazol-5-yl)-1-methyl-ethyl]-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [(S)-1-(3,3-difluoro-azetidine-1-carbonyl)-2,2-dimethyl-propyl]-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [(S)-1-(3,3-difluoro-azetidine-1-carbonyl)-3-methyl-butyl]-amide;

2-[(6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carbonyl)-amino]-2-ethyl-butyric acid ethyl ester;

5-Cyclopropyl-6-((R)-3-hydroxy-1-trifluoromethyl-propoxy)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;

5-Cyclopropyl-6-((R)-4,4,4-trifluoro-3-hydroxy-butoxy)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (3-methyl-1-pyridin-2-yl-butyl)-amide;

6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid [1-(3,3-difluoro-azetidine-1-carbonyl)-1-ethyl-propyl]-amide;

6-[(4-Fluoro-phenyl)-hydroxy-methyl]-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;

6-[(4-Fluoro-phenyl)-hydroxy-methyl]-pyridine-2-carboxylic acid [(S)-3-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-butyl]-amide;

5-Cyclopropyl-6-((S)-3-hydroxy-1-trifluoromethyl-propoxy)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;

5-Cyclopropyl-6-((S)-4,4,4-trifluoro-3-hydroxy-butoxy)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (3-methyl-1-pyridazin-3-yl-butyl)-amide;

6-Cyclopropylmethoxy-5-(3-oxo-azetidin-1-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(+)-1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(-)-1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (3-methyl-1-pyridin-3-yl-butyl)-amide;

5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;

5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(S)-carbamoyl-(4-fluoro-phenyl)-methyl]-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(S)-carbamoyl-(4-chloro-phenyl)-methyl]-amide;

6-(2-Methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;

6-Isobutylsulfanyl-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;

5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid ((S)-2,2,2-trifluoro-1-pyridin-2-yl-ethyl)-amide;

2-{[5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carbonyl]-amino}-2-ethyl-butyric acid;

6-Cyclopropylmethoxy-5-(3-oxo-pyrrolidin-1-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

6-(2-Methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid [(S)-3-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-butyl]-amide;

(S)-2-{[5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carbonyl]-amino}-4-methyl-pentanoic acid;

2-{[5-Cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carbonyl]-amino}-2-ethyl-butyric acid;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-methyl-1-(4-methyl-5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (3-methyl-1-pyrimidin-2-yl-butyl)-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [2-cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methylsulfanyl-propyl)-amide;

6-(3-Chloro-4-fluoro-phenyl)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid {(S)-3-methyl-1-[(7-nitro-benzo[1,2,5]oxadiazol-4-ylamino)-methyl]-butyl}-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methanesulfonyl-propyl)-amide;

5-Cyclopropyl-6-isobutylsulfanyl-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;

6-(3-Fluoro-phenyl)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

6-(4-Fluoro-3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (3-methanesulfonyl-1,1-dimethyl-propyl)-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-thiazol-2-yl)-ethyl]-amide;

5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;

5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-thiazol-2-yl)-ethyl]-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((R)-3-methyl-1-pyridazin-3-yl-butyl)-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-3-methyl-1-pyridazin-3-yl-butyl)-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-ethyl-1-(2-hydroxy-ethylcarbamoyl)-propyl]-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(+)-2-cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(-)-2-cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid tert-butylamide;

2-{[5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carbonyl]-amino}-2-ethyl-butyric acid ethyl ester;

5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid ((S)-3,3-dimethyl-1-methylcarbamoyl-butyl)-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-2-oxo-tetrahydro-furan-3-yl)-amide;

N′-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-N-cyclopropylmethyl-hydrazinecarboxylic acid tert-butyl ester;

5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid ((S)-2,2-dimethyl-1-methylcarbamoyl-propyl)-amide;

5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid ((S)-2,2,2-trifluoro-1-pyridin-3-yl-ethyl)-amide;

(S)-2-[(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-amino]-4-methyl-pentanoic acid tert-butyl ester;

5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid tert-butylamide;

5-Cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid tert-butylamide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (3-methyl-oxetan-3-yl)-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (2-oxo-[1,3]oxazin-3-yl)-amide;

5-Cyclopropyl-6-(2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;

5-Cyclopropyl-6-(2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((+)-carbamoyl-cyclopropyl-methyl)-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((-)-carbamoyl-cyclopropyl-methyl)-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((+)-carbamoyl-cyclopropyl-methyl)-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((-)-carbamoyl-cyclopropyl-methyl)-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1-trifluoromethyl-cyclopropyl)-amide;

(+)-5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(3-hydroxy-pyrrolidin-1-ylcarbamoyl)-ethyl]-amide;

(-)-5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(3-hydroxy-pyrrolidin-1-ylcarbamoyl)-ethyl]-amide;

(+)-5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid [1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide; and

(-)-5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid [1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide.

The present invention also particularly relates to compounds of formula (I) selected from:

5-Cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-2-cyclopropyl-1-dimethylcarbamoyl-ethyl)-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((+)-dimethylcarbamoyl-phenyl-methyl)-amide;

6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3-dimethyl-1-methylcarbamoyl-butyl)-amide;

6-(3-Chloro-4-fluoro-phenyl)-pyridine-2-carboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide;

2-{[5-Cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carbonyl]-amino}-2-ethyl-butyric acid methyl ester;

6-Cyclopropylmethoxy-5-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-pyridine-2-carboxylic acid ((S)-3,3-dimethyl-1-methylcarbamoyl-butyl)-amide;

2-Ethyl-2-{[6-(tetrahydro-pyran-4-ylmethoxy)-5-trifluoromethyl-pyridine-2-carbonyl]-amino}-butyric acid methyl ester;

(S)-2-[(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-amino]-3,3-dimethyl-butyric acid methyl ester;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(+)-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-butyl]-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((-)-1-cyano-3-methyl-butyl)-amide;

(S)-3-Cyclopropyl-2-[(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-amino]-propionic acid methyl ester;

6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;

6-(3-Chloro-4-fluoro-phenyl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1-hydroxymethyl-1,3-dimethyl-butyl)-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-ethyl-1-(ethyl-methyl-carbamoyl)-propyl]-amide;

6-(4-Fluoro-benzyl)-pyridine-2-carboxylic acid ((R)-2,2,2-trifluoro-1-pyridin-2-yl-ethyl)-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-hydroxymethyl-1,2-dimethyl-propyl)-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-(3,3-difluoro-azetidine-1-carbonyl)-1-ethyl-propyl]-amide;

5-Cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;

5-Cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid ((S)-3,3-dimethyl-1-methylcarbamoyl-butyl)-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [1-(3,3-difluoro-azetidine-1-carbonyl)-1-ethyl-propyl]-amide;

5-Cyclopropyl-6-((R)-4,4,4-trifluoro-3-hydroxy-butoxy)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;

6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid [1-(3,3-difluoro-azetidine-1-carbonyl)-1-ethyl-propyl]-amide;

6-[(4-Fluoro-phenyl)-hydroxy-methyl]-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;

5-Cyclopropyl-6-((S)-4,4,4-trifluoro-3-hydroxy-butoxy)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(+)-1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (3-methyl-1-pyridin-3-yl-butyl)-amide;

5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(S)-carbamoyl-(4-fluoro-phenyl)-methyl]-amide;

5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid ((S)-2,2,2-trifluoro-1-pyridin-2-yl-ethyl)-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [2-cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

6-(3-Chloro-4-fluoro-phenyl)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid {(S)-3-methyl-1-[(7-nitro-benzo[1,2,5]oxadiazol-4-ylamino)-methyl]-butyl}-amide;

5-Cyclopropyl-6-isobutylsulfanyl-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;

5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-thiazol-2-yl)-ethyl]-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((R)-3-methyl-1-pyridazin-3-yl-butyl)-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(+)-2-cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(-)-2-cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid tert-butylamide;

5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid ((S)-2,2,2-trifluoro-1-pyridin-3-yl-ethyl)-amide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((+)-carbamoyl-cyclopropyl-methyl)-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1-trifluoromethyl-cyclopropyl)-amide; and

(+)-5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid [1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide.

The compounds of the present invention can be prepared, for example, by the following general synthetic procedures.

In the following schemes and descriptions, unless otherwise specified, R ¹ to R ⁴ have the meanings of R ¹ to R ⁴ defined above.

The coupling agent for the reaction of the compound of formula II with the acid of formula III is, for example, N, N'-carbonyldiimidazole (CDI), N, N'-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridine-3-oxide hexafluorophosphate (HATU), 1-hydroxy-1,2,3-benzotriazole (HOBT), O-benzotriazole-1-yl-N, N, N', N'-tetramethyluronium tetrafluoroborate (TBTU) or O-benzotriazole-N, N, N', N'-tetramethyl-urea-hexafluoro-phosphate (HBTU). A particular coupling agent is HBTU. Suitable bases include triethylamine, diisopropylethylamine and, in particular, N-methylmorpholine.

The synthesis of compounds having the general structure I can be accomplished, for example, according to the following scheme.

According to the procedure according to Scheme 1, compound AA (X = Cl, Br, I, triflate; R' = H, methyl, ethyl, isopropyl, tert-butyl or another suitable protecting group as 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 a starting material. AA is either commercially available, described in the literature, or can be synthesized by a person skilled in the art, as described in Schemes 3 and 6 or as described in the experimental section.

Solution 1

Compounds AC can be prepared from AA by coupling an appropriately substituted aryl, heteroaryl or alkenyl metal species of formula AB (step a), in particular an arylboronic acid or arylboronic ester, in the presence of a suitable catalyst, in particular a palladium catalyst and more in particular a palladium(II) acetate/triphenylphosphine mixture or a palladium(II) chloride-dppf (1,1′-bis(diphenylphosphino)ferrocene) complex and a base such as triethylamine, sodium carbonate or potassium phosphate in an inert solvent such as dimethylformamide, toluene, tetrahydrofuran, acetonitrile and dimethoxyethane. Optionally, the alkenyl-containing ^R1 residue can be converted to the corresponding alkyl analog AC by hydrogenation using conditions described in the literature, such as, for example, hydrogen in the presence of a catalyst such as palladium on carbon in a solvent such as ethanol or ethyl acetate, in particular at ambient temperature.

Esters of general formula AC (R'≠H) are saponified by methods well known to those skilled in the art (i.e., using, for example, aqueous LiOH, NaOH or KOH in tetrahydrofuran/ethanol or another suitable solvent at a temperature between 0°C and the reflux temperature of the solvent used) to give acids of general formula II (step b).

Compound I can be prepared by suitable amide bond formation reaction of amine or hydrazine of II and corresponding formula III (step c). These reactions are known in the art. For example, coupling agents such as N, N'-carbonyl-diimidazole (CDI), N, N'-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridine-3-oxide hexafluorophosphate (HATU), 1-hydroxy-1,2,3-benzotriazole (HOBT), O-benzotriazole-1-base-N, N, N', N'-tetramethyluronium tetrafluoroborate (TBTU), and O-benzotriazole-N, N, N', N'-tetramethyl-urea-hexafluoro-phosphate (HBTU) can be used to achieve this transformation. A convenient method is to use, for example, HBTU and a base, such as 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 those skilled in the art (i.e., using, for example, aqueous LiOH, NaOH or KOH in tetrahydrofuran/ethanol or another suitable solvent at a temperature between 0°C and the reflux temperature of the solvent used) to give acids of general formula AD (step b').

Compound AE can be prepared by suitable amide bond formation reaction of AD and corresponding amine or hydrazine of formula III (step c'). These reactions are known in the art. For example, coupling agents such as N, N'-carbonyl-diimidazole (CDI), N, N'-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridine-3-oxide hexafluorophosphate (HATU), 1-hydroxy-1,2,3-benzotriazole (HOBT), O-benzotriazole-1-yl-N, N, N', N'-tetramethyluronium tetrafluoroborate (TBTU), and O-benzotriazole-N, N, N', N'-tetramethyl-urea-hexafluoro-phosphate (HBTU) can be used to achieve this transformation. A convenient method is to use, for example, HBTU and a base, such as N-methylmorpholine, in an inert solvent, such as, for example, dimethylformamide, at room temperature.

Compounds I can be prepared from AE by coupling an appropriately substituted aryl, heteroaryl or alkenyl metal species of formula AB (step a'), in particular an arylboronic acid or arylboronic ester, in the presence of a suitable catalyst, in particular a palladium catalyst and more in particular a palladium(II) acetate/triphenylphosphine mixture or a palladium(II) chloride-dppf (1,1'-bis(diphenylphosphino)ferrocene) complex and a base such as triethylamine, sodium carbonate or potassium phosphate in an inert solvent such as dimethylformamide, toluene, tetrahydrofuran, acetonitrile and dimethoxyethane. Optionally, the alkenyl-containing ^R residue can be converted to the corresponding alkyl analog AE using conditions described in the literature, such as, for example, via hydrogenation using hydrogen in the presence of a catalyst such as palladium on carbon in a solvent such as ethanol or ethyl acetate, in particular at ambient temperature.

Amines or hydrazines III are either commercially available, described in the literature, can be synthesized by one skilled in the art or as described in the experimental part.

If one of the starting materials, i.e., compounds of formula AA, AB or III, contains one or more functional groups that are unstable or reactive under the reaction conditions of one or more reaction steps, a suitable protecting group (P) can be introduced prior to the key step using methods well known in the art (as described, for example, in T. W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3rd edition). Such protecting groups can be removed at a later stage of the synthesis using standard methods known in the art.

If one or more of the compounds of formula AA to AE, II or III contain a chiral center, the picoline of formula I may be obtained as a mixture of diastereomers or enantiomers, which can be separated by methods well known in the art, such as (chiral) HPLC or crystallization. Racemic compounds can be separated into their enantiomers, for example, by crystallization of diastereomeric salts or by enantiomeric separation by specific chromatographic methods using chiral adsorbents or chiral eluents.

According to the procedure according to Scheme 2, compound BA (R' = H, methyl, ethyl, isopropyl, tert-butyl or other suitable protecting groups as described 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 commercially available, described in the literature or can be synthesized by those skilled in the art.

Option 2

Compound BB can be prepared from BA by oxidation with a suitable oxidizing agent under conditions known to those skilled in the art (step a), for example by treatment with 3-chloroperbenzoic acid in dichloromethane at ambient temperature.

The conversion of compound BB to 6-chloro or 6-bromo-methylpyridine AA' (X = Cl, Br) can be achieved, for example, by treatment with phosphoryl trichloride or tribromide (step b) without using additional solvent or in a suitable solvent such as chloroform at a temperature between 20 ° C and the boiling point of the solvent, or by using other conditions known in the literature.

6-Chloro- or bromo-methylpyridine AA' (X = Cl, Br) can be converted to compound BD by reaction with an appropriately substituted primary or secondary alcohol BC in the presence of a base such as sodium hydride, with or without an inert solvent such as dimethylformamide, at a temperature ranging from room temperature to the reflux temperature of the solvent, in particular at room temperature (step c). Alternatively, compound AA' can be converted to an amino derivative BD by treatment with an amine BC using methods well known in the art (step c), for example using a palladium-promoted amination reaction with palladium(II) acetate/2-(dicyclohexylphosphino)biphenyl as a 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 compound 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 as 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 to its acid analog AA′ (R′=H), as described in step b of Scheme 1; ii) converted to the corresponding amide or hydrazide by treatment with an amine or hydrazine III, as described in step c of Scheme 1; and iii) reacted with an alcohol BC, as described in step c, to provide compound I.

If one of the starting materials, i.e., compounds of formula BA, BC or III, contains one or more functional groups that are unstable or reactive under the reaction conditions of one or more reaction steps, a suitable protecting group (P) can be introduced prior to the key step using methods well known in the art (as described, for example, in T. W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3rd edition). Such protecting groups can be removed at a later stage of the synthesis using standard methods known in the art.

If one or more of the compounds of formula BA to BD, AA', II or III contain a chiral center, the picoline of formula I may be obtained as a mixture of diastereomers or enantiomers, which can be separated by methods well known in the art, such as (chiral) HPLC or crystallization. Racemic compounds can be separated into their enantiomers, for example, by crystallization of diastereomeric salts or by enantiomeric separation by specific chromatographic methods using chiral adsorbents or chiral eluents.

Compound CA (R' = H, methyl, ethyl, isopropyl, tert-butyl or another suitable protecting group as 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 a starting material according to the procedure according to Scheme 3. CA is commercially available (for example, for R' = methyl: 5-bromo-6-chloro-pyridine-2-carboxylic acid methyl ester CAN 1214353-79-3), described in the literature or can be synthesized by a person skilled in the art.

Option 3

Compound AA" can be prepared from CA by coupling an appropriately substituted aryl, heteroaryl or alkenyl metal species of formula CB (step a), for example a potassium salt of an organotrifluoroborate, in the presence of a palladium catalyst such as palladium(II) acetate/butyl-1-adamantylphosphine and a base such as cesium carbonate, in an inert solvent such as toluene at a temperature 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, particularly a palladium catalyst and more particularly a palladium(II) acetate/triphenylphosphine mixture or a palladium(II) chloride-dppf (1,1'-bis(diphenylphosphino)ferrocene) complex and a base such as triethylamine, sodium carbonate or potassium phosphate, in an inert solvent such as dimethylformamide, toluene, tetrakis(III) phosphate. Hydrofuran, acetonitrile or dimethoxyethane. Optionally, compound CB can also be an amine or amide, which is coupled to CA by methods well known to those skilled in the art, for example using a palladium catalyst such as tris(dibenzylideneacetone)dipalladium/dimethylbisphenyl-phosphinoxanthene and a base such as cesium carbonate in a solvent such as 1,4-dioxane, preferably at the boiling point of the solvent. Alternatively, compound CB can also be a sulfonamide, which reacts with the copper(I)-mediated reaction of CA to form AA according to procedures described in the literature, for example using copper(I) iodide and 1,3-di(pyridin-2-yl)propane-1,3-dione in the presence of a base such as potassium carbonate in a solvent such as dimethylformamide at elevated temperature, preferably at the boiling point of the solvent. Optionally, alkenyl-containing ^R2 residues can be converted to the corresponding alkyl analogs AA" by hydrogenation using conditions described in the literature, such as, for example, hydrogen in the presence of a catalyst such as palladium on carbon in a solvent such as ethanol or ethyl acetate, especially 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.

Additionally, compound CA can be converted to compound CC by treatment with compound BC as described in step c of Scheme 2 (step b).

The subsequent conversion of compound CC to compound BD can be achieved as discussed for the conversion of CA to 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 as described, for example, in T. W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3rd ed.) can be: i) converted to its acid analog CC (R′=H) as described in step b of Scheme 1; ii) converted to the corresponding amide or hydrazide CD by treatment with an amine or hydrazine III as described in step c of Scheme 1; and iii) reacted with CB as described in step a to provide compound I.

In addition, compound I can also be synthesized using the following reaction sequence: i) saponification of compound CA (R' = methyl, ethyl, isopropyl, tert-butyl, or another suitable protecting group as 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 analog CC (R' = H), as described in step b of Scheme 1; ii) conversion to the corresponding amide or hydrazide by treatment with an 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, steps iii) and iv) can be interchanged.

If one of the starting materials, i.e., compounds of formula CA, CB or BC, contains one or more functional groups that are unstable or reactive under the reaction conditions of one or more reaction steps, a suitable protecting group (P) can be introduced prior to the key step using methods well known in the art (as described, for example, in T. W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3rd edition). Such protecting groups can be removed at a later stage of the synthesis using standard methods known in the art.

If one or more of the compounds of formula CA, CB or BC contains a chiral center, the picolinyls of formula AA" and BD may be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art, such as (chiral) HPLC or crystallization. Racemic compounds can be separated into their enantiomers, for example, by crystallization of diastereomeric salts or by enantiomeric separation by specific chromatographic methods using chiral adsorbents or chiral eluents.

Compound CC (R' = H, methyl, ethyl, isopropyl, tert-butyl or another suitable protecting group as 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 a starting material according to the procedure according to Scheme 4. CC is commercially available, described in the literature, and can be synthesized by the method described in Scheme 3 or by other methods known to those skilled in the art.

Option 4

Compounds BD can be prepared from CC by coupling an appropriately substituted aryl, heteroaryl or alkenyl metal species of formula CB (step a), for example a potassium salt of an organotrifluoroborate, in the presence of a palladium catalyst such as palladium(II) acetate/butyl-1-adamantylphosphine and a base such as cesium carbonate, in an inert solvent such as toluene, at a temperature 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, particularly a palladium catalyst and more particularly a palladium(II) acetate/triphenylphosphine mixture or a palladium(II) chloride-dppf (1,1′-bis(diphenylphosphino)ferrocene) complex 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 converted to the corresponding alkyl analogs BD by hydrogenation using conditions described in the literature, such as, for example, hydrogen in the presence of a catalyst such as palladium on carbon in a solvent such as ethanol or ethyl acetate, especially at ambient temperature.

Alternatively, compound CC can be converted into the amino derivative BD by treatment with an amine BC using methods well known in the art (step b), for example using 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 with CC by methods well known to those skilled in the art, for example using a palladium catalyst such as tris(dibenzylideneacetone)dipalladium/dimethylbisbiphenyl-phosphinoxanthene and a base such as cesium carbonate in a solvent such as 1,4-dioxane, preferably at the boiling point of the solvent.

Compound CC can be further reacted with ketone DA (R ^2′ = alkyl, cycloalkyl, or oxyoxetane) to obtain compound BD by following procedures known to those skilled in the art, for example: i) treatment with n-butyllithium in a solvent such as tetrahydrofuran at a temperature of −78° C.; ii) addition of ketone DA or optionally another suitable electrophile at a temperature 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, i.e., compounds of formula CC, CB, BC or DA, contains one or more functional groups that are unstable or reactive under the reaction conditions of one or more reaction steps, a suitable protecting group (P) can be introduced prior to the key step using methods well known in the art (e.g., as described in T. W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3rd edition). Such protecting groups can be removed at a later stage of the synthesis using standard methods known in the art.

If one or more of the compounds of formula CC, CB, BC or DA contains a chiral center, the picolinamide of formula BD may be obtained as a mixture of diastereomers or enantiomers, which can be separated by methods well known in the art, such as (chiral) HPLC or crystallization. Racemic compounds can be separated into their enantiomers, for example, by crystallization of diastereomeric salts or by enantiomeric separation by specific chromatographic methods using chiral adsorbents or chiral eluents.

Following the procedure according to Scheme 5, compound AA" (R'=H) can be used as starting material. AA" is commercially available, described in the literature and can be synthesized as described in Scheme 2 or by other methods known to those skilled in the art.

Option 5

Compound EA can be prepared from AA" (step a), for example, 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 those skilled in the art.

The subsequent esterification of EA to compound EB (R' = methyl, ethyl, isopropyl, tert-butyl or another suitable protecting group (P) (as 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 carried out, for example, using a solution of hydrogen chloride in methanol at ambient temperature, or by an alternative method as described, for example, in T. W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3rd edition (step b).

The sulfonic acid EB can be converted into the sulfonamide ED (step c) by reaction with a suitable amine EC (R ^1′ = alkyl, R 1″ = alkyl, or R ^1′ and R ^{1 ″} together with the nitrogen atom to which they are attached form a cyclic amine), in particular at ambient temperature or by using any other method known to those skilled in the art.

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, i.e., compounds of formula AA", EC or III, contains one or more functional groups that are unstable or reactive under the reaction conditions of one or more reaction steps, a suitable protecting group (P) can be introduced prior to the key step using methods well known in the art (as described, for example, in T. W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3rd edition). Such protecting groups can be removed at a later stage in the synthesis using standard methods known in the art.

If one or more of the compounds of formula AA", EA to ED, II or III contains a chiral center, the picoline of formula I may be obtained as a mixture of diastereomers or enantiomers, which can be separated by methods well known in the art, such as (chiral) HPLC or crystallization. Racemic compounds can be separated into their enantiomers, for example, by crystallization of diastereomeric salts or by enantiomeric separation by specific chromatographic methods using chiral adsorbents or chiral eluents.

Compound FA (X = Cl, Br, I, triflate; R' = H, methyl, ethyl, isopropyl, tert-butyl or another suitable protecting group as 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 a starting material according to the procedure according to Scheme 6. FA is commercially available, described in the literature or can be synthesized by a person skilled in the art.

Option 6

Compounds BA can be prepared from FA by coupling an appropriately substituted aryl, heteroaryl or alkenyl metal species of formula CB (step a), for example a potassium salt of an organotrifluoroborate, in the presence of a palladium catalyst such as palladium(II) acetate/butyl-1-adamantylphosphine and a base such as cesium carbonate, in an inert solvent such as toluene, at a temperature 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 in particular a palladium(II) acetate/triphenylphosphine mixture or a palladium(II) chloride-dppf (1,1′-bis(diphenylphosphino)ferrocene) complex 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 those skilled in the art, for example using a palladium catalyst such as tris(dibenzylideneacetone)dipalladium/dimethylbisphenyl-phosphinoxanthene and a base such as cesium carbonate in a solvent such as 1,4-dioxane, preferably at the boiling point of the solvent. Optionally, an alkenyl-containing ^R residue can be converted to the corresponding alkyl analog BA by hydrogenation using conditions described in the literature, such as, for example, hydrogen in the presence of a catalyst such as palladium on carbon in a solvent such as ethanol or ethyl acetate, especially at ambient temperature.

Compound BB can be prepared from BA (step b) by oxidation with a suitable oxidizing agent as described in Scheme 2, step a.

Conversion of compound BB to 6-chloro- or 6-bromo-methylpyridine AA' (X = Cl, Br) can be achieved as described in step b of scheme 2 (step c).

Compounds AC can be prepared from AA' by coupling an appropriately substituted aryl, heteroaryl or alkenyl metal species of formula AB (step d), in particular an arylboronic acid or arylboronic ester, in the presence of a suitable catalyst, in particular a palladium catalyst and more particularly a palladium(II) acetate/triphenylphosphine mixture or a palladium(II) chloride-dppf (1,1'-bis(diphenylphosphino)ferrocene) complex 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 ^R residues can be converted to the corresponding alkyl analogs AC by hydrogenation using conditions described in the literature, such as, for example, hydrogen gas in the presence of a catalyst such as palladium on carbon in a solvent such as ethanol or ethyl acetate, in particular 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 the starting material, i.e., one of the compounds of formula FA, CB, AB or III, contains one or more functional groups that are unstable or reactive under the reaction conditions of one or more reaction steps, a suitable protecting group (P) can be introduced prior to the key step using methods well known in the art (as described, for example, in T. W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3rd edition). Such protecting groups can be removed at a later stage of the synthesis using standard methods known in the art.

If one or more of the compounds of formula FA, CB, BA, BB, AA', AB, AC, II or III contain a chiral center, the picoline of formula I may be obtained as a mixture of diastereomers or enantiomers, which can be separated by methods known in the art, such as (chiral) HPLC or crystallization. Racemic compounds can be separated into their enantiomers, for example, by crystallization of diastereomeric salts or by enantiomeric separation by specific chromatographic methods using chiral adsorbents or chiral eluents.

Compound GA can be used as starting material following the procedure according to Scheme 7. GA is commercially available, described in the literature or can be synthesized by a person skilled in the art.

Option 7

Compound GB can be prepared from GA by oxidation with a suitable oxidizing agent under conditions known to those skilled in the art (step a), for example by treatment with 3-chloroperbenzoic acid in dichloromethane at ambient temperature.

The conversion of compound GB to 6-chloro or 6-bromo compound GC (X = Cl, Br) can be achieved, for example, by treatment with phosphoryl trichloride or tribromide (step b), without additional solvent or in a suitable solvent such as chloroform, at a temperature between 20° C. and the boiling point of the solvent, or by using other conditions known in the literature.

The hydrolysis of compound GC gives picolinyl GD and can be carried out under acidic or basic conditions known to those skilled in the art, for example by treatment with aqueous sodium hydroxide at 100° C. (step c).

Compound II can be prepared from GD by coupling an appropriately substituted aryl, heteroaryl or alkenyl metal species of formula AB (step d) as described in step d of Scheme 6. Optionally, an alkenyl-containing ^R1 residue can be converted to the corresponding alkyl analog II by hydrogenation using conditions described in the literature, such as, for example, 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 the event that the acid group in compound GD is incompatible with the conditions for introduction of the ^R1 residue, a suitable protecting group such as an ester protecting group, for example, a methyl ester, can be introduced prior to step d and removed at a later point in the synthesis. The introduction and removal of protecting groups can be carried out by suitable methods known in the art (for further details, see TW 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 accomplished by employing amide bond forming conditions as described in step c of Scheme 1 (step e).

If one of the starting materials, i.e., compounds of formula GA, AB or III, contains one or more functional groups that are unstable or reactive under the reaction conditions of one or more reaction steps, a suitable protecting group (P) can be introduced prior to the key step using methods well known in the art (as described, for example, in T. W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3rd edition). Such protecting groups can be removed at a later stage of the synthesis using standard methods known in the art.

If one or more of the compounds of formula GA, to GD, AB, II or III contain a chiral center, the picoline of formula I may be obtained as a mixture of diastereomers or enantiomers, which can be separated by methods well known in the art, such as (chiral) HPLC or crystallization. Racemic compounds can be separated into their enantiomers, for example, by crystallization of diastereomeric salts or by enantiomeric separation by specific chromatographic methods using chiral adsorbents or chiral eluents.

Compound HA can be used as starting material (R ¹⁰ = hydrogen or alkyl; R ¹¹ = hydrogen or alkyl) following the procedure according to Scheme 8. HA is commercially available, described in the literature or can be synthesized by a person skilled in the art.

Option 8

Compound HC can be prepared from HA using methods described in the literature, for example by treatment with methyl propiolate in ammonia at elevated temperature in an autoclave (step a).

The conversion of compound HC to HD can be carried out, for example, using trifluoromethanesulfonic anhydride in the presence of a base such as triethylamine in a solvent such as dichloromethane at a temperature preferably between -50°C and ambient temperature, or by any other suitable method known to those skilled in the art (step b). Alternatively, other groups other than trifluoromethanesulfonate suitable for the conversion of HD to HE can be introduced according to procedures described in the literature.

Compound HE (R' = methyl, ethyl, isopropyl, tert-butyl or another suitable protecting group) can be synthesized from HD as follows: via palladium-catalyzed carbonylation, using a palladium catalyst such as palladium(II) chloride-dppf (1,1'-bis(diphenylphosphino)ferrocene) complex, under a carbon monoxide atmosphere, preferably at a pressure of 70 bar, in the presence of an amine such as triethylamine, in a solvent system consisting, for example, of methanol and ethyl acetate, at elevated temperature (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 the starting material, i.e., one of the compounds of formula HA or III, contains one or more functional groups that are unstable or reactive under the reaction conditions of one or more reaction steps, a suitable protecting group (P) can be introduced prior to the key step using methods well known in the art (as described, for example, in T. W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3rd edition). Such protecting groups can be removed at a later stage of the synthesis using standard methods known in the art.

If one or more of the compounds of formula HA, HC to HE, II or III contains a chiral center, the picoline of formula I may be obtained as a mixture of diastereomers or enantiomers, which can be separated by methods known in the art, such as (chiral) HPLC or crystallization. Racemic compounds can be separated into their enantiomers, for example, by crystallization of diastereomeric salts or by enantiomeric separation by specific chromatographic methods using chiral adsorbents or chiral eluents.

Commercially available 5-bromo-6-methyl-pyridine-2-carbonitrile IA (CAN 1173897-86-3) can be used as starting material according to the procedure according to Scheme 9. In Scheme 9, R ¹ is benzyl or halobenzyl; R ^1′ is phenyl or halobenyl.

Option 9

Compound IB can be prepared from IA by treatment with compound CB as described in step a of Scheme 6 (step a).

Further conversion of IB to IC can be achieved by oxidation with a suitable oxidizing agent as described in step a of Scheme 7 (step b).

Conversion of N-oxide IC to alcohol ID can be carried out under conditions well known to those skilled in the art, for example by reaction with trifluoroacetic anhydride in a solvent such as dichloromethane, preferably at ambient temperature, and subsequent treatment with a base such as sodium hydroxide (step c).

The reaction of converting alcohol ID into compound IE containing a leaving group (Y═Cl, Br or another suitable leaving group) is well described in the literature and known to those skilled in the art (step d). For example, alcohol ID can be converted into compound IE wherein Y═Br by reacting with carbon tetrabromide and triphenylphosphine in a solvent such as tetrahydrofuran at a temperature between 0° C. and the boiling point of the solvent, preferably at 40° C.

The conversion of compound IE to compound IF can be accomplished, for example, by coupling an appropriately substituted aryl metal species of formula AB′, in particular an aryl boronic acid or aryl boronic ester, in the presence of a suitable catalyst, in particular a palladium catalyst and more in particular a palladium(II) acetate/triphenylphosphine mixture or a palladium(II) chloride-dppf (1,1′-bis(diphenylphosphino)ferrocene) complex 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 using the method described in step c of Scheme 7 (step f).

Further conversion of compound II to compound I can be accomplished by employing amide bond forming conditions as described in step c of Scheme 1 (step e).

If the starting material, i.e., one of the compounds of formula IA, CB, AB' or III, contains one or more functional groups that are unstable or reactive under the reaction conditions of one or more reaction steps, a suitable protecting group (P) can be introduced prior to the key step using methods well known in the art (as described, for example, in T. W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3rd edition). Such protecting groups can be removed at a later stage of the synthesis using standard methods known in the art.

If one or more of the compounds of formula IA to IF, CB, AB ', II or III contain a chiral center, the picoline of formula I may be obtained as a mixture of diastereomers or enantiomers, which can be separated by methods well known in the art, such as (chiral) HPLC or crystallization. Racemic compounds can be separated into their enantiomers, for example, by crystallization of diastereomeric salts or by enantiomeric separation by specific chromatographic methods using chiral adsorbents or chiral eluents.

Compound I can be further elaborated by methods known in the art to give additional compounds of general structure I. Some examples are shown in Scheme 10. In Scheme 10, R ¹² is isobutyl and n is 0, 1 or 2.

Compounds of general structure KB (subgroup of I) can be prepared from compounds of general structure KA (another subgroup of I) by oxidation methods well known in the art, for example by Swern-oxidation, using DMSO and a suitable activating agent such as, for example, oxalyl chloride, in an inert solvent such as, for example, dichloromethane, in the presence of a suitable base, at a temperature in the range of -70°C to room temperature.

Compounds of general structure KD (a subset of I) can be prepared from compounds of general structure KC (another subset of I) by converting the alcohol functionality into an azide functionality by methods known in the art. This conversion can be achieved, for example, by treating a solution of the alcohol in an inert solvent such as DMF with sodium azide, triphenylphosphine, and carbon tetrachloride at an elevated temperature, such as 90°C. Further elaboration to the corresponding amine KE is accomplished by reduction methods well known in the art, such as, for example, by reduction with sodium borohydride in 2-propanol in the presence of 1,3-propanedithiol and triethylamine at ambient temperature. Amine KD can be further converted to compounds of general structure KF by reaction with 7-nitro-2,1,3-benzoxadiazol-4-amine in an inert solvent such as THF at a temperature ranging from room temperature to the boiling point of the solvent.

Plan 10

If one of the starting materials, i.e., compounds of formula KA or KC, contains one or more functional groups that are unstable or reactive under the reaction conditions of one or more reaction steps, a suitable protecting group (P) can be introduced prior to the key step using methods well known in the art (as described, for example, in T. W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3rd edition). Such protecting groups can be removed at a later stage of the synthesis using standard methods known in the art.

If one or more of the compounds of formula KA or KC contains a chiral center, the picoline of formula I may be obtained as a mixture of diastereomers or enantiomers, which can be separated by methods well known in the art, such as (chiral) HPLC or crystallization. Racemic compounds can be separated into their enantiomers, for example, via diastereomeric salts by crystallization or by enantiomeric separation by specific chromatographic methods using chiral adsorbents or chiral eluents.

The present invention also relates to a method for preparing a compound of formula (I), comprising reacting a compound of formula (A) in the presence of NHR ³ R ⁴ , an amide bond-forming coupling agent and a base,

wherein R ¹ to R ⁴ are as defined above.

Examples of coupling agents that form amide bonds are N,N′-carbonyl-diimidazole (CDI), N,N′-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridine-3-oxide hexafluorophosphate (HATU), 1-hydroxy-1,2,3-benzotriazole (HOBT), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) and O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate (HBTU).

Examples of suitable bases are tertiary amine bases such as triethylamine, N-methylmorpholine, N,N-diisopropylethylamine or 4-(dimethylamino)-pyridine.

The reaction temperature is, for example, room temperature.

A convenient method is to use, for example, HBTU and a base, such as N-methylmorpholine, in an inert solvent such as, for example, dimethylformamide at room temperature.

The invention further relates to compounds of formula (I) for use as therapeutically active substances.

The present invention further relates to pharmaceutical compositions comprising a compound of formula (I) and a therapeutically inert carrier.

Another object of the present invention is the use of the compounds of formula (I) for the treatment or prevention of pain, in particular chronic pain, atherosclerosis, bone regulation, inflammation, ischemia, reperfusion injury, systemic fibrosis, liver fibrosis, pulmonary fibrosis, renal fibrosis, chronic allograft nephropathy, congestive heart failure, myocardial infarction, systemic sclerosis, glomerulonephropathy, thermal injury, burns, hypertrophic scars, keloids, gingivitis fever, cirrhosis or tumors.

Another object of the present invention is the use of a compound of formula (I) for the preparation of a medicament for treating or preventing chronic pain, in particular chronic pain, atherosclerosis, bone regulation, inflammation, ischemia, reperfusion injury, systemic fibrosis, liver fibrosis, pulmonary fibrosis, renal fibrosis, chronic allograft nephropathy, congestive heart failure, myocardial infarction, systemic sclerosis, glomerulonephropathy, thermal injury, burns, hypertrophic scars, keloids, gingivitis and fever, cirrhosis or tumors.

The present invention also relates to compounds of formula (I) for use in the treatment or prevention of pain, in particular chronic pain, atherosclerosis, bone regulation, inflammation, ischemia, reperfusion injury, systemic fibrosis, liver fibrosis, pulmonary fibrosis, renal fibrosis, chronic allograft nephropathy, congestive heart failure, myocardial infarction, systemic sclerosis, glomerulonephropathy, thermal injury, burns, hypertrophic scars, keloids, gingivitis fever, cirrhosis or tumors.

The present invention particularly relates to compounds of formula (I) for use in treating or preventing ischemia, reperfusion injury, liver fibrosis or kidney fibrosis, in particular ischemia or reperfusion injury.

The present invention further relates to compounds of formula (I) prepared by the process according to the invention.

The present invention also relates to a method for treating or preventing pain, in particular chronic pain, atherosclerosis, bone remodeling, inflammation, ischemia, reperfusion injury, systemic fibrosis, liver fibrosis, pulmonary fibrosis, renal fibrosis, chronic allograft nephropathy, congestive heart failure, myocardial infarction, systemic sclerosis, glomerulonephropathy, thermal injury, burns, hypertrophic scars, keloids, gingivitis fever, liver cirrhosis or tumors, which comprises administering an effective amount of a compound of formula (I).

Another embodiment of the present invention provides a pharmaceutical composition or medicine comprising a compound of the present invention and a therapeutically inert carrier, diluent or excipient, and methods for preparing such compositions and medicines using the compounds of the present invention. In one example, the compound of formula (I) can be formulated as follows: by mixing into a galenic dosage form at ambient temperature at a suitable pH, and at a desired degree of purity, with a physiologically acceptable carrier, i.e., a carrier that is nontoxic to the recipient at the dosage and concentration employed. The pH of the preparation depends primarily on the specific purposes and concentration of the compound, but is preferably anywhere within the range of about 3 to about 8. In one example, the compound of formula (I) is formulated in acetate buffer at pH 5. In another embodiment, the compound of formula (I) is sterile. The compound can be, for example, as a solid or amorphous composition, as a lyophilized preparation or as an aqueous solution for storage.

The composition is formulated, dosed, and administered in a manner consistent with good medical practice. Factors for consideration include the specific condition being treated, the specific mammal being treated, the clinical condition of the individual patient, the cause of the condition, the site of delivery of the agent, the method of administration, the timing of administration, and other factors known to practitioners.

The compounds of the present invention can 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 can be administered in any convenient administration form, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain conventional components of pharmaceutical preparations, for example, diluents, carriers, pH adjusters, sweeteners, fillers, and other active agents.

Typical formulations are prepared by mixing a compound of the invention with a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, for example, 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 formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, flavoring agents, flavor enhancers, diluents and other known additives to provide a good presentation of the drug (i.e., the compound of the present invention or its pharmaceutical composition) or to assist in the preparation of a pharmaceutical product (i.e., a drug).

The invention will now be illustrated by the following non-limiting examples.

Example

abbreviation

MS = mass spectrometry; EI = electron impact; ISP = ion spray, corresponding to ESI (electrospray); NMR data are reported in parts per million (δ) relative to the internal standard tetramethylsilane and 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-isopropylpropan-2-amine; DMF = dimethylformamide; DMSO = dimethyl sulfoxide; dppf = 1,1′-bis(diphenylphosphino)ferrocene; HATU = 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3 , 3-tetramethylisourea hexafluorophosphate (V); HBTU = O-benzotriazole-N,N,N',N'-tetramethyl-urea-hexafluoro-phosphate; HPLC = LC = high performance liquid chromatography; m-CPBA = meta-chloroperbenzoic acid; Rt = retention time; TBTU = O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyl-urea-tetrafluoroborate; TEMPO = 2,2,6,6-tetramethylpiperidin 1-oxyl free radical; THF = tetrahydrofuran; tlc = thin layer chromatography.

Example 1

Methyl 2-(6-(3-chlorophenyl)picolinamido)-2-methylpropanoate

A solution of 6-(3-chlorophenyl)-2-picolinic acid (CAN 863704-38-5, 0.2 mmol), 2-methyl-alanine methyl ester (0.2 mmol), and HBTU (CAN 94790-37-1, 114 mg, 0.3 mmol) in DMF (0.5 mL) was stirred at room temperature for 20 h. The crude reaction mixture was concentrated in vacuo by centrifugation and purified by flash chromatography (silica gel, 20 g, 0% to 100% ethyl acetate in heptane) to give the desired product (73 mg, 116%) as a light yellow oil along with some impurities; MS (LC/MS): 333.1 (M+H).

Example 2

Methyl 2-(6-(2-chlorophenyl)picolinamido)-2-methylpropanoate

The title compound was synthesized similarly to Example 1 using 6-(2-chlorophenyl)-2-pyridinecarboxylic acid (CAN 887982-21-0) and 2-methyl-alanine methyl ester as starting materials, MS (LC/MS): 333.1 (M+H).

Example 3

6-(4-Chloro-phenyl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized similarly to Example 1 using 6-(4-chlorophenyl)-2-pyridinecarboxylic acid (CAN 135432-77-8) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (LC/MS): 357.1 (M+H).

Example 4

Methyl 2-methyl-2-(5-methyl-6-(2,2,2-trifluoroethoxy)picolinamido)propanoate

a) 5-Methyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid

A mixture of 6-chloro-5-methyl-pyridine-2-carboxylic acid (CAN 1166828-13-2, 200 mg, 1.17 mmol), 2,2,2-trifluoroethanol (466 mg, 336 μl, 4.66 mmol) and 1,8-diazabicyclo(5.4.0)undec-7-ene (CAN 83329-50-4, 887 mg, 870 μl, 5.83 mmol) was shaken in a sealed tube at 140° C. for 2 days and then at 150° C. for another 5 days. The brown solution was poured into 25 mL of ice/0.1 N HCl and extracted with i-PrOAc (2×25 mL). The organic layer was washed with ice/brine (2×25 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to give the title compound (198 mg, 58%) as an off-white solid containing traces of starting material, MS (EI): m/e = 233.9 [MH] ⁻ .

b) Methyl 2-methyl-2-(5-methyl-6-(2,2,2-trifluoroethoxy)picolinamido)propanoate

A solution of 5-methyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (30 mg, 128 μmol), 2-methyl-alanine methyl ester hydrochloride (23.5 mg, 153 μmol), HATU (CAN 148893-10-1, 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 yield 53 mg of a yellow solid. This solid was purified by preparative TLC (silica gel, 2.0 mm, 1:1 heptane/i-PrOAc) eluting from the silica gel with i-PrOAc. Filtration through speedex and evaporation under reduced pressure yielded the title compound (10 mg, 23%) as a colorless liquid. MS (EI): m/e = 335.2 [M+H] ⁺ .

Example 5

Methyl 2-(5-cyclopropyl-6-(2,4-dichlorophenylamino)picolinamido)-2-methylpropanoate

a) 6-Chloro-5-cyclopropyl-pyridine-2-carboxylic acid methyl ester

To palladium acetate (II) (17.9mg, 79.8μmol) under argon atmosphere, butyl-1-adamantylphosphine (42.9mg, 120μmol), cyclopropyl trifluoroborate potassium (597mg, 4.03mmol) and cesium carbonate (3.9g, 12.0mmol) mixture, add 5-bromo-6-chloro-pyridine-2-formic acid methyl ester (CAN 1214353-79-3,1g, 3.99mmol) under argon atmosphere in toluene (25.2ml) and water (2.8mL).Reaction mixture is heated to 100 ℃ and lasts for 20h, diluted with water (17.5ml), poured on 100ml ice/brine and extracted with i-PrOAc (2x 100mL).The extracts merged are dried over sodium sulfate and concentrated in vacuo to obtain a yellow liquid. The crude material was purified by column chromatography (70 g _SiO2 , n-heptane/i-PrOAc 0-10% in 120 min) to give the title compound (497 mg, 59%) as a yellow solid, MS (EI): m/e = 212.0 [M+H] ⁺ .

b) 5-Cyclopropyl-6-(2,4-dichloro-phenylamino)-pyridine-2-carboxylic acid methyl ester

By palladium acetate (II) (4.24mg under argon atmosphere, 18.9 μ mol) and 2-(dicyclohexylphosphino) biphenyl (13.2mg, 37.8 μ mol) solution in diox (1.9ml) stirs 10min at envrionment temperature, and join 6-chloro-5-cyclopropyl-pyridine-2-methyl-formiate (100mg under argon atmosphere, 472 μ mol), 2,4-dichloroaniline (76.6mg, 472 μ mol) and salt of wormwood (1.31g, 9.45mmol) suspension in diox (3.24ml).Yellow suspension is heated to reflux and stirs 20h.Reaction mixture is poured in 20mL ice/salt water and extracted with i-PrOAc (2x 50mL).The organic layer merged is washed with ice/salt water (1x 50mL), with dried over sodium sulfate and concentrated in a vacuum, obtain 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 a light brown liquid, MS (EI): m/e = 337.2 [M+H] ⁺ .

c) 5-Cyclopropyl-6-(2,4-dichloro-phenylamino)-pyridine-2-carboxylic acid

A solution of 5-cyclopropyl-6-(2,4-dichloro-phenylamino)-pyridine-2-carboxylic acid methyl ester (62 mg, 184 μmol) and lithium hydroxide hydrate (9.3 mg, 221 μmol) in THF (100 μl) and water (50 μl) was stirred at ambient temperature for 20 h. The reaction mixture was poured onto 1M HCl/ice water (1 x 20 mL) and extracted with i-PrOAc (2 x 25 mL). The combined organic layers were dried over sodium sulfate. The solvent was removed under reduced pressure to obtain the title compound (6 mg, 10%) as a colorless liquid of sufficient purity to be used in the next reaction step. MS (EI): m/e=323.3[M+H] ⁺ .

d) Methyl 2-(5-cyclopropyl-6-(2,4-dichlorophenylamino)picolinamido)-2-methylpropanoate

The title compound was synthesized similarly to Example 4b using 5-cyclopropyl-6-(2,4-dichloro-phenylamino)-pyridine-2-carboxylic acid and 2-methyl-alanine methyl ester as starting materials, MS (EI): m/e 422.1 [M+H] ⁺ .

Example 6

2-(6-(2,4-dichlorophenylamino)-5-methylpicolinamido)-2-methylpropionic acid methyl ester

a) 6-(2,4-Dichloro-phenylamino)-5-methyl-pyridine-2-carboxylic acid methyl ester

Analogously to Example 5b, 6-(2,4-dichloro-phenylamino)-5-methyl-pyridine-2-carboxylic acid methyl ester was synthesized using 6-chloro-5-methyl-pyridine-2-carboxylic acid methyl ester (CAN 178421-22-2) and 2,4-dichloroaniline as starting materials. MS (EI): m/e 311.3 [M+H] ⁺ .

b) 6-(2,4-Dichloro-phenylamino)-5-methyl-pyridine-2-carboxylic acid

Analogously to Example 5c, 6-(2,4-dichloro-phenylamino)-5-methyl-pyridine-2-carboxylic acid was synthesized using 6-(2,4-dichloro-phenylamino)-5-methyl-pyridine-2-carboxylic acid methyl ester as starting material. MS (EI): m/e 297.2 [M+H] ⁺ .

c) Methyl 2-(6-(2,4-dichlorophenylamino)-5-methylpicolinamido)-2-methylpropanoate

The title compound was synthesized similarly to Example 4b using 6-(2,4-dichloro-phenylamino)-5-methyl-pyridine-2-carboxylic acid and 2-methyl-alanine methyl ester as starting materials, MS (EI): m/e 396.0 [M+H] ⁺ .

Example 7

2-[(6-Cyclohexyl-pyridine-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester

a) 6-Cyclohexenyl-pyridine-2-carboxylic acid

Under a nitrogen atmosphere, a solution of 6-bromopyridine-2-carboxylic acid (CAN 1190-87-4, 3 g, 6.4 mol), cyclohexenylboronic acid (CAN 21190-87-4, 0.89 g, 7.1 mmol), 1,1′-bis(biphenylphosphino)ferrocene-palladium(II) dichloromethane complex (CAN 95464-05-4, 8 mg, 0.13 mmol), and 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 adding 1N hydrochloric acid, and the resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by preparative-HPLC to give the title compound (0.8 g, 3.94 mmol, 61.2%) as a yellow oil; MS (EI): m/e = 204.2 [M+H] ⁺ .

b) 6-Cyclohexyl-pyridine-2-carboxylic acid

To a solution of 6-cyclohexenyl-pyridine-2-carboxylic acid (0.8 g, 3.94 mmol) in ethanol (50 mL) was added 10% palladium on carbon (20%, 0.16 g) under a nitrogen atmosphere. The suspension was degassed under vacuum and exchanged with hydrogen several times. The mixture was stirred at ambient temperature overnight under hydrogen bubbling. The reaction mixture was filtered through a celite pad, 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 in the next reaction step without further purification; MS (EI): m/e 206.2 [M+H] ⁺

c) 2-[(6-Cyclohexyl-pyridine-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester

The title compound was synthesized similarly to Example 1 using 6-cyclohexyl-pyridine-2-carboxylic acid and 2-methyl-alanine methyl ester as starting materials, MS (LC/MS): 305.1 (M+H).

Example 8

6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid (1-methyl-1-oxazol-2-yl-ethyl)-amide

a) 2-(Benzyloxycarbonylamino)-2-methylpropanoic acid

To a solution of 2-methylalanine (CAN 62-57-7, 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), and then the aqueous layer was adjusted to pH = 2 with concentrated 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 in the next step without further purification; MS: m/e 238.0 [M+H] ⁺

b) Benzyl 1-(2,2-dimethoxyethylamino)-2-methyl-1-oxopropan-2-ylcarbamate

A mixture of 2-(benzyloxycarbonylamino)-2-methylpropionic acid (20 g, 0.084 mol), HATU (CAN 148893-10-1, 41.56 g, 0.11 mol) and N-methylmorpholine (CAN 109-02-4, 25.54 g, 0.253 mol) in DMF (400 mL) was stirred at room temperature for 10 min. 2,2-dimethoxyethylamine (CAN 22483-09-6, 9.75 g, 0.093 mol) was added and the mixture was stirred overnight. After evaporation of the solvent, the residue was diluted with dichloromethane (500 mL) and saturated sodium bicarbonate solution (500 mL). After separation, the organic layer was washed with 5N citric acid solution (500 mL), brine (500 mL) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to leave a yellow oil (27 g, 99%) which was used in the next reaction step without further purification. ¹ H NMR (, 300 MHz, CDCl ₃ ): 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-methyl-1-oxo-1-(2-oxoethylamino)propan-2-ylcarbamate

To a solution of benzyl 1-(2,2-dimethoxyethylamino)-2-methyl-1-oxopropan-2-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 complete. 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 sulfate, and concentrated to give the product (0.445 g, 100%) as a yellow oil, which was used directly in the next step without purification; MS: m/e 279.1 [M+H] ⁺ .

d) Benzyl 2-(oxazol-2-yl)propan-2-ylcarbamate

A solution of benzyl 2-methyl-1-oxo-1-(2-oxoethylamino)propan-2-ylcarbamate (2.23 g, 8 mmol) in dichloromethane (50 mL) was added to a freshly prepared solution of _PPh (3.15 g, 12 mmol), _I (3.05 g, 12 mmol), and _EtN (2.43 g, 24 mmol) in dichloromethane (100 mL). The resulting mixture was stirred at room temperature until TLC indicated the reaction was complete. Water (150 mL) was then added. The organic layer was washed with 5% sodium bisulfite (150 mL x 2), brine (150 mL), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to leave a yellow oil, which was purified by column chromatography (silica gel, 50 g, eluting with 25% ethyl acetate in petroleum ether) to give the title compound (0.63 g, 30%) as a colorless oil; MS: m/e 261.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CDCl ₃ ): 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-dimethyl-2-oxazolylmethylamine

A mixture of benzyl 2-(oxazol-2-yl)propan-2-ylcarbamate (0.63 g, 24 mmol) and 10% palladium on carbon (0.06 g) in ethanol (20 mL) was added under a hydrogen bubble and stirred at room temperature for 2 h. TLC indicated the reaction was complete; the mixture was filtered and concentrated to give a yellow oil (0.1 g, 33%); MS: m/e 127.1 [M+H] ⁺ . ¹ H NMR (300 MHz, CDCl ₃ ): 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)-pyridine-2-carboxylic acid (1-methyl-1-oxazol-2-yl-ethyl)-amide

The title compound was synthesized similarly to Example 1 using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and α,α-dimethyl-2-oxazolylmethanamine (CAN 1211519-76-4) as starting materials, MS (LC/MS): 341.9 [M+H] ⁺ .

Example 9

2-{[6-Cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester

a) 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate

Under a nitrogen atmosphere, n-butyllithium (10.4 mL, 2.5 M solution in hexane, 26 mmol) was added to a solution of diisopropylamine (CAN 180-18-9, 2.42 g, 0.024 mol) in THF (40 mL) at -78°C. The reaction mixture was allowed to react at -50°C for 30 min. Tetrahydropyran-4-one (CAN 29943-42-8, 2 g, 0.020 mol) in THF (10 mL) was then added dropwise to the solution at -78°C. The reaction mixture was allowed to react at -78°C for 30 min. Trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (CAN 37595-74-7, 7.85 g, 0.022 mol) in THF (50 mL) was then added dropwise to the solution at -78°C. The reaction mixture was stirred at room temperature for 10 min. 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 give the title compound (0.7 g, 3 mmol, 15.1%) as a yellow oil. ¹ H 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-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Under nitrogen atmosphere, a solution of 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (0.7 g, 3.0 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (CAN 3183-34-3, 0.84 g, 3.3 mmol), 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (CAN 95464-05-4, 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 was then 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 give the title compound (0.32 g, 2 mmol, 50.5%) as a colorless oil. ¹ H NMR (300 MHz, CDCl ₃ ): δ 6.53 (s, 1H), 4.20 (t, J=3 Hz, 2H), 3.76 (t, J=6 Hz, 2H), 2.24 (dd, J ₁ =6 Hz, J ₂ =6 Hz, 2H), 1.28 (s, 12H).

c) 5-Bromo-6-chloro-pyridine-2-carboxylic acid methyl ester

The mixture of 5-bromo-pyridine-2-formic acid methyl ester (CAN 29682-15-3,50g, 0.23mol) and m-CPBA (CAN 937-14-4,80g, 0.46mol) in 400mL dry dichloromethane is heated to 60 ℃ and lasts 20h.After this, the mixture is quenched with saturated sodium sulfite solution and extracted with ethyl acetate (2x 200mL).The organic layer is washed with salt water (2x 200mL) and evaporated to dryness.Residue is passed through column chromatography (silica gel, 300g, eluted with 15% ethyl acetate in petroleum ether) purifying, obtain brown oil. The brown oil, 5-bromo-2-(methoxycarbonyl)pyridine 1-oxide (30 g, 0.13 mol), was added to phosphoryl trichloride (CAN 10025-87-3, 80 mL) at 0° C. over 1 h, and the mixture was then heated to 95° C. for 1 h. After the mixture was evaporated to dryness, the residue was dissolved in water (50 mL), extracted with ethyl acetate (3×50 mL), and the organic layer was evaporated to dryness to give the product as a white solid (19 g, 59%); MS (EI): m/e=249.9 [M+H] ⁺ .

d) 5-Bromo-6-cyclopropylmethoxy-pyridine-2-carboxylic acid

Sodium hydride (4.83 g, 0.12 mol) was added to cyclopropanemethanol (CAN 2516-33-8, 30 g) at 0°C and the mixture was stirred at 0°C for 1 h. Methyl 5-bromo-6-chloro-pyridine-2-carboxylate (3 g, 12.75 mmol) was then added to the mixture. The resulting solution was heated to 90°C for 2 h. The mixture was then evaporated to dryness, the residue was dissolved in 40 mL of water, adjusted to pH = 4 with hydrochloric acid (3N), and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were 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)-5-(tetrahydro-2H-pyran-4-yl)-pyridine-2-carboxylic acid

Under nitrogen atmosphere, a solution of 5-bromo-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid (300 mg, 1.1 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (278 mg, 1.3 mmol), 1,1′-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (CAN 95464-05-4, 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 and extracted with ethyl acetate (30 mL), the pH of the aqueous layer was adjusted to 2 by adding 1N hydrochloric acid and the resulting mixture was extracted with ethyl acetate (3×30 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 give the title compound (0.15 g, 1 mmol, 49.4%) as a white solid; MS (EI): m/e 276.0 [M+H] ⁺ .

f) 6-Cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid

Analogously to the procedure described in Example 7b, starting from 6-(cyclopropylmethoxy)-5-(3,6-dihydro-2H-pyran-4-yl)-pyridine-2-carboxylic acid, the title compound (0.15 g, 1 mmol, 99%) was obtained as a yellow solid; MS (EI): m/e 270.8 [M+H] ⁺

g) 2-{[6-Cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester

The title compound was synthesized similarly to Example 1 using 6-cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid and 2-methyl-alanine methyl ester as starting materials. MS (EI): m/e 377.2 [M+H] ⁺ .

Example 10

6-Cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized similarly to Example 1 using 6-cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid (Example 9f) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials. MS (EI): m/e 401.1 [M+H] ⁺ .

Example 11

6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid piperidin-1-ylamide

The title compound was synthesized similarly to Example 1 using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and 1-piperidinamine (CAN 2213-43-6) as starting materials, MS (EI): m/e 316.0 [M+H] ⁺ .

Example 12

6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide

a) tert-Butyl 1-amino-2-methyl-1-oxopropan-2-ylcarbamate

A mixture of 2-(tert-butoxycarbonylamino)-2-methylpropanoic acid (CAN: 30992-29-1, 20 g, 98 mmol), di-tert-butyl dicarbonate (CAN 24424-99-5, 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 over 20 min. The resulting reaction mixture was stirred for 4 h. After most of the solvent was removed under reduced pressure, the solid was filtered and washed with acetonitrile. The solid was dried under reduced pressure to give the title compound (17.5 g, 88%) as a white solid; MS (EI): m/e 225.1 [M+Na] ⁺ .

b) tert-Butyl 1-amino-2-methyl-1-thioprop-2-ylcarbamate

To a mixture of tert-butyl 1-amino-2-methyl-1-oxopropan-2-ylcarbamate (10 g, 49 mmol) in toluene (200 mL) was added Lawesson's reagent (CAN 19172-47-5, 10 g, 25 mmol). The suspension was heated to 90° C. and stirred for 6 h. After evaporation of the solvent, the residue was purified by column chromatography (silica gel, 120 g) eluting with 30% ethyl acetate in petroleum ether to give the title compound (6 g, 56%); MS: m/e 241.2 [M+Na] ⁺ .

c) α,α-dimethyl-2-thiazolidinemethylamine

A mixture of tert-butyl 1-amino-2-methyl-1-thiopropan-2-ylcarbamate (5.31 g, 24 mmol), 2-bromo-1,1-dimethoxyethane (CAN: 7252-83-7, 5.11 g, 30 mmol) and TsOH (0.49 g, 3 mmol) in acetic acid (50 mL) was stirred at 120° C. for 4 h. After evaporation of the solvent, the residue was diluted with ethyl acetate (50 mL) and water (50 mL). The aqueous phase was washed with ethyl acetate (3 x 50 mL). The aqueous phase was then lyophilized to give the title compound as a brown solid (2.1 g, 65%); MS (LC/MS): 143.1 [M+H] ⁺ .

d) 6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide

The title compound was synthesized similarly to Example 1 using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and α,α-dimethyl-2-thiazolidinemethanamine (CAN 1082393-38-1) as starting materials, MS (LC/MS): 358.0 [M+H] ⁺ .

Example 13

2-{[6-Cyclopropylmethoxy-5-(1H-pyrazol-3-yl)-pyridine-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester

a) 6-Cyclopropylmethoxy-5-(1H-pyrazol-3-yl)-pyridine-2-carboxylic acid

Under nitrogen atmosphere, a solution of 5-bromo-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid (Example 9d, 0.4 g, 1.5 mmol), 1H-pyrazol-3-ylboronic acid (CAN 376584-63-3, 0.2 g, 1.8 mmol), 1,1′-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (CAN 95464-05-4, 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 adding 1N 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 evaporated. The residue was purified by column chromatography (silica gel, 15 g, eluting with 30% ethyl acetate in petroleum ether) to give the title compound (0.23 g, 1 mmol, 60.3%) as a white solid; MS (EI): m/e 260.1 [M+H] ⁺ .

b) 2-{[6-Cyclopropylmethoxy-5-(1H-pyrazol-3-yl)-pyridine-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester

The title compound was synthesized similarly to Example 1 using 6-cyclopropylmethoxy-5-(1H-pyrazol-3-yl)-pyridine-2-carboxylic acid and 2-methyl-alanine methyl ester as starting materials. MS (LC/MS): 359.1 [M+H] ⁺ .

Example 14

6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide

a) 6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid

A mixture of 5-bromo-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid (Example 9d, 600 mg, 2 mmol), pyrrolidine (CAN 123-75-1, 1.57 g, 22 mmol), tris(dibenzylideneacetone)dipalladium (CAN 52409-22-0, 202 mg, 0.2 mmol), rac-BINAP (CAN 76189-55-4, 275 mg, 0.4 mmol) and Cs ₂ CO ₃ (2.88 mg 9 mmol) in toluene (50 mL) was heated to 95° C. for 20 h under a nitrogen atmosphere. The mixture was then diluted with methanol (30 mL), filtered and the filtrate evaporated to dryness. The residue was purified by column chromatography (silica gel, 5 g, eluting with 10% ethyl acetate in petroleum ether) to afford the product as a white solid (0.26 g, 45%), MS (LC/MS): 263.1 [M+H] ⁺ .

b) 6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide

The title compound was synthesized similarly to Example 1 using 6-cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid and (2S)-2-amino-4-methyl-1-pentanol (CAN 7533-40-6) as starting materials. MS (LC/MS): 362.2 [M+H] ⁺ .

Example 15

(6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridin-2-yl)-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)-methanone

The title compound was synthesized similarly to Example 1 using 6-cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid (Example 14a) and 1,1-dioxide-thiomorpholine (CAN 39093-93-1) as starting materials. MS (LC/MS): 380.1 [M+H] ⁺ .

Example 16

(6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridin-2-yl)-thiomorpholin-4-yl-methanone

The title compound was synthesized similarly to Example 1 using 6-cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid (Example 14a) and thiomorpholine (CAN123-90-0) as starting materials, MS (LC/MS): 348.1 [M+H] ⁺ .

Example 17

6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid (1-methyl-1-[1,3,4]oxadiazol-2-yl-ethyl)-amide

a) Benzyl 1-(2-formylhydrazino)-2-methyl-1-oxopropan-2-ylcarbamate

A mixture of 2-(benzyloxycarbonylamino)-2-methylpropanoic acid (Example 8a, 1.9 g, 8 mmol), HATU (CAN 148893-10-1, 3.97 g, 10 mmol), and N-methylmorpholine (CAN 109-02-4, 2.43 g, 24 mmol) in DMF (20 mL) was stirred at room temperature for 15 min. Hydrazine carboxaldehyde (CAN 624-84-0, 0.53 g, 9 mmol) was then added, and the reaction mixture was stirred at room temperature overnight. After evaporation of the solvent, 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. The solvent was removed under reduced pressure to leave the title compound as a yellow oil (2.1 g, 94%); MS: m/e 280.1 [M+H] ⁺ .

b) Benzyl 2-(1,3,4-oxadiazol-2-yl)propan-2-ylcarbamate

To a suspension of benzyl 1-(2-carboxyhydrazide)-2-methyl-1-oxopropyl-2-ylcarbamate (0.9 g, 3 mmol) and _PPh (CAN 603-35-0, 1.268 g, 5 mmol) in acetonitrile (20 mL) was added DIPEA (CAN 7087-68-5, 1.249 g, 10 mmol) and hexachloroethane (CAN 67-72-1, 0.991 g, 4 mmol). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 4 h. After evaporation of the solvent, 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 a colorless oil containing _OPPh3 and _PPh3 ; MS: m/e 262.2 [M+H] ⁺ .

c) 1-Methyl-1-[1,3,4]oxadiazol-2-yl-ethylamine

A solution of benzyl 2-(1,3,4-oxadiazol-2-yl)propan-2-ylcarbamate (1 g, 30% purity) and 10% Pd/C (0.06 g) in ethanol (30 mL) was charged under hydrogen bubbling and stirred at room temperature overnight. After filtration, it was concentrated to obtain a crude product, which was used directly in the next reaction step without further purification, but still contained OPPh ₃ and PPh ₃ ; MS: m/e 128.1 [M+H] ⁺ .

d) 6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid (1-methyl-1-[1,3,4]oxadiazol-2-yl-ethyl)-amide

The title compound was synthesized similarly to Example 1 using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and 1-methyl-1-[1,3,4]oxadiazol-2-yl-ethylamine as starting materials, MS (LC/MS): 343.0 [M+H] ⁺ .

Example 18

6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid cyclohexylamide

The title compound was synthesized similarly to Example 1 using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and cyclohexylamine (CAN 108-91-8) as starting materials, MS (EI) m/e: 315.1 [M+H] ⁺ .

Example 19

6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid phenylamide

The title compound was synthesized similarly to Example 1 using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and aniline (CAN 62-53-3) as starting materials, MS (EI) m/e: 309.1 [M+H] ⁺ .

Example 20

6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid pyridin-2-ylamide

The title compound was synthesized similarly to Example 1 using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and 2-pyridinamine (CAN 504-29-0) as starting materials, MS (EI) m/e: 310.0 [M+H] ⁺ .

Example 21

6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid (tetrahydro-pyran-4-yl)-amide

The title compound was synthesized similarly to Example 1 using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and tetrahydro-2H-pyran-4-amine (CAN38041-19-9) as starting materials, MS (LC/MS): 317.1 [M+H] ⁺ .

Example 22

6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid [1-methyl-1-(3-methyl-[1,2,4]thiadiazol-5-yl)-ethyl]-amide

a) tert-Butyl 1-(1-(dimethylamino)ethyleneamino)-2-methyl-1-thioprop-2-ylcarbamate

A mixture of tert-butyl 1-amino-2-methyl-1-thiopropan-2-ylcarbamate (Example 12b, 0.218 g, 1 mmol) and 1,1-dimethoxy-N,N-dimethylethanamine (CAN 18871-66-4, 0.16 g, 1.2 mmol) in dichloromethane (10 mL) was stirred at room temperature for 24 h. It was then concentrated to give the crude product, which was used directly in the next step without further purification (0.28 g, 98%) as a yellow oil; MS (EI): m/e 288.2 [M+H] ⁺ .

b) tert-Butyl 2-(3-methyl-1,2,4-thiadiazol-5-yl)propan-2-ylcarbamate

A mixture of tert-butyl 1-(1-(dimethylamino)ethylideneamino)-2-methyl-1-thiopropan-2-ylcarbamate (2.9 g, 10 mmol), hydroxylamine-O-sulfonic acid (CAN 2950-43-8, 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 the solvent, 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 the crude product (2.5 g, 96%) as a 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-1-(3-methyl-[1,2,4]thiadiazol-5-yl)-ethylamine

A solution of tert-butyl 2-(3-methyl-1,2,4-thiadiazol-5-yl)propan-2-ylcarbamate (0.15 g, 0.58 mmol) in saturated hydrochloric acid in ethyl acetate (10 mL) was stirred at room temperature for 1 h. Water (20 mL) was then added. The aqueous phase was washed with ethyl acetate (2 x 20 mL). The aqueous phase was then adjusted to pH 9-10 with sodium hydroxide solution (2 M) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to afford the product (0.08 g, 87%) as a yellow oil; MS (EI): m/e 231.1 [M+H] ⁺ .

d) 6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid [1-methyl-1-(3-methyl-[1,2,4]thiadiazol-5-yl)-ethyl]-amide

The title compound was synthesized in a similar manner to Example 1 using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and 1-methyl-1-(3-methyl-[1,2,4]thiadiazol-5-yl)-ethanamine as starting materials, MS (LC/MS): 373.0 (M+H).

Example 23

6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid (1-dimethylcarbamoyl-1-ethyl-propyl)-amide

a) 2-(tert-Butoxycarbonylamino)-2-ethylbutanoic acid

3-Aminopentane-3-formic acid (CAN 2566-29-2, 2.0 g, 15.3 mmol) was combined with dioxane (100 mL) to obtain a colorless suspension. Sodium hydroxide (22.7 ml, 22.7 mmol, 1 N) was added dropwise at 0 ° C. over 10 min to obtain a colorless solution. Di-tert-butyl dicarbonate (CAN 24424-99-5, 6.7 g, 30.9 mmol) was added in three portions. The reaction was stirred for 30 min to obtain a colorless suspension. Dioxane (30 mL) (using less solvent resulted in a thick suspension) was then added and the mixture was stirred at ambient temperature for 17 h. The reaction mixture was concentrated to a volume of 50 mL in a vacuum and poured into 200 mL of water. The mixture was then 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 the product (1.0 g, 28%).

b) tert-Butyl 3-(dimethylcarbamoyl)pentan-3-ylcarbamate

2-(tert-Butoxycarbonylamino)-2-ethylbutanoic acid (200 mg, 0.87 mmol), HATU (CAN 148893-10-1, 660 mg, 1.74 mmol) and triethylamine (CAN 121-44-8, 260 mg, 2.61 mmol) were added to a solution of dimethylamine hydrochloride (CAN 506-59-2, 117 mg, 1.74 mmol) in DMF (10 mL). The mixture was stirred at room temperature overnight. The mixture was added to water (20 mL) and extracted with ethyl acetate (30 mL). The organic extract was washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by preparative-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-Amino-2-ethyl-N,N-dimethylbutanamide hydrochloride

Tert-butyl 3-(dimethylcarbamoyl)pentan-3-ylcarbamate (0.12 g, 0.47 mmol) was added to a saturated solution of hydrogen chloride in ethyl acetate (5 mL) and the mixture was stirred overnight. The solvent was removed under reduced pressure to give the crude product (0.1 g); MS (EI): m/e=159.2 [M+H] ⁺ .

d) 6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid (1-dimethylcarbamoyl-1-ethyl-propyl)-amide

The title compound was synthesized similarly to Example 1 using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and 2-amino-2-ethyl-N,N-dimethyl-butyramide as starting materials, MS (EI): 374.2 [M+H] ⁺ .

Example 24

6-Cyclohexyl-pyridine-2-carboxylic acid piperidin-1-ylamide

The title compound was synthesized similarly to Example 1 using 6-cyclohexyl-pyridine-2-carboxylic acid (Example 7b) and 1-piperidinamine (CAN 2213-43-6) as starting materials, MS (EI): 288.3 [M+H] ⁺ .

Example 25

[5-Methyl-6-(piperidin-1-sulfonyl)-pyridin-2-yl]-piperidin-1-yl-methanone

a) 5-Methyl-2-pyridinecarboxylic acid 1-oxide

m-CPBA (CAN 937-14-4, 5.0 g, 29.2 mmol) was added to a solution of 5-methyl-pyridine-2-carboxylic acid (CAN4434-13-3, 2.0 g, 14.6 mmol) in dichloromethane (50 mL) and the mixture was stirred at room temperature overnight. The solid was filtered off, quenched with a saturated solution of sodium thiosulfate (50 mL), and the mixture was extracted with dichloromethane (3 x 60 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a yellow solid, which was washed with diethyl ether (5 x 20 mL) to give the product (0.9 g, 40.3%); MS (EI): m/e = 154.1 [M+H] ⁺ .

b) 6-Chloro-5-methyl-pyridine-2-carboxylic acid

5-Methyl-2-pyridinecarboxylic 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 cooling to room temperature, the mixture was slowly added to ice water and extracted with dichloromethane (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] ⁺ .

c) 5-Methyl-6-sulfonyl-pyridine-2-carboxylic acid

6-Chloro-5-methyl-pyridine-2-carboxylic acid (0.85 g, 4.97 mmol) and sodium sulfite (CAN7757-83-7, 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 the mixture was cooled to room temperature, the precipitated solid 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). The aqueous phase was subsequently adjusted to pH = 2 with 2N hydrochloric acid. The water was removed in vacuo to give the product as a solid (1.2 g); MS (EI): m/e = 218.0 [M+H] ⁺ .

d) 5-Methyl-6-sulfonic acid-pyridine-2-carboxylic acid methyl ester

To a mixture of 5-methyl-6-sulfonic-pyridine-2-carboxylic acid (0.8 g, 3.69 mmol) in methanol (20 mL) was added 4N hydrogen chloride in dioxane (8 mL). The mixture was stirred at room temperature overnight. Undissolved solids were filtered off, and the filtrate was concentrated to give the product as a yellow solid, 0.5 g; MS (EI): m/e = 232.0 [M+H] ⁺ .

e) 5-Methyl-6-(piperidin-1-sulfonyl)-pyridine-2-carboxylic acid methyl ester

5-Methyl-6-sulfonic acid pyridine-2-carboxylic acid methyl ester (340 mg, 1.47 mmol), thionyl chloride (CAN7719-09-7, 1 mL) and 1 drop of DMF were added to dichloromethane (10 mL), and the mixture was stirred at 40°C for 2 h. The mixture was cooled to room temperature, and piperidine (CAN 110-89-4, 1.0 g, 12 mmol) in dichloromethane (10 mL) was added to the mixture. The solvent was removed in vacuo, and the crude product was purified by preparative HPLC (eluting with 50% ethyl acetate in petroleum ether) to give the product (53 mg, 12%); MS (EI): m/e = 299.1 [M+H] ⁺ .

f) 5-Methyl-6-(piperidin-1-sulfonyl)-pyridine-2-carboxylic acid

Methyl 5-methyl-6-(piperidin-1-sulfonyl)-pyridine-2-carboxylate (53 mg, 0.178 mmol) in dioxane (2 mL) was added to a solution of lithium hydroxide monohydrate (CAN 1310-66-3, 0.1 g, 2.38 mmol) in water (2 mL), and the mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo, water (10 mL) was added, and the pH was adjusted to 3 with 1N hydrochloric acid. The mixture was extracted with 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] ⁺ .

g) [5-Methyl-6-(piperidin-1-sulfonyl)-pyridin-2-yl]-piperidin-1-yl-methanone

The title compound was synthesized similarly to Example 1 using 5-methyl-6-(piperidine-1-sulfonyl)-pyridine-2-carboxylic acid and piperidine (CAN 110-89-4) as starting materials, MS (EI): 352.2 [M+H] ⁺ .

Example 26

6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid (2-methyl-tetrahydro-pyran-4-yl)-amide

The title compound was synthesized similarly to Example 1 using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and tetrahydro-2-methyl-2H-pyran-4-amine (CAN 89584-06-5) as starting materials. MS (EI): m/e = 331.1 [M+H] ⁺ .

Example 27

2-[(6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester

The title compound was synthesized similarly to Example 1 using 6-cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid (Example 14a) and 2-methyl-alanine methyl ester as starting materials. MS (LC/MS): 362.2 [M+H] ⁺ .

Example 28

6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid [1-methyl-1-(3-methyl-isoxazol-5-yl)-ethyl]-amide

a) 1-Methyl-1-(3-methyl-isoxazol-5-yl)-ethylamine

To a solution of (E)-acetaldehyde oxime (CAN 107-29-9, 1.0 g, 16.9 mmol), 2-methylbut-3-yn-2-amine (CAN 2978-58-7, 1.4 g, 16.9 mmol) and triethylamine (CAN 121-44-8, 0.17 g, 1.69 mmol) in dichloromethane (25 mL) at 0°C was added 5% aqueous sodium hypochlorite solution (5%, 42.6 g) over 3 h. The reaction was allowed to warm to 4°C and stirring was continued for 5 h. The organic layer was separated and the aqueous layer was extracted with dichloromethane (50 mL). The combined dichloromethane extracts were washed with saturated aqueous sodium chloride solution (60 mL) and dried over anhydrous magnesium sulfate. The solvent was removed to obtain a yellow oil. The crude product was purified by column chromatography (silica gel 30 g, eluting with 30% ethyl acetate in petroleum ether) to give the product as a yellow solid (0.1 g, 4.2%); MS (EI): m/e = 141.2 [M+H] ⁺ .

b) 6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid [1-methyl-1-(3-methyl-isoxazol-5-yl)-ethyl]-amide

The title compound was synthesized similarly to Example 1 using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and 1-methyl-1-(3-methyl-isoxazol-5-yl)-ethylamine as starting materials, MS (EI): 356.0 (M+H) ⁺ .

Example 29

6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid (1-ethyl-1-hydroxymethyl-propyl)-amide

The title compound was synthesized similarly to Example 1 using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and 2-amino-2-ethyl-1-butanol (CAN 19792-52-0) as starting materials, MS (LC/MS): 333.1 (M+H).

Example 30

6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid (tetrahydro-pyran-3-yl)-amide

The title compound was synthesized similarly to Example 1 using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and tetrahydro-2H-pyran-3-amine (CAN120811-32-7) as starting materials, MS (LC/MS): 317.1 (M+H).

Example 31

(6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridin-2-yl)-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-methanone

The title compound was synthesized similarly to Example 1 using 6-cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid (Example 14a) and 2-oxa-6-azaspiro[3.3]heptane (CAN 174-78-7) as starting materials. MS (EI): m/e=344.3 [M+H] ⁺ .

Example 32

6-Cyclopropylmethoxy-5-(2-methyl-pyrrolidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide

a) 6-Cyclopropylmethoxy-5-(2-methyl-pyrrolidin-1-yl)-pyridine-2-carboxylic acid

Under nitrogen atmosphere, a solution of 5-bromo-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid (Example 9d, 0.4 g, 1.5 mmol), 2-methylpyrrolidine (CAN 765-38-8, 188 mg, 2.2 mmol), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (CAN 76189-55-4, 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 adding 1N 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 give the title compound (0.15 g, 36.9%) as a yellow solid; MS (EI): m/e = 277.2 [M+H] ⁺ .

b) 6-Cyclopropylmethoxy-5-(2-methyl-pyrrolidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide

The title compound was synthesized similarly to Example 1 using 6-cyclopropylmethoxy-5-(2-methyl-pyrrolidin-1-yl)-pyridine-2-carboxylic acid and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (LC/MS): 389.2 [M+H] ⁺ .

Example 33

6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

a) tert-Butyl 2-cyanopropan-2-ylcarbamate

To a solution of tert-butyl 1-amino-2-methyl-1-oxopropan-2-ylcarbamate (Example 12a, 12.5 g) and triethylamine (CAN 121-44-8, 29 g) in dichloromethane (150 mL) was added trifluoroacetic anhydride (CAN 407-25-0, 27.2 g) dropwise at 0°C. The resulting mixture was allowed to warm to room temperature and stirred for 4 h. After washing the mixture with water, 5N citric acid, and brine, the organic phase was dried over anhydrous sodium sulfate and concentrated to afford the title compound (11 g, 97%) as a yellow solid; MS: m/e = 207.1 [M+Na] ⁺ .

b) Tert-butyl (Z)-1-amino-1-(hydroxyimino)-2-methylpropan-2-ylcarbamate

Potassium carbonate (3.64 g) was dissolved in water (12 mL) and hydroxylammonium chloride (CAN: 5470-11-1, 1.7 g, mmol) was added. A solution of tert-butyl 2-cyanopropan-2-ylcarbamate (4.84 g, 26 mmol) in ethanol (42 mL) was added and the resulting reaction mixture was stirred at ambient temperature for 18 h. The solvent was removed under reduced pressure and the residue was diluted with ethyl acetate (20 mL). The mixture was filtered and the filtrate was concentrated to give the crude product (5 g, 87.6%) as a yellow solid. MS: m/e = 218.2 [M+H] ⁺ .

c) tert-Butyl 2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-ylcarbamate

To a solution of acetic acid (1.8 g) in DMF (50 mL) was added N,N′-carbonyldiimidazole (CAN530-62-1, 4.865 g, mmol). The solution was stirred at ambient temperature for 0.5 h. (Z)-tert-butyl 1-amino-1-(hydroxyimino)-2-methylpropan-2-ylcarbamate (6.07 g) was added, and the reaction mixture was stirred at 120° C. for 10 h. The solvent was removed under reduced pressure to leave a yellow oil, which was purified by column chromatography (silica gel 120 g, eluting with 30% ethyl acetate in petroleum ether) to afford the title compound (5.38 g, 80%) as a colorless oil; MS: m/e = 264.1 [M+Na] ⁺ .

d) α,α,5-trimethyl-1,2,4-oxadiazole-3-methylamine

Tert-butyl 2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-ylcarbamate (5.38 g) was dissolved in ethyl acetate (30 mL) saturated with hydrochloric acid and stirred at room temperature for 1 h. Water (50 mL) was then added. The aqueous phase was washed with ethyl acetate (2 x 30 mL) and the pH was adjusted to 9-10 with 1 M sodium hydroxide solution. The solution was extracted with ethyl acetate (2 x 30 mL). The combined extracts were washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to leave the title compound (1.7 g, 54%) as a colorless oil; MS: m/e 142.2 [M+H] ⁺ .

e) 6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized similarly to Example 1 using 6-cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid (Example 14a) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials. MS (LC/MS): 386.2 [M+H] ⁺ .

Example 34

6-Cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 6-cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid (Example 9f) and α,α-dimethyl-2-thiazolidinemethanamine (CAN 1082393-38-1) as starting materials, MS (LC/MS): 402.1 [M+H] ⁺ .

Example 35

6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid (1,1-dimethyl-3-morpholin-4-yl-propyl)-amide

a) 3-(tert-Butoxycarbonylamino)-3-methylbutanoic acid

3-Amino-3-methylbutanoic acid (CAN 625-05-8, 2.0g, 17mmol) is combined with dioxane (60mL) to obtain a colorless suspension. 1N sodium hydroxide solution (17.0mL, 17.0mmol) is added dropwise at 0°C over 10min. Di-tert-butyl dicarbonate (4.8g, 22.2mmol) is added in three portions. The reaction is stirred for 30min to obtain a colorless suspension. Dioxane (30mL) (using less solvent results in a thick suspension) is then added and the mixture is stirred at ambient temperature for 17 hours. The reaction mixture is concentrated to a volume of 50mL in a vacuum and poured into 200mL water. The mixture is then washed with ethyl acetate (3x 80ml). The aqueous layers are combined, 2N HCl is added and after the pH is adjusted to 2, the mixture is extracted with ethyl acetate (3x 60mL). The organic layers are combined, dried over sodium sulfate and concentrated in a vacuum to obtain product (2.7g, 72.9%).

b) tert-Butyl 2-methyl-4-morpholino-4-oxobutan-2-ylcarbamate

3-(tert-Butoxycarbonylamino)-3-methylbutanoic acid (2.7 g, 12.4 mmol), HBTU (CAN94790-37-1, 6.1 g, 16.1 mmol), and tristriethylamine (CAN 121-44-8, 2.5 g, 24.8 mmol) were added to a solution of morpholine (CAN 110-91-8, 2.2 g, 24.8 mmol) in dichloromethane (50 mL). The mixture was stirred at room temperature overnight. Aqueous hydrochloric acid (1 N, 50 mL) was added, and the mixture was extracted with dichloromethane. The organic extract was washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (silica gel, 50 g, eluted 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-Amino-3-methyl-1-morpholinobutan-1-one hydrochloride

Tert-butyl 2-methyl-4-morpholino-4-oxobutan-2-ylcarbamate (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 under reduced pressure to give a crude product (0.55 g).

d) 1,1-Dimethyl-3-morpholin-4-yl-propylamine

3-Amino-3-methyl-1-morpholinobutan-1-one (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, and another portion of borane in THF (6 mL) was added and the mixture was 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). LC-MS showed that the product was still in the aqueous phase, which was then extracted with dichloromethane (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-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid (1,1-dimethyl-3-morpholin-4-yl-propyl)-amide

The title compound was synthesized analogously to Example 1 using 6-cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid (Example 14a) and 1,1-dimethyl-3-morpholin-4-yl-propylamine as starting materials, MS (EI): 417.2 [M+H] ⁺ .

Example 36

6-Cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid (1-methyl-1-methylcarbamoyl-ethyl)-amide

a) 5-Methyl-2-pyridinecarbonitrile

A solution of 2-fluoro-5-methylpyridine (CAN: 2369-19-9, 10 g, 90 mmol) and sodium cyanide (8.8 g, 180 mmol) in DMSO (15 mL) was heated to 150° C. for 48 h. Water was then added, and the resulting mixture was extracted with ethyl acetate (3×50 mL). 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 give the title compound (3.2 g, 27 mmol, 30.1%) as a yellow solid; MS (EI): m/e=119.1 [M+H] ⁺ .

b) 5-Methyl-1-oxy-pyridine-2-carbonitrile

m-CPBA (CAN 937-14-4, 0.58 g, 3.4 mmol) was added portionwise to a solution of 5-methyl-2-pyridinecarbonitrile (3 g, 25 mmol) in dichloromethane (60 mL) at room temperature and the reaction mixture was heated to 60° C. overnight. The reaction mixture was then washed with sodium thiosulfate 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 give the title compound (2.6 g, 19 mmol, 77.6%) as a yellow solid; MS (EI): m/e=135.1 [M+H] ⁺ .

c) 6-chloro-5-methylpyridinecarbonitrile

5-Methyl-1-oxy-pyridine-2-carbonitrile (2.6 g, 19 mmol) was added portionwise to phosphorus oxychloride (CAN10025-87-3, 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. The 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 give the title compound (1.6 g, 10 mmol, 54.1%) as a yellow solid; MS (EI): m/e=153.1 [M+H] ⁺ .

d) 6-Cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid

Sodium hydride (CAN 7646-69-7, 1.24 g, 37 mmol) was added portionwise to a cyclopropane methanol solution (CAN 2516-33-8, 20 mL) and the reaction mixture was allowed to react at ambient temperature for 30 min. 6-Chloro-5-methylpicolinonitrile (1.1 g, 7.2 mmol) was then 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 and extracted with ethyl acetate (50 mL). The pH of the aqueous layer was adjusted to 2 by adding 1N 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 chromatography (silica gel, 25 g, 50% ethyl acetate in petroleum ether) to give the title compound (1 g, 5 mmol, 67%) as a yellow solid; MS (EI): m/e = 208.1 [M+H] ⁺ .

e) 6-Cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid (1-methyl-1-methylcarbamoyl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 6-cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid and 2-amino-N,2-dimethyl-propionamide (CAN 106914-07-2) as starting materials, MS (EI): m/e=318.1 [M+H] ⁺ .

Example 37

6-(Tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid piperidin-1-ylamide

a) 6-(3,6-Dihydro-2H-pyran-4-yl)-pyridine-2-carboxylic acid

Under a nitrogen atmosphere, a solution of 6-bromo-pyridine-2-carboxylic acid (CAN: 21190-87-4, 1 g, 4.9 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Example 9-d, 1.1 g, 5.4 mmol), 1,1′-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (CAN 95464-05-4, 0.08 g, 0.1 mmol) and potassium carbonate (1.37 g, 10 mmol) in water (50 mL) was stirred at 100° C. for 24 h. The reaction mixture was extracted with ethyl acetate (50 mL), the pH of the aqueous layer was adjusted to 2 by adding 1N hydrochloric acid, and the resulting mixture was extracted with ethyl acetate (3×50 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 preparative-HPLC to give the title compound (0.3 g, 1.5 mmol, 29.5%) as a white solid; MS (EI): m/e = 206.1 [M+H] ⁺ .

b) 6-(Tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid

The title compound was synthesized similarly to Example 7b using 6-(3,6-dihydro-2H-pyran-4-yl)-pyridine-2-carboxylic acid and 10% Pd/C as starting materials, MS (EI): m/e 208.1 [M+H] ⁺ .

c) 6-(Tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid piperidin-1-ylamide

The title compound was synthesized analogously to Example 1 using 6-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid and 1-piperidinamine (CAN 2213-43-6) as starting materials, MS (LC/MS): 290.2 [M+H] ⁺ .

Example 38

6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-1,2,4]oxadiazol-3-yl)-ethyl]-amide

a) (S)-tert-Butyl 1-amino-3-cyclopropyl-1-oxopropan-2-ylcarbamate

A mixture of (S)-2-(tert-butoxycarbonylamino)-3-cyclopropylpropanoic acid (CAN 89483-06-7, 10 g, 44 mmol), di-tert-butyl dicarbonate (CAN: 24424-99-5, 14.28 g, 66 mmol), and pyridine (2.4 mL) in acetonitrile (200 mL) was stirred at room temperature for 20 min. Ammonia (10 mL) was added dropwise over 20 min. The resulting reaction mixture was stirred for 4 h. During the removal of most of the solvent under reduced pressure, the product precipitated, and the solid was filtered and washed with acetonitrile (20 mL). The solid was dried under reduced pressure to give the title compound (7.73 g, 78%) as a white solid; MS (EI): m/e 251.2 [M+Na] ⁺ .

b) (S)-tert-Butyl 1-cyano-2-cyclopropylethylcarbamate

To a solution of tert-butyl (S)-1-amino-3-cyclopropyl-1-oxopropan-2-ylcarbamate (3.7 g, 16 mmol) and triethylamine (6.55 g, 65 mmol) in dichloromethane (50 mL) was added trifluoroacetic 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 afford the product (3.31 g, 97%) as a yellow solid; MS (EI): m/e 233.1 [M+Na] ⁺ .

c) tert-Butyl (S,Z)-1-amino-3-cyclopropyl-1-(hydroxyimino)propan-2-ylcarbamate

Potassium carbonate (2.18 g, 16 mmol) was dissolved in water (8 mL) and hydroxylamine hydrochloride (1.1 g, 16 mmol) was added. To this was added a solution of (S)-tert-butyl 1-cyano-2-cyclopropylethylcarbamate (3.31 g, 16 mmol) in ethanol (24 mL) and the resulting reaction mixture was stirred for 72 h. After evaporation of the solvent, the residue was dissolved in ethyl acetate (20 mL) and filtered. The filtrate was concentrated to give the crude product as a yellow solid (3.61 g, 94%); MS (EI): m/e 244.2 [M+H] ⁺ .

d) (S)-tert-Butyl 2-cyclopropyl-1-(5-methyl-1,2,4-oxadiazol-3-yl)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 at room temperature for 0.5 h. (S,Z)-tert-butyl 1-amino-3-cyclopropyl-1-(hydroxyimino)propan-2-ylcarbamate (0.84 g, 3 mmol) was added and the mixture was heated to 120° C. and stirred for 4 h. After evaporation of the solvent, the residue was purified by column chromatography (silica gel, 20 g, eluted with 10% ethyl acetate in petroleum ether) to give the title compound (0.5 g; 54%) as a yellow solid; MS (EI): m/e 290.1 [M+Na] ⁺ .

e) (S)-2-Cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine

A solution of (S)-tert-butyl 2-cyclopropyl-1-(5-methyl-1,2,4-oxadiazol-3-yl)ethylcarbamate (0.5 g, 2 mmol) in saturated hydrochloric acid (10 mL) was stirred at room temperature for 1 h. Water (20 mL) was then added. The aqueous phase was washed with ethyl acetate (2 x 20 mL) and adjusted to pH 9-10 with 2 M sodium hydroxide solution. 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 the crude product as a white solid (0.25 g, 80%); MS (EI): m/e 168.2 [M+H] ⁺ .

f) 6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized similarly to Example 1 using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and (S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethanamine as starting materials, MS (EI): m/e 383.1 [M+H] ⁺ .

Example 39

(5-Cyclopentyl-6-cyclopropylmethoxy-pyridin-2-yl)-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)-methanone a) 5-Cyclopentenyl-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid

A mixture of 5-bromo-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid (Example 9d, 1.0 g, 4 mmol), 2-cyclopentenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAN 287944-10-9, 0.86 g, 4 mmol), 1,1′-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (CAN 95464-05-4, 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; the solution was then diluted with water (15 mL) and extracted with ethyl acetate (30 mL). The aqueous layer was adjusted to pH 3.0 with hydrochloric acid (3N) and extracted with ethyl acetate (2×50 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, eluted with 15% ethyl acetate in petroleum ether) to afford the product (0.85 g, 89%) as a white solid; MS (LC/MS): 260.1 [M+H] ⁺ .

b) 5-Cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid

A mixture of 5-cyclopentenyl-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid (0.95 g, 4 mmol) and Pd/C (10% w/w, 0.2 g) in 30 mL of ethanol was stirred at room temperature under a hydrogen atmosphere for 4 h. The mixture was filtered and the filtrate evaporated to dryness to afford the product (0.76 g, 79%) as a white solid. The product was used directly in the next step; MS (LC/MS): 262.1 [M+H] ⁺ .

c) (5-Cyclopentyl-6-cyclopropylmethoxy-pyridin-2-yl)-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)-methanone

The title compound was synthesized analogously to Example 1 using 5-cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid and 1,1-dioxide-thiomorpholine (CAN 39093-93-1) as starting materials, MS (LC/MS): 379.2 [M+H] ⁺ .

Example 40

5-Cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-methyl-1-methylcarbamoyl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 5-cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 39b) and 2-amino-N,2-dimethyl-propionamide (CAN 106914-07-2) as starting materials, MS (LC/MS): 360.2 [M+H] ⁺ .

Example 41

6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized analogously to Example 1 using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (Example 33d, CAN 1153831-97-0) as starting materials, MS (LC/MS): 357.1 [M+H] ⁺ .

Example 42

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid piperidin-1-ylamide

a) 5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid

A mixture of 5-bromo-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid (Example 9d, 1.5 g, 5.5 mmol), cyclopropylboronic acid (CAN 411235-57-9, 0.57 g, 7 mmol), palladium diacetate (CAN 3375-31-3, 62 mg, 0.28 mmol), tricyclohexylphosphine (CAN 2622-14-2, 154 mg, 0.1 mmol) and potassium phosphate (4.1 g, 19 mmol) in toluene/water (20/1 v/v, 30 mL) was heated to 100° C. overnight. After evaporating the mixture to dryness, it was dissolved in 30 mL of water, extracted with ethyl acetate (30 mL) and the organic layer was discarded. The aqueous layer was adjusted to pH=3 and extracted with ethyl acetate (2×30 mL). The organic layer was washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate and then evaporated to dryness. The residue was purified by column chromatography (silica gel, 10 g, eluting with 15% ethyl acetate in petroleum ether) to afford the title compound (0.96 g, 75%) as a white solid; MS (LC/MS): 234.1 [M+H] ⁺ .

b) 5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid piperidin-1-ylamide

The title compound was synthesized similarly to Example 1 using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid and 1-piperidinamine (CAN2213-43-6) as starting materials, MS (LC/MS): 316.2 [M+H] ⁺ .

Example 43

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-methyl-1-methylcarbamoyl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42a) and 2-amino-N,2-dimethyl-propionamide (CAN 106914-07-2) as starting materials, MS (LC/MS): 332.2 [M+H] ⁺ .

Example 44

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42a) and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (LC/MS): 358.1 [M+H] ⁺ .

Example 45

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized analogously to Example 1 using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42a) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (LC/MS): 357.1 [M+H] ⁺ .

Example 46

6-(4-Chloro-phenyl)-pyridine-2-carboxylic acid piperidin-1-ylamide

The title compound was synthesized similarly to Example 1 using 6-(4-chlorophenyl)-2-pyridinecarboxylic acid (CAN 135432-77-8) and 1-piperidinamine (CAN 2213-43-6) as starting materials, MS (EI): m/e=316.1 [M+H] ⁺ .

Example 47

6-Cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid piperidin-1-ylamide

The title compound was synthesized analogously to Example 1 using 6-cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid (Example 36d) and 1-piperidinamine (CAN 2213-43-6) as starting materials, MS (EI): m/e 290.2 [M+H] ⁺ .

Example 48

[6-(3-Chloro-phenyl)-5-cyclopropyl-pyridin-2-yl]-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)-methanone

a) 5-Cyclopropyl-pyridine-2-carboxylic acid methyl ester

5-Bromo-pyridine-2-carboxylic acid methyl ester (CAN 29682-15-3, 2.16 g, 0.01 mol), cyclopropylboronic acid (CAN 411235-57-9, 0.9 g, 0.01 mol), tris(dibenzylideneacetone)dipalladium (CAN 52409-22-0, 0.2 g), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (CAN 161265-03-8, 0.3 g) and cesium carbonate (CAN 534-17-8, 3.3 g, 0.01 mol) were added to 1.4-dioxane (40 mL). The mixture was stirred at 110° C. under a nitrogen atmosphere for 12 h. Subsequently, the mixture was filtered and concentrated. The residue was poured into water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give a crude product. The crude product was purified by flash column chromatography (silica gel, 50 g, eluted with 20% ethyl acetate in petroleum ether) to give the product (0.8 g, 45%); MS (EI): m/e 178.1 [M+H] ⁺ .

b) 5-Cyclopropyl-1-oxy-pyridine-2-carboxylic acid methyl ester

5-Cyclopropyl-pyridine-2-carboxylic acid methyl ester (0.8 g, 5 mmol) and m-CPBA (CAN 937-14-4, 1.2 g, 7 mmol) were added to dichloromethane (15 mL). The mixture was stirred at 60°C for 6 hours. The mixture was then concentrated to a crude product. The crude product was purified by flash column chromatography (silica gel, 20 g, eluted with ethyl acetate) to give the product (0.3 g, 34%); MS (EI): m/e 194.1 [M+H] ⁺ .

c) 6-Bromo-5-cyclopropyl-pyridine-2-carboxylic acid methyl ester

5-Cyclopropyl-1-oxy-pyridine-2-carboxylic acid methyl ester (0.3 g, 2 mmol) was added to phosphorus oxybromide (CAN 7789-59-5, 5 g, 17 mmol). The mixture was stirred at 80 ° C for 2 h. Subsequently, the reaction solution was poured into water (30 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was purified by flash column chromatography (silica gel, 10 g, 20%, ethyl acetate in petroleum ether) to obtain the product (0.1 g, 25%); MS: (EI) m / e 256.0 [M + H] ⁺ .

d) 6-(3-Chloro-phenyl)-5-cyclopropyl-pyridine-2-carboxylic acid methyl ester

Under a nitrogen atmosphere, methyl 6-bromo-5-cyclopropyl-pyridine-2-carboxylate (0.1 g, 0.4 mmol), 3-chlorophenylboronic acid (CAN 63503-60-6, 0.08 g, 0.5 mmol), 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane adduct (CAN 95464-05-4, 50 mg), and cesium carbonate (CAN 534-17-8, 0.2 g, 0.6 mmol) were added to 1,4-dioxane (10 mL). The mixture was stirred at 110°C for 12 h. Subsequently, the mixture was concentrated to obtain a crude product. The crude product was purified by flash column chromatography (silica gel, 5 g, 20% ethyl acetate in petroleum ether) to yield the product (80 mg, 71%); MS: (EI) m/e 288.1 [M+H] ⁺ .

e) 6-(3-Chloro-phenyl)-5-cyclopropyl-pyridine-2-carboxylic acid

6-(3-Chloro-phenyl)-5-cyclopropyl-pyridine-2-carboxylic acid methyl ester (80 mg, 0.28 mmol) and sodium hydroxide (CAN1310-73-2, 30 mg) were added to water (10 mL). The mixture was stirred at ambient temperature for 2 h. The pH was then adjusted to 3 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate (3 x 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to afford the product (60 mg, 78%); MS (EI): m/e 274.1 [M+H] ⁺ .

f) [6-(3-Chloro-phenyl)-5-cyclopropyl-pyridin-2-yl]-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)-methanone

The title compound was synthesized analogously to Example 1 using 6-(3-chloro-phenyl)-5-cyclopropyl-pyridine-2-carboxylic 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)-5-methyl-pyridine-2-carboxylic acid (1-methyl-1-oxazol-2-yl-ethyl)-amide

a) 5-Methyl-pyridine-2-carbonitrile

2-Fluoro-5-methylpyridine (CAN 2369-19-9, 50 g, 90 mmol) and sodium cyanide (CAN 143-33-9, 70 g, 1.43 mol) were dissolved in DMSO (200 mL), and the mixture was stirred at 150° C. for 3 days. The mixture was cooled to room temperature, ice water (200 mL) was added, and the product was obtained by filtration and drying as a red solid (26.5 g, 50%); MS (EI): m/e 119.1 [M+H] ⁺ .

b) 5-Methyl-1-oxy-pyridine-2-carbonitrile

Hydrogen peroxide (CAN 7722-84-1, 30%, 30 mL) was added to a solution of 5-methyl-pyridine-2-carbonitrile (3.0 g, 25 mmol) in acetic acid (30 mL) and the mixture was stirred at 60° C. overnight. The solvent was removed under reduced pressure to give the crude product (3.0 g, 88%); MS (EI): m/e 135.1 [M+H] ⁺ . c) 6-Bromo-5-methyl-pyridine-2-carbonitrile

5-Methyl-1-oxy-pyridine-2-carbonitrile (Example 36b, 1.5 g, 11 mmol) and phosphorus oxybromide (CAN7789-59-5, 10 g) were combined. The mixture was stirred at 100°C for 1 hour. Ice water was added, and the mixture was 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] ⁺ .

d) 6-Bromo-5-methyl-pyridine-2-carboxylic acid

6-Bromo-5-methyl-pyridine-2-carbonitrile (1.0 g, 5.0 mmol) was added to a solution of sodium hydroxide (0.3 g, 7 mmol) in water (20 mL), and the mixture was stirred at 120° C. overnight. Subsequently, the mixture was adjusted to pH=3 and extracted with ethyl acetate (2×15 mL). The organic extract was 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)-5-methyl-pyridine-2-carboxylic acid

3-Chlorophenylboronic acid (CAN 63503-60-6, 0.61 g, 3.9 mmol), 1,1'-bis(biphenylphosphino)ferrocene-palladium(II) dichloromethane complex (CAN 95464-05-4, 53 mg, 0.065 mmol), and potassium carbonate (CAN 584-08-7, 0.54 g, 3.9 mmol) were added to a solution of 6-bromo-5-methyl-pyridine-2-carboxylic 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 extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to yield the product (0.55 g, 56.9%); MS (EI): m/e 248.1 [M+H] ⁺ .

f) 6-(3-Chloro-phenyl)-5-methyl-pyridine-2-carboxylic acid (1-methyl-1-oxazol-2-yl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 6-(3-chloro-phenyl)-5-methyl-pyridine-2-carboxylic acid and α,α-dimethyl-2-oxazolemethanamine (CAN 1211519-76-4) as starting materials, MS (EI): 356.1 (M+H) ⁺ .

Example 50

6-(3-Chloro-phenyl)-5-methyl-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 6-(3-chloro-phenyl)-5-methyl-pyridine-2-carboxylic acid (Example 49e) and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (EI): 372.0 [M+H] ⁺ .

Example 51

6-(3-Chloro-phenyl)-5-methyl-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized analogously to Example 1 using 6-(3-chloro-phenyl)-5-methyl-pyridine-2-carboxylic acid (Example 49e) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methylamine (CAN 1153831-97-0) as starting materials, MS (EI): 371.1 [M+H] ⁺ .

Example 52

6-(3-Chloro-phenyl)-5-methyl-pyridine-2-carboxylic acid piperidin-1-yl-amide

The title compound was synthesized analogously to Example 1 using 6-(3-chloro-phenyl)-5-methyl-pyridine-2-carboxylic acid (Example 49e) and 1-piperidinamine (CAN 2213-43-6) as starting materials, MS (EI): 330.1 [M+H] ⁺ .

Example 53

5-Cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized in analogy to Example 1 using 5-cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 39b) and (S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 38e) as starting materials, MS (LC/MS): 411.2 [M+H] ⁺ .

Example 54

5-Cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized analogously to Example 1 using 5-cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 39b) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methylamine (CAN 1153831-97-0, Example 33d) as starting materials, MS (LC/MS): 385.2 [M+H] ⁺ .

Example 55

5-Cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 5-cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 39b) and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (LC/MS): 386.1 [M+H] ⁺ .

Example 56

6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid ((S)-3-methyl-1-thiazol-2-yl-butyl)-amide

a) (S)-2-(tert-Butoxycarbonylamino)-4-methylpentanoic acid

To a mixture of L-leucine (CAN: 61-90-5, 8 g, 0.061 mmol) in 1,4-dioxane (200 mL) was added aqueous sodium hydroxide solution (1 N, 8.5 mL) and di-tert-butyl dicarbonate (17.5 g, 80 mmol), and the mixture was stirred overnight. After evaporation of the solvent, 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 layers were washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, and concentrated to give the product (6.75 g, 48%) as a white solid; MS (EI): m/e = 232.2 [M+H] ⁺ .

b) (S)-tert-Butyl 1-amino-4-methyl-1-oxopentan-2-ylcarbamate

A mixture of (S)-2-(tert-butoxycarbonylamino)-4-methylpentanoic acid (1.8 g), di-tert-butyl dicarbonate (CAN: 24424-99-5, 12 mmol), and pyridine (3 mL) in _CH₃CN (50 mL) was stirred at room temperature for 20 min. Ammonium hydroxide solution (25%-28% _NH₃ , 15 mL) was added dropwise over 30 min. The resulting reaction mixture was stirred overnight. During solvent removal, the product precipitated and was collected by filtration and dried to afford the title compound as a white solid (1.55 g, 86%). MS (EI): m/e = 253.2 [M+Na] ^⁺ .

c) ((S)-3-Methyl-1-thiocarbamoyl-butyl)-carbamic acid tert-butyl ester

A mixture of (S)-tert-butyl 1-amino-4-methyl-1-oxopentan-2-ylcarbamate (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 removing the solvent under reduced pressure, the residue was purified by column chromatography (silica gel, 30 g, ethyl acetate/MeOH, 20/1) to give the title compound (1.38 g, 72%) as a yellow solid; MS: m/e 269.2 [M+H] ⁺ .

d)(S)-α-(2-Methylpropyl)-2-thiazolecarboxamine acetate

A mixture of ((S)-3-methyl-1-thiocarbamoyl-butyl)-carbamic acid tert-butyl ester (1.38 g, 6 mmol), 2-bromo-1,1-dimethoxyethane (CAN: 7252-83-7, 1.14 g, 7 mmol) and p-toluenesulfonic acid (50 mg) in acetic acid (20 mL) was stirred at 120° C. for 4 h. After evaporation of the solvent, the residue was diluted with ethyl acetate (20 mL) and water (20 mL). The aqueous phase was washed with ethyl acetate (3×20 mL) and lyophilized to give a brown solid (0.6 g, 63%); MS: m/e 171.1 [M+H ⁺ ].

e) 6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid ((S)-3-methyl-1-thiazol-2-yl-butyl)-amide

The title compound was synthesized similarly to Example 1 using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and (S)-α-(2-methylpropyl)-2-thiazolemethanamine as starting materials, MS (LC/MS): 386.1 [M+H] ⁺ .

Example 57

6-Cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized by analogy to Example 1 using 6-cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid (Example 36d) and (S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 38e) as starting materials, MS (EI): m/e 357.2 [M+H] ⁺ .

Example 58

5-Chloro-6-(3-chloro-phenyl)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide

a) 5-Chloro-1-oxy-pyridine-2-carboxylic acid

A mixture of 5-chloro-pyridine-2-carboxylic acid (CAN 86873-60-1, 6.3 g, 0.04 mol) and m-CPBA (CAN 937-14-4, 20.7 g, 0.12 mol) in dichloromethane (200 ml) was stirred overnight at 40° C. After evaporation of the solvent, the crude product was purified by column chromatography (silica gel, 200 g, first petroleum ether/ethyl acetate 4/1, then methanol/ethyl acetate 1/1) to give the title compound (6.5 g, 94%) as a yellow solid; MS (EI): m/e=174.0 [M+H] ⁺ .

b) 6-Bromo-5-chloro-pyridine-2-carboxylic acid

5-Chloro-1-oxy-pyridine-2-carboxylic acid (3.5 g, 20 mmol) was added to phosphorus oxybromide (CAN7789-59-5, 30 g) at 80°C and 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 the 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 afford the title compound (1.12 g, 23%) as a gray solid; MS (EI): m/e 236.0 [M+H] ⁺ .

c) 5-Chloro-6-(3-chloro-phenyl)-pyridine-2-carboxylic acid

Under a nitrogen atmosphere, 6-bromo-5-chloro-pyridine-2-carboxylic acid (0.38 g, 1.6 mmol), 3-chlorophenylboronic acid (CAN 63503-60-6, 0.33 g, 2.1 mmol), 1,1'-bis(diphenylphosphino)-ferrocene-dichloropalladium(II) dichloromethane complex (CAN 95464-05-4, 30 mg) and cesium carbonate (CAN 534-17-8, 1.6 g, 4.8 mmol) were added to DMF (30 mL). The mixture was stirred at 80° C. overnight. After evaporation of the solvent, the crude product was purified by column chromatography (silica gel, 12 g, first petroleum ether/ethyl acetate 4/1, then methanol/dichloromethane 1/10) to give the title compound (0.14 g, 32%) as a brown solid; MS (EI): m/e = 268.0 [M+H] ⁺ .

d) 5-Chloro-6-(3-chloro-phenyl)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 5-chloro-6-(3-chloro-phenyl)-pyridine-2-carboxylic acid and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (LC/MS): 392.0 [M+H] ⁺ .

Example 59

6-Cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid ((S)-2-cyclopropyl-1-thiazol-2-yl-ethyl)-amide

a) (S)-tert-Butyl 1-amino-3-cyclopropyl-1-thiopropan-2-ylcarbamate

A mixture of (S)-tert-butyl 1-amino-3-cyclopropyl-1-oxopropan-2-ylcarbamate (Example 38a, 6.7 g, 29 mmol) and Lawesson's reagent (CAN 19172-47-5, 6.06 g, 15 mmol) in toluene (60 mL) was stirred at 90° C. for 2.5 h. After removing the solvent in vacuo, the residue was purified by column chromatography (silica gel, 100 g, eluted with 5% methanol in ethyl acetate) to give the title compound (5.1 g, 71%) as a yellow solid; MS: m/e=267.1 [M+Na] ⁺

b) (S)-2-Cyclopropyl-1-thiazol-2-yl-ethylamine acetate

Analogously to the procedure described in Example 56d, starting from (S)-tert-butyl 1-amino-3-cyclopropyl-1-thioxopropan-2-ylcarbamate, the title compound was obtained as a yellow oil (0.75 g, 31%); MS: m/e = 169.1 [M+H] ⁺ .

c) 6-Cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid ((S)-2-cyclopropyl-1-thiazol-2-yl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 6-cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid (Example 9f) and (S)-2-cyclopropyl-1-thiazol-2-yl-ethylamine as starting materials, MS (LC/MS): 428.2 [M+H] ⁺ .

Example 60

6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid ((S)-2-cyclopropyl-1-thiazol-2-yl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and (S)-2-cyclopropyl-1-thiazol-2-yl-ethylamine (Example 59b) as starting materials, MS (LC/MS): 384.1 [M+H] ⁺ .

Example 61

6-Cyclopropylmethoxy-5-(2-oxo-pyrrolidin-1-yl)-pyridine-2-carboxylic acid (1-methyl-1-oxazol-2-yl-ethyl)-amide

a) 4-chlorobutanamide

A solution of 4-chlorobutyryl chloride (CAN 4635-59-0, 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 and 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 in the next step without purification. ¹ H-NMR (d ⁶ -DMSO): δ 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) Pyrrolidin-2-one

A solution of 4-chlorobutyramide (4.4 g, 36 mmol) and potassium tert-butoxide (CAS 865-47-4, 8.1 g, 72 mmol) in THF (50 mL) was stirred at room temperature for 36 h. 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, 100 g, 0% to 50% ethyl acetate in petroleum ether) to give the desired product (2.7 g) as a colorless oil. ^1H -NMR ( ^d6 -DMSO): δ 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-5-(2-oxo-pyrrolidin-1-yl)-pyridine-2-carboxylic acid

Under a nitrogen atmosphere, pyrrolidin-2-one (375 mg, 4.4 mmol), dimethylbis(biphenyl-phosphinoxanthene) (CAS 161265-03-8, 127 mg, 2.4 mmol), tris(dibenzylideneacetone)dipalladium (CAS 51364-51-3, 67 mg, 0.1 mmol) and cesium carbonate (CAS 534-17-8, 1.8 g, 6 mmol) in 1,4-dioxane (100 mL) were added to a solution of 5-bromo-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 9d, 1 g, 4 mmol) and the reaction mixture was stirred at 110° C. overnight. The reaction mixture was concentrated in vacuo, dissolved in water and extracted with ethyl acetate (3×30 mL). The aqueous layer was adjusted to pH=2 with aqueous hydrochloric acid (1 N) and 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-5-(2-oxo-pyrrolidin-1-yl)-pyridine-2-carboxylic acid (1-methyl-1-oxazol-2-yl-ethyl)-amide

The title compound was synthesized similarly to Example 1 using 6-cyclopropylmethoxy-5-(2-oxo-pyrrolidin-1-yl)-pyridine-2-carboxylic acid and α,α-dimethyl-2-oxazolemethanamine (CAN 1211519-76-4) as starting materials, MS (EI): m/e=358.2 [M+H] ⁺ .

Example 62

6-Cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 6-cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid (Example 36d) and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (EI): m/e=332.2 [M+H] ⁺ .

Example 63

6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid [1-(4,5-dihydro-oxazol-2-yl)-1-methyl-ethyl]-amide

a) 1-(4,5-Dihydro-oxazol-2-yl)-1-methyl-ethylamine

A mixture of benzyl 2-(oxazol-2-yl)propan-2-ylcarbamate (Example 8d, 0.63 g) and palladium on carbon (10% w/w, 0.06 g) in ethanol (20 mL) was charged under a hydrogen bubble and stirred at room temperature for 2 h. TLC indicated the reaction was complete; the mixture was filtered and concentrated to afford the product as a yellow oil (0.1 g, 33%); MS (EI): m/e = 129.1 [M+H] ⁺ .

b) 6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid [1-(4,5-dihydro-oxazol-2-yl)-1-methyl-ethyl]-amide

The title compound was synthesized analogously to Example 1 using 6-cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid (Example 14a) and 1-(4,5-dihydro-oxazol-2-yl)-1-methyl-ethanamine as starting materials, MS (EI): m/e=373.2 [M+H] ⁺ .

Example 64

6-Cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid ((S)-3-methyl-1-thiazol-2-yl-butyl)-amide

The title compound was synthesized similarly to Example 1 using 6-cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid (Example 36d) and (S)-α-(2-methylpropyl)-2-thiazolemethanamine (Example 56d) as starting materials, MS (EI): m/e=360.2 [M+H] ⁺ .

Example 65

6-Cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid ((S)-2-cyclopropyl-1-thiazol-2-yl-ethyl)-amide

The title compound was synthesized in analogy to Example 1 using 6-cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid (Example 36d) and (S)-2-cyclopropyl-1-thiazol-2-yl-ethylamine (Example 59b) as starting materials, MS (LC/MS): 358.2 [M+H] ⁺ .

Example 66

5-Chloro-6-(3-chloro-phenyl)-pyridine-2-carboxylic acid piperidin-1-ylamide

The title compound was synthesized analogously to Example 1 using 5-chloro-6-(3-chloro-phenyl)-pyridine-2-carboxylic acid (Example 58c) and 1-piperidinamine (CAN 2213-43-6) as starting materials, MS (LC/MS): 350.1 [M+H] ⁺ .

Example 67

6-(3-Chloro-phenyl)-5-cyclopropyl-pyridine-2-carboxylic acid (1-methyl-1-methylcarbamoyl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 6-(3-chloro-phenyl)-5-cyclopropyl-pyridine-2-carboxylic acid (Example 48e) and 2-amino-N,2-dimethyl-propionamide (CAN 106914-07-2) as starting materials, MS (EI) m/e: 372.1 [M+H] ⁺ .

Example 68

6-Cyclopropylmethoxy-pyridine-2-carboxylic acid piperidin-1-ylamide

The title compound was synthesized in analogy to Example 1 using 6-cyclopropylmethoxy-pyridine-2-carboxylic acid (CAN1248077-05-5) and 1-piperidinamine (CAN 2213-43-6) as starting materials, MS (LC/MS): 276.1 (M+H).

Example 69

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide

a) 6-Chloro-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid methyl ester

A mixture of methyl 5-bromo-6-chloro-pyridine-2-carboxylate (Example 9c, 2 g, 8 mmol), 3,3-difluoroazetidine hydrochloride (CAN 288315-03-7, 1 g, 8 mmol), tris(dibenzylideneacetone)dipalladium (CAN 51364-51-3, 0.16 g, 0.16 mmol), (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (CAN 76189-55-4, 0.19 g, 0.32 mmol) and cesium carbonate (3.9 g, 12 mmol) in toluene (50 mL) was stirred overnight at 110° C. under a nitrogen atmosphere. After concentration, the residue was partitioned between water (50 mL) and ethyl acetate (40 mL), and the aqueous phase was extracted with ethyl acetate (2×40 mL). The combined organic phases were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to yield a residue. The residue was purified by column chromatography (silica gel, 20 g, 10% ethyl acetate in petroleum ether) to afford the title compound (0.44 g, 21%) as a light-yellow solid; MS (EI): m/e = 263.0 [M+H] ⁺ .

b) 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid

Sodium hydride (0.29g, 8.4mmol) is added portionwise to a solution of cyclopropylmethanol (CAN 2516-33-8,0.36g, 5mmol) in DMF (3mL), and the mixture is stirred at room temperature for 2h. 6-chloro-5-(3,3-difluoro-azetidine-1-yl)-pyridine-2-formic acid methyl esters (0.44g, 1.68mmol) are added to the mixture, and the resulting solution is stirred at 110 ℃ and spent the night. After concentration, water (20mL) is added to the residue, and the solution is acidified with aqueous hydrochloric acid (6N), then extracted with ethyl acetate (2x20mL). The organic phase merged is washed with salt water (20mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain residue. The residue was purified by preparative-TLC (eluting with 50% ethyl acetate in petroleum ether) to give the title compound (0.07 g, 14%); MS (EI): m/e = 285.1 [M+H] ⁺ .

c) 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide

The title compound was synthesized similarly to Example 1 using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (EI): m/e=409.1 [M+H] ⁺ .

Example 70

6-(3-Chloro-phenyl)-5-methyl-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide

a) tert-Butyl 3-(methylcarbamoyl)pentan-3-ylcarbamate

A mixture of 2-(tert-butoxycarbonylamino)-2-ethylbutanoic acid (Example 23a, 400 mg 2 mmol), HBTU (CAN 94790-37-1, 1.3 g, 3 mmol), Et N (0.7 g, 7 mmol) in DMF (10 mL) was stirred for 30 min, then methylamine hydrochloride (CAN 593-51-1, 260 mg, 6 mmol) was added to the mixture and the solution was stirred overnight. After this, the solution was diluted with water (20 mL) and extracted with ethyl acetate (3x30 mL), and the combined organic layers were washed with water (3x50 mL) and brine (60 mL), then evaporated to dryness. The crude product (0.18 g, 45%) obtained was a light yellow solid and was used directly in the next step.

b) 2-Amino-2-ethyl-N-methyl-butyramide

A mixture of tert-butyl 3-(methylcarbamoyl)pentan-3-ylcarbamate (0.18 g, 0.74 mmol) in 10 ml of saturated hydrogen chloride in ethyl acetate was stirred at room temperature for 60 min. The solution was then evaporated to dryness to give the product (80 mg, 75%) as a light yellow solid; MS (LC/MS): 145.2 [M+H] ⁺ .

c) 6-(3-Chloro-phenyl)-5-methyl-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide

The title compound was synthesized analogously to Example 1 using 6-(3-chloro-phenyl)-5-methyl-pyridine-2-carboxylic acid (Example 49e) and 2-amino-2-ethyl-N-methyl-butyramide as starting materials, MS (LC/MS): 374.2 [M+H] ⁺ .

Example 71

6-(3-Chloro-phenyl)-5-cyclopropyl-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide

The title compound was synthesized analogously to Example 1 using 6-(3-chloro-phenyl)-5-cyclopropyl-pyridine-2-carboxylic acid (Example 48e) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70b) as starting materials, MS (EI): m/e=400.2 [M+H] ⁺ .

Example 72

6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid (1-methyl-1-[1,2,4]oxadiazol-3-yl-ethyl)-amide

a) tert-Butyl 2-(1,2,4-oxadiazol-3-yl)propan-2-ylcarbamate

To a solution of tert-butyl (Z)-1-amino-1-(hydroxyimino)-2-methylpropan-2-ylcarbamate (Example 33b, 2 g, 9.2 mmol) in acetonitrile (10 mL) were added triethoxymethane (CAN 122-51-0, 4.8 mL) and trifluoroacetic acid (CAN 76-05-1, 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 the solvent, the residue was purified by column chromatography (silica gel, 60 g, eluting with 30% to 50% ethyl acetate in petroleum ether) to give the desired product (0.668 g, 32%). MS (EI): m/e = 250.1 [M+H] ⁺ .

b) 1-Methyl-1-[1,2,4]oxadiazol-3-yl-ethylamine hydrochloride

Tert-butyl 2-(1,2,4-oxadiazol-3-yl)propan-2-ylcarbamate (0.668 g, 2.9 mmol) was dissolved in ethyl acetate (10 mL) saturated with hydrochloric acid and stirred at room temperature for 0.5 h. It was then concentrated to give the product (0.45 g, 94%); MS (EI): m/e = 128.2 [M+H] ⁺ .

c) 6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid (1-methyl-1-[1,2,4]oxadiazol-3-yl-ethyl)-amide

The title compound was synthesized similarly to Example 1 using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and 1-methyl-1-[1,2,4]oxadiazol-3-yl-ethylamine (CAN 1153757-41-5) as starting materials, MS (EI): m/e=343.1 [M+H] ⁺ .

Example 73

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-methyl-1-[1,2,4]oxadiazol-3-yl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42a) and 1-methyl-1-[1,2,4]oxadiazol-3-yl-ethylamine (CAN 1153757-41-5) as starting materials, MS (LC/MS): 343.1 (M+H).

Example 74

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide

The title compound was synthesized in analogy to Example 1 using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42a) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70b) as starting materials, MS (LC/MS): 360.2 (M+H).

Example 75

6-Cyclopropylmethoxy-5-(3-hydroxy-azetidin-1-yl)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide

a) 6-Cyclopropylmethoxy-5-(3-hydroxy-azetidin-1-yl)-pyridine-2-carboxylic acid

Under nitrogen atmosphere, to a mixture of azetidine-3-ol (CAN 45347-82-8, 200 mg, 3 mmol), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (CAS 98327-87-8, 114 mg, 0.185 mmol), tris(dibenzylideneacetone)dipalladium (CAS 51364-51-3, 85 mg, 0.1 mmol) and cesium carbonate (CAS534-17-8, 1.8 mg, 5.55 mmol) in toluene (8 mL) was added a solution of 5-bromo-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 9d, 500 mg, 1.85 mmol). The reaction mixture was stirred at 110 ° C overnight. The reaction mixture was concentrated in vacuo and the residue was dissolved in water and extracted with ethyl acetate (1 x 30 mL). The aqueous layer was adjusted to pH = 2 by adding 1N hydrochloric acid, and the resulting precipitate was collected by filtration, and 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] ⁺ .

b) 6-Cyclopropylmethoxy-5-(3-hydroxy-azetidin-1-yl)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide

The title compound was synthesized similarly to Example 1 using 6-cyclopropylmethoxy-5-(3-hydroxy-azetidin-1-yl)-pyridine-2-carboxylic acid and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (EI): m/e=389.1 [M+H] ⁺ .

Example 76

6-(4-Chloro-phenyl)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide

The title compound was synthesized analogously to Example 1 using 6-(4-chlorophenyl)-2-pyridinecarboxylic acid (CAN 135432-77-8) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70b) as starting materials, MS (EI): m/e=360.1 [M+H] ⁺ .

Example 77

6-(Cyclopropylmethoxy)-5-(1,1-dioxo-isothiazolidin-2-yl)-N-[2-(1,3-thiazol-2-yl)propan-2-yl]pyridine-2-carboxamide

a) 3-Chloropropane-1-sulfonamide

Ammonia gas was bubbled through a stirred solution of 3-chloropropane-1-sulfonyl chloride (CAN 1633-82-5, 10 g, 56 mmol) in dichloromethane (100 mL) at 0° C. over 30 min. The reaction mixture was stirred at room temperature for ¹ h. The ammonium chloride precipitate was removed by filtration. The solvent was removed under reduced pressure, and the solid was purified by recrystallization from dichloromethane to give the title compound (7.9 g, 0.05 mol, 88.7%) as a white solid. 1H NMR (300 MHz, d ⁶ -DMSO): δ 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

Sodium (1.6 g, 70 mmol) was added portionwise to ethanol (50 mL) at room temperature. After the sodium was completely dissolved, 3-chloropropane-1-sulfonamide (7.9 g, 50 mmol) was added to the solution. The reaction mixture was allowed to react at 90°C for 2 h. After 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 in the next reaction step without further purification. ¹ H NMR (300 MHz, d ⁶ -DMSO): δ 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-5-(1,1-dioxo-isothiazolidin-2-yl)-pyridine-2-carboxylic acid methyl ester

Under nitrogen atmosphere, make 5-bromo-6-chloro-pyridine-2-carboxylic acid methyl ester (embodiment 9c, 1g, 4mmol), isothiazolidine 1,1-dioxide (730mg, 0.6mmol), copper (I) iodide (150mg, 0.8mmol), 1,3-bis(pyridin-2-yl)propane-1,3-dione (CAN 10198-89-7,180mg, 0.8mmol) and potassium carbonate (1.1g, 8mmol) in DMF (20mL) solution at 110 ℃ and react 24h.Reaction mixture is poured into water, and extracted with ethyl acetate (3x 50mL).The organic extracts merged are 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 give the title compound (0.048 g, 1.6 mmol, 41.4%) as a yellow solid; MS (EI): m/e = 291.0 [M+H] ⁺ .

d) 6-Cyclopropylmethoxy-5-(1,1-dioxo-isothiazolidin-2-yl)-pyridine-2-carboxylic acid

Sodium hydride (0.029g, 0.86mmol) is added in portion to the solution of cyclopropanemethanol (CAN2516-33-8, 20mL) and the reaction mixture is stirred at room temperature for 30min. Add 6-chloro-5-(1,1-dioxy-isothiazolidine-2-yl)-pyridine-2-formic acid methyl esters (0.050g, 0.17mmol) and the mixture is heated to 100 ℃ and spend the night, quench with water and under reduced pressure concentrate. Residue is dissolved in water, extracted with ethyl acetate (50mL). By adding 1N hydrochloric acid, the pH value of water layer is adjusted to 2 and extracted with ethyl acetate (3x 20mL) subsequently. The extract water and salt water washing merged are used anhydrous sodium sulfate drying and under reduced pressure concentrate to obtain crude product. The crude product was purified by column chromatography (silica gel, 4 g, 33% ethyl acetate in petroleum ether) to give the title compound (25 mg, 0.08 mmol, 46%) as a yellow solid; MS (EI): m/e = 313.1 [M+H] ⁺ .

e) 6-(Cyclopropylmethoxy)-5-(1,1-dioxo-isothiazolidin-2-yl)-N-[2-(1,3-thiazol-2-yl)propan-2-yl]pyridine-2-carboxamide

The title compound was synthesized similarly to Example 1 using 6-cyclopropylmethoxy-5-(1,1-dioxo-isothiazolidin-2-yl)-pyridine-2-carboxylic acid and α,α-dimethyl-2-thiazolidinemethanamine (CAN 1082393-38-1) as starting materials, MS (EI): m/e=437.0 [M+H] ⁺ .

Example 78

6-Cyclopropylmethoxy-5-(3,3-difluoro-pyrrolidin-1-yl)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide

a) 6-Chloro-5-(3,3-difluoro-pyrrolidin-1-yl)-pyridine-2-carboxylic acid methyl ester

Under nitrogen atmosphere, a suspension of 5-bromo-6-chloro-pyridine-2-carboxylic acid methyl ester (Example 9c, 1.5 g, 6 mmol), 3,3-difluoropyrrolidine hydrochloride (CAN 163457-23-6, 0.64 g, 6 mmol), tris(dibenzylideneacetone)dipalladium (CAN 51364-51-3, 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 (2×30 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude product. The crude product was purified by column chromatography (silica gel, 15 g, 10% ethyl acetate in petroleum ether) to afford the title compound (0.5 g, 30%) as a light-yellow solid; MS (EI): m/e = 277.0 [M+H] ⁺ .

b) 6-Cyclopropylmethoxy-5-(3,3-difluoro-pyrrolidin-1-yl)-pyridine-2-carboxylic acid

Sodium hydride (0.27 g, 8 mmol) was added portionwise to cyclopropylmethanol (CAN 2516-33-8, 6 mL), and the mixture was stirred at room temperature for 2 hours. 6-Chloro-5-(3,3-difluoro-pyrrolidin-1-yl)-pyridine-2-carboxylic 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 phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford the title compound, which was used directly in the next step without further purification; MS (EI): m/e = 299.1 [M+H] ⁺ .

c) 6-Cyclopropylmethoxy-5-(3,3-difluoro-pyrrolidin-1-yl)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide

The title compound was synthesized analogously to Example 1 using 6-cyclopropylmethoxy-5-(3,3-difluoro-pyrrolidin-1-yl)-pyridine-2-carboxylic acid and 2-amino-2-ethyl-N-methyl-butyramide (Example 70b) as starting materials, MS (EI): m/e=425.3 [M+H] ⁺ .

Example 79

[6-Cyclopropylmethoxy-5-(3,3-difluoro-pyrrolidin-1-yl)-pyridin-2-yl]-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)-methanone

The title compound was synthesized analogously to Example 1 using 6-cyclopropylmethoxy-5-(3,3-difluoro-pyrrolidin-1-yl)-pyridine-2-carboxylic acid (Example 78b) and 1,1-dioxide-thiomorpholine (CAN 39093-93-1) as starting materials, MS (EI): m/e=416.1 [M+H] ⁺ .

Example 80

6-Cyclopropylmethoxy-5-(3,3-difluoro-pyrrolidin-1-yl)-pyridine-2-carboxylic acid (1-methyl-1-methylcarbamoyl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 6-cyclopropylmethoxy-5-(3,3-difluoro-pyrrolidin-1-yl)-pyridine-2-carboxylic acid (Example 78b) and 2-amino-N,2-dimethyl-propionamide (CAN 106914-07-2) as starting materials, MS (EI): m/e=397.1 [M+H] ⁺ .

Example 81

6-(3-Chloro-phenyl)-5-methoxy-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide

a) 5-Methoxy-1-oxy-pyridine-2-carboxylic acid

A mixture of 5-methoxy-pyridine-2-carboxylic acid (CAN 29082-92-6, 3 g, 20 mmol) and m-CPBA (CAN 937-14-4, 8 g, 47 mmol) in dichloromethane (100 mL) was stirred at 60° C. for 12 hours. The reaction mixture was cooled to ambient temperature, filtered, concentrated, and purified by column chromatography (silica gel, 100 g, eluting with 10% methanol in dichloromethane) to give the title compound (1.2 g, 36%); MS (EI): m/e=170.2 [M+H] ⁺ .

b) 6-Bromo-5-methoxy-pyridine-2-carboxylic acid

5-Methoxy-1-oxy-pyridine-2-carboxylic acid (1.2 g, 7 mmol) was added to phosphorus oxybromide (CAN7789-59-5, 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, eluted with 10% methanol in dichloromethane) to give the title compound (1 g, 61%); MS (EI): m/e = 232.0 [M+H] ⁺ .

c) 6-(3-Chlorophenyl)-5-methoxy-pyridine-2-carboxylic acid

A mixture of 6-bromo-5-methoxy-pyridine-2-carboxylic acid (0.3 g, 1 mmol), 3-chlorophenylboronic acid (CAN 63503-60-6, 0.23 g, 1 mmol), tris(dibenzylideneacetone)-dipalladium(0) (CAN 52409-22-0, 0.12 g), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (CAN 161265-03-8, 0.15 g) and potassium carbonate (0.21 g, 2 mmol) in 1,4-dioxane (10 mL) was stirred at 110° C. for 12 h under a nitrogen atmosphere. The reaction mixture was filtered, concentrated under reduced pressure and purified by column chromatography (silica gel, 10 g, eluted with 10% methanol in dichloromethane) to give the title compound (0.1 g, 29%); MS (EI): m/e=264.0 [M+H] ⁺ .

d) 6-(3-Chloro-phenyl)-5-methoxy-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide

The title compound was synthesized analogously to Example 1 using 6-(3-chloro-phenyl)-5-methoxy-pyridine-2-carboxylic acid and 2-amino-2-ethyl-N-methyl-butyramide (Example 70b) as starting materials, MS (EI): m/e=390.2 [M+H] ⁺ .

Example 82

6-(3-Chloro-phenyl)-5-methoxy-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 6-(3-chloro-phenyl)-5-methoxy-pyridine-2-carboxylic acid (Example 81c) and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (EI): m/e=388.0 [M+H] ⁺ .

Example 83

5-Chloro-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-methyl-1-[1,2,4]oxadiazol-3-yl-ethyl)-amide

a) 5,6-Dichloro-pyridine-2-carboxylic acid

A mixture of 5-chloro-pyridine-2-carboxylic acid (CAN 86873-60-1, 9.8 g, 62 mmol) and m-CPBA (CAN 937-14-4, 21.5 g, 0.124 mol) in dichloromethane (100 mL) was heated to reflux for 48 h. The reaction mixture was quenched with a saturated sodium sulfite solution (70 mL), filtered, and extracted with dichloromethane (50 mL). The organic layer was washed with water (2 x 100 ml) and brine (100 mL) and evaporated to dryness. The residue was purified by column chromatography (silica gel, 80 g, eluted with 15% ethyl acetate in petroleum ether) to obtain a colorless oil (3.3 g, 30%). The colorless oil, 5-chloro-1-oxy-pyridine-2-carboxylic acid (1.2 g, 7 mmol) was added to POCl ₃ (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 of water and extracted with ethyl acetate (2 x 15 mL), the combined organic layers were washed with water (2 x 30 mL) and brine (30 mL), then evaporated to dryness to afford the title compound (1 g, 75%) as a yellow solid, MS (EI): m/e = 191.9 [M+H] ⁺ .

b) 5-Chloro-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid

Sodium hydride (CAN 7646-69-7, 60% w/w, 1.05 g, 26 mmol) was added to cyclopropylmethanol (CAN 2516-33-8, 7.5 g) at 0°C and the mixture was stirred for 1 h. 5,6-Dichloro-pyridine-2-carboxylic 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 with hydrochloric acid (3N). 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 a crude product (0.35 g, 25%), which was used in the next step without further purification, MS (EI): m/e = 228.1 [M+H] ⁺ .

c) 5-Chloro-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-methyl-1-[1,2,4]oxadiazol-3-yl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 5-chloro-6-cyclopropylmethoxy-pyridine-2-carboxylic acid and 1-methyl-1-[1,2,4]oxadiazol-3-ylethylamine (CAN 1153757-41-5) as starting materials, MS (LC/MS): m/e=337.1 [M+H] ⁺ .

Example 84

6-Cyclohexyl-pyridine-2-carboxylic acid (2-hydroxy-cyclohexyl)-amide

The title compound was synthesized in analogy to Example 1 using 6-cyclohexyl-pyridine-2-carboxylic acid (Example 7b) and 2-aminocyclohexanol (CAN6850-38-0) as starting materials, MS (EI): m/e=303.2 [M+H] ⁺ .

Example 85

6-Cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide

The title compound was synthesized in analogy to Example 1 using 6-cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid (Example 9f) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70b) as starting materials, MS (EI): m/e=404.2 [M+H] ⁺ .

Example 86

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide

The title compound was synthesized in analogy to Example 1 using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69b) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70b) as starting materials, MS (EI): m/e=411.1 [M+H] ⁺ .

Example 87

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1-methyl-1-methylcarbamoyl-ethyl)-amide

The title compound was synthesized in analogy to Example 1 using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69b) and 2-amino-N,2-dimethyl-propionamide (CAN106914-07-2) as starting materials, MS (EI): m/e=383.1 [M+H] ⁺ .

Example 88

5-Chloro-6-(3-chloro-phenyl)-pyridine-2-carboxylic acid (1-methyl-1-[1,2,4]oxadiazol-3-yl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 5-chloro-6-(3-chloro-phenyl)-pyridine-2-carboxylic acid (Example 58c) and 1-methyl-1-[1,2,4]oxadiazol-3-ylethylamine (CAN 1153757-41-5) as starting materials, MS (EI): m/e=377.0 [M+H] ⁺ .

Example 89

6-(3-Chloro-phenyl)-5-methoxy-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized analogously to Example 1 using 6-(3-chloro-phenyl)-5-methoxy-pyridine-2-carboxylic acid (Example 81c) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methylamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e=387.0 [M+H] ⁺ .

Example 90

6-(3-Chloro-phenyl)-5-methoxy-pyridine-2-carboxylic acid (1-methyl-1-oxazol-2-yl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 6-(3-chloro-phenyl)-5-methoxy-pyridine-2-carboxylic acid (Example 81c) and α,α-dimethyl-2-oxazolemethanamine (CAN 1211519-76-4) as starting materials, MS (EI): m/e=372.1 [M+H] ⁺ .

Example 91

5-Chloro-6-(3-chloro-phenyl)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide

The title compound was synthesized analogously to Example 1 using 5-chloro-6-(3-chloro-phenyl)-pyridine-2-carboxylic acid (Example 58c) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70b) as starting materials, MS (EI): m/e=394.1 [M+H] ⁺ .

Example 92

2-[(6-Cyclohexyl-pyridine-2-carbonyl)-amino]-cyclohexanecarboxylic acid methyl ester

The title compound was synthesized analogously to Example 1 using 6-cyclohexyl-pyridine-2-carboxylic acid (Example 7b) and 2-aminocyclohexane-1-carboxylic acid methyl ester (CAN 40015-88-1) as starting materials, MS (EI): m/e=345.2 [M+H] ⁺ .

Example 93

6-Cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid (1-methyl-1-oxazol-2-yl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 6-cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid (Example 9f) and α,α-dimethyl-2-oxazolemethanamine (CAN 1211519-76-4) as starting materials, MS (EI): m/e=386.2 [M+H] ⁺ .

Example 94

6-Cyclopentyl-pyridine-2-carboxylic acid piperidin-1-ylamide

a) 6-Cyclopentenyl-pyridine-2-carboxylic acid

A mixture of 6-bromo-pyridine-2-carboxylic acid (CAN 21190-87-4, 0.375 g, 1.86 mmol), 2-cyclopentenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAN 287944-10-9, 0.3 g, 1.6 mmol), Pd(dppf _{) Cl2} (CAN95464-05-4, 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 a white solid; MS (EI): m/e = 190.1 [M+H] ⁺ .

b) 6-Cyclopentyl-pyridine-2-carboxylic acid

A mixture of 6-cyclopentenyl-pyridine-2-carboxylic 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 under hydrogen bubbling and stirred at room temperature overnight. The reaction mixture was filtered and the filtrate was concentrated to give the crude product as a 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-pyridine-2-carboxylic acid piperidin-1-ylamide

The title compound was synthesized similarly to Example 1 using 6-cyclopentyl-pyridine-2-carboxylic acid and 1-piperidinamine (CAN2213-43-6) as starting materials, MS (EI): m/e=274.1 [M+H] ⁺ .

Example 95

6-(3-Chloro-phenyl)-5-cyclopropyl-pyridine-2-carboxylic acid (1-methyl-1-oxazol-2-yl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 6-(3-chloro-phenyl)-5-cyclopropyl-pyridine-2-carboxylic acid (Example 48e) and α,α-dimethyl-2-oxazolemethanamine (CAN 1211519-76-4) as starting materials, MS (EI): m/e=382.1 [M+H] ⁺ .

Example 96

6-(3-Chloro-phenyl)-5-cyclopropyl-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized analogously to Example 1 using 6-(3-chloro-phenyl)-5-cyclopropyl-pyridine-2-carboxylic acid (Example 48e) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methylamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e=397.1 [M+H] ⁺ .

Example 97

6-(3-Chloro-phenyl)-5-cyclopropyl-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide

a) (S)-2-Amino-3-cyclopropylpropionamide hydrochloride

(S-2-(tert-Butoxycarbonylamino)-3-cyclopropylpropanoic acid (CAN 89483-06-7, 1.2 g, 5 mmol) was dissolved in ethyl acetate (30 mL) saturated with hydrochloric acid 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] ⁺ .

b) 6-(3-Chloro-phenyl)-5-cyclopropyl-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 6-(3-chloro-phenyl)-5-cyclopropyl-pyridine-2-carboxylic acid (Example 48e) and (S)-2-amino-3-cyclopropyl-propionamide hydrochloride as starting materials, MS (EI): m/e=384.2 [M+H] ⁺ .

Example 98

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42a) and (S)-2-amino-3-cyclopropyl-propionamide (CAN 156077-93-9) as starting materials, MS (LC/MS): m/e=344.3 [M+H] ⁺ .

Example 99

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-2-cyclopropyl-1-thiazol-2-yl-ethyl)-amide

The title compound was synthesized in analogy to Example 1 using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42a) and (S)-2-cyclopropyl-1-thiazol-2-yl-ethylamine (Example 59b) as starting materials, MS (LC/MS): m/e=384.3 [M+H] ⁺ .

Example 100

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide

The title compound was synthesized analogously to Example 1 using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42a) and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (LC/MS): m/e=346.2 [M+H] ⁺ .

Example 101

6-(3-Chloro-phenyl)-5-(tetrahydro-furan-3-yl)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide

a) 5-(2,5-dihydrofuran-3-yl)-pyridine-2-carboxylic acid methyl ester (a1) and 5-(4,5-dihydrofuran-2-yl)-pyridine-2-carboxylic acid methyl ester (a2)

A mixture of 5-bromo-pyridine-2-carboxylic acid methyl ester (CAN 29682-15-3, 15 g, 69 mmol), 2,5-dihydrofuran (CAN36620-92-5, 48 g, 0.69 mol), palladium diacetate (CAN 3375-31-3, 0.8 g, 3.6 mmol), sodium acetate (6.9 g, 84 mmol) and tri-tert-butylphosphine (CAN 13716-12-6, 10%, 14 g, 7 mmol) in DMF (50 ml) was stirred in a sealed tube at 120° C. 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, eluted with 30% ethyl acetate in petroleum ether) to give 5-(2,5-dihydrofuran-3-yl)-pyridine-2-carboxylic acid methyl ester (a1) and 5-(4,5-dihydrofuran-2-yl)-pyridine-2-carboxylic acid methyl ester (a2) (mixture, at UV 254 nm, a1/a2=1/0.94, 10.8 g, 76%) as colorless oils; MS (EI): m/e=206.1 [M+H] ⁺ .

b) 5-(tetrahydrofuran-3-yl)-pyridine-2-carboxylic acid methyl ester (b1) and 5-(tetrahydrofuran-2-yl)-pyridine-2-carboxylic acid methyl ester (b2)

To a solution of 5-(2,5-dihydrofuran-3-yl)-pyridine-2-carboxylic acid methyl ester (a1) and 5-(4,5-dihydrofuran-2-yl)-pyridine-2-carboxylic acid methyl ester (a2) (mixture from Example 101a, 8 g, 39 mmol) in methanol (200 ml) was added palladium on carbon (10% w/w, 0.8 g). The mixture was stirred at room temperature under hydrogen bubbling overnight. After concentration, the crude product was purified by column chromatography (silica gel, 100 g, eluted with 30% ethyl acetate in petroleum ether) to give 5-(tetrahydrofuran-3-yl)-pyridine-2-carboxylic acid methyl ester (b1) and 5-(tetrahydrofuran-2-yl)-pyridine-2-carboxylic acid methyl ester (b2) (mixture, at UV 254 nm, b1/b2=1/0.85, 7.8 g, 97%) as colorless oils; MS (EI): m/e=208.1 [M+H] ⁺ .

c) 1-Oxy-5-(tetrahydro-furan-3-yl)-pyridine-2-carboxylic acid methyl ester (c1) and 1-Oxy-5-(tetrahydro-furan-2-yl)-pyridine-2-carboxylic acid methyl ester (c2)

A mixture of 5-(tetrahydrofuran-3-yl)-pyridine-2-carboxylic acid methyl ester (b1) and 5-(tetrahydrofuran-2-yl)-pyridine-2-carboxylic acid methyl ester (b2) (mixture from Example 101b, 8 g, 39 mmol) and m-CPBA (CAN 937-14-4, 13.3 g, 77 mmol) in dichloromethane (100 ml) was stirred at 40° C. overnight. After concentration, the crude product was purified by column chromatography (silica gel, 100 g, eluted first with 25% ethyl acetate in petroleum ether and then with 50% methanol in ethyl acetate) to give 1-oxy-5-(tetrahydro-furan-3-yl)-pyridine-2-carboxylic acid methyl ester (c1) and 1-oxy-5-(tetrahydro-furan-2-yl)-pyridine-2-carboxylic acid methyl ester (c2) (mixture, at UV 254 nm, c1/c2=1/0.67, 8 g, 93%) as yellow oils; MS (EI): m/e=224.1 [M+H] ⁺ .

d) 6-bromo-5-(tetrahydrofuran-3-yl)-pyridine-2-carboxylic acid methyl ester (d1) and 6-bromo-5-(tetrahydrofuran-2-yl)-pyridine-2-carboxylic acid methyl ester (d2)

Phosphorus oxybromide (CAN 7789-59-5, 11 g, 38 mmol) was added to a solution of 1-oxo-5-(tetrahydro-furan-3-yl)-pyridine-2-carboxylic acid methyl ester (c1) and 1-oxo-5-(tetrahydro-furan-2-yl)-pyridine-2-carboxylic acid methyl ester (c2) (the mixture from Example 101c, 2.86 g, 13 mmol) in dichloromethane. The reaction mixture was stirred at room temperature overnight and poured into 100 ml of methanol. After the solvent was removed 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 purified by column chromatography (silica gel, 40 g, petroleum ether/ethyl acetate 3/1) to give 6-bromo-5-(tetrahydrofuran-3-yl)-pyridine-2-carboxylic acid methyl ester (d1) (185 g, 5%) as a yellow solid, MS (EI): m/e = 286.0, and additional 6-bromo-5-(tetrahydrofuran-2-yl)-pyridine-2-carboxylic acid methyl ester (d2) (0.138 g, 4%) as a yellow solid; MS (EI): m/e = 286.0 [M+H] ⁺ .

e) 6-(3-chlorophenyl)-5-(tetrahydrofuran-3-yl)-pyridine-2-carboxylic acid methyl ester

A solution of methyl 6-bromo-5-(tetrahydrofuran-3-yl)-pyridine-2-carboxylate (0.185 g, 0.65 mmol), 3-chlorophenylboronic acid (CAN 63503-60-6, 0.15 g, 0.96 mmol), 1,1′-bis(diphenylphosphino)-ferrocene-dichloropalladium(II) dichloromethane complex (CAN 95464-05-4, 20 mg) and cesium carbonate (CAN 534-17-8, 0.63 g, 2 mmol) in DMF (10 mL) was stirred at 80° C. under a nitrogen atmosphere overnight. After filtration, the reaction mixture was poured into water (20 mL) and washed with ethyl acetate (2×20 mL). The organic layer was concentrated in vacuo to provide the title compound (0.75 g, 73%) as a 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)-5-(tetrahydro-furan-3-yl)-pyridine-2-carboxylic acid

A mixture of methyl 6-(3-chlorophenyl)-5-(tetrahydrofuran-3-yl)-pyridine-2-carboxylate (0.15 g, 0.5 mmol) and lithium hydroxide monohydrate (CAN 1310-66-3, 88 mg, 2.1 mmol) in THF/ _H₂O 1/1 (20 mL) was stirred at room temperature for 1 h. After removing the organic solvent under reduced pressure, the aqueous phase was washed with ethyl acetate (10 mL) and acidified to pH = 3 with 1N HCl. The resulting solution was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were concentrated under reduced pressure to provide the title compound (0.12 g, 81%) as a 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)-5-(tetrahydro-furan-3-yl)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 6-(3-chloro-phenyl)-5-(tetrahydro-furan-3-yl)-pyridine-2-carboxylic acid and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (EI): m/e=428.1 [M+H] ⁺ .

Example 102

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized in analogy to Example 1 using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69b) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methylamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e=408.1 [M+H] ⁺ .

Example 103

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69b) and (S)-2-amino-3-cyclopropyl-propionamide (CAN 156077-93-9) as starting materials, MS (EI): m/e=395.2 [M+H] ⁺ .

Example 104

5-Chloro-6-(3-chloro-phenyl)-pyridine-2-carboxylic acid (1-methyl-1-oxazol-2-yl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 5-chloro-6-(3-chloro-phenyl)-pyridine-2-carboxylic acid (Example 58c) and α,α-dimethyl-2-oxazolemethanamine (CAN 1211519-76-4) as starting materials, MS (EI): m/e=376.0 [M+H] ⁺ .

Example 105

5-Chloro-6-(3-chloro-phenyl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide

The title compound was synthesized analogously to Example 1 using 5-chloro-6-(3-chloro-phenyl)-pyridine-2-carboxylic acid (Example 58c) and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=380.0 [M+H] ⁺ .

Example 106

6-(3-Chloro-phenyl)-5-cyclopentyl-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

a) 5-Cyclopentenyl-pyridine-2-carboxylic acid

5-Bromo-pyridine-2-carboxylic acid (CAN 30766-11-1, 3.4 g, 17 mmol), 1,1′-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (CAN 95464-05-4, 530 mg, 0.65 mmol) and Cs ₂ CO ₃ (6.3 g, 19 mmol) were added to a solution of 2-cyclopentenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAN 287944-10-9, 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 (3×40 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-pyridine-2-carboxylic acid

A suspension of 5-cyclopentenyl-pyridine-2-carboxylic acid (2.0 g, 11 mmol) and palladium on carbon (10% w/w, 0.5 g) in methanol (20 mL) was stirred overnight at ambient temperature under a hydrogen atmosphere. The mixture was filtered and the filtrate was 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-Cyclopentyl-1-oxy-pyridine-2-carboxylic acid

m-CPBA (CAN 937-14-4, 4.5 g, 22 mmol) was added to a solution of 5-cyclopentyl-pyridine-2-carboxylic acid (1.4 g, 7.3 mmol) in dichloromethane (20 mL). The mixture was stirred at room temperature overnight. The solid was filtered off, a saturated solution of sodium thiosulfate (50 mL) was added, and the mixture was extracted with dichloromethane (3 x 60 mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a crude product. The crude product was purified by column chromatography (silica gel, 200 g, eluted 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-Bromo-5-cyclopentyl-pyridine-2-carboxylic acid methyl ester

5-Cyclopentyl-1-oxy-pyridine-2-carboxylic acid (1.0 g, 4.8 mmol) was added to _POBr₃ (15 g) and the mixture was stirred at 80°C for 2 h. Ice water was added and the mixture was extracted with dichloromethane (3 x 50 mL). The combined organic layers were 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)-5-cyclopentyl-pyridine-2-carboxylic acid

6-Bromo-5-cyclopentyl-pyridine-2-carboxylic acid methyl ester (0.6 g, 2.1 mmol), bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (CAN 95464-05-4, 90 mg, 0.11 mmol) and potassium carbonate (0.37 g, 2.68 mmol) were added to a solution of 3-chlorophenylboronic acid (CAN 63503-60-6, 0.42 g, 2.69 mmol) in water (20 mL) and DMF (2 mL). The mixture was stirred at 100° C. for 48 h. The pH was adjusted to pH=3 with dilute hydrochloric acid. The mixture was extracted with dichloromethane (3×20 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)-5-cyclopentyl-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized analogously to Example 1 using 6-(3-chloro-phenyl)-5-cyclopentyl-pyridine-2-carboxylic acid and α,α,5-trimethyl-1,2,4-oxadiazole-3-methylamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e=425.2 [M+H] ⁺ .

Example 107

5-Cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 5-cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 39b) and (S)-2-amino-3-cyclopropyl-propionamide (CAN 156077-93-9) as starting materials, MS (EI): m/e=372.3 [M+H] ⁺ .

Example 108

5-Chloro-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized analogously to Example 1 using 5-chloro-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 83b) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methylamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e=351.1 [M+H] ⁺ .

Example 109

5-Chloro-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide

The title compound was synthesized in analogy to Example 1 using 5-chloro-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 83b) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70b) as starting materials, MS (EI): m/e=354.2 [M+H] ⁺ .

Example 110

5-Bromo-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 5-bromo-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 9d) and (S)-2-amino-3-cyclopropyl-propionamide (CAN 156077-93-9) as starting materials, MS (EI): m/e=382.0 [M+H] ⁺ .

Example 111

5-Cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide

The title compound was synthesized in analogy to Example 1 using 5-cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 39b) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70b) as starting materials, MS (EI): m/e=388.2 [M+H] ⁺ .

Example 112

6-Cyclopropylmethoxy-5-(3,3-difluoro-pyrrolidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 6-cyclopropylmethoxy-5-(3,3-difluoro-pyrrolidin-1-yl)-pyridine-2-carboxylic acid (Example 78b) and (S)-2-amino-3-cyclopropyl-propionamide (CAN 156077-93-9) as starting materials, MS (EI): m/e=409.3 [M+H] ⁺ .

Example 113

6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide

a) 5-(Trifluoromethyl)-pyridine-2-carboxylic acid methyl ester

A solution of 5-(trifluoromethyl)-pyridine-2-carboxylic acid (CAN 80194-69-0, 3 g, 15.7 mmol) and sulfurous dichloride (0.1 mL) in methanol (30 mL) was stirred under reflux 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 afford the title compound (2.7 g, 84%) as a white solid; MS (EI): m/e = 206.1 [M+H] ⁺ .

b) 1-Oxy-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester

A mixture of methyl 5-(trifluoromethyl)-pyridine-2-carboxylate (2.7 g, 13 mmol) and m-CPBA (CAN 937-14-4, 6.7 g, 39 mmol) in dry dichloromethane (30 mL) was stirred overnight under reflux conditions. The solvent was removed in vacuo and the obtained residue was purified by column chromatography (silica gel, 15 g, 20% ethyl acetate in petroleum ether) to provide the title compound (2.2 g, 76%) as a light-yellow solid; MS (EI): m/e=222.1 [M+H] ⁺ .

c) 6-Chloro-5-(trifluoromethyl)-pyridine-2-carboxylic acid methyl ester

1-Oxy-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (2.2 g, 10 mmol) was added portionwise to phosphoryl trichloride (CAN 10025-87-3, 10 mL) at 0°C, and the resulting mixture was stirred at 50°C overnight. The solvent was removed in vacuo to yield a brown oil, which was dissolved in ethyl acetate (30 mL) and carefully neutralized with aqueous sodium carbonate. The mixture was extracted with ethyl acetate (2 x 30 mL), and the combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to yield a light-brown solid. The solid was purified by column chromatography (silica gel, 15 g, 3% ethyl acetate in petroleum ether) to yield the title compound (1.5 g, 63%) as a white solid; MS (EI): m/e = 240.0 [M+H] ⁺ .

d) 6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid

Sodium hydride (1.1 g, 31.4 mmol) was added portionwise to cyclopropylmethanol (20 mL), and the mixture was stirred at room temperature for 0.5 h. 6-Chloro-5-(trifluoromethyl)-pyridine-2-carboxylic 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 6N 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 phases were 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 a white solid; MS (EI): m/e = 262.0 [M+H] ⁺ . e) 6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 6-cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid and (S)-2-amino-3-cyclopropyl-propionamide (CAN 156077-93-9) as starting materials, MS (EI): m/e=372.1 [M+H] ⁺ .

Example 114

6-Cyclopropylmethoxy-5-(tetrahydro-furan-3-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide

a) 5-Bromo-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid methyl ester

A solution of 5-bromo-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid (Example 9d, 0.4 g, 1.5 mmol), iodomethane (CAN 16519-98-5, 0.42 g, 3 mmol), and sodium carbonate (0.16 g, 1.5 mmol) in DMF (10 mL) was stirred at room temperature overnight. 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 give the title compound (0.2 g, 0.7 mmol, 48%) as a white solid; MS (EI): m/e = 286.0 [M+H] ⁺ .

b) 6-(cyclopropylmethoxy)-5-(2,5-dihydrofuran-3-yl)-pyridine-2-carboxylic acid methyl ester (b1) and 6-(cyclopropylmethoxy)-5-(4,5-dihydrofuran-2-yl)-pyridine-2-carboxylic acid methyl ester (b2)

By 5-bromo-6-(cyclopropylmethoxy)-pyridine-2-formic acid methyl ester (0.5g, 1.7mmol), 2,5-dihydrofuran (CAN 1708-29-8, 1.2g, 17mmol), palladium (II) acetate (CAN 3375-31-3, 0.02g, 0.09mmol), sodium acetate (0.17g, 2mmol) and tri-tert-butylphosphine (CAN 13716-12-6, 0.037g, 0.2mmol) in DMF (10mL) was stirred at 120 ℃ under nitrogen atmosphere for 2.5h. Water is poured into the reaction mixture and the resulting mixture is extracted with ethyl acetate (3x30mL). The combined organic extracts are washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (silica gel, 10 g, eluted with 5% ethyl acetate in petroleum ether) to give 6-(cyclopropylmethoxy)-5-(2,5-dihydrofuran-3-yl)-pyridine-2-carboxylic acid methyl ester (b1) and 6-(cyclopropylmethoxy)-5-(4,5-dihydrofuran-2-yl)-pyridine-2-carboxylic acid methyl ester (b2) (mixture b1:b2=3:2, 0.38 g, 1.4 mmol, 79%) as yellow oils; MS (EI): m/e=376.1 [M+H] ⁺ .

c) 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-3-yl)-pyridine-2-carboxylic acid methyl ester (c1) and 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-2-yl)-pyridine-2-carboxylic acid methyl ester (c2)

Under N ₂ , to 6-(cyclopropylmethoxy)-5-(2,5-dihydrofuran-3-yl)-pyridine-2-carboxylic acid methyl esters (b1) and 6-(cyclopropylmethoxy)-5-(4,5-dihydrofuran-2-yl)-pyridine-2-carboxylic acid methyl esters (b2) (from the mixture of Example 114b, 0.38g, 1.38mmol) in EtOH (50mL) solution was added Pd/C (20%, 0.08g). The suspension was degassed under vacuum and purged with H ₂ several times. The mixture was stirred at room temperature under H ₂ bubbling overnight. The reaction mixture was filtered through a celite pad, the pad was washed with EtOH and the combined filtrate was concentrated to dryness. The crude products 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-3-yl)-pyridine-2-carboxylic acid methyl ester (c1) and 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-2-yl)-pyridine-2-carboxylic acid methyl ester (c2) (mixture, c1:c2=3:2, 0.36 g) were used in the next step without further purification; MS (EI): m/e=278.1 [M+H] ⁺ , Rt=1.71 min.

d) 6-(Cyclopropylmethoxy)-5-(tetrahydrofuran-3-yl)-pyridine-2-carboxylic acid (d1) and 6-(Cyclopropylmethoxy)-5-(tetrahydrofuran-2-yl)-pyridine-2-carboxylic acid (d2)

A solution of 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-3-yl)-pyridine-2-carboxylic acid methyl ester (c1) and 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-2-yl)-pyridine-2-carboxylic acid methyl ester (c2) (a mixture from Example 114c, 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 adding 1N hydrochloric acid and the resulting precipitate was collected by filtration and dried in vacuo to give 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-3-yl)-pyridine-2-carboxylic acid (d1) and 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-2-yl)-pyridine-2-carboxylic acid (d2) (mixture, d1:d2=3:2, 0.33 g, 1.3 mmol, 100%) as yellow solids; MS (EI): m/e=264.2 [M+H] ⁺ .

e) 6-Cyclopropylmethoxy-5-(tetrahydro-furan-3-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide

The title compound was synthesized analogously to Example 1 and using a mixture of 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-3-yl)-pyridine-2-carboxylic acid and 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-2-yl)-pyridine-2-carboxylic acid (the mixture from Example 114d) and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=376.2 [M+H] ⁺ .

Example 115

6-Cyclopropylmethoxy-5-(tetrahydro-furan-2-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide

The title compound was synthesized analogously to Example 1 and using a mixture of 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-3-yl)-pyridine-2-carboxylic acid and 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-2-yl)-pyridine-2-carboxylic acid (the mixture from Example 114d) and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=376.2 [M+H] ⁺ .

Example 116

6-(3-Chloro-phenyl)-5-cyclopropyl-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 6-(3-chloro-phenyl)-5-cyclopropyl-pyridine-2-carboxylic acid (Example 48e) and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (EI): m/e=398.1 [M+H] ⁺ .

Example 117

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-amide

The title compound was synthesized analogously to Example 1 using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42a) and 2-(2-methoxy-ethoxy)-1,1-dimethyl-ethylamine (CAN 947723-29-7) as starting materials, MS (EI): m/e=363.2 [M+H] ⁺ .

Example 118

6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide

The title compound was synthesized analogously to Example 1 using 6-cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Example 113d) and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=374.1 [M+H] ⁺ .

Example 119

6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (1-methyl-1-[1,2,4]oxadiazol-3-yl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 6-cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Example 113d) and 1-methyl-1-[1,2,4]oxadiazol-3-ylethylamine (CAN 1153757-41-5) as starting materials, MS (EI): m/e=371.2 [M+H] ⁺ .

Example 120

6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized analogously to Example 1 using 6-cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Example 113d) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methylamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e=385.1 [M+H] ⁺ .

Example 121

6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 6-cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Example 113d) and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (EI): m/e=386.0 [M+H] ⁺ .

Example 122

6-Cyclohexyl-pyridine-2-carboxylic acid (2-hydroxymethyl-cyclohexyl)-amide

The title compound was synthesized analogously to Example 1 using 6-cyclohexyl-pyridine-2-carboxylic acid (Example 7b) and 2-amino-cyclohexanemethanol (CAN 89854-92-2) as starting materials, MS (EI): m/e=317.2 [M+H] ⁺ .

Example 123

6-Cyclopropylmethoxy-5-(tetrahydro-furan-2-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized analogously to Example 1 and using a mixture of 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-3-yl)-pyridine-2-carboxylic acid and 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-2-yl)-pyridine-2-carboxylic acid (the mixture from Example 114d) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e=387.2 [M+H] ⁺ .

Example 124

6-Cyclopropylmethoxy-5-(tetrahydro-furan-3-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized analogously to Example 1 and using a mixture of 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-3-yl)-pyridine-2-carboxylic acid and 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-2-yl)-pyridine-2-carboxylic acid (the mixture from Example 114d) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e=387.2 [M+H] ⁺ .

Example 125

6-(3-Chloro-phenyl)-5-(tetrahydro-furan-2-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

a) 6-(3-chlorophenyl)-5-(tetrahydrofuran-2-yl)-pyridine-2-carboxylic acid methyl ester

A solution of 6-bromo-5-(tetrahydrofuran-2-yl)-pyridine-2-carboxylic acid methyl ester (mixture of Example 101d, 0.296 g, 1 mmol), 3-chlorophenylboronic acid (CAN 63503-60-6, 0.24 g, 1.5 mmol), 1,1′-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (CAN 95464-05-4, 34 mg) and cesium carbonate (CAN 534-17-8, 1 g, 3 mmol) in DMF (10 mL) was stirred at 80° C. under nitrogen overnight. After filtration, the reaction mixture was poured into 20 mL of H ₂ O and washed with ethyl acetate (2×20 mL). The organic layer was concentrated under reduced pressure to provide the title compound (0.3 g, 91%) as a black oil, which was used in the next step without further purification; MS (EI): m/e = 318.1 [M+H] ⁺ .

b) 6-(3-Chloro-phenyl)-5-(tetrahydro-furan-2-yl)-pyridine-2-carboxylic acid

A mixture of methyl 6-(3-chlorophenyl)-5-(tetrahydrofuran-2-yl)-pyridine-2-carboxylate (0.3 g, 1 mmol) and lithium hydroxide monohydrate (CAN 1310-66-3, 130 mg, 3 mmol) in THF/ _H₂O 1/1 (20 mL) was stirred at room temperature for 1 h. After removing the organic solvent under reduced pressure, the aqueous phase was washed with ethyl acetate (10 mL) and acidified to pH = 3 with 1N HCl. 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 a black oil, which was used in the next step without further purification; MS (EI): m/e = 304.0 [M+H] ^⁺ .

c) 6-(3-Chloro-phenyl)-5-(tetrahydro-furan-2-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized analogously to Example 1 using 6-(3-chloro-phenyl)-5-(tetrahydro-furan-2-yl)-pyridine-2-carboxylic acid and α,α,5-trimethyl-1,2,4-oxadiazole-3-methylamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e=427.1 [M+H] ⁺ .

Example 126

6-(3-Chloro-phenyl)-5-(tetrahydro-furan-2-yl)-pyridine-2-carboxylic acid (1-methyl-1-oxazol-2-yl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 6-(3-chloro-phenyl)-5-(tetrahydro-furan-2-yl)-pyridine-2-carboxylic acid (Example 125b) and α,α-dimethyl-2-oxazolemethanamine (CAN 1211519-76-4) as starting materials, MS (EI): m/e=412.1 [M+H] ⁺ .

Example 127

6-(3-Chloro-phenyl)-5-(tetrahydro-furan-2-yl)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 6-(3-chloro-phenyl)-5-(tetrahydro-furan-2-yl)-pyridine-2-carboxylic acid (Example 125b) and α,α-dimethyl-2-thiazolidinemethanamine (CAN 1082393-38-1) as starting materials, MS (EI): m/e=428.1 [M+H] ⁺ .

Example 128

6-(3-Chloro-phenyl)-5-cyclopentyl-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 6-(3-chloro-phenyl)-5-cyclopentyl-pyridine-2-carboxylic acid (Example 106e) and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (EI): m/e=426.1 [M+H] ⁺ .

Example 129

6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (1-methyl-1-oxazol-2-yl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 6-cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Example 113d) and α,α-dimethyl-2-oxazolemethanamine (CAN 1211519-76-4) as starting materials, MS (EI): m/e=370.1 [M+H] ⁺ .

Example 130

6-Cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 6-cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid (Example 36d) and (S)-2-amino-3-cyclopropyl-propionamide (CAN 156077-93-9) as starting materials, MS (EI): m/e=318.2 [M+H] ⁺ .

Example 131

6-Cyclopropylmethoxy-5-(3-hydroxy-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide

The title compound was synthesized analogously to Example 1 using 6-cyclopropylmethoxy-5-(3-hydroxy-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 75a) and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=377.2 [M+H] ⁺ .

Example 132

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide

The title compound was synthesized analogously to Example 1 using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69b) and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=397.2 [M+H] ⁺ .

Example 133

5-Cyclopropylamino-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide

a) 5-(Cyclopropylamino)-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid methyl ester

Under nitrogen atmosphere, cyclopropylamine (CAS 765-30-0, 158mg, 2.8mmol), bis(diphenylphosphino)-1,1′-binaphthyl (CAS 98327-87-8, 115mg, 0.19mmol), tris(dibenzylideneacetone)dipalladium (CAS 51364-51-3, 84mg, 0.093mmol) and cesium carbonate (CAS 534-17-8, 1.8g, 6.6mmol) are added to a solution of 5-bromo-6-(cyclopropylmethoxy)-pyridine-2-formic acid methyl esters (embodiment 114a, 530mg, 1.85mmol) in toluene (20mL). The reaction mixture is stirred at 110°C overnight and concentrated in vacuo. The residue is dissolved in water and extracted with ethyl acetate (30mL). The pH of the aqueous layer was adjusted to 2 by adding 1N HCl, and 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 give the title compound (400 mg, 82%) as a yellow solid; MS (EI): m/e = 263.1 [M+H] ⁺ .

b) 5-Cyclopropylamino-6-cyclopropylmethoxy-pyridine-2-carboxylic acid

A solution of methyl 5-(cyclopropylamino)-6-(cyclopropylmethoxy)-pyridine-2-carboxylate (400 mg, 1.53 mmol) and sodium hydroxide (244 mg, 6.1 mmol) in THF/ _H₂O 1/1 (10 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. Water was added and the pH was adjusted to 2 by adding 1N HCl. The mixture was extracted with ethyl acetate (30 mL) and washed 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 give the title compound (350 mg, 92%) as a yellow solid; MS (EI): m/e = 249.3 [M+H] ⁺ .

c) 5-Cyclopropylamino-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 5-cyclopropylamino-6-cyclopropylmethoxy-pyridine-2-carboxylic acid and (S)-2-amino-3-cyclopropyl-propionamide (CAN 156077-93-9) as starting materials, MS (EI): m/e=359.2 [M+H] ⁺ .

Example 134

5-Cyclopropylamino-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide

The title compound was synthesized analogously to Example 1 using 5-cyclopropylamino-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 133b) and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=361.3 [M+H] ⁺ .

Example 135

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-cyclopropylmethyl-2-hydroxy-2-methyl-propyl)-amide

a) Methyl (S)-2-(tert-Butoxycarbonylamino)-3-cyclopropylpropionate

To a mixture of (S)-2-(tert-butoxycarbonylamino)-3-cyclopropylpropanoic acid (CAN 89483-06-7, 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 at room temperature overnight. After filtration, the filtrate was concentrated to give the title compound as a yellow oil (6.44 g, 89%); MS (EI): m/e = 266.2 [M+Na] ⁺ .

b) (S)-tert-Butyl 1-cyclopropyl-3-hydroxy-3-methylbutan-2-ylcarbamate

To a solution of (S)-methyl 2-(tert-butoxycarbonylamino)-3-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. It was then quenched with water. The mixture was diluted with ethyl acetate (20 mL) and brine (20 mL). The organic layer was washed again with brine (20 mL), dried over anhydrous sodium sulfate and concentrated to give the title compound as a white solid (0.8 g, 82%); MS (EI): m/e = 266.2 [M+Na] ⁺ .

c) (S)-3-Amino-4-cyclopropyl-2-methyl-butan-2-ol

A solution of (S)-tert-butyl 1-cyclopropyl-3-hydroxy-3-methylbutan-2-ylcarbamate (0.8 g, 3 mmol) in ethyl acetate was saturated with hydrochloric acid (10 mL) and stirred at room temperature for 1 h. After dilution with water (20 mL), the layers were separated and the aqueous phase was washed with ethyl acetate (20 mL). It was then adjusted to pH 8-9 with 1N NaOH and extracted with dichloromethane (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the title compound as a yellow oil (0.3 g, 64%); MS (EI): m/e = 144.2 [M+Na] ⁺ .

d) 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-cyclopropylmethyl-2-hydroxy-2-methyl-propyl)-amide

The title compound was synthesized in analogy to Example 1 using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69b) and (S)-3-amino-4-cyclopropyl-2-methyl-butan-2-ol as starting materials, MS (EI): m/e=410.2 [M+H] ⁺ .

Example 136

6-Cyclopropylmethoxy-5-(tetrahydro-furan-3-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide

The title compound was synthesized analogously to Example 1 and using a mixture of 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-3-yl)-pyridine-2-carboxylic acid and 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-2-yl)-pyridine-2-carboxylic acid (the mixture from Example 114d) and (S)-2-amino-3-cyclopropyl-propionamide (CAN 156077-93-9) as starting materials, MS (EI): m/e=374.2 [M+H] ⁺ .

Example 137

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (2-hydroxy-cyclohexyl)-amide

The title compound was synthesized analogously to Example 1 using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69b) and 2-amino-cyclohexanol (CAN 6850-38-0) as starting materials, MS (EI): m/e=382.2 [M+H] ⁺ .

Example 138

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized by analogy to Example 1 using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69b) and (S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 38e) as starting materials, MS (EI): m/e=434.2 [M+H] ⁺ .

Example 139

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-cyclopropylmethyl-2-hydroxy-2-methyl-propyl)-amide

The title compound was synthesized in analogy to Example 1 using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42a) and (S)-3-amino-4-cyclopropyl-2-methyl-butan-2-ol (Example 135c) as starting materials, MS (EI): m/e=359.2 [M+H] ⁺ .

Example 140

6-(3-Chloro-phenyl)-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide

a) 6-(3-Chloro-phenyl)-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid

By 6-chloro-5-(3,3-difluoroazetidine-1-yl)-pyridine-2-carboxylic acid methyl ester (Example 69a, 0.3g, 1.15mmol), 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (CAN 72287-26-4, 47mg, 0.058mmol) and cesium carbonate (CAN 534-17-8, 0.56g, 1.72mmol) to 3-chlorophenylboronic acid (CAN63503-60-6, 0.27g, 1.72mmol) in water (20mL) and DMF (10mL) solution.The mixture was stirred at 100 ℃ for 48h.The reaction mixture was adjusted to pH=3 and extracted with dichloromethane (3x20mL). 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)-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide

The title compound was synthesized analogously to Example 1 using 6-(3-chloro-phenyl)-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=437.2 [M+H] ⁺ .

Example 141

6-Cyclopropylmethoxy-5-(tetrahydro-furan-3-yl)-pyridine-2-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide

The title compound was synthesized analogously to Example 1 and using a mixture of 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-3-yl)-pyridine-2-carboxylic acid and 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-2-yl)-pyridine-2-carboxylic acid (the mixture from Example 114d) and 2-amino-2-methyl-1-propanol (CAN 124-68-5) as starting materials, MS (EI): m/e=335.1 [M+H] ⁺ .

Example 142

5-Cyclopropyl-6-(2-methoxy-ethoxy)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide

a) 5-Bromo-6-(2-methoxyethoxy)-pyridine-2-carboxylic acid

NaH (2.26 g, 66 mmol) was added portionwise to a solution of 2-methoxyethanol (30 mL). The mixture was stirred at room temperature for 30 min. 5-Bromo-6-chloro-pyridine-2-carboxylic acid methyl ester (Example 9c, 3 g, 12 mmol) was then 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 adding 1N hydrochloric acid, and the resulting mixture was extracted with ethyl acetate (3x50 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 in the next reaction step without further purification; MS (EI): m/e 276.0 [M+H] ⁺ .

b) 5-Bromo-6-(2-methoxyethoxy)-pyridine-2-carboxylic acid methyl ester

A solution of 5-bromo-6-(2-methoxyethoxy)-pyridine-2-carboxylic 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 at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate (3x50 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 give the title compound (1.7 g, 6 mmol, 65%) as a yellow solid; MS (EI): m/e 290.0 [M+H] ⁺ .

c) 5-Cyclopropyl-6-(2-methoxyethoxy)-pyridine-2-carboxylic acid methyl ester

Under nitrogen atmosphere, a solution of 5-bromo-6-(2-methoxyethoxy)-pyridine-2-carboxylic acid methyl ester (0.2 g, 0.7 mmol), cyclopropylboronic acid (CAN 411235-57-9, 81 mg, 0.9 mmol), palladium acetate (CAN 3375-31-3, 8 mg, 0.037 mmol), tricyclohexylphosphine (CAN 2622-14-2, 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. The reaction mixture was concentrated under reduced pressure, dissolved in water, extracted with ethyl acetate (3×30 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 give the title compound (0.16 g, 1 mmol, 93%) as a yellow oil; MS (EI): m/e 252.2 [M+H] ⁺ .

d) 5-Cyclopropyl-6-(2-methoxyethoxy)-pyridine-2-carboxylic acid

A solution of methyl 5-cyclopropyl-6-(2-methoxyethoxy)-pyridine-2-carboxylate (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 adding 1N hydrochloric acid, and the resulting precipitate was collected by filtration and dried in vacuo to afford the title compound (0.11 g, 0.5 mmol; 73%) as a yellow oil; MS: m/e = 238.1 [M+H] ⁺ .

e) 5-Cyclopropyl-6-(2-methoxy-ethoxy)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide

The title compound was synthesized analogously to Example 1 using 5-cyclopropyl-6-(2-methoxy-ethoxy)-pyridine-2-carboxylic acid and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=350.2 [M+H] ⁺ .

Example 143

7,7-Dimethyl-5,6,7,8-tetrahydro-quinoline-2-carboxylic acid ((R)-2-cyclopropyl-2-hydroxy-propyl)-amide

a) 7,7-Dimethyl-5,6,7,8-tetrahydro-1H-quinolin-2-one

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 in an autoclave at 140° C. and stirred for 16 h. The autoclave was cooled to ambient temperature, and the reaction mixture was transferred to a 1 L round-bottom flask and 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 a colorless oil; LC-MS (UV peak area/EIC) 85%, 178.1228 (M+H) ⁺ .

b) Trifluoromethanesulfonic acid 7,7-dimethyl-5,6,7,8-tetrahydro-quinolin-2-yl ester

7,7-Dimethyl-5,6,7,8-tetrahydro-1H-quinolin-2-one (2.0 g, 11.3 mmol) was dissolved in _CH₂Cl₂ (50 _mL ). After adding 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 slowly added over 10 minutes at -50 to -45°C. The mixture was stirred at this temperature for 15 minutes. The cooling bath was removed and the reaction mixture was stirred at room temperature for 1 hour; then poured onto ice (50 mL) and stirred for 5 minutes after adding 20 mL of 15% NaOH solution. The phases were separated and the aqueous phase was extracted with _CH₂Cl₂ ( ₂ x 30 mL). The organic layers were combined, washed with 15% NaOH (2 x 20 mL), dried _{over Na₂SO₄} , and concentrated in vacuo. The resulting light brown oil was purified by gradient chromatography on silica with ethyl acetate in heptane to afford 3.3 g (94%) of the title compound as a colorless oil; LC-MS (UV peak area/EIC) 100%, 310.0722 (M+H) ⁺ .

c) 7,7-Dimethyl-5,6,7,8-tetrahydro-quinoline-2-carboxylic acid methyl ester

Trifluoromethanesulfonic acid 7,7-dimethyl-5,6,7,8-tetrahydroquinolin-2-yl ester (3.1 g, 10.0 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 under 70 bar CO₂ pressure for 24 h. The solvent was evaporated to give a reddish-brown oily residue, which was purified by gradient chromatography on silica using ethyl acetate in heptane. Chromatography afforded 1.9 g (86%) of the title compound as a white solid; LC-MS (UV peak area/EIC) 100%, 220.1335 (M+H) ^⁺ .

d) 7,7-Dimethyl-5,6,7,8-tetrahydro-quinoline-2-carboxylic acid

Methyl 7,7-dimethyl-5,6,7,8-tetrahydroquinoline-2-carboxylate (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 for 1 h. The mixture was cooled, acidified to pH 5 with 2N HCl, and extracted with ethyl acetate. The organic phases were combined, dried _{over 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 was continued at room temperature for 30 min. The precipitate was filtered and dried to yield 1.7 g (96%) of the title compound as a white solid; MS (ISP): m/e 206.1 [M+H] ^⁺ .

e) 7,7-Dimethyl-5,6,7,8-tetrahydro-quinoline-2-carboxylic acid ((R)-2-cyclopropyl-2-hydroxy-propyl)-amide

The title compound was synthesized by analogy to Example 1 using 7,7-dimethyl-5,6,7,8-tetrahydro-quinoline-2-carboxylic acid and (αR)-α-(aminomethyl)-α-methyl-cyclo-propanemethanol (CAN 912454-48-9) 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-oxadiazol-3-yl)propan-2-yl)-5,6,7,8-tetrahydroquinoline-2-carboxamide

The title compound was synthesized by analogy to Example 1 using 7,7-dimethyl-5,6,7,8-tetrahydro-quinoline-2-carboxylic acid (Example 143d) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methylamine (CAN 1153831-97-0) as starting materials, LC-MS (UV peak area/EIC) 100%, 329.1977 (M+H) ⁺ .

Example 145

N-(1-Hydroxy-2-methylpropan-2-yl)-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-2-carboxamide

The title compound was synthesized similarly to Example 1 using 7,7-dimethyl-5,6,7,8-tetrahydro-quinoline-2-carboxylic acid (Example 143d) and 2-amino-2-methyl-1-propanol (CAN 124-68-5) as starting materials, LC-MS (UV peak area/EIC) 99.7%, 277.1910 (M+H) ⁺ .

Example 146

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-2-cyclopropyl-1-thiazol-2-yl-ethyl)-amide

The title compound was synthesized in analogy to Example 1 using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69b) and (S)-2-cyclopropyl-1-thiazol-2-yl-ethylamine (Example 59b) as starting materials, MS (EI): m/e=435.1 [M+H] ⁺ .

Example 147

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (pyridin-2-ylmethyl)-amide

The title compound was synthesized analogously to Example 1 using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69b) and pyridin-2-yl-methylamine (CAN 3731-51-9) as starting materials, MS (EI): m/e=375.2 [M+H] ⁺ .

Example 148

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69b) and 2-amino-2-methyl-1-propanol (CAN 124-68-5) as starting materials, MS (EI): m/e=356.2 [M+H] ⁺ .

Example 149

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-methanone

The title compound was synthesized analogously to Example 1 using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69b) and (S)-1-pyrrolidin-2-yl-methanol (CAN 23356-96-9) as starting materials, MS (EI): m/e=368.2 [M+H] ⁺ .

Example 150

6-Cyclopropylmethoxy-5-(3-hydroxy-oxetan-3-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide

a) 6-Cyclopropylmethoxy-5-(3-hydroxy-oxetan-3-yl)-pyridine-2-carboxylic acid

Under a nitrogen atmosphere, n-BuLi (3.23 mL, 5.6 mmol) was added dropwise to a solution of 5-bromo-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 9d, 1.1 g, 4.0 mmol) in THF (50 mL) at -78°C and stirred at this temperature for 1 h. A solution of oxetane-3-one (CAN 6704-31-0, 0.73 g, 10 mmol) in THF (5 mL) was then added at -78°C. The reaction mixture was stirred at room temperature for 1 h and quenched with aqueous _NH₄Cl . The pH was adjusted to 2 with concentrated HCl. The mixture was extracted with ethyl acetate (3 x 50 mL), and 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 on 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-5-(3-hydroxy-oxetan-3-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide

The title compound was synthesized analogously to Example 1 using 6-cyclopropylmethoxy-5-(3-hydroxy-oxetan-3-yl)-pyridine-2-carboxylic acid and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=378.2 [M+H] ⁺ .

Example 151

6-(3-Chloro-phenyl)-5-(tetrahydro-furan-3-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized analogously to Example 1 using 6-(3-chloro-phenyl)-5-(tetrahydro-furan-3-yl)-pyridine-2-carboxylic acid (Example 101f) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methylamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e=427.1 [M+H] ⁺ .

Example 152

6-(3-Chloro-phenyl)-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-amide

The title compound was synthesized in analogy to Example 1 using 6-(3-chloro-phenyl)-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 140a) and 2-(2-methoxy-ethoxy)-1,1-dimethyl-ethylamine (CAN 947723-29-7) as starting materials, MS (EI): m/e=454.1 [M+H] ⁺ .

Example 153

5-Cyclopropyl-6-(2-methoxy-ethoxy)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized in analogy to Example 1 using 5-cyclopropyl-6-(2-methoxyethoxy)-pyridine-2-carboxylic acid (Example 142d) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e=361.1 [M+H] ⁺ .

Example 154

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1,1-dimethyl-3-morpholin-4-yl-propyl)-amide

The title compound was synthesized in analogy to Example 1 using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42a) and 1,1-dimethyl-3-morpholin-4-yl-propylamine (Example 35d) as starting materials, MS (EI): m/e=388.3 [M+H] ⁺ .

Example 155

5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide

a) 5-Bromo-6-methyl-pyridine-2-carbonitrile

NaCN (4 g, 82 mmol) was added to a solution of 3-bromo-6-fluoro-2-methyl-pyridine ( ₄ g, 21 mmol) in DMSO (100 mL). The mixture was stirred at 100°C for 2 h, poured into _H₂O (100 mL), and extracted with ethyl acetate (2 x 100 mL). The organic layer was dried over _Na₂SO₄ , concentrated, and purified by flash column chromatography (silica gel, 10 g, eluting with 10% ethyl acetate in petroleum ether) to afford the title compound (0.6 g, 15%) as a white solid; MS (EI): m/e = 197.0 [M+H] ^⁺ .

b) 5-Cyclopropyl-6-methyl-pyridine-2-carbonitrile

Under nitrogen atmosphere, 5-bromo-6-methyl-pyridine-2-carbonitrile (0.5 g, 2.5 mmol), cyclopropylboronic acid (CAN: 411235-57-9, 0.36 g, 4 mmol), _Pd2 (dba) ₃ (CAN: 411235-57-9, 0.1 g, 0.2 mmol), xantphos (CAN: 161265-03-8, 0.15 g, 0.26 mmol) and _Cs2CO3 (1.1 g, 3 mmol) were suspended in 1,4- _dioxane (30 mL). The mixture was stirred at 110°C for 12 h, filtered, concentrated under reduced pressure and purified by column chromatography (silica gel, 5 g, eluted with 10% ethyl acetate in petroleum ether) to give the title compound (0.3 g, 75%) as a yellow solid; MS (EI): m/e = 159.2 [M+H] ⁺ .

c) 5-Cyclopropyl-6-methyl-1-oxy-pyridine-2-carbonitrile

A mixture of 5-cyclopropyl-6-methyl-pyridine-2-carbonitrile (0.2 g, 1.3 mmol) and m-CPBA (0.5 g, 3 mmol) in CH ₂ Cl ₂ (10 mL) was stirred at 60° C. for 12 hours. After cooling to ambient temperature, the mixture was filtered, concentrated under reduced pressure and purified by column chromatography (silica gel, 3 g, eluted with 50% ethyl acetate in petroleum ether) to give the title compound (0.2 g, 91%) as a yellow solid; MS (EI): m/e=175.0 [M+H] ⁺ .

d) 5-Cyclopropyl-6-hydroxymethyl-pyridine-2-carbonitrile

Trifluoroacetic anhydride (CAN 457-25-0, 1 mL) was added to a solution of 5-cyclopropyl-6-methyl-1-oxy-pyridine-2-carbonitrile (0.2 g, 1.1 mmol) in _CH₂Cl₂ (10 _mL ). The reaction mixture was stirred at ambient temperature for 12 h and then partitioned between 6N aqueous NaOH (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, eluted with 1% methanol in dichloromethane) to give the title compound (0.1 g, 50%) as a yellow oil; MS (EI): m/e = 175.2 [M+H] ^⁺ .

e) 6-Bromomethyl-5-cyclopropyl-pyridine-2-carbonitrile

A solution of 5-cyclopropyl-6-hydroxymethyl-pyridine-2-carbonitrile (0.1 g, 0.6 mmol), CBr ₄ (0.8 g, 1.2 mmol), and PPh ₃ (0.3 g, 1.2 mmol) in THF (10 mL) was stirred at 40° C. for 12 h. The solvent was removed under reduced pressure, and the crude product was purified by flash column chromatography (silica gel, 3 g, eluted with 25% ethyl acetate in petroleum ether) to give the title compound (0.1 g, 74%) as a yellow solid; MS (EI): m/e = 236.9 [M+H] ⁺ .

f) 5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carbonitrile

A mixture of 6-bromomethyl-5-cyclopropyl-pyridine-2-carbonitrile (0.1 g, 0.4 mmol), 4-fluoro-benzylboronic acid (CAN 1765-93-1, 0.1 g, 0.7 mmol), Pd(dppf) _Cl₂ (CAN 95464-05-4, ₅₀ mg, 0.068 mmol), and _Cs₂CO₃ (0.2 g, 0.6 mmol) in 1.4-dioxane (10 mL) was stirred at 110° C. under a nitrogen atmosphere for 12 h. The mixture was filtered, concentrated, and purified by flash column chromatography (silica gel, 3 g, eluted with 25% ethyl acetate in petroleum ether) to give the title compound (80 mg, 75%) as a yellow solid; MS (EI): m/e=253.2 [M+H] ^⁺ .

g) 5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid

A solution of 5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carbonitrile (0.08 g, 0.3 mmol) and NaOH (0.05 g, 1.2 mmol) in _H2O (10 mL) was stirred at 90°C for 2 hours. 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 a yellow solid; MS (EI): m/e = 272.1 [M+H] ⁺ .

h) 5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide

The title compound was synthesized analogously to Example 1 using 5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=384.2 [M+H] ⁺ .

Example 156

6-(3-Chloro-phenyl)-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide

The title compound was synthesized in analogy to Example 1 using 6-(3-chloro-phenyl)-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 140a) and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (EI): m/e=449.1 [M+H] ⁺ .

Example 157

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(2-methoxy-ethoxymethyl)-ethyl]-amide

a) (S)-tert-Butyl 1-cyclopropyl-3-hydroxypropan-2-ylcarbamate

_NaBH₄ (1.5 g, 39 mmol) was added portionwise to a solution of (S)-methyl 2-(tert-butoxycarbonylamino)-3-cyclopropylpropanoate (Example 135a, 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 a 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-3-(2-methoxyethoxy)propan-2-ylcarbamate

NaH (70%, 0.504 g, 15 mmol) was added portionwise to a solution of (S)-tert-butyl 1-cyclopropyl-3-hydroxypropan-2-ylcarbamate (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-2-methoxyethane (2.07 g, 15 mmol) was added and stirring was continued for 2 h. The reaction was quenched by the careful addition of _H₂O (5 mL). After evaporation of the 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 a yellow oil (1.01 g, 50%); MS (EI): m/e = 296.2 [M+Na] ^⁺ .

c) (S)-1-cyclopropyl-3-(2-methoxyethoxy)propan-2-amine

Tert-butyl (S)-1-cyclopropyl-3-(2-methoxyethoxy)propan-2-ylcarbamate (1.01 g, 4 mmol) was dissolved in HCl/ethyl acetate (10 mL) and stirred at room temperature for 30 min. The reaction mixture was then concentrated to a residue, which was dissolved in _H₂O (10 mL) and washed with ethyl acetate (2 x 10 mL). The pH of the aqueous layer was adjusted to 9-10 with 5N 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 afford the title product (0.072 g, 11%) as a yellow oil; MS (EI): m/e = 174.2 [M+Na] ^⁺ .

d) 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(2-methoxy-ethoxymethyl)-ethyl]-amide

The title compound was synthesized in analogy to Example 1 using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69b) and (S)-2-cyclopropyl-1-(2-methoxy-ethoxymethyl)-ethylamine as starting materials, MS (EI): m/e=440.1 [M+H] ⁺ .

Example 158

5-(3,3-Difluoro-azetidin-1-yl)-6-(2-methoxy-ethoxy)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide

a) 5-(3,3-Difluoroazetidin-1-yl)-6-(2-methoxyethoxy)-pyridine-2-carboxylic acid methyl ester

Under nitrogen atmosphere, a mixture of 5-bromo-6-(2-methoxyethoxy)-pyridine-2-carboxylic acid methyl ester (Example 142b, 0.42 g, 1.45 mmol), 3,3-difluoroazetidine hydrochloride (0.22 g, 1.74 mmol), tris(dibenzylideneacetone)dipalladium (CAN51364-51-3, 27 mg, 0.03 mmol), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (CAN 76189-55-4, 36 mg, 0.06 mmol) and cesium carbonate (1.4 g, 4.35 mmol) in toluene (50 mL) was stirred overnight at 110° C. After evaporation of the solvent, the residue was partitioned between water (30 mL) and ethyl acetate (30 mL), and the aqueous phase was extracted with ethyl acetate (2×30 mL). The combined organic phases were 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 a white solid; MS (EI): m/e = 303.1 [M+H] ⁺ .

b) 5-(3,3-Difluoro-azetidin-1-yl)-6-(2-methoxy-ethoxy)-pyridine-2-carboxylic acid

A solution of 5-(3,3-difluoroazetidin-1-yl)-6-(2-methoxyethoxy)-pyridine-2-carboxylic acid methyl ester (0.3 g, 1 mmol) and lithium hydroxide monohydrate (0.25 g, 6 mmol) in THF/H ₂ O (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 to pH 2 with 6N hydrochloric acid. A precipitate formed, which was collected by filtration and dried under reduced pressure to give the title compound (0.24 g, 84%) as an off-white solid, which was used directly in the next step without further purification; MS (EI): m/e=289.1 [M+H] ⁺ .

c) 5-(3,3-Difluoro-azetidin-1-yl)-6-(2-methoxy-ethoxy)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide

The title compound was synthesized analogously to Example 1 using 5-(3,3-difluoro-azetidin-1-yl)-6-(2-methoxy-ethoxy)-pyridine-2-carboxylic acid and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=401.1 [M+H] ⁺ .

Example 159

5-Cyclopropylamino-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 5-cyclopropylamino-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 133b) and 2-amino-2-methyl-1-propanol (CAN 124-68-5) as starting materials, MS (E1): m/e=401.1 [M+H] ⁺ .

Example 160

6-Cyclopropylmethoxy-5-(1-hydroxy-cyclobutyl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

a) 6-Cyclopropylmethoxy-5-(1-hydroxy-cyclobutyl)-pyridine-2-carboxylic acid

Under a nitrogen atmosphere, BuLi (0.58 mL, 0.89 mmol) was added dropwise to a solution of 5-bromo-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 9d, 0.2 g, 0.74 mmol) in THF (20 mL) at -78°C. The reaction mixture was stirred at -78°C for 1 h, after which cyclobutanone (CAN 1191-95-3, 1.11 mL, 1.47 mmol) in THF (3 mL) was added to the -78°C solution. 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 adding 1N 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 in the next step without further purification; MS (EI): m/e = 264.1 [M+H] ⁺ .

b) 6-Cyclopropylmethoxy-5-(1-hydroxy-cyclobutyl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized similarly to Example 1 using 6-cyclopropylmethoxy-5-(1-hydroxy-cyclobutyl)-pyridine-2-carboxylic acid and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e=387.2 [M+H] ⁺ .

Example 161

5-Cyclopropyl-6-(2-methoxy-ethoxy)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 5-cyclopropyl-6-(2-methoxyethoxy)-pyridine-2-carboxylic acid (Example 142d) and (S)-2-amino-3-cyclopropyl-propionamide (CAN 156077-93-9) as starting materials, MS (EI): m/e=348.1 [M+H] ⁺ .

Example 162

5-[Bis-(2,2,2-trifluoro-ethyl)-amino]-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide

a) 5-(bis(2,2,2-trifluoroethyl)amino)-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid methyl ester

Under a nitrogen atmosphere, a solution of 5-bromo-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid methyl ester (Example 114a, 1 g, 3.5 mmol), bis(2,2,2-trifluoroethyl)amine (1.90 g, 10 mmol), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (CAN 98327-87-8, 0.435 g, 1 mmol), tris(dibenzylideneacetone)dipalladium (CAN 51364-51-3, 0.32 g, 0.35 mmol) and cesium carbonate (CAN 534-17-8, 3.4 g, 10 mmol) in toluene (50 mL) was reacted at 110° C. overnight. The reaction mixture was concentrated under reduced pressure, dissolved in water, extracted with ethyl acetate (50 mL), and the aqueous layer was adjusted to pH 2 with concentrated HCl, then extracted with ethyl acetate (3 x 50 mL), washed with brine (2 x 50 mL), dried over Na ₂ SO ₄ , and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 10 g, 20% ethyl acetate in petroleum ether) to give 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]-6-cyclopropylmethoxy-pyridine-2-carboxylic acid

A solution of methyl 5-(bis(2,2,2-trifluoroethyl)amino)-6-(cyclopropylmethoxy)-pyridine-2-carboxylate (60 mg, 0.16 mmol) and sodium hydroxide (9 mg, 0.23 mmol) in ethanol (20 mL) was reacted at 90°C for 2 h. 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 adding 1N 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 product). The crude product was used in the next step without further purification; MS: m/e = 373.1 [M+H] ^⁺ .

c) 5-[Bis-(2,2,2-trifluoro-ethyl)-amino]-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide

The title compound was synthesized analogously to Example 1 using 5-[bis-(2,2,2-trifluoro-ethyl)-amino]-6-cyclopropylmethoxy-pyridine-2-carboxylic acid and (S)-2-amino-3-cyclopropyl-propionamide (CAN 156077-93-9) as starting materials, MS (EI): m/e=483.1 [M+H] ⁺ .

Example 163

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized by analogy to Example 1 using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42a) and (S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 38e) as starting materials, MS (EI): m/e=383.2 [M+H] ⁺ .

Example 164

6-(3-Chloro-phenyl)-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized in analogy to Example 1 using 6-(3-chloro-phenyl)-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 140a) and (S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 38e) as starting materials, MS (EI): m/e=474.1 [M+H] ⁺ .

Example 165

5-[Bis-(2,2,2-trifluoro-ethyl)-amino]-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide

The title compound was synthesized in analogy to Example 1 using 5-[bis-(2,2,2-trifluoro-ethyl)-amino]-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 162b) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70b) as starting materials, MS (EI): m/e=499.2 [M+H] ⁺ .

Example 166

5-Cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

a) 5-Bromo-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid

5-bromo-6-chloropicolinic acid (200mg, 846 μmol; CAN 959958-25-9) and powdered potassium hydroxide (190mg, 3.38mmol) are merged with DMSO (1.93mL) to obtain a colorless solution, which is stirred at ambient temperature for 15min. Tetrahydro-2-furan methanol (130mg, 123 μl, 1.27mmol, CAN 97-99-4) is added afterwards, and stirring is continued at ambient temperature for 1 day. The reaction mixture is poured into a mixture of ice-water and 1M NaOH, and extracted with tert-butyl methyl ether (2x25mL) and washed with ice-water/salt water. Aqueous phases are merged, acidified with ice/1N HCl and extracted with isopropyl acetate (2x30mL). The organic layer was washed with ice-water/brine (2 x 30 mL), _dried over _Na2SO4 and concentrated in vacuo to give the title compound (254 mg, 99%) as a light brown oil; MS (ESI): 301.8 [MH] ^- .

b) 5-Cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid

By palladium (II) acetate (1.19 mg, 5.3 μmol), butyl bis (tricyclo [3.3.1.13, 7] dec-1-yl) -phosphine (2.85 mg, 7.94 μmol, CAN 321921-71-5), cyclopropyl trifluoroborate potassium (39.6 mg, 267 μmol) and cesium carbonate (259 mg, 794 μmol) are combined to give a white solid. To this solid is added a degassed solution of 5-bromo-6- (tetrahydro-furan-2-ylmethoxy) -pyridine-2-carboxylic acid (80 mg, 265 μmol) in toluene (2.02 mL) / water (224 μL) through a septum cap. The reaction mixture is 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 of ice water/brine/1N HCl, extracted with isopropyl acetate (2 _x 40 mL), and washed with 20 mL of ice water/brine. The organic layer was dried over _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 a light yellow liquid; MS (ESI): 262.0 [MH] ⁻ .

b) 5-Cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized in analogy to Example 1 using 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 166b) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methylamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e=387.0 [M+H] ⁺ .

Example 167

N-(2-Cyanoprop-2-yl)-5-cyclopropyl-6-(cyclopropylmethoxy)picolinamide

The title compound was synthesized by analogy to Example 1 using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42a) and 2-amino-2-methyl-propionitrile (CAN 19355-69-2) as starting materials, LC-MS (UV peak area/ESI) 89%, 300.1702 (M+H) ⁺ .

Example 168

(S)-5-Cyclopropyl-6-(cyclopropylmethoxy)-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)picolinamide

The title compound was synthesized by analogy to Example 1 using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42a) and (2S)-2-amino-N,3,3-trimethyl-butyramide (CAN 89226-12-0) as starting materials, LC-MS (UV peak area/ESI) 96%, 360.2272 (M+H) ⁺ .

Example 169

N-(1-amino-2,3-dimethyl-1-oxobutan-2-yl)-5-cyclopropyl-6-(cyclopropylmethoxy)picolinamide

The title compound was synthesized in analogy to Example 1 using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42a) and 2-amino-2,3-dimethyl-butyramide (CAN 40963-14-2) as starting materials, LC-MS (UV peak area/ESI) 96%, 346.2136 (M+H) ⁺ .

Example 170

N-(1-amino-2-methyl-1-oxobutan-2-yl)-5-cyclopropyl-6-(cyclopropylmethoxy)picolinamide

The title compound was synthesized in analogy to Example 1 using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42a) and 2-amino-2-methyl-butyramide (CAN 59209-90-4) as starting materials, LC-MS (UV peak area/ESI) 96%, 332.1982 (M+H) ⁺ .

Example 171

5-Cyclopropyl-6-(cyclopropylmethoxy)-N-(1-(5-methyl-1,2,4-oxadiazol-3-yl)cyclobutyl)picolinamide

The title compound was synthesized by analogy to Example 1 using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42a) and 1-(5-methyl-1,2,4-oxadiazol-3-yl)-cyclobutanamine hydrochloride (1:1) (CAN 1170897-28-5) as starting materials, LC-MS (UV peak area/ESI) 97.8%, 369.1914 (M+H) ⁺ .

Example 172

(S)-N-(2-amino-2-oxo-1-phenylethyl)-5-cyclopropyl-6-(cyclopropylmethoxy)picolinamide

The title compound was synthesized by analogy to Example 1 using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42a) and (αS)-α-amino-phenylacetamide hydrochloride (1:1) (CAN 60079-51-8) as starting materials, LC-MS (UV peak area/ESI) 98%, 366.1814 (M+H) ⁺ .

Example 173

(R)-N-(2-amino-2-oxo-1-phenylethyl)-5-cyclopropyl-6-(cyclopropylmethoxy)picolinamide

The title compound was synthesized by analogy to Example 1 using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42a) and (αR)-α-amino-phenylacetamide hydrochloride (1:1) (CAN 63291-39-4) as starting materials, LC-MS (UV peak area/ESI) 100%, 366.1808 (M+H) ⁺ .

Example 174

(R)-5-Cyclopropyl-6-(cyclopropylmethoxy)-N-(1-hydroxy-4-methylpentan-2-yl)picolinamide

The title compound was synthesized in analogy to Example 1 using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42a) and (2R)-2-amino-4-methyl-1-pentanol (CAN 53448-09-2) as starting materials, LC-MS (UV peak area/ESI) 100%, 333.2165 (M+H) ⁺ .

Example 175

5-Cyclopropyl-6-(cyclopropylmethoxy)-N-(1-(hydroxymethyl)cyclopentyl)picolinamide

The title compound was synthesized analogously to Example 1 using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42a) and 1-amino-cyclopentanemethanol (CAN 10316-79-7) as starting materials, LC-MS (UV peak area/ESI) 100%, 331.2014 (M+H) ⁺ .

Example 176

5-Cyclopropyl-6-(cyclopropylmethoxy)-N-(2-(3-methyl-1,2,4-oxadiazol-5-yl)propan-2-yl)picolinamide

The title compound was synthesized in analogy to Example 1 using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42a) and α,α,3-trimethyl-1,2,4-oxadiazole-5-methylamine (CAN 1248289-21-5) as starting materials, LC-MS (UV peak area/ESI) 100%, 357.1921 (M+H) ⁺ .

Example 177

5-Bromo-6-(4-fluoro-phenoxy)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide

a) 5-Bromo-6-chloro-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide

The title compound was synthesized similarly to Example 1 using 5-bromo-6-chloropicolinic acid (CAN 959958-25-9) and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=350.0 [M+H] ⁺ .

b) 5-Bromo-6-(4-fluoro-phenoxy)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide

5-Bromo-6-chloro-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide (50 mg, 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 sequentially 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 of water. The mixture was extracted with isopropyl acetate (2 _x 40 mL), and the organic phases were combined, dried over _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 a colorless oil. MS (ESI): m/e = 421.9 [MH] ⁻ .

Example 178

N-(1-amino-2,4-dimethyl-1-oxopentan-2-yl)-5-cyclopropyl-6-(cyclopropylmethoxy)picolinamide

The title compound was synthesized in analogy to Example 1 using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42a) and 2-amino-2,4-dimethyl-pentanamide (CAN 113509-60-7) as starting materials, LC-MS (UV peak area/ESI) 100%, 360.2287 (M+H) ⁺ .

Example 179

N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-5-cyclopropyl-6-(cyclopropylmethoxy)picolinamide

The title compound was synthesized in analogy to Example 1 using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42a) and 2-amino-3,3-dimethyl-butyramide hydrochloride (1:1) (CAN 359844-68-1) as starting materials, LC-MS (UV peak area/ESI) 100%, 346.2113 (M+H) ⁺ .

Example 180

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (4-carbamoyl-tetrahydro-pyran-4-yl)-amide

The title compound was synthesized analogously to Example 1 using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42a) and 4-aminotetrahydro-2H-pyran-4-carboxamide (CAN 1183378-09-7) as starting materials, MS (EI): m/e=360.1 [M+H] ⁺ .

Example 181

(S)-5-Cyclopropyl-6-(cyclopropylmethoxy)-N-(4-methyl-1-(methylamino)-1-oxopentan-2-yl)picolinamide

The title compound was synthesized by analogy to Example 1 using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42a) and (2S)-2-amino-N,4-dimethyl-pentanamide monohydrochloride (CAN 99145-71-8) as starting materials, MS (EI): m/e=360.1 [M+H] ⁺ .

Example 182

(S)-5-Cyclopropyl-6-(cyclopropylmethoxy)-N-(4,4-dimethyl-1-(methylamino)-1-oxopentan-2-yl)picolinamide

The title compound was synthesized analogously to Example 1 using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42a) and (2S)-2-amino-N,4,4-trimethyl-pentanamide (CAN 1160161-70-5) as starting materials, MS (EI): m/e=374.1 [M+H] ⁺ .

Example 183

5-Cyclopropyl-N-((S)-3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-6-((tetrahydrofuran-2-yl)methoxy)picolinamide

The title compound was synthesized in analogy to Example 1 using 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 166b) and (2S)-2-amino-N,3,3-trimethyl-butyramide (CAN 89226-12-0) as starting materials, MS (EI): m/e=390.4 [M+H] ⁺ .

Example 184

5-Cyclopropyl-N-((S)-4-methyl-1-(methylamino)-1-oxopentan-2-yl)-6-((tetrahydrofuran-2-yl)methoxy)picolinamide

The title compound was synthesized by analogy to Example 1 using 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 166b) and (2S)-2-amino-N,4-dimethyl-pentanamide monohydrochloride (CAN 99145-71-8) as starting materials, MS (EI): m/e=390.0 [M+H] ⁺ .

Example 185

5-Cyclopropyl-N-((S)-4,4-dimethyl-1-(methylamino)-1-oxopentan-2-yl)-6-((tetrahydrofuran-2-yl)methoxy)picolinamide

The title compound was synthesized analogously to Example 1 using 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 166b) and (2S)-2-amino-N,4,4-trimethyl-pentanamide (CAN 1160161-70-5) as starting materials, MS (EI): m/e=404.1 [M+H] ⁺ .

Example 186

N-((S)-1-amino-4-methyl-1-oxopentan-2-yl)-5-cyclopropyl-6-((tetrahydrofuran-2-yl)methoxy)picolinamide

a) 5-Bromo-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide

The title compound was synthesized analogously to Example 1 using 5-bromo-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 166a) and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=416.0 [M+H] ⁺ .

b) N-((S)-1-amino-4-methyl-1-oxopentan-2-yl)-5-cyclopropyl-6-((tetrahydrofuran-2-yl)methoxy)picolinamide

The title compound was synthesized by analogy to Example 166b using 5-bromo-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide (Example 186a) and potassium cyclopropyltrifluoroborate as starting materials, MS (EI): m/e=376.2 [M+H] ⁺ .

Example 187

5-Cyclopropyl-6-(4-fluoro-phenoxy)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide

The title compound was synthesized by analogy to Example 166b using 5-bromo-6-(4-fluoro-phenoxy)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide (Example 177b) and potassium cyclopropyltrifluoroborate as starting materials, MS (EI): m/e=386.0 [M+H] ⁺ .

Example 188

5-Bromo-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid ((S)-2,2-dimethyl-1-methylcarbamoyl-propyl)-amide

The title compound was synthesized analogously to Example 1 using 5-bromo-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 166a) and (2S)-2-amino-N,3,3-trimethyl-butyramide (CAN 89226-12-0) as starting materials, MS (EI): m/e=428.0 [M+H] ⁺ .

Example 189

5-Cyclopropyl-N-(1-(5-methyl-1,2,4-oxadiazol-3-yl)cyclobutyl)-6-(pyridin-2-ylmethoxy)picolinamide

a) 5-Bromo-6-(pyridin-2-ylmethoxy)-pyridine-2-carboxylic acid

The title compound was synthesized similarly to Example 9d using 5-bromo-6-chloro-pyridine-2-carboxylic acid and 2-pyridinemethanol (CAN 586-98-1) as starting materials, LC-MS (UV peak area/ESI) 100%, 308.9876 (M+H) ⁺ .

b) 5-Cyclopropyl-6-(pyridin-2-ylmethoxy)-pyridine-2-carboxylic acid

The title compound was synthesized by analogy to Example 42a using 5-bromo-6-(pyridin-2-ylmethoxy)-pyridine-2-carboxylic acid and cyclopropylboronic acid (CAN 411235-57-9) as starting materials, LC-MS (UV peak area/ESI) 100%, 271.1081 (M+H) ⁺ .

c) 5-Cyclopropyl-N-(1-(5-methyl-1,2,4-oxadiazol-3-yl)cyclobutyl)-6-(pyridin-2-ylmethoxy)picolinamide

The title compound was synthesized by analogy to Example 1 using 5-cyclopropyl-6-(pyridin-2-ylmethoxy)-pyridine-2-carboxylic acid and 1-(5-methyl-1,2,4-oxadiazol-3-yl)-cyclobutaneamine hydrochloride (1:1) (CAN 1170897-28-5) as starting materials, MS (EI): m/e=406.2 [M+H] ⁺ .

Example 190

5-Cyclopropyl-N-(cyclopropyl(5-methyl-1,2,4-oxadiazol-3-yl)methyl)-6-(cyclopropylmethoxy)picolinamide

The title compound was synthesized analogously to Example 1 and using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42a) and cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methylamine (which can be prepared, for example, in a manner analogous to (S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 38e)) as starting materials, MS (EI): m/e=369.2 [M+H] ⁺ .

Example 191

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((R)-1-hydroxymethyl-1,2-dimethyl-propyl)-amide

The title compound was synthesized analogously to Example 1 using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42a) and (R)-2-amino-2,3-dimethyl-butan-1-ol [CAN 155158-75-1] as starting materials, MS (EI): m/e=333.2 [M+H] ⁺ .

Example 192

(S)-6-(3-chlorophenyl)-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)picolinamide

The title compound was synthesized similarly to Example 1 using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and (2S)-2-amino-N,3,3-trimethyl-butyramide (CAN 89226-12-0) as starting materials, MS (EI): m/e=360.0 [M+H] ⁺ .

Example 193

(S)-6-(3-chlorophenyl)-N-(4,4-dimethyl-1-(methylamino)-1-oxopentan-2-yl)picolinamide

The title compound was synthesized similarly to Example 1 using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and (2S)-2-amino-N,4,4-trimethyl-pentanamide (CAN 1160161-70-5) as starting materials, MS (EI): m/e=374.1 [M+H] ⁺ .

Example 194

5-Cyclopropyl-6-(cyclopropylmethoxy)-N-(4-hydroxy-2-methylbutan-2-yl)picolinamide

The title compound was synthesized analogously to Example 1 using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42a) and 3-amino-3-methyl-butan-1-ol (CAN 42514-50-1) as starting materials, LC-MS (UV peak area/ESI) 100%, 319.1 (M+H) ⁺ .

Example 195

(S)-5-Cyclopropyl-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-6-((tetrahydro-2H-pyran-4-yl)methoxy)picolinamide

The title compound was synthesized analogously to Example 1 and using 5-cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carboxylic acid (which can be prepared, for example, in a manner analogous to 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 166b)) and (2S)-2-amino-N,3,3-trimethyl-butyramide (CAN 89226-12-0) as starting materials, MS (EI): m/e=404.3 [M+H] ⁺ .

Example 196

(S)-5-Cyclopropyl-N-(4,4-dimethyl-1-(methylamino)-1-oxopentan-2-yl)-6-((tetrahydro-2H-pyran-4-yl)methoxy)picolinamide

The title compound was synthesized analogously to Example 1 and using 5-cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carboxylic acid (which can be prepared, for example, in a manner analogous to 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 166b)) and (2S)-2-amino-N,4,4-trimethyl-pentanamide (CAN 1160161-70-5) as starting materials, MS (EI): m/e=418.3 [M+H] ⁺ .

Example 197

(-)-5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide

The title compound was obtained by chiral chromatography from 5-cyclopropyl-N-(cyclopropyl(5-methyl-1,2,4-oxadiazol-3-yl)methyl)-6-(cyclopropylmethoxy)picolinamide (Example 190), MS (EI): m/e=369.2 [M+H] ⁺ .

Example 198

(+)-5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide

The title compound was obtained by chiral chromatography from 5-cyclopropyl-N-(cyclopropyl(5-methyl-1,2,4-oxadiazol-3-yl)methyl)-6-(cyclopropylmethoxy)picolinamide (Example 190), MS (EI): m/e=369.2 [M+H] ⁺ .

Example 199

5-Cyclopropyl-N-(2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-yl)-6-(pyridin-2-ylmethoxy)picolinamide

The title compound was synthesized in analogy to Example 1 using 5-cyclopropyl-6-(pyridin-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 189b) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e=394.2 [M+H] ⁺ .

Example 200

(S)-N-(1-amino-4-methyl-1-oxopentan-2-yl)-5-cyclopropyl-6-(pyridin-2-ylmethoxy)picolinamide

The title compound was synthesized analogously to Example 1 using 5-cyclopropyl-6-(pyridin-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 189b) and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=383.2 [M+H] ⁺ .

Example 201

(S)-5-Cyclopropyl-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-6-(pyridin-2-ylmethoxy)picolinamide

The title compound was synthesized in analogy to Example 1 using 5-cyclopropyl-6-(pyridin-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 189b) and (2S)-2-amino-N,3,3-trimethyl-butyramide (CAN 89226-12-0) as starting materials, MS (EI): m/e=397.2 [M+H] ⁺ .

Example 202

5-Cyclopropyl-N-(2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-yl)-6-((tetrahydro-2H-pyran-4-yl)methoxy)picolinamide

The title compound was synthesized analogously to Example 1 and using 5-cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carboxylic acid (which can be prepared, for example, in a manner analogous to 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 166b)) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methylamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e=401.2 [M+H] ⁺ .

Example 203

(S)-5-Cyclopropyl-N-(4-methyl-1-(methylamino)-1-oxopentan-2-yl)-6-((tetrahydro-2H-pyran-4-yl)methoxy)picolinamide

The title compound was synthesized analogously to Example 1 and using 5-cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carboxylic acid (which can be prepared, for example, in a manner analogous to 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 166b)) and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=404.2 [M+H] ⁺ .

Example 204

(S)-N-(3,3-Dimethyl-1-(methylamino)-1-oxobutan-2-yl)-6-phenylpicolinamide

The title compound can be prepared analogously to Example 1 using 6-phenyl-pyridine-2-carboxylic acid (CAN 39774-28-2) and (2S)-2-amino-N,3,3-trimethyl-butyramide (CAN 89226-12-0) as starting materials, MS (EI): m/e=326.2 [M+H] ⁺ .

Example 205

(S)-N-(4-Methyl-1-(methylamino)-1-oxopentan-2-yl)-6-phenylpicolinamide

The title compound can be prepared analogously to Example 1 using 6-phenyl-pyridine-2-carboxylic acid (CAN 39774-28-2) and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=326.2 [M+H] ⁺ .

Example 206

5-(3,3-difluoroazetidin-1-yl)-N-((S)-3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-6-((tetrahydrofuran-2-yl)methoxy)picolinamide

The title compound was synthesized by addition of 3,3-difluoroazetidine hydrochloride (CAN 288315-03-7) to 5-bromo-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid ((S)-2,2-dimethyl-1-methylcarbamoyl-propyl)-amide (Example 188) in analogy to the procedure described in Example 69a, MS (EI): m/e = 441.0 [M+H] ⁺ .

Example 207

2-(6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinamido)-2-ethylbutanoic acid

The title compound can be synthesized, for example, by i) coupling of 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69b) with 2-amino-2-ethyl-butyric acid methyl ester (CAN 70974-26-4) analogously to Example 1; and ii) saponification of the ester group under conditions analogous to those described in Example 48e), MS (EI): m/e=396.1 [MH] ⁻ .

Example 208

(S)-6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)picolinamide

The title compound was synthesized in analogy to Example 1 using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69b) and (2S)-2-amino-N,3,3-trimethyl-butyramide (CAN 89226-12-0) as starting materials, MS (EI): m/e=411.4 [M+H] ⁺ .

Example 209

(S)-6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-N-(4,4-dimethyl-1-(methylamino)-1-oxopentan-2-yl)picolinamide

The title compound was synthesized in analogy to Example 1 using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69b) and (2S)-2-amino-N,4,4-trimethyl-pentanamide (CAN 1160161-70-5) as starting materials, MS (EI): m/e=425.0 [M+H] ⁺ .

Example 210

(S)-6-(3-Fluorophenyl)-N-(4-methyl-1-(methylamino)-1-oxopentan-2-yl)picolinamide

The title compound can be prepared analogously to Example 1 and using 6-(3-fluoro-phenyl)-pyridine-2-carboxylic acid (CAN 887982-40-3) and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, LC-MS (UV peak area/ESI) 100%, 344.1768 (M+H) ⁺ .

Example 211

(S)-N-(4-Methyl-1-(methylamino)-1-oxopentan-2-yl)-6-(3-(trifluoromethyl)phenyl)picolinamide

The title compound can be prepared analogously to Example 1 and using 6-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid (CAN 887982-06-1) and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, LC-MS (UV peak area/ESI) 99.5%, 394.1734 (M+H) ⁺ .

Example 212

(S)-6-(3-chloro-4-fluorophenyl)-N-(4-methyl-1-(methylamino)-1-oxopentan-2-yl)picolinamide

The title compound can be prepared analogously to Example 1 and using 6-(3-chloro-4-fluoro-phenyl)-pyridine-2-carboxylic acid (CAN 1261922-29-5) and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, LC-MS (UV peak area/ESI) 97.8%, 378.1376 (M+H) ⁺ .

Example 213

(S)-N-(3,3-Dimethyl-1-(methylamino)-1-oxobutan-2-yl)-6-(3-fluorophenyl)picolinamide

The title compound can be prepared analogously to Example 1 and using 6-(3-fluoro-phenyl)-pyridine-2-carboxylic acid (CAN 887982-40-3) and (2S)-2-amino-N,3,3-trimethyl-butyramide (CAN 89226-12-0) as starting materials, LC-MS (UV peak area/ESI) 99.1%, 344.1774 (M+H) ⁺ .

Example 214

(S)-N-(3,3-Dimethyl-1-(methylamino)-1-oxobutan-2-yl)-6-(3-(trifluoromethyl)phenyl)-picolinamide

The title compound can be prepared analogously to Example 1 and using 6-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid (CAN 887982-06-1) and (2S)-2-amino-N,3,3-trimethyl-butyramide (CAN 89226-12-0) as starting materials, LC-MS (UV peak area/ESI) 99.0%, 394.1735 (M+H) ⁺ .

Example 215

(S)-N-(3,3-Dimethyl-1-(methylamino)-1-oxobutan-2-yl)-6-(3-methoxyphenyl)picolinamide

The title compound can be prepared analogously to Example 1 and using 6-(3-methoxy-phenyl)-pyridine-2-carboxylic acid (CAN 887982-11-8) and (2S)-2-amino-N,3,3-trimethyl-butyramide (CAN 89226-12-0) as starting materials, LC-MS (UV peak area/ESI) 99.1%, 356.1961 (M+H) ⁺ .

Example 216

(S)-6-(3-chloro-4-fluorophenyl)-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)picolinamide

The title compound can be prepared analogously to Example 1 and using 6-(3-chloro-4-fluoro-phenyl)-pyridine-2-carboxylic acid (CAN 1261922-29-5) and (2S)-2-amino-N,3,3-trimethyl-butyramide (CAN 89226-12-0) as starting materials, LC-MS (UV peak area/ESI) 98.4%, 378.1372 (M+H) ⁺ .

Example 217

(S)-5-Cyclopropyl-6-(cyclopropylmethoxy)-N-(2,2,2-trifluoro-1-(pyridin-3-yl)ethyl)-picolinamide

The title compound was synthesized analogously to Example 1 using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42a) and (S)-2,2,2-trifluoro-1-pyridin-3-yl-ethylamine (CAN 336105-46-5) as starting materials, MS (EI): m/e=392.2 [M+H] ⁺ .

Example 218

(R)-5-Cyclopropyl-6-(cyclopropylmethoxy)-N-(2,2,2-trifluoro-1-(pyridin-3-yl)ethyl)-picolinamide

The title compound was synthesized analogously to Example 1 using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42a) and (R)-2,2,2-trifluoro-1-pyridin-3-yl-ethylamine (CAN 1212813-98-3) as starting materials, MS (EI): m/e=392.2 [M+H] ⁺ .

Example 219

5-Cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide

The title compound was synthesized analogously to Example 1 and using 5-cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carboxylic acid (which can be prepared, for example, in a manner analogous to 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 166b)) and cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methylamine (which can be prepared, for example, in a manner analogous to (S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 38e)) as starting materials, MS (EI): m/e=413.1 [M+H] ⁺ .

Example 220

2-({5-[Bis-(2,2,2-trifluoro-ethyl)-amino]-6-cyclopropylmethoxy-pyridine-2-carbonyl}-amino)-2-ethyl-butyric acid methyl ester

The title compound was synthesized analogously to Example 1 using 5-[bis-(2,2,2-trifluoro-ethyl)-amino]-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 162b) and 2-amino-2-ethylbutyric acid methyl ester hydrochloride (CAN 92398-54-4) as starting materials, MS (EI): m/e=500.1 [M+H] ⁺ .

Example 221

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide

The title compound was synthesized in analogy to Example 1 using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69b) and cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methylamine (which can be prepared, for example, in a manner analogous to (S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 38e)) as starting materials, MS (EI): m/e=420.0 [M+H] ⁺ .

Example 222

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-2-cyclopropyl-1-dimethylcarbamoyl-ethyl)-amide

a) (S)-tert-Butyl 3-cyclopropyl-1-(dimethylamino)-1-oxopropan-2-ylcarbamate

The title compound was synthesized in analogy to Example 1 using (S)-2-(tert-butoxycarbonylamino)-3-cyclopropylpropionic acid (CAN 89483-06-7) and dimethylamine hydrochloride as starting materials. MS (EI): m/e = 256.3 [M] ⁺ .

b) (S)-2-Amino-3-cyclopropyl-N,N-dimethylpropionamide hydrochloride

A 4M solution of HCl in dioxane (4.68 mL, 18.7 mmol) was added to a solution of tert-butyl (S)-3-cyclopropyl-1-(dimethylamino)-1-oxopropan-2-ylcarbamate (1.2 g, 4.68 mmol) in ethanol (10 mL). After stirring at ambient temperature for 16 h, the solvent was removed under reduced pressure. The remaining solid was digged with diethyl ether (10 mL), filtered, washed with diethyl ether (3 x 5 mL) and dried in vacuo at 40 ° C for 3 h to give the title compound as an off-white solid (820 mg, 91%). MS (EI): m/e = 157.1 [M+H] ⁺ .

c) 5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-2-cyclopropyl-1-dimethylcarbamoyl-ethyl)-amide

The title compound was synthesized by analogy to Example 1 using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and (S)-2-amino-3-cyclopropyl-N,N-dimethylpropionamide hydrochloride as starting materials, LC-MS (UV peak area/ESI) 100%, 372.2278 (M+H) ⁺ .

Example 223

5-Cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carboxylic acid (2,2,2-trifluoro-1-pyridin-2-yl-ethyl)-amide

The title compound was synthesized analogously to Example 1 and using 5-cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carboxylic acid (which can be prepared, for example, in a manner analogous to 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 166b)) and 2,2,2-trifluoro-1-(pyridin-2-yl)ethanamine (CAN 503173-14-6) as starting materials, MS (EI): m/e=436.1 [M+H] ⁺ .

Example 224

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (2,2,2-trifluoro-1-pyridin-2-yl-ethyl)-amide

The title compound was synthesized in analogy to Example 1 using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69b) and 2,2,2-trifluoro-1-(pyridin-2-yl)ethanamine (CAN 503173-14-6) as starting materials, MS (EI): m/e=443.1 [M+H] ⁺ .

Example 225

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((-)-methylcarbamoyl-phenyl-methyl)-amide

The title compound was synthesized analogously to Example 1 using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and (αR)-α-amino-N-methyl-phenylacetamide hydrochloride (1:1) (CAN 97549-10-5) as starting materials. Racemization occurred during the synthesis and the products were separated by chiral chromatography on a Chiralpak AD using heptane/20% ethanol as eluent. The (-)-enantiomer was separated. LC-MS (UV peak area/ESI) 100%, 380.1968 (M+H) ⁺ ,

Example 226

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((+)-dimethylcarbamoyl-phenyl-methyl)-amide

The title compound was synthesized analogously to Example 1 using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and (αR)-α-amino-N,N-dimethyl-phenylacetamide hydrochloride (1:1) (CAN 129157-29-5) as starting materials. Racemization occurred during the synthesis and the products were separated by chiral chromatography on Reprosil Chiral NR using heptane/20% ethanol as eluent. The (+)-enantiomer was separated. LC-MS (UV peak area/ESI) 100%, 394.2120 (M+H) ⁺ ,

Example 227

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((-)-dimethylcarbamoyl-phenyl-methyl)-amide

The title compound was synthesized analogously to Example 1 using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and (αR)-α-amino-N,N-dimethyl-phenylacetamide hydrochloride (1:1) (CAN 129157-29-5) as starting materials. Racemization occurred during the synthesis, and the products were separated by chiral chromatography on Reprosil Chiral NR using heptane/20% ethanol as eluent. The (-)-enantiomer was separated. LC-MS (UV peak area/ESI) 100%, 394.2126 (M+H) ⁺ ,

Example 228

6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3-dimethyl-1-methylcarbamoyl-butyl)-amide

The title compound was synthesized in analogy to Example 1 using 6-cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Example 113d) and (2S)-2-amino-N,4,4-trimethyl-pentanamide (CAN 1160161-70-5) as starting materials. MS (EI): m/e=402.1 [M+H] ⁺ .

Example 229

6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide

The title compound was synthesized in analogy to Example 1 using 6-cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Example 113d) and cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methylamine (which can be prepared, for example, in a manner analogous to (S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 38e)) as starting materials, MS (EI): m/e=397.0 [M+H] ⁺ .

Example 230

6-(Tetrahydro-pyran-4-ylmethoxy)-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3-dimethyl-1-methylcarbamoyl-butyl)-amide

a) 6-Chloro-5-(trifluoromethyl)picolinic acid

The title compound was synthesized in analogy to the procedure described in Example 125b) using methyl 6-chloro-5-(trifluoromethyl)picolinate (Example 113c) as starting material. MS (EI): m/e = 223.9 [MH] ⁻ .

b) 6-((tetrahydro-2H-pyran-4-yl)methoxy)-5-(trifluoromethyl)picolinic acid

6-Chloro-5-(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 at ambient temperature for 15 min. (Tetrahydro-2H-pyran-4-yl)methanol (170 mg, 170 μL, 1.46 mmol; CAN 14774-37-9) was added. The mixture was stirred at ambient temperature for 1 day, poured onto ice water/brine/1N HCl (75 mL), and extracted with EtOAc ( ₂ x 150 mL). The combined extracts were washed with ice water/brine (75 mL) and dried over _Na₂SO₄ . The solvent was removed under reduced pressure to give the title compound as a gray solid (385 mg, 86%), which was used in the next step without further purification. MS: 304.0 [MH] ⁻ .

c) 6-(Tetrahydro-pyran-4-ylmethoxy)-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3-dimethyl-1-methylcarbamoyl-butyl)-amide

The title compound was synthesized in a similar manner to Example 1 using 6-((tetrahydro-2H-pyran-4-yl)methoxy)-5-(trifluoromethyl)picolinic acid and (2S)-2-amino-N,4,4-trimethyl-pentanamide (CAN 1160161-70-5) as starting materials. MS (EI): m/e=446.4 [M+H] ⁺ .

Example 231

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-dimethylcarbamoyl-3-methyl-butyl)-amide

The title compound was synthesized in a similar manner to Example 1 using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and (2S)-2-amino-N,N,4-trimethyl-pentanamide hydrochloride (1:1) (CAN 207595-81-1) as starting materials. LC-MS (UV peak area/ESI) 100%, 374.2240 (M+H) ⁺ .

Example 232

6-(3-Chloro-4-fluoro-phenyl)-pyridine-2-carboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide

a) 6-Bromo-pyridine-2-carboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide

The title compound was prepared analogously to Example 1 using 6-bromo-2-pyridinecarboxylic acid (CAN 21190-87-4) and cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methylamine (which can be prepared, for example, in a manner analogous to (S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 38e)) as starting materials. LC-MS (UV peak area/ESI) 97%, 337.0289 (M+H) ⁺ .

b) 6-(3-Chloro-4-fluoro-phenyl)-pyridine-2-carboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide

The title compound can be prepared analogously to Example 177b using 6-bromo-pyridine-2-carboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide (Example 232a) and B-(3-chloro-4-fluorophenyl)-boronic acid (CAN 144432-85-9) as starting materials, MS (EI): m/e=387.1 [M+H] ⁺ .

Example 233

2-{[5-Cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carbonyl]-amino}-2-ethyl-butyric acid methyl ester

The title compound was synthesized in analogy to Example 1 using 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 166b) and 2-amino-2-ethylbutyric acid methyl ester hydrochloride (CAN 92398-54-4) as starting materials. MS (EI): m/e=391.3 [M+H] ⁺ .

Example 234

6-Cyclopropylmethoxy-5-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-pyridine-2-carboxylic acid ((S)-3,3-dimethyl-1-methylcarbamoyl-butyl)-amide

a) 6-Cyclopropylmethoxy-5-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-pyridine-2-carboxylic acid methyl ester

The title compound was synthesized in a similar manner to the procedure described in Example 32a) using 5-bromo-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid methyl ester (Example 9d) and 6-oxa-1-azaspiro[3.3]heptane oxalate (CAN 1359655-43-8) as starting materials. MS (EI): m/e = 305.0 [M+H] ⁺ .

b) 6-Cyclopropylmethoxy-5-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-pyridine-2-carboxylic acid

The title compound was synthesized in analogy to the procedure described in Example 125b) using 6-cyclopropylmethoxy-5-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-pyridine-2-carboxylic acid methyl ester as starting material. MS (EI): m/e=289.0 [MH] ⁻ .

c) 6-Cyclopropylmethoxy-5-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-pyridine-2-carboxylic acid ((S)-3,3-dimethyl-1-methylcarbamoyl-butyl)-amide

The title compound was synthesized similarly to Example 1 using 6-(cyclopropylmethoxy)-5-(6-oxa-1-azaspiro[3.3]hept-1-yl)picolinic acid and (2S)-2-amino-N,4,4-trimethylpentanamide (CAN 1160161-70-5) as starting materials. MS (EI): m/e = 431.1 [M+H] ⁺ .

Example 235

6-Cyclopropylmethoxy-5-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized in a similar manner to Example 1 using 6-(cyclopropylmethoxy)-5-(6-oxa-1-azaspiro[3.3]hept-1-yl)picolinic acid (Example 234b) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials. MS (EI): m/e = 414.1 [M+H] ⁺ .

Example 236

6-Cyclopropylmethoxy-5-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-pyridine-2-carboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide

The title compound was synthesized in analogy to Example 1 using 6-(cyclopropylmethoxy)-5-(6-oxa-1-azaspiro[3.3]hept-1-yl)picolinic acid (Example 234b) and cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methanamine (which can be prepared, for example, in a manner analogous to (S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethanamine (Example 38e)) as starting materials. MS (EI): m/e = 426.0 [M+H] ⁺ .

Example 237

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((R)-2,2,2-trifluoro-1-pyridin-3-yl-ethyl)-amide

The title compound was synthesized in analogy to Example 1 using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69b) and (R)-2,2,2-trifluoro-1-pyridin-3-yl-ethylamine (CAN 1212813-98-3) as starting materials. MS (EI): m/e = 443.1 [M+H] ⁺ .

Example 238

2-Ethyl-2-{[6-(tetrahydro-pyran-4-ylmethoxy)-5-trifluoromethyl-pyridine-2-carbonyl]-amino}-butyric acid methyl ester

The title compound was synthesized in a similar manner to Example 1 using 6-((tetrahydro-2H-pyran-4-yl)methoxy)-5-(trifluoromethyl)picolinic acid (Example 230b) and methyl 2-amino-2-ethylbutanoate hydrochloride (CAN 92398-54-4) as starting materials. MS (EI): m/e=433.5 [M+H] ⁺ .

Example 239

(S)-2-[(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-amino]-3,3-dimethyl-butyric acid methyl ester

The title compound was synthesized similarly to Example 1 using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and 3-methyl-L-valine methyl ester hydrochloride (1:1) (CAN 63038-27-7) as starting materials, MS (ESI) 361.3 (M+H) ⁺ .

Example 240

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((-)-2,2,2-trifluoro-1-pyridin-2-yl-ethyl)-amide

The title compound was synthesized similarly to Example 1 using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and α-(trifluoromethyl)-2-pyridinemethanamine (CAN 503173-14-6) as starting materials. The product was separated by chiral chromatography on Reprosil Chiral NR using heptane/20% ethanol as eluent. The (S)-(-)-enantiomers were separated. LC-MS (UV peak area/ESI) 100%, 392.1950 (M+H) ⁺ ;

Example 241

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(-)-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized similarly to Example 1 using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and α,5-dimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153834-40-2) as starting materials. The product was separated by chiral chromatography on a Chiralpak AD using heptane/20% ethanol as eluent. The (-)-enantiomer was separated. LC-MS (UV peak area/ESI) 98.1%, 343.1767 (M+H) ⁺ ,

Example 242

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(+)-3-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-butyl]-amide

The title compound was synthesized similarly to Example 1 using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and 5-methyl-α-(2-methylpropyl)-1,2,4-oxadiazole-3-methanamine (CAN 1155538-06-9) as starting materials. The product was separated by chiral chromatography on a Chiralpak AD using heptane/8% ethanol as eluent. The (+)-enantiomer was separated. LC-MS (UV peak area/ESI) 100%, 385.2234 (M+H) ⁺ ,

Example 243

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(-)-3-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-butyl]-amide

The title compound was synthesized similarly to Example 1 using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and 5-methyl-α-(2-methylpropyl)-1,2,4-oxadiazole-3-methanamine (CAN 1155538-06-9) as starting materials. The product was separated by chiral chromatography on a Chiralpak AD using heptane/8% ethanol as eluent. The (-)-enantiomer was separated. LC-MS (UV peak area/ESI) 100%, 385.2234 (M+H) ⁺ ,

Example 244

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(+)-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-propyl]-amide

The title compound was synthesized analogously to Example 1 using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and α-ethyl-5-methyl-1,2,4-oxadiazole-3-methanamine hydrochloride (1:1) (CAN 111997-68-3) as starting materials. The product was separated by chiral chromatography on a Chiralpak AD using heptane/8% ethanol as eluent. The (+)-enantiomer was separated. LC-MS (UV peak area/ESI) 98.5%, 357.1925 (M+H) ⁺ ,

Example 245

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(-)-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-propyl]-amide

The title compound was synthesized analogously to Example 1 using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and α-ethyl-5-methyl-1,2,4-oxadiazole-3-methanamine hydrochloride (1:1) (CAN 111997-68-3) as starting materials. The product was separated by chiral chromatography on a Chiralpak AD using heptane/8% ethanol as eluent. The (-)-enantiomer was separated. LC-MS (UV peak area/ESI) 100%, 357.1913 (M+H) ⁺ ,

Example 246

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((-)-cyano-methyl-methyl)-amide

The title compound was synthesized similarly to Example 1 using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and 2-amino-propionitrile monohydrochloride (CAN 2134-48-7) as starting materials. The product was separated by chiral chromatography on Reprosil Chiral NR using heptane/15% ethanol as eluent. The (-)-enantiomer was separated. LC-MS (UV peak area/ESI) 100%, 286.1552 (M+H) ⁺ ,

Example 247

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((-)-1-cyano-3-methyl-butyl)-amide

The title compound was synthesized analogously to Example 1 using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and 2-amino-4-methyl-pentanenitrile (CAN 65451-12-9) as starting materials. The product was separated by chiral chromatography on Reprosil Chiral NR using heptane/15% ethanol as eluent. The (-)-enantiomer was separated. LC-MS (UV peak area/ESI) 100%, 328.2026 (M+H) ⁺ ,

Example 248

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((+)-cyano-cyclopropyl-methyl)-amide

The title compound was synthesized analogously to Example 1 using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and α-amino-cyclopropaneacetonitrile (CAN 149357-92-6) as starting materials. The products were separated by chiral chromatography on Reprosil Chiral NR using heptane/20% ethanol as eluent. The (+)-enantiomers were separated. LC-MS (UV peak area/ESI) 100%, 312.1706 (M+H) ⁺ ,

Example 249

2-[(6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carbonyl)-amino]-2-ethyl-butyric acid methyl ester

The title compound was synthesized similarly to Example 1 using 6-cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Example 113d) and 2-amino-2-ethylbutyric acid methyl ester hydrochloride (CAN 92398-54-4) as starting materials. MS (EI): m/e = 389.0 [M+H] ⁺ .

Example 250

5-Cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide

a) 2-(5-cyclopropyl-6-((tetrahydrofuran-2-yl)methoxy)picolinamido)-2-ethylbutanoic acid

Methyl 2-(5-cyclopropyl-6-((tetrahydrofuran-2-yl)methoxy)picolinamido)-2-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 at ambient temperature for 48 h. Additional sodium hydroxide (24.6 mg, 614 μmol) was added and stirring was continued at 70 ° C for another 3 days. The mixture was poured onto ice water/brine/1N HCl (25 mL) and extracted with EtOAc (2x30 mL). The combined extracts were washed with ice water/brine (25 mL) and dried over Na ₂ SO _4. Concentration in vacuo provided the title compound (49 mg, 85%) as a light yellow waxy solid. MS: 375.3 [MH] ^- .

b) 5-Cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide

The title compound was synthesized similarly to Example 1 using 2-(5-cyclopropyl-6-((tetrahydrofuran-2-yl)methoxy)picolinamido)-2-ethylbutanoic acid and methylamine hydrochloride as starting materials. MS (EI): m/e=390.3 [M+H] ⁺ .

Example 251

2-[(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-amino]-2-ethyl-butyric acid methyl ester

The title compound was synthesized similarly to Example 1 using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and 2-amino-2-ethyl-butyric acid ethyl ester hydrochloride (1:1) (CAN 70974-26-4) as starting materials, LC-MS (UV peak area/ESI) 100%, 361.2120 (M+H) ⁺ .

Example 252

2-[(6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carbonyl)-amino]-2-ethyl-butyric acid

a) Ethyl 2-(6-(cyclopropylmethoxy)-5-(trifluoromethyl)picolinamido)-2-ethylbutanoate

The title compound was synthesized similarly to Example 1 using 6-cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Example 113d) and ethyl 2-amino-2-ethylbutyrate hydrochloride (CAN 1135219-29-2) as starting materials. MS (EI): m/e=403.4 [M+H] ⁺ .

b) 2-[(6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carbonyl)-amino]-2-ethyl-butyric acid

Ethyl 2-(6-(cyclopropylmethoxy)-5-(trifluoromethyl)picolinamido)-2-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 days, 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 yield the title compound (58 mg, quantitative) as a pale yellow solid. MS: 373.1 [MH] ^⁻ .

Example 253

6-(Tetrahydro-pyran-4-ylmethoxy)-5-trifluoromethyl-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide

a) 2-Ethyl-2-(6-((tetrahydro-2H-pyran-4-yl)methoxy)-5-(trifluoromethyl)picolinamido)butanoic acid

The title compound was synthesized in a similar manner to the procedure described in Example 252b) using methyl 2-ethyl-2-(6-((tetrahydro-2H-pyran-4-yl)methoxy)-5-(trifluoromethyl)picolinamido)butanoate (Example 238) as a starting material. MS (EI): m/e = 417.0 [MH] ⁻ .

b) 6-(Tetrahydro-pyran-4-ylmethoxy)-5-trifluoromethyl-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide

The title compound was synthesized similarly to Example 1 using 2-ethyl-2-(6-((tetrahydro-2H-pyran-4-yl)methoxy)-5-(trifluoromethyl)picolinamido)butanoic acid and methylamine hydrochloride as starting materials. MS (EI): m/e = 432.3 [M+H] ⁺ .

Example 254

2-Ethyl-2-{[6-(tetrahydro-furan-2-ylmethoxy)-5-trifluoromethyl-pyridine-2-carbonyl]-amino}-butyric acid ethyl ester

a) 6-((tetrahydrofuran-2-yl)methoxy)-5-(trifluoromethyl)picolinic acid

The title compound was prepared in analogy to the procedure described in Example 230b) using 6-chloro-5-(trifluoromethyl)picolinic acid and (tetrahydrofuran-2-yl)methanol (CAN 97-99-4) as starting materials. MS: 290.0 [MH] ⁻ .

b) 2-Ethyl-2-{[6-(tetrahydro-furan-2-ylmethoxy)-5-trifluoromethyl-pyridine-2-carbonyl]-amino}-butyric acid ethyl ester

The title compound was synthesized similarly to Example 1 using 6-((tetrahydrofuran-2-yl)methoxy)-5-(trifluoromethyl)picolinic acid and ethyl 2-amino-2-ethylbutanoate hydrochloride (CAN 1135219-29-2) as starting materials. MS (EI): m/e = 433.4 [M+H] ⁺ .

Example 255

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (dimethylcarbamoyl-phenyl-methyl)-amide

The title compound was synthesized in a similar manner to Example 1 using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69b) and 2-amino-N,N-dimethyl-2-phenylacetamide hydrochloride (CAN 1214036-19-7) as starting materials. MS (EI): m/e = 445.1 [M+H] ⁺ .

Example 256

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-2-cyclopropyl-1-dimethylcarbamoyl-ethyl)-amide

The title compound was synthesized in a similar manner to Example 1 using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69b) and (S)-2-amino-3-cyclopropyl-N,N-dimethylpropionamide hydrochloride (Example 222b) as starting materials. MS (EI): m/e = 423.0 [M+H] ⁺ .

Example 257

2-[(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-amino]-2-ethyl-butyric acid ethyl ester

The title compound was synthesized similarly to Example 1 using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and ethyl 2-amino-2-ethylbutyrate hydrochloride (CAN 1135219-29-2) as starting materials. MS (EI): m/e = 375.0 [M+H] ⁺ .

Example 258

(S)-3-Cyclopropyl-2-[(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-amino]-propionic acid methyl ester

The title compound was synthesized in a similar manner to Example 1 using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and (αS)-α-amino-cyclopropanepropionic acid methyl ester hydrochloride (1:1) (CAN 206438-31-5) as starting materials. LC-MS (UV peak area/ESI) 100%, 359.153 (M+H) ⁺ .

Example 259

6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide

a) 2-(6-(cyclopropylmethoxy)-5-(trifluoromethyl)picolinamido)-2-ethylbutanoic acid

The title compound was synthesized in a similar manner to the procedure described in Example 252b) using methyl 2-(6-(cyclopropylmethoxy)-5-(trifluoromethyl)picolinamido)-2-ethylbutanoate (Example 249) as a starting material. MS (EI): m/e = 373.1 [MH] ⁻ .

b) 6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide

The title compound was synthesized similarly to Example 1 using 2-(6-(cyclopropylmethoxy)-5-(trifluoromethyl)picolinamido)-2-ethylbutanoic acid and methylamine hydrochloride as starting materials. MS (EI): m/e = 388.0 [M+H] ⁺ .

Example 260

6-(3-Chloro-4-fluoro-phenyl)-pyridine-2-carboxylic acid [(-)-cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-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 separated; MS (EI) 387.4 (M+H) ⁺ .

Example 261

6-(3-Chloro-4-fluoro-phenyl)-pyridine-2-carboxylic acid [(+)-cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-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 separated; MS (EI) 387.3 (M+H) ⁺ .

Example 262

6-(Tetrahydro-pyran-4-ylmethoxy)-5-trifluoromethyl-pyridine-2-carboxylic acid (1-dimethylcarbamoyl-1-ethyl-propyl)-amide

The title compound was synthesized similarly to Example 1 using 2-ethyl-2-(6-((tetrahydro-2H-pyran-4-yl)methoxy)-5-(trifluoromethyl)picolinamido)butanoic acid (Example 253a) and dimethylamine hydrochloride as starting materials. MS (EI): m/e = 463.4 [M+NH ₄ ] ⁺ .

Example 263

2-{[6-Cyclopropylmethoxy-5-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-pyridine-2-carbonyl]-amino}-2-ethyl-butyric acid ethyl ester

The title compound was synthesized in analogy to Example 1 using 6-cyclopropylmethoxy-5-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-pyridine-2-carboxylic acid (Example 234b) and ethyl 2-amino-2-ethylbutyrate hydrochloride (CAN 1135219-29-2) as starting materials. MS (EI): m/e=432.3 [M+H] ⁺ .

Example 264

6-(Tetrahydro-furan-2-ylmethoxy)-5-trifluoromethyl-pyridine-2-carboxylic acid (1-dimethylcarbamoyl-1-ethyl-propyl)-amide

The title compound was synthesized in a similar manner to Example 1 using 2-ethyl-2-(6-((tetrahydro-2H-pyran-4-yl)methoxy)-5-(trifluoromethyl)picolinamido)butanoic acid (Example 253a) and dimethylamine hydrochloride as starting materials. MS (EI): m/e = 432.1 [M+H] ⁺ .

Example 265

2-[(5-Bromo-6-cyclopropylmethoxy-pyridine-2-carbonyl)-amino]-2-ethyl-butyric acid ethyl ester

The title compound was synthesized similarly to Example 1 using 5-bromo-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid (Example 9d) and ethyl 2-amino-2-ethylbutyrate hydrochloride (CAN 1135219-29-2) as starting materials. MS (EI): m/e = 415.0 [M+H] ⁺ .

Example 266

2-{[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-amino}-2-ethyl-butyric acid ethyl ester

The title compound was synthesized in a similar manner to the procedure described in Example 69a using ethyl 2-(5-bromo-6-(cyclopropylmethoxy)picolinamido)-2-ethylbutanoate (Example 265) and 3,3-difluoroazetidine hydrochloride (CAN 288315-03-7) as starting materials. MS (EI): m/e = 426.0 [M+H] ⁺ .

Example 267

6-(4-Chloro-3-fluoro-phenyl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

a) 6-Bromo-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was prepared similarly to Example 1 using 6-bromo-2-pyridinecarboxylic acid (CAN 21190-87-4) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine hydrochloride (1:1) (CAN 1240526-27-5) as starting materials. LC-MS (UV peak area/ESI) 85%, 325.0293 (M+H) ⁺ .

b) 6-(4-Chloro-3-fluoro-phenyl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound can be prepared analogously to Example 177b using 6-bromo-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide (Example 267a) and B-(4-chloro-3-fluorophenyl)-boronic acid (CAN 137504-86-0) as starting materials, LC-MS (UV peak area/ESI) 100%, 375.1017 (M+H) ⁺ .

Example 268

6-(3-Chloro-4-fluoro-phenyl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized similarly to Example 267b using 6-bromo-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide (Example 267a) and B-(3-chloro-4-fluorophenyl)-boronic acid (CAN 144432-85-9) as starting materials, LC-MS (UV peak area/ESI) 91%, 375.1018 (M+H) ⁺ .

Example 269

2-{[6-Cyclopropylmethoxy-5-(3,3-difluoro-2-oxo-azetidin-1-yl)-pyridine-2-carbonyl]-amino}-2-ethyl-butyric acid methyl ester

The title compound was isolated in less than 1% yield in a reaction combining 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69b) and methyl 2-amino-2-ethylbutyrate hydrochloride (CAN92398-54-4) as starting materials in a procedure similar to that described in Example 1. The inventors believe that 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid was contaminated with a small amount of 6-cyclopropylmethoxy-5-(3,3-difluoro-2-oxo-azetidin-1-yl)-pyridine-2-carboxylic acid; MS (EI): m/e = 426.0 [M+H] ⁺ .

Example 270

(S)-2-[(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-amino]-4-methyl-pentanoic acid methyl ester

The title compound was synthesized in a similar manner to Example 1 using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and L-leucine methyl ester hydrochloride (1:1) (CAN 7517-19-3) as starting materials, LC-MS (UV peak area/ESI) 100%, 361.2120 (M+H) ⁺ .

Example 271

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1-cyano-3-methyl-butyl)-amide

The title compound was synthesized in analogy to Example 1 using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69b) and 2-amino-4-methylpentanenitrile hydrochloride (CAN 72177-82-3) as starting materials. MS (EI): m/e=379.1 [M+H] ⁺ .

Example 272

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [3-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-butyl]-amide

The title compound was synthesized in a similar manner to Example 1 using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69b) and 5-methyl-α-(2-methylpropyl)-1,2,4-oxadiazole-3-methanamine (CAN 1155538-06-9) as starting materials. MS (EI): m/e = 436.0 [M+H] ⁺ .

Example 273

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1-hydroxymethyl-1,3-dimethyl-butyl)-amide

The title compound was synthesized in analogy to Example 1 using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69b) and 2-amino-2,4-dimethylpentan-1-ol (CAN 13893-55-5) as starting materials. MS (EI): m/e = 398.1 [M+H] ⁺ .

Example 274

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-(azetidine-1-carbonyl)-1-ethyl-propyl]-amide

a) 2-(5-Cyclopropyl-6-(cyclopropylmethoxy)picolinamido)-2-ethylbutanoic acid

The title compound was synthesized in a similar manner to the procedure described in Example 252b) using ethyl 2-(5-cyclopropyl-6-(cyclopropylmethoxy)picolinamido)-2-ethylbutanoate (Example 257) as a starting material. MS (EI): m/e = 347.1 [M+H] ⁺ .

b) 5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-(azetidine-1-carbonyl)-1-ethyl-propyl]-amide

The title compound was synthesized similarly to Example 1 using 2-(5-cyclopropyl-6-(cyclopropylmethoxy)picolinamido)-2-ethylbutanoic acid and azetidine (CAN 503-29-7) as starting materials. MS (EI): m/e = 386.0 [M+H] ⁺ .

Example 275

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-ethyl-1-(2-methoxy-ethylcarbamoyl)-propyl]-amide

The title compound was synthesized similarly to Example 1 using 2-(5-cyclopropyl-6-(cyclopropylmethoxy)picolinamido)-2-ethylbutanoic acid (Example 274a) and 2-methoxyethylamine (CAN 109-85-3) as starting materials. MS (EI): m/e = 404.4 [M+H] ⁺ .

Example 276

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-ethyl-1-(ethyl-methyl-carbamoyl)-propyl]-amide

The title compound was synthesized similarly to Example 1 using 2-(5-cyclopropyl-6-(cyclopropylmethoxy)picolinamido)-2-ethylbutanoic acid (Example 274a) and N-methylethylamine (CAN 624-78-2) as starting materials. MS (EI): m/e = 388.0 [M+H] ⁺ .

Example 277

6-(4-Fluoro-benzyl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide

a) 6-(4-Fluorobenzyl)picolinic acid

6-(4-Fluorobenzyl)picolinonitrile (24 mg, 113 μmol; CAN 1237431-32-1) 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 continued for another 2.5 h. The reaction mixture was poured onto 25 mL of ice/0.1 N HCl and extracted with EtOAc (2×20 mL). The combined organic layers were washed with ice water/brine (25 mL), dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound (21 mg, 80%) as a light yellow oil, which was used in the next step without further purification. MS (EI): m/e=230.1 [MH] ⁻ .

b) 6-(4-Fluoro-benzyl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide

The title compound was synthesized similarly to Example 1 using 6-(4-fluorobenzyl)picolinic acid and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials. MS (EI): m/e = 344.0 [M+H] ⁺ .

Example 278

6-(4-Fluoro-benzyl)-pyridine-2-carboxylic acid ((R)-2,2,2-trifluoro-1-pyridin-2-yl-ethyl)-amide

The title compound was synthesized similarly to Example 1 using 6-(4-fluorobenzyl)picolinic acid (Example 277a) and (R)-2,2,2-trifluoro-1-(pyridin-2-yl)ethanamine hydrochloride (CAN 1228565-87-4) as starting materials. MS (EI): m/e = 390.1 [M+H] ⁺ .

Example 279

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-hydroxymethyl-1,2-dimethyl-propyl)-amide

The title compound was synthesized in a similar manner to Example 1 using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and (2S)-2-amino-2,3-dimethyl-1-butanol (CAN 956102-64-0) as starting materials. LC-MS (UV peak area/ESI) 100%, 333.2175 (M+H) ⁺ .

Example 280

5-Bromo-6-(3-methyl-oxetan-3-ylmethoxy)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide

a) 5-Bromo-6-chloropicolinic acid

In a 500 ml two-necked round-bottom flask, 3-bromo-2-chloro-6-methylpyridine (CAN 185017-72-5) (4.0 g, 19.4 mmol) was suspended in _H₂O (160 ml) to give a colorless suspension. Sodium lauryl sulfate (64 mg, 222 μmol) and KMnO₄ (9.19 g, 58.1 mmol) were added with stirring. The reaction mixture was stirred at 100°C for 18 h. The reaction was then cooled to room temperature and 100 ml of a 40% _NaHSO₃ solution (decolorized) was added dropwise with ice cooling. A white precipitate formed and the mixture was stirred for an additional 30 min. The reaction mixture was acidified with 120 ml of 2N HCl and extracted with ethyl acetate (2 x 200 ml). The _combined organic layers were dried over _Na₂SO₄ , filtered, and concentrated in vacuo to give a white solid containing a mixture of starting material and product. The solid was dissolved in 50 ml of TBME/THF (9:1) and 15 ml of 2N-NaOH was added with stirring, resulting in a suspension. The suspension was then extracted with 100 ml of water. The aqueous layer was washed with 50 ml of TBME. The aqueous layer was acidified with 20 ml of 2N-HCl and then extracted with a 9: ₁ mixture of TBME/THF (2 x 50 ml). The combined organic layers were dried over _Na₂SO₄ , filtered, and concentrated to dryness in vacuo to afford the title compound (1.8 g, 39%) as a white solid; MS (LC/MS): 235.9 [MH] ^⁺ .

b) 5-Bromo-6-(3-methyl-oxetan-3-ylmethoxy)-pyridine-2-carboxylic acid

To a solution of 5-bromo-6-chloropicolinic acid (Example 280a) (0.75 g, 3.17 mmol) in dry DMF (18 ml) under argon was added (3-methyloxetan-3-yl)-methanol (389 mg, 3.81 mmol) and NaH (279 mg, 6.98 mmol) was added portionwise. The reaction mixture was stirred at room temperature for 20 min until gas evolution ceased. The reaction mixture was then stirred at 110° C. for 16 h. The reaction mixture was diluted with ethyl acetate and the solution was poured into a separatory funnel containing 10 ml of 1.0 M aqueous HCl. After extraction, the organic phase was collected and the aqueous phase was back-extracted with ethyl acetate. The organic phases were combined, dried over Na ₂ SO ₄ and evaporated in vacuo. The residue was purified by preparative HPLC to give the title compound (260 mg, 27%), MS (EI): m/e = 302.0 [M+H] ⁺ .

c) 5-Bromo-6-(3-methyl-oxetan-3-ylmethoxy)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide

To a solution of 5-bromo-6-(3-methyl-oxetan-3-ylmethoxy)-pyridine-2-carboxylic acid (Example 280b) (30 mg, 100 μmol) in dry DMF (1 ml) was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (29.1 mg, 105 μmol) and Hunig's base (52.4 uL, 300 μmol). The reaction was stirred at room temperature for 30 min, followed by the addition of α,α-dimethyl-2-thiazolemethanamine (Example 12c) (14.2 mg, 100 μmol). The reaction was stirred at room temperature overnight and monitored by LC-MS. Upon completion of the reaction, purification was performed directly by preparative HPLC without any workup to yield the title compound (9.8 mg, 23%). MS (EI): m/e = 425.9 [M+H] ⁺ .

Example 281

5-Bromo-6-(3-methyl-oxetan-3-ylmethoxy)-pyridine-2-carboxylic acid (3-thiazol-2-yl-oxetan-3-yl)-amide

a) 2-Methyl-propane-2-sulfinic acid (3-thiazol-2-yl-oxetan-3-yl)-amide

At -78 ℃, a solution of n-butyllithium in hexane (1.6M, 2.5mL, 3.99mmol) was added dropwise to a solution of thiazole (364mg, 4.23mmol) in tetrahydrofuran (30mL). The resulting mixture was stirred at -78 ℃ for 30min, followed by a solution of 2-methyl-n-(oxetane-3-ylidene)propane-2-sulfinamide (CAN 1158098-73-7) (500mg, 2.85mmol) in tetrahydrofuran (3.5mL) at -78 ℃. The reaction solution was stirred for another 30min at -78 ℃, then warmed to 22 ℃ and quenched with saturated aqueous ammonium chloride solution. The crude reaction mixture was then distributed between water and ethyl acetate. The aqueous layer was further extracted with ethyl acetate and the organic layers were merged. The combined layer was washed with saturated aqueous sodium chloride solution, and the washing solution was dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was purified by flash column chromatography (40% ethyl acetate-hexane, gradually increasing to 100% ethyl acetate, then eluting with 10% methanol-dichloromethane) to give the title compound (495 mg, 67%). MS (EI): m/e = 261.0 [M+H] ⁺ .

b) 3-(Thiazol-2-yl)oxetane-3-amine hydrochloride

A 4.0 M solution of hydrochloric acid in dioxane (117 μL, 467 μmol) was added to a solution of 2-methyl-propane-2-sulfinic acid (3-thiazol-2-yl-oxetane-3-yl)-amide (Example 281a) (81 mg, 311 μmol) in methanol (0.5 mL) at 0°C. The mixture was stirred at 0°C for 5 min, after which the solvent was 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 give the title compound (42 mg, 70%) as a white solid, MS (EI): m/e=157.1 [M+H] ⁺ .

c) 5-Bromo-6-(3-methyl-oxetan-3-ylmethoxy)-pyridine-2-carboxylic acid (3-thiazol-2-yl-oxetan-3-yl)-amide

The title compound was synthesized in analogy to Example 280c using 5-bromo-6-(3-methyl-oxetan-3-ylmethoxy)-pyridine-2-carboxylic acid (Example 280b) and 3-(thiazol-2-yl)oxetan-3-amine hydrochloride (Example 281b) as starting materials, MS (EI): m/e=440.4 [M+H] ⁺ .

Example 282

5-Bromo-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (3-thiazol-2-yl-oxetan-3-yl)-amide

a) 5-Bromo-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid

In a 25mL round-bottom flask, 5-bromo-6-chloropicolinic acid (433mg, 1.83mmol) and powdered potassium hydroxide (411mg, 7.32mmol) were combined with DMSO (1.9ml) to give a colorless solution, which was stirred at room temperature for 15min. 2,2,2-trifluoroethanol (275mg, 198μl, 2.75mmol, Eq: 1.5) was added. The reaction mixture was stirred at ambient temperature for 24h. Due to the completion of the reaction, 0.75 additional equivalents of 2,2,2-trifluoroethanol were added and the reaction was stirred at ambient temperature for 48h. The reaction mixture was poured onto 1M HCl/ice water (1x 20mL) and extracted with iPrOAc (2x 25mL). The organic layer was dried _{over Na2SO4} and filtered, removed under reduced pressure to give the title compound after recrystallization from _CH2Cl2 and _heptane as a white solid (409 mg, 1.36 mmol, 74.4% yield), MS (EI): m/e = 299.9 [M+H] ⁺ .

b) 5-Bromo-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (3-thiazol-2-yl-oxetan-3-yl)-amide

The title compound was synthesized in a similar manner to Example 280c using 5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 282a) and 3-(thiazol-2-yl)oxetane-3-amine hydrochloride (Example 281b) as starting materials. MS (EI): m/e=438.0 [M+H] ⁺ .

Example 283

5-Bromo-6-(3-methyl-oxetan-3-ylmethoxy)-pyridine-2-carboxylic acid (2,2,2-trifluoro-1-pyridin-2-yl-ethyl)-amide

The title compound was synthesized in analogy to Example 280c using 5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 282a) and 2,2,2-trifluoro-1-(pyridin-2-yl)ethanamine (CAN 35272-15-2) as starting materials, MS (EI): m/e=460.4 [M+H] ⁺ .

Example 284

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-(cyclopropylmethyl-carbamoyl)-1-ethyl-propyl]-amide

The title compound was synthesized similarly to Example 1 using 2-(5-cyclopropyl-6-(cyclopropylmethoxy)picolinamido)-2-ethylbutanoic acid (Example 274a) and cyclopropylmethylamine (CAN 2516-47-4) as starting materials. MS (EI): m/e = 400.1 [M+H] ⁺ .

Example 285

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-methyl-1-pyridin-2-yl-ethyl)-amide

The title compound was synthesized in a similar manner to Example 1 using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and α,α-dimethyl-2-pyridiniummethanamine (CAN 52568-28-2) as starting materials. LC-MS (UV peak area/ESI) 100%, 352.2021 (M+H) ⁺ .

Example 286

6-(4-Fluoro-benzyl)-pyridine-2-carboxylic acid ((S)-3,3-dimethyl-1-methylcarbamoyl-butyl)-amide

The title compound was synthesized in analogy to Example 1 using 6-(4-fluorobenzyl)picolinic acid (Example 277a) and (2S)-2-amino-N,4,4-trimethyl-pentanamide (CAN 1160161-70-5) as starting materials. MS (EI): m/e = 372.0 [M+H] ⁺ .

Example 287

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-(3,3-difluoro-azetidine-1-carbonyl)-1-ethyl-propyl]-amide

The title compound was synthesized similarly to Example 1 using 2-(5-cyclopropyl-6-(cyclopropylmethoxy)picolinamido)-2-ethylbutanoic acid (Example 274a) and 3,3-difluoroazetidine hydrochloride (CAN 288315-03-7) as starting materials. MS (EI): m/e = 422.0 [M+H] ⁺ .

Example 288

5-(3,3-Difluoro-azetidin-1-yl)-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide

a) 5-Bromo-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide

The title compound was synthesized in analogy to Example 280c using 5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 282a) and α,α-dimethyl-2-thiazolidinemethanamine (Example 12c) as starting materials. MS (EI): m/e=424.3 [M+H] ⁺ .

b) 5-(3,3-Difluoro-azetidin-1-yl)-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide

To a solution of 5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide (Example 288a) (63.6 mg, 150 μmol) in dry toluene (1 ml) was added 3,3-difluoroazetidine hydrochloride (21.4 mg, 165 μmol), BINAP (9.34 mg, 15.0 μmol), Pd(OAc)2 (337 mg, 15.0 μmol) and _{Cs2CO3 (} 122 mg, 375 μmol). The reaction was stirred at 120°C overnight and monitored by LC-MS. The volatiles were evaporated, and the residue was redissolved in DMF and directly purified by preparative HPLC to give the title compound (21 mg, 48 μmol, 32%), MS (EI): m/e = 437.4 [M+H] ⁺ .

Example 289

2-[(6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carbonyl)-amino]-2-ethyl-butyric acid ethyl ester

The title compound was synthesized in a similar manner to the procedure described in Example 32a using 2-[(5-bromo-6-cyclopropylmethoxy-pyridine-2-carbonyl)-amino]-2-ethyl-butyric acid ethyl ester (Example 265) and pyrrolidine (CAN 123-75-1) as starting materials. MS (EI): m/e = 404.4 [M+H] ⁺ .

Example 290

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1-methyl-5-oxo-pyrrolidin-3-yl)-amide

The title compound was synthesized in analogy to Example 1 using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69b) and 4-amino-1-methylpyrrolidin-2-one hydrochloride (CAN 1228838-07-0) as starting materials. MS (EI): m/e=381.3 [M+H] ⁺ .

Example 291

2-[(6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carbonyl)-amino]-2-ethyl-butyric acid

Analogously to the procedure described in Example 252b, 2-[(6-cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carbonyl)-amino]-2-ethyl-butyric acid ethyl ester (Example 289) was treated with sodium hydroxide to afford the title compound as a colorless oil. MS: 376.3 [M+H] ⁺ .

Example 292

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1,1-dioxo-tetrahydro-1λ ⁶ -thiophen-3-yl)-amide

The title compound was synthesized similarly to Example 1 using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69b) and 1,1-dioxotetrahydrothiophen-3-ylamine (CAN 6338-70-1) as starting materials. MS (EI): m/e=402.1 [M+H] ⁺ .

Example 293

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid N′-(1,1-dioxo-tetrahydro-1λ ⁶ -thiophen-3-yl)-hydrazide

6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinic acid (10 mg, 35.2 μmol, Example 69b), 3-sulfanylhydrazine hydrochloride (6.34 mg, 42.2 μmol; CAN1004-15-5), 1-hydroxybenzotriazole hydrate (10.8 mg, 70.4 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (12.1 mg, 70.4 μmol) and N-ethyl-N-isopropylpropan-2-amine (18.2 mg, 24.6 μL, 141 μmol) were dissolved in DMF (100 μL). The reaction mixture was stirred at ambient temperature for 1 day, poured onto 1 M HCl/ice water (20 mL) and extracted with EtOAc (2 x 25 mL). The combined extracts were washed with ice water (2 x 25 mL), dried over Na ₂ SO ₄ 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, eluted with EtOAc) to give the title compound (5 mg, 34%) as a colorless oil. MS (EI): m/e = 417.3 [M+H] ⁺ .

Example 294

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-methyl-1-(4-methyl-thiazol-2-yl)-ethyl]-amide

The title compound was synthesized similarly to Example 1 using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and α,α,5-trimethyl-2-thiazolidinemethanamine (CAN 1155530-59-8) as starting materials, LC-MS (UV peak area/ESI) 97%, 372.1742 (M+H) ⁺ .

Example 295

5-(3,3-Difluoro-azetidin-1-yl)-6-(3-methyl-oxetan-3-ylmethoxy)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide

The title compound was synthesized in analogy to Example 288b using 5-bromo-6-(3-methyl-oxetan-3-ylmethoxy)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide (Example 281c) and 3,3-difluoroazetidine hydrochloride as starting materials. MS (EI): m/e=439.3 [M+H] ⁺ .

Example 296

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-(5-amino-[1,2,4]oxadiazol-3-yl)-1-methyl-ethyl]-amide

a) [1-(5-Amino-[1,2,4]oxadiazol-3-yl)-1-methyl-ethyl]-carbamic acid tert-butyl ester

To a colorless solution of [1-(N-hydroxycarbamoyl)-1-methyl-ethyl]-carbamic acid tert-butyl ester (CAN1251430-04-2, 5.9 g, 27.2 mmol) in DMF (11.8 mL) was added 1-piperidinecarbonitrile (CAN 1530-87-6) (3.29 g, 3.46 mL, 29.9 mmol) under an inert atmosphere with stirring. The reaction mixture was heated at 130° C. and stirred for 2.5 hours. After cooling to room temperature, ice-water (400 mL) was added and the mixture was extracted with ethyl acetate (3×200 mL). The organic phases were washed with ice-water (200 mL), combined, dried over Na ₂ SO ₄ , and concentrated in vacuo. The residue was purified by chromatography on silica gel using a mixture of ethyl acetate/n-heptane as eluent to give the title compound as a white solid (5.0 g, 76%); LC-MS (UV peak area/ESI) 83%, 243.1453 (M+H) ⁺ .

b) 3-(1-Amino-1-methyl-ethyl)-[1,2,4]oxadiazol-5-ylamine hydrochloride (1:1)

To a solution of [1-(5-amino-[1,2,4]oxadiazol-3-yl)-1-methyl-ethyl]-carbamic acid tert-butyl 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 at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and dried at 40° C. by applying high vacuum for 4 hours to give the title compound as an off-white solid (1.2 g, quantitative); LC-MS (UV peak area/ESI) 99.9%, 143.0927 (M+H) ⁺ . c) 5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-(5-amino-[1,2,4]oxadiazol-3-yl)-1-methyl-ethyl]-amide

The title compound was synthesized in a similar manner to Example 1 using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and 3-(1-amino-1-methyl-ethyl)-[1,2,4]oxadiazol-5-ylamine 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)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide

a) 5-Bromo-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid

5-Bromo-6-chloro-2-pyridinecarboxylic acid (CAN 959958-25-9; 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. 2,2,3,3,3-pentafluoro-1-propanol (CAN 422-05-9; 3.01 g, 2 ml, 20.1 mmol) was added to the suspension and the mixture was heated to 140° C. for 20 hours. After cooling, the mixture was poured into ethyl acetate (75 mL) and the combined mixture was washed with cold 1M HCl (1×10 mL). The aqueous layer was extracted with ethyl acetate (50 mL). The organic layers were combined, dried over Na ₂ SO ₄ 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 afford the title compound (0.176 g 20%) as an off-white solid; MS (EI) 350.1 (M+H) ⁺ .

b) 6-(2,2,3,3,3-Pentafluoro-propoxy)-pyridine-2-carboxylic acid and 5-cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid

Palladium(II) acetate (2.44 mg, 10.9 μmol), butylbis(tricyclo[3.3.1.1 ^3,7 ]dec-1-yl)-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 was added a solution of 5-bromo-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid (190 mg, 543 μmol) in toluene (4.8 mL) and water (532 μl) (evacuated and flushed with argon) through a septum cap. The reaction mixture was heated to 120° C. and stirred for 20 hours. After being cooled to environment temperature, reaction mixture is diluted with water (20mL), poured on the mixture of ice-water/salt water/1N HCl (200mL) and extracted with ethyl acetate (2x200mL).Organic phase is washed with 200mL ice water/salt water, merged, use Na _{SO dry} and concentrate in a vacuum to obtain a yellow oil.Crude material is passed through flash chromatography (silica gel, 20g, ethyl acetate) purification to obtain a 1/1 mixture of two products of 195mg, which is a yellow solid, which is used without further purification.

c) 6-(2,2,3,3,3-Pentafluoro-propoxy)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide

The title compound was synthesized in analogy to Example 1 using a mixture of 6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid and 5-cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid (Example 297b) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70b) as starting materials, and the product was separated by preparative HPLC; LC-MS (UV peak area/ESI) 100%, 398.1488 (M+H) ⁺ .

Example 298

5-Cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide

The title compound was synthesized in analogy to Example 1 using a mixture of 6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid and 5-cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid (Example 297b) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70b) as starting materials, and the product was separated by preparative HPLC; LC-MS (UV peak area/ESI) 97%, 438.1810 (M+H) ⁺ .

Example 299

5-Cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid ((S)-3,3-dimethyl-1-methylcarbamoyl-butyl)-amide

The title compound was synthesized in analogy to Example 1 using a mixture of 6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid and 5-cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid (Example 297b) and (2S)-2-amino-N,4,4-trimethyl-pentanamide (CAN 1160161-70-5) as starting materials, and the product was separated by preparative HPLC; LC-MS (UV peak area/ESI) 100%, 452.1962 (M+H) ⁺ .

Example 300

5-Cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized in analogy to Example 1 using a mixture of 6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid and 5-cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid (Example 297b) and (S)-2-cyclopropyl-1-5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 38e) as starting materials, and the product was separated by preparative HPLC; LC-MS (UV peak area/ESI) 100%, 461.1607 (M+H) ⁺ .

Example 301

5-Cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid ((S)-carbamoyl-phenyl-methyl)-amide

a) 5-Cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid

In a 150 ml round-bottom flask, Pd(OAc) _₂ (15.7 mg, 70.0 μmol), butyl-1-adamantylphosphine (37.6 mg, 105 μmol), potassium cyclopropyltrifluoroborate (523 mg, 3.53 mmol), cesium carbonate (3.42 g, 10.5 mmol), and 5-bromo-6-(2,2,2-trifluoroethoxy)picolinic acid (Example 282a) (1.05 g, 3.5 mmol) were combined. The flask was evacuated in vacuo and flushed three times with argon, followed by the addition of a mixture of toluene (25 ml) and _H₂O (3 ml) through the septum cap. The reaction mixture was heated to 120° C., stirred for 20 h, and then cooled to ambient temperature. The volatiles were evaporated in vacuo, and the residue was redissolved in ethyl acetate and extracted with 1 M HCl (12.5 ml). 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, 50 g, 0% to 5% MeOH in DCM) to give the title compound (530 mg, 58%). MS (EI): m/e = 262.2 [M+H] ⁺ .

b) 5-Cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid ((S)-carbamoyl-phenyl-methyl)-amide

The title compound was synthesized in analogy to Example 280c using 5-cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 301a) and (S)-2-amino-2-phenyl-acetamide hydrochloride (CAN 60079-51-8) as starting materials, MS (EI): m/e=394.1 [M+H] ⁺ .

Example 302

5-Cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (2,2,2-trifluoro-1-pyridin-2-yl-ethyl)-amide

The title compound was synthesized in analogy to Example 280c using 5-cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 301a) and 2,2,2-trifluoro-1-(pyridin-2-yl)ethanamine (CAN 35272-15-2) as starting materials, MS (EI): m/e=420.1 [M+H] ⁺ .

Example 303

5-Cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide

The title compound was synthesized in analogy to Example 280c using 5-cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 301a) and L-leucinol (CAN 17016-87-4) as starting materials. MS (EI): m/e=361.3 [M+H] ⁺ .

Example 304

5-Cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (3-thiazol-2-yl-oxetan-3-yl)-amide

The title compound was synthesized in a similar manner to Example 280c using 5-cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 301a) and 3-(thiazol-2-yl)oxetane-3-amine hydrochloride (Example 281b) as starting materials. MS (EI): m/e=400.1 [M+H] ⁺ .

Example 305

5-Cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide

The title compound was synthesized in a similar manner to Example 280c using 5-cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 301a) and α,α-dimethyl-2-thiazolidinemethanamine (Example 12c) as starting materials. MS (EI): m/e=386.3 [M+H] ⁺ .

Example 306

5-Cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (2,2-dimethyl-1-thiazol-2-yl-propyl)-amide

a) (E)-N-(2,2-Dimethylpropylene)-2-methylpropane-2-sulfenamide

To a solution of pivalaldehyde (2 g, 2.56 ml, 23.2 mmol) in dry dichloromethane (150 mL) under an argon atmosphere were added 2-methylpropane-2-sulfenamide (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 room temperature overnight and quenched by slowly adding water while still stirring the reaction until a precipitate formed. The reaction mixture was then filtered through a pad of celite. The filtrate was extracted with water, and the organic phase was collected, _dried over _Na₂SO₄ and evaporated in vacuo to give the title compound (3.6 gr, 82%) as a crude oil. The crude oil was used in the next step without any further purification, MS (EI): m/e=190.3 [M+H] ^⁺ .

b) N-(2,2-Dimethyl-1-(thiazol-2-yl)propyl)-2-methylpropane-2-sulfenamide

To a solution of thiazole (247 mg, 206 μl, 2.91 mmol) in 10 mL of dry THF was slowly added 1.6 M BuLi in hexane (1.82 ml, 2.91 mmol) at -73 ° C under argon. The resulting reaction mixture was stirred at -75 ° C for 30 min and a solution of (E)-N-(2,2-dimethylpropylene)-2-methylpropane-2-sulfinamide (Example 306a) (500 mg, 2.64 mmol) in 5 mL of dry THF was added. The reaction mixture was stirred at -75 ° C for 30 min, then the cooling bath was removed and the reaction was stirred at room temperature for 1 h. The reaction was quenched by adding a few drops of water, the reaction mixture was poured into ethyl acetate, and the solution was extracted with a 1 M aqueous solution of NaHCO _3. The organic phase was collected, dried over Na ₂ SO ₄ and evaporated to dryness to give the title compound (666 mg, 92%) as a crude dark orange oil. The crude dark orange oil was used without any further purification, MS (EI): m/e = 275.2 [M+H] ⁺ .

c) 5-Cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (2,2-dimethyl-1-thiazol-2-yl-propyl)-amide

To a solution of N-(2,2-dimethyl-1-(thiazol-2-yl)propyl)-2-methylpropane-2-sulfenamide (Example 306c) (666 mg, 2.43 mmol) in methanol (15 ml) was added a 4.0 M solution of HCl in dioxane (3.03 ml, 12.1 mmol) to give a light red solution. The reaction mixture was stirred at room temperature for 1 h, and then the reaction was evaporated to dryness. The crude solid was triturated in diethyl ether, filtered off, and dried under high vacuum to give the title compound (346 mg, 69%) as an off-white solid, which was used to synthesize the title compound in analogy to Example 280c using 5-cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 301a) as a starting material. MS (EI): m/e = 414.3 [M+H] ⁺ .

Example 307

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [1-(3,3-difluoro-azetidine-1-carbonyl)-1-ethyl-propyl]-amide

a) 2-(6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinamido)-2-ethylbutanoic acid

In analogy to the procedure described in Example 252b), 2-{[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-amino}-2-ethyl-butyric acid ethyl ester (Example 266) was treated with sodium hydroxide to give the title compound as a colorless oil. MS: 396.2 [MH] ⁻ .

b) 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [1-(3,3-difluoro-azetidine-1-carbonyl)-1-ethyl-propyl]-amide

The title product was condensed from 2-(6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinamido)-2-ethylbutanoic acid and 3,3-difluoroazetidine (CAN 679431-52-8) in a manner analogous to that described in Example 293. MS (EI): m/e = 471.4 [MH] ⁻ .

Example 308

6-(4-Fluoro-benzyl)-pyridine-2-carboxylic acid N′-(1,1-dioxo-tetrahydro-1λ ⁶ -thiophen-3-yl)-hydrazide

6-(4-Fluorobenzyl)picolinic acid (Example 277a) and 3-sulfanylhydrazine hydrochloride (CAN 1004-15-5) were condensed to give the title product in analogy to the procedure described in Example 293. MS (EI): m/e = 364.1 [M+H] ⁺ .

Example 309

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-(3-amino-[1,2,4]oxadiazol-5-yl)-1-methyl-ethyl]-amide

a) [1-(3-Amino-[1,2,4]oxadiazol-5-yl)-1-methyl-ethyl]-carbamic acid tert-butyl ester

To a colorless solution of N-[(1,1-dimethylethoxy)carbonyl]-2-methyl-alanine (CAN 30992-29-1; 1.0 g, 4.92 mmol) in DMF (24 mL) was added (benzotriazol-1-yloxy)tripyrrolidinyl hexafluorophosphate (3.07 g, 5.9 mmol) and DIEA (1.72 mL, 4.9 mmol), and the resulting light yellow solution was stirred at room temperature under argon for 30 minutes. This mixture was added dropwise to a suspension of hydroxyguanidine sulfate monohydrate (3.93 g, 14.8 mmol), DIEA (2.6 mL, 7.4 mmol), and molecular sieves (2 g) in DMF (35 mL) under argon over 40 minutes, without exceeding 25° C. Once the addition was complete, another 2 g of molecular sieves were added and the reaction mixture (light yellow suspension) was stirred at room temperature under argon for 1.5 hours and then at 130° C. for 20 hours. After cooling to room temperature, the mixture was filtered. The filtrate was concentrated in vacuo (HV pump) and the residue was vigorously stirred for 20 h with 2-methoxy-2-methylpropane (40 mL) and 1N NaOH (40 mL). The phases were separated; the aqueous phase was washed with 2-methoxy-2-methylpropane (2x10 mL). The combined organic extracts were washed with water, then dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel, 50 g, 0% to 100% EtOAc in hexane) to give the title compound (106 mg, 8.9%), which was used without further purification.

b) 5-(1-Amino-1-methyl-ethyl)-[1,2,4]oxadiazol-3-ylamine hydrochloride (1:1)

To a solution of [1-(3-amino-[1,2,4]oxadiazol-5-yl)-1-methyl-ethyl]-carbamic acid tert-butyl 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 at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and dried at 40° C. for 4 hours by applying high vacuum to give the title compound as a white solid (75 mg, quantitative); LC-MS (UV peak area/ESI) nd, 143.0928 (M+H) ⁺ .

c) 5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-(3-amino-[1,2,4]oxadiazol-5-yl)-1-methyl-ethyl]-amide

The title compound was synthesized in a similar manner to Example 1 using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and 5-(1-amino-1-methyl-ethyl)-[1,2,4]oxadiazol-3-ylamine hydrochloride (1:1) (Example 309b) as starting materials, LC-MS (UV peak area/ESI) 100%, 358.1872 (M+H) ⁺ .

Example 310

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [(S)-1-(3,3-difluoro-azetidine-1-carbonyl)-2,2-dimethyl-propyl]-amide

a) (S)-methyl 2-(6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinamido)-3,3-dimethylbutanoate

The title compound was synthesized in a similar manner to Example 1 using 6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinic acid (Example 69b) and (S)-methyl 2-amino-3,3-dimethylbutanoate hydrochloride (CAN 63038-27-7) as starting materials. MS (EI): m/e = 412.3 [M+H] ⁺ .

b) (S)-2-(6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinamido)-3,3-dimethylbutanoic acid

In a similar manner to the procedure described in Example 5c), (S)-methyl 2-(6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinamido)-3,3-dimethylbutanoate was saponified with lithium hydroxide to give the title compound. MS (EI): m/e = 396.1 [MH] ⁻ .

c) 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [(S)-1-(3,3-difluoro-azetidine-1-carbonyl)-2,2-dimethyl-propyl]-amide

The title compound was synthesized in a similar manner to Example 1 using (S)-2-(6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinamido)-3,3-dimethylbutanoic acid and 3,3-difluoroazetidine hydrochloride (CAN 288315-03-7) as starting materials. MS (EI): m/e = 473.0 [M+H] ⁺ .

Example 311

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [(S)-1-(3,3-difluoro-azetidine-1-carbonyl)-3-methyl-butyl]-amide

a) (S)-ethyl 2-(6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinamido)-4-methylpentanoate

The title compound was synthesized similarly to Example 1 using 6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinic acid (Example 69b) and (S)-ethyl 2-amino-4-methylpentanoate hydrochloride (CAN 2743-40-0) as starting materials. MS (EI): m/e = 426.3 [M+H] ⁺ .

b) (S)-2-(6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinamido)-4-methylpentanoic acid

In a similar manner to the procedure described in Example 5c), (S)-ethyl 2-(6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinamido)-4-methylpentanoate was saponified with lithium hydroxide to give the title compound. MS (EI): m/e = 396.3 [MH] ⁻ .

c) 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [(S)-1-(3,3-difluoro-azetidine-1-carbonyl)-2,2-dimethyl-propyl]-amide

The title compound was synthesized similarly to Example 1 using (S)-2-(6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinamido)-4-methylpentanoic acid and 3,3-difluoroazetidine hydrochloride (CAN 288315-03-7) as starting materials. MS (EI): m/e = 473.3 [M+H] ⁺ .

Example 312

2-[(6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carbonyl)-amino]-2-ethyl-butyric acid ethyl ester

6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Example 113d) and ethyl 2-amino-2-ethylbutyrate hydrochloride (CAN1135219-29-2) were condensed to give the title product in analogy to the procedure described in Example 293. MS (EI): m/e = 403.4 [M+H] ⁺ .

Example 313

5-Cyclopropyl-6-((R)-3-hydroxy-1-trifluoromethyl-propoxy)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide

a) 5-Cyclopropyl-6-((R)-3-hydroxy-1-trifluoromethyl-propoxy)-pyridine-2-carboxylic acid

6-Chloro-5-cyclopropyl-2-pyridinecarboxylic acid (CAN 1211530-95-8; 100 mg, 506 μmol), (R)-4,4,4-trifluorobutane-1,3-diol (219 mg, 1.52 mmol), and potassium tert-butoxide (114 mg, 1.01 mmol) were combined in 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 _{over 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) ^⁺ .

b) 5-Cyclopropyl-6-((R)-3-hydroxy-1-trifluoromethyl-propoxy)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide

The title compound was synthesized in analogy to Example 1 using 5-cyclopropyl-6-((R)-3-hydroxy-1-trifluoromethyl-propoxy)-pyridine-2-carboxylic acid (Example 313a) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70b) as starting materials; MS (EI) 432.4 (M+H) ⁺ .

Example 314

5-Cyclopropyl-6-((R)-4,4,4-trifluoro-3-hydroxy-butoxy)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide

a) 5-Cyclopropyl-6-((R)-3-hydroxy-1-trifluoromethyl-propoxy)-pyridine-2-carboxylic acid

6-Chloro-5-cyclopropyl-2-pyridinecarboxylic acid (CAN 1211530-95-8; 100 mg, 506 μmol), (R)-4,4,4-trifluorobutane-1,3-diol (219 mg, 1.52 mmol), and potassium tert-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 _{over 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) ^⁺ .

b) 5-Cyclopropyl-6-((R)-4,4,4-trifluoro-3-hydroxy-butoxy)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide

The title compound was synthesized in analogy to Example 1 using 5-cyclopropyl-6-((R)-3-hydroxy-1-trifluoromethyl-propoxy)-pyridine-2-carboxylic acid (Example 314a) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70b) as starting materials; MS (EI) 432.4 (M+H) ⁺ .

Example 315

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (3-methyl-1-pyridin-2-yl-butyl)-amide

The title product was prepared by condensing 6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinic acid (Example 69b) and 3-methyl-1-(pyridin-2-yl)butan-1-amine (CAN 825647-69-6) in a manner analogous to that described in Example 293. MS (EI): m/e = 431.4 [M+H] ⁺ .

Example 316

6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid [1-(3,3-difluoro-azetidine-1-carbonyl)-1-ethyl-propyl]-amide

2-[(6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carbonyl)-amino]-2-ethyl-butyric acid (Example 252b) and 3,3-difluoroazetidine hydrochloride (CAN 288315-03-7) were condensed to give the title product in a manner analogous to that described in Example 293. MS (EI): m/e = 450.0 [M+H] ⁺ .

Example 317

6-[(4-Fluoro-phenyl)-hydroxy-methyl]-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide

a) Methyl 6-((4-fluorophenyl)(hydroxy)methyl)picolinate

A suspension of (6-bromopyridin-2-yl)(4-fluorophenyl)methanol (1 g, 3.54 mmol; CAN 875562-77-9), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (174 mg, 0.06 equiv; CAN 95464-05-4), and triethylamine (464 mg, 639 μL, 4.6 mmol) in methanol (10 mL) was shaken in an autoclave at 110° C. under 70 bar carbon monoxide pressure 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 a light yellow oil. MS (EI): m/e = 262.0 [M+H] ⁺ .

b) 6-((4-Fluorophenyl)(hydroxy)methyl)picolinic acid

In analogy to the procedure described in Example 5c), methyl 6-((4-fluorophenyl)(hydroxy)methyl)picolinate was saponified with lithium hydroxide to give the title compound. MS (EI): m/e = 246.1 [MH] ⁻ .

c) 6-[(4-Fluoro-phenyl)-hydroxy-methyl]-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide

The title compound was synthesized similarly to Example 1 using 6-((4-fluorophenyl)(hydroxy)methyl)picolinic acid and (2S)-2-amino-4-methyl-pentanamide (CAN687-51-4) as starting materials. MS (EI): m/e = 360.1 [M+H] ⁺ .

Example 318

6-[(4-Fluoro-phenyl)-hydroxy-methyl]-pyridine-2-carboxylic acid [(S)-3-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-butyl]-amide

The title compound was synthesized in analogy to Example 1 using 6-((4-fluorophenyl)(hydroxy)methyl)picolinic acid and (S)-5-methyl-α-(2-methylpropyl)-1,2,4-oxadiazole-3-methanamine hydrochloride (prepared from (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid (CAN 13139-15-6) in analogy to the procedures described in Example 38a to e) as starting materials. MS (EI): m/e=399.2 [M+H] ⁺ .

Example 319

5-Cyclopropyl-6-((S)-3-hydroxy-1-trifluoromethyl-propoxy)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide

a) 5-Cyclopropyl-6-((S)-3-hydroxy-1-trifluoromethyl-propoxy)-pyridine-2-carboxylic acid

6-Chloro-5-cyclopropyl-2-pyridinecarboxylic acid (CAN 1211530-95-8; 180 mg, 901 μmol), (S)-4,4,4-trifluorobutane-1,3-diol (394 mg, 2.73 mmol), and potassium tert-butoxide (307 mg, 2.73 mmol) were combined in 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 _{over 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) ^⁺ .

b) 5-Cyclopropyl-6-((S)-3-hydroxy-1-trifluoromethyl-propoxy)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide

The title compound was synthesized in analogy to Example 1 using 5-cyclopropyl-6-((S)-3-hydroxy-1-trifluoromethyl-propoxy)-pyridine-2-carboxylic acid (Example 319a) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70b) as starting materials; MS (EI) 432.4 (M+H) ⁺ .

Example 320

5-Cyclopropyl-6-((S)-4,4,4-trifluoro-3-hydroxy-butoxy)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide

a) 5-Cyclopropyl-6-((S)-3-hydroxy-1-trifluoromethyl-propoxy)-pyridine-2-carboxylic acid

6-Chloro-5-cyclopropyl-2-pyridinecarboxylic acid (CAN 1211530-95-8; 180 mg, 901 μmol), (S)-4,4,4-trifluorobutane-1,3-diol (394 mg, 2.73 mmol), and potassium tert-butoxide (307 mg, 2.73 mmol) were combined in 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 _{over 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) ^⁺ .

b) 5-Cyclopropyl-6-((S)-4,4,4-trifluoro-3-hydroxy-butoxy)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide

The title compound was synthesized in analogy to Example 1 using 5-cyclopropyl-6-((S)-3-hydroxy-1-trifluoromethyl-propoxy)-pyridine-2-carboxylic acid (Example 320a) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70b) as starting materials; MS (EI) 432.4 (M+H) ⁺ .

Example 321

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (3-methyl-1-pyridazin-3-yl-butyl)-amide

a) 3-Methyl-1-(pyridazin-3-yl)butan-1-amine

A suspension of 3-methyl-1-(pyridazin-3-yl)butan-1-one (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. The aqueous layer was basified with 10% aqueous NaOH and extracted with EtOAc. The combined extracts were washed with brine and dried over Na ₂ SO _4. Filtration and evaporation afforded the title compound (233 mg, 27%) as a brown oil sufficiently pure for use in the next step. MS (EI): m/e=166.2 [M+H] ⁺ .

b) 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (3-methyl-1-pyridazin-3-yl-butyl)-amide

The title product was prepared by condensing 6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinic acid (Example 69b) and 3-methyl-1-(pyridazin-3-yl)butan-1-amine in analogy to the procedure described in Example 293. MS (EI): m/e = 432.4 [M+H] ⁺ .

Example 322

6-Cyclopropylmethoxy-5-(3-oxo-azetidin-1-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

a) 5-Bromo-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized similarly to Example 1 using 5-bromo-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 9d) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methylamine (Example 33d) as starting materials; MS (EI) 455.1 (M+H) ⁺ .

b) 6-Cyclopropylmethoxy-5-(3-hydroxy-azetidin-1-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

5-Bromo-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide (150 mg, 380 μmol) was dissolved in toluene (6.0 mL) to give a colorless solution. The solution was degassed under a stream of argon 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 18621-18-6; 49.9 mg, 455 μmol) were added and the mixture was heated to 100°C in a microwave oven for 18 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate (5 mL) and water (3 mL), filtered, and the filter pad was washed with water (10 mL) and ethyl acetate (30 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (20 mL). The organic phases were combined, dried over Na ₂ SO ₄ , 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 a yellow solid; NMR was consistent.

c) 6-Cyclopropylmethoxy-5-(3-oxo-azetidin-1-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

To a solution of oxalyl chloride (14.4 mg, 9.94 μl, 114 μmol) in dichloromethane (1 mL) was added DMSO (17.7 mg, 16.1 μl, 227 μmol) at -60°C under stirring. The mixture was stirred at -60°C to -50°C for 15 minutes. A solution of 6-cyclopropylmethoxy-5-(3-hydroxy-azetidin-1-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide (40 mg, 103 μmol) in dichloromethane (1 mL) was added at -50°C over 2 minutes. Stirring was continued at -60°C to -50°C for 1 hour. Triethylamine (52.2 mg, 72.0 μl, 516 μmol) was then added and the reaction mixture was slowly warmed to room temperature and stirred at room temperature for another 16 hours. Water (10 mL) was added and the mixture was extracted with dichloromethane (3x10 mL). The organic phases were combined, dried over Na ₂ SO ₄ , 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 an off-white solid; LC-MS (UV peak area/ESI) 92%, 386.1820 (M+H) ⁺ .

Example 323

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(+)-1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized similarly to Example 1 using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and α-cyclopropyl-α,5-dimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1155536-64-3) as starting materials. The product was separated by chiral chromatography on Lux 5u Amylose-2 using heptane/15% 2-propanol as eluent. The (+)-enantiomer was separated. LC-MS (UV peak area/ESI) 100%, 383.2090 (M+H) ⁺ ,

Example 324

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(-)-1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized similarly to Example 1 using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and α-cyclopropyl-α,5-dimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1155536-64-3) as starting materials. The product was separated by chiral chromatography on Lux 5u Amylose-2 using heptane/15% 2-propanol as eluent. The (-)-enantiomer was separated. LC-MS (UV peak area/ESI) 100%, 383.2082 (M+H) ⁺ ,

Example 325

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (3-methyl-1-pyridin-3-yl-butyl)-amide

The title product was condensed from 6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinic acid (Example 69b) and 3-methyl-1-(pyridin-3-yl)butan-1-amine (CAN 938459-12-2) in a manner analogous to that described in Example 293. MS (EI): m/e = 431.5 [M+H] ⁺ .

Example 326

5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide

The title compound was synthesized similarly to Example 1 using 5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid (Example 155g) and (S)-2-amino-3-cyclopropylpropionamide hydrochloride (Example 97a) as starting materials. MS (EI): m/e=382.1 [M+H] ⁺ .

Example 327

5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized in a similar manner to Example 1 using 5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid (Example 155g) and (S)-2-cyclopropyl-1-5-methyl-[1,2,4]oxadiazol-3-yl)-ethanamine (Example 38e) as starting materials. MS (EI): m/e = 421.1 [M+H] ⁺ .

Example 328

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(S)-carbamoyl-(4-fluoro-phenyl)-methyl]-amide

The title compound was synthesized similarly to Example 1 using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and (αS)-α-amino-4-fluoro-phenylacetamide (CAN 785041-04-5) as starting materials; LC-MS (UV peak area/ESI) 100%, 384.1716 (M+H) ⁺ .

Example 329

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(S)-carbamoyl-(4-chloro-phenyl)-methyl]-amide

The title compound was synthesized similarly to Example 1 using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and (αS)-α-amino-4-chloro-phenylacetamide (CAN 488836-04-0) as starting materials; LC-MS (UV peak area/ESI) 95%, 400.1434 (M+H) ⁺ .

Example 330

6-(2-Methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide

a) 6-(Isobutylsulfonyl)pyridinecarbonitrile

A mixture of 6-(isobutylthio)picolinonitrile (109 mg, 567 μmol; CAN 1342094-07-8) and 3-chloroperoxybenzoic acid (293 mg, 1.7 mmol) in dichloromethane (3 mL) was stirred at ambient temperature for 24 h, quenched with _{aqueous Na₂S₂O₃ ,} and diluted with dichloromethane. The organic layer was washed with saturated aqueous _NaHCO₃ , dried _{over Na₂SO₄} , and concentrated in vacuo to afford the title compound (126 mg, 99%) as a white solid sufficiently pure for use in the next step. MS (EI): m/e = 225.1 [M+H] ^⁺ .

b) 6-(Isobutylsulfonyl)picolinic acid

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 (1:1), and extracted three times with EtOAc. The organic layer was washed with ice water/brine (1:1), dried over Na ₂ SO ₄ , and concentrated in vacuo to afford the title compound (116 mg, 85%) as a white solid sufficiently pure for use in the next step. MS (EI): m/e = 241.9 [MH] ⁻ .

c) 6-(2-Methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide

The title compound was synthesized using 6-(isobutylsulfonyl)picolinic acid and (2S)-2-amino-4-methyl-pentanamide (CAN687-51-4) as starting materials in a similar manner to Example 1. MS (EI): m/e = 356.2 [M+H] ⁺ .

Example 331

6-Isobutylsulfanyl-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide

The title compound was synthesized using 6-(isobutylthio)picolinic acid (CAN 1247607-03-9) and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials in analogy to Example 1. MS (EI): m/e = 324.2 [M+H] ⁺ .

Example 332

5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid ((S)-2,2,2-trifluoro-1-pyridin-2-yl-ethyl)-amide

The title compound was synthesized similarly to Example 1 using 5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid (Example 155g) and (S)-2,2,2-trifluoro-1-(pyridin-2-yl)ethanamine hydrochloride (CAN 336105-45-4) as starting materials. MS (EI): m/e=430.3 [M+H] ⁺ .

Example 333

2-{[5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carbonyl]-amino}-2-ethyl-butyric acid

a) Ethyl 2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethylbutanoate

The title compound was synthesized similarly to Example 1 using 5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid (Example 155g) and ethyl 2-amino-2-ethylbutyrate hydrochloride (CAN 1135219-29-2) as starting materials. MS (EI): m/e=413.1 [M+H] ⁺ .

b) 2-{[5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carbonyl]-amino}-2-ethyl-butyric acid

In analogy to the procedure described in Example 252b), ethyl 2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethylbutanoate was treated with sodium hydroxide to give the title compound as a white solid. MS: 383.3 [MH] ⁻ .

Example 334

6-Cyclopropylmethoxy-5-(3-oxo-pyrrolidin-1-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

a) 6-Cyclopropylmethoxy-5-((S)-3-hydroxy-pyrrolidin-1-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized similarly to Example 322b using 5-bromo-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide (Example 322a) and (3S)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-pyrrolidine (CAN 207113-36-8) as starting materials. The protecting group was removed using tetrabutylammonium fluoride in THF; LC-MS (UV peak area/ESI) 100%, 402.2134 (M+H) ⁺ .

c) 6-Cyclopropylmethoxy-5-(3-oxo-pyrrolidin-1-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized similarly to Example 322c using 6-cyclopropylmethoxy-5-((S)-3-hydroxy-pyrrolidin-1-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide (Example 334a) as starting material; LC-MS (UV peak area/ESI) 100%, 400.1987 (M+H) ⁺ .

Example 335

6-(2-Methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid [(S)-3-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-butyl]-amide

The title compound was synthesized in analogy to Example 1 using 6-(isobutylsulfonyl)picolinic acid (Example 330b) and (S)-5-methyl-α-(2-methylpropyl)-1,2,4-oxadiazole-3-methanamine hydrochloride (prepared from (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid (CAN 13139-15-6) in a similar manner to the procedure described in Examples 38a to e). MS (EI): m/e = 395.2 [M+H] ⁺ .

Example 336

(S)-2-{[5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carbonyl]-amino}-4-methyl-pentanoic acid

a)(S)-2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-4-methylpentanoic acid ethyl ester

The title compound was synthesized similarly to Example 1 using 5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid (Example 155g) and (S)-2-amino-4-methylpentanoic acid ethyl ester hydrochloride (CAN 2743-40-0) as starting materials. MS (EI): m/e=413.2 [M+H] ⁺ .

b) (S)-2-{[5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carbonyl]-amino}-4-methyl-pentanoic acid

In analogy to the procedure described in Example 5c), (S)-ethyl 2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-4-methylpentanoate was saponified with lithium hydroxide to give the title compound. MS (EI): m/e = 385.2 [M+H] ⁺ .

Example 337

2-{[5-Cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carbonyl]-amino}-2-ethyl-butyric acid

a) Ethyl 2-(5-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)picolinamido)-2-ethylbutanoate

The title compound was synthesized in analogy to Example 1 using 5-cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carboxylic acid (which can be prepared, for example, in a manner analogous to 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 166b)) and ethyl 2-amino-2-ethylbutyrate hydrochloride (CAN1135219-29-2) as starting materials. MS (EI): m/e = 419.3 [M+H] ⁺ .

b) 2-{[5-Cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carbonyl]-amino}-2-ethyl-butyric acid

In analogy to the procedure described in Example 252b), ethyl 2-(5-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)picolinamido)-2-ethylbutanoate was treated with sodium hydroxide to give the title compound as a white solid. MS: 389.3 [MH] ⁻ .

Example 338

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-methyl-1-(4-methyl-5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

a) [1-Methyl-1-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-ethyl]-carbamic acid tert-butyl ester

To a colorless solution of [1-(N-hydroxycarbamoyl (carbamidoyl))-1-methyl-ethyl]-carbamic acid tert-butyl ester (CAN1251430-04-2, 1.0 g, 4.6 mmol) in DMF (7.5 mL), pyridine (455 mg, 465 μl, 5.75 mmol) was added. 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 and stirred at room temperature for another 90 minutes. The solvent was removed in vacuo and the residue was distributed between ethyl acetate (30 mL) and water (15 mL). The aqueous phase was extracted with ethyl acetate (30 mL), the organic phases were combined, dried over MgSO ₄ and concentrated in vacuo. The residue (1.2 g white solid) was combined with pyridine (5 mL) and stirred at reflux temperature for 3 hours. The pyridine was removed in vacuo to give the title compound (1.0 g, 89%) as an off-white solid; LC-MS (ESI) 242.1151 (MH) ⁻ .

b) [1-Methyl-1-(4-methyl-5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-ethyl]-carbamic acid tert-butyl ester

To a colorless solution of [1-methyl-1-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-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 slowly added at a maximum of 5° C. over a period of 20 minutes. The mixture was stirred at 0-5° C. for another 30 minutes and at room temperature for 16 hours. The solvent was removed in vacuo and the residue was purified by flash chromatography (silica gel, 70 g, 0% to 100% ethyl acetate in heptane) to give the title compound (1.4 g, 89%) as a white solid; GC-MS (EI) 98%, 257.0 (M) ⁺ .

c) 3-(1-Amino-1-methyl-ethyl)-4-methyl-4H-[1,2,4]oxadiazol-5-one hydrochloride (1:1)

To a solution of [1-methyl-1-(4-methyl-5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-ethyl]-carbamic acid tert-butyl ester (1.45 g, 5.64 mmol) in ethanol (15 mL) was added 4M-HCl (5.64 mL, 22.5 mmol) in dioxane, and the reaction mixture was stirred at room temperature for 16 hours. The solution was concentrated to a volume of 5 mL in vacuo. Diethyl ether (15 mL) was added dropwise with stirring over a period of 30 minutes and stirring was continued for another 30 minutes. The precipitate was separated by filtration, washed with diethyl ether (3x1 mL) and dried in vacuo to give the title compound (1.0 g, 95%) as a white solid; GC-MS (EI) 157.0 (M) ⁺ .

d) 5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-methyl-1-(4-methyl-5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized in a similar manner to Example 1 using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and 3-(1-amino-1-methyl-ethyl)-4-methyl-4H-[1,2,4]oxadiazol-5-one hydrochloride (1:1) (Example 338c) as starting materials; LC-MS (UV peak area/ESI) 99%, 373.1870 (M+H) ⁺ .

Example 339

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (3-methyl-1-pyrimidin-2-yl-butyl)-amide

The title compound was synthesized in analogy to Example 1 using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69b) and 3-methyl-1-(pyrimidin-2-yl)butan-1-amine (CAN 1178500-15-6) as starting materials. MS (EI): m/e=432.4 [M+H] ⁺ .

Example 340

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized in a similar manner to Example 1 using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69b) and α-cyclopropyl-α,5-dimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1155536-64-3) as starting materials. MS (EI): m/e = 434.5 [M+H] ⁺ .

Example 341

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [2-cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

a) 2-Amino-3-cyclopropyl-2-methyl-propionitrile

To a solution of 1-cyclopropyl-propan-2-one (1.0 g, 10.2 mmol; CAN 4160-75-2) and 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. Potassium cyanide (900 mg, 15.3 mmol) was added portionwise 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 ( ₃ x 50 mL). The organic phases were washed with ice water, combined, dried over _Na₂SO₄ and concentrated in vacuo to give the title compound (0.8 g, 63%) as a yellow oil. ¹ H-NMR (DMSO, 400MHz): 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).

b)(Cyano-cyclopropylmethyl-methyl-methyl)-carbamic acid tert-butyl ester

To a solution of 2-amino-3-cyclopropyl-2-methyl-propionitrile (0.8 g, 6.45 mmol) and diisopropylethylamine (3.36 mL, 19.8 mmol) in dichloromethane (20 mL) was added di-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 _{over 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 a light yellow liquid. ¹ H-NMR (DMSO, 400MHz): 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&7.2Hz, 1H); 1.82-1.87(dd, 13.8Hz&7.2Hz, 1H); 7.47(br s, 1H).

c) [2-Cyclopropyl-1-(N-hydroxycarbamimidoyl)-1-methyl-ethyl]-carbamic acid tert-butyl ester

Sodium bicarbonate (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) (0.7 g, 2.67 mmol) in ethanol (5 mL) was added and the resulting reaction mixture was heated at 80°C for 12 hours. After evaporation of the solvent, 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 a white solid; LC-MS (ELSD peak area, ESI) 100%, 258.2 [M+H] ⁺ .

d) [2-Cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-carbamic acid tert-butyl ester

A solution of tert-butyl [2-cyclopropyl-1-(N-hydroxycarbamimidoyl)-1-methyl-ethyl]-carbamate (300 mg, 1.16 mmol) in acetic anhydride (10 mL) was heated to 100° C. and stirred for 5 hours. After evaporation of the solvent, the residue was dissolved in H ₂ O (20 mL) and basified with aqueous NaHCO ₃ (pH 7-8). The aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over Na ₂ SO ₄ , and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, 100-200 mesh, 20 g, eluted with 20% ethyl acetate in petroleum ether) to afford the title compound (0.15 g; 46%) as a colorless, sticky solid. ¹ H-NMR (DMSO, 400MHz): 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-Cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine hydrochloride

To a solution of [2-cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-carbamic acid tert-butyl ester (0.4 g, 1.43 mmol) in methanol (10 mL) was added hydrochloric acid (4 N 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. ¹ H-NMR (DMSO, 400MHz): 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-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [2-cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized in a similar manner to Example 1 using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69b) and 2-cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethanamine hydrochloride as starting materials. MS (EI): m/e = 448.5 [M+H] ⁺ .

Example 342

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methylsulfanyl-propyl)-amide

The title compound was synthesized in a similar manner to Example 1 using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69b) and (2S)-2-amino-4-(methylthio)-butyramide, monohydrochloride (CAN 14510-08-1) as starting materials. MS (FI): m/e = 415.16 [M+H] ⁺ .

Example 343

6-(3-Chloro-4-fluoro-phenyl)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl ^] -amide

a) 6-Bromo-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound can be prepared analogously to Example 1 using 6-bromo-2-pyridinecarboxylic acid (CAN 21190-87-4) and (S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 38e) as starting materials, MS (EI) 353.0 (M+H) ⁺ .

b) 6-(3-Chloro-4-fluoro-phenyl)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound can be prepared in analogy to Example 177b using 6-bromo-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide (Example 343a) and B-(3-chloro-4-fluorophenyl)-boronic acid (CAN 144432-85-9) as starting materials, LC-MS (UV peak area/ESI) 100%, 401.1179 (M+H) ⁺ .

Example 344

6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid {(S)-3-methyl-1-[(7-nitro-benzo[1,2,5]oxadiazol-4-ylamino)-methyl]-butyl}-amide

a) 6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid ((S)-1-azidomethyl-3-methyl-butyl)-amide

To a colorless solution of 6-cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-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 over _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 a white solid; MS (ESI) 387.3 (M+H) + .

b) 6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid ((S)-1-aminomethyl-3-methyl-butyl)-amide

6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid ((S)-1-azidomethyl-3-methyl-butyl)-amide (107 mg, 277 μmol) was combined with 2-propanol (725 μl) to give an off-white suspension. To this suspension were 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. The volatiles were removed in vacuo and the residue was stirred with a mixture of 10% citric acid solution (5 mL) and ethyl acetate/heptane (5 mL, 1:1). The aqueous layer was brought to pH = 12 with 2N NaOH and extracted twice with ethyl acetate. The organic phases were combined, dried _{over Na2SO4} , and concentrated in vacuo to give the title compound (32 mg, 32%) as a colorless, gummy oil, which was used in the next step without further purification; MS (ESI) 361.3 (M+H) ⁺ .

c) 6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid {(S)-3-methyl-1-[(7-nitro-benzo[1,2,5]oxadiazol-4-ylamino)-methyl]-butyl}-amide

To a colorless solution of 6-cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid ((S)-1-aminomethyl-3-methyl-butyl)-amide (30 mg, 83.2 μmol) in THF (555 μl) was added 7-nitro-2,1,3-benzoxadiazol-4-amine (CAN 10199-91-4, 19.9 mg, 100 μmol). The reaction mixture was stirred at room temperature for 30 minutes, then 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; the aqueous phase was extracted with ethyl acetate. _The organic phases were combined, dried over _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 a brown solid; LC-MS (UV peak area/ESI) 100%, 524.2609 (M+H) ⁺ .

Example 345

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methanesulfonyl-propyl)-amide

(S)-N-(1-amino-4-(methylthio)-1-oxobutan-2-yl)-6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinamide (10 mg, 24.1 μmol; Example 342) was dissolved in dichloromethane (200 μL). The yellow solution was cooled to 0°C. 3-Chloroperoxybenzoic acid (8.33 mg, 48.3 μmol) was added. The reaction mixture was stirred at ambient temperature for 1 day. Poured onto ice water/saturated _NaHCO₃ solution (20 mL) and extracted with dichloromethane (30 mL). The extract was washed with ice water/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, eluting 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

5-Cyclopropyl-6-isobutylsulfanyl-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide

a) 5-Bromo-6-(isobutylthio)picolinic acid

5-Bromo-6-chloropicolinic acid (2 g, 8.46 mmol; CAN 959958-25-9), 2-methylpropane-1-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 day, then poured onto ice water/1N HCl (100 mL). The aqueous layer was extracted with EtOAc (2 x 250 mL). The combined extracts were washed with ice water/brine (100 mL), _dried over _Na₂SO₄ , and concentrated in vacuo to afford 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 [MH] ⁻ .

b) Methyl 5-bromo-6-(isobutylthio)picolinate

5-Bromo-6-(isobutylthio)picolinic acid (500mg, 1.72mmol) was dissolved in methanol (5mL) to give a yellow solution. Sulfuric acid (169mg, 92.3μL, 1.72mmol) was added. The reaction mixture was heated to 80°C and stirred for 1 day. The reaction mixture was cooled to 0°C and poured onto ice water/brine (25mL). The aqueous layer was extracted with EtOAc (2x40mL) and washed with ice water/brine (20mL). The organic layers were combined, dried over Na ₂ SO ₄ and concentrated in vacuo to give the crude title compound as a yellow oil. The oil was purified by flash chromatography (silica gel, 5g, 0% to 15% EtOAc in heptane) to give the title product (205mg, 39%) as a colorless oil. MS (EI): m/e=306.3[M+H] ⁺ .

c) 5-Cyclopropyl-6-(isobutylthio)picolinic acid

The title compound was prepared in analogy to the procedure described in Example 5a) using methyl 5-bromo-6-(isobutylthio)picolinate as starting material. MS (EI): m/e = 252.4 [M+H] ⁺ .

d) 5-Cyclopropyl-6-isobutylsulfanyl-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide

The title compound was synthesized using 5-cyclopropyl-6-(isobutylthio)picolinic acid and (2S)-2-amino-4-methyl-pentanamide (CAN687-51-4) as starting materials in a similar manner to Example 1. MS (EI): m/e = 364.5 [M+H] ⁺ .

Example 347

6-(3-Fluoro-phenyl)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound can be prepared in analogy to Example 177b using 6-bromo-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide (Example 343a) and B-(3-fluorophenyl)-boronic acid (CAN 768-35-4) as starting materials, LC-MS (UV peak area/ESI) 99%, 367.1571 (M+H) ⁺ .

Example 348

6-(4-Fluoro-3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound can be prepared in analogy to Example 177b using 6-bromo-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide (Example 343a) and B-(4-fluoro-3-(trifluoromethyl)-phenyl)-boronic acid (CAN 182344-23-6) as starting materials, LC-MS (UV peak area/ESI) 100%, 435.1442 (M+H) ⁺ .

Example 349

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (3-methanesulfonyl-1,1-dimethyl-propyl)-amide

The title compound was synthesized similarly to Example 1 using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and 2-methyl-4-(methylsulfonyl)-2-butylamine (CAN 1250515-16-2) as starting materials; LC-MS (UV peak area/ESI) 95%, 381.1843 (M+H) ⁺ .

Example 350

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-thiazol-2-yl)-ethyl]-amide

The title compound was synthesized similarly to Example 1 using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and α,α,5-trimethyl-2-thiazolidinemethanamine (CAN 1155530-59-8) as starting materials; LC-MS (UV peak area/ESI) 94%, 372.1743 (M+H) ⁺ .

Example 351

5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide

a) Methyl 5-bromo-6-(isobutylsulfonyl)picolinate

Methyl 5-bromo-6-(isobutylthio)picolinate (30 mg, 98.6 μmol, Example 346b) was dissolved in dichloromethane (1 mL). The solution was cooled to 0°C. 3-chloroperoxybenzoic acid (34.0 mg, 197 μmol) was added. The reaction mixture was stirred at ambient temperature for 1 day, poured onto ice water (20 mL) and extracted with dichloromethane (2x30 mL). The extract was washed with 10% Na ₂ O ₃ S ₂ -water solution (15 mL). The aqueous layer was back-extracted with dichloromethane (30 mL). The combined organic layers were washed with 10% sodium bicarbonate aqueous solution, dried over Na ₂ SO ₄ 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] ⁺ .

b) 5-Cyclopropyl-6-(isobutylsulfonyl)picolinic acid

The title compound was prepared in analogy to the procedure described in Example 5a) using methyl 5-bromo-6-(isobutylsulfonyl)picolinate as starting material. MS (EI): m/e = 284.3 [M+H] ⁺ .

c) 5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide

The title compound was synthesized similarly to Example 1 using 5-cyclopropyl-6-(isobutylsulfonyl)picolinic acid and (S)-2-amino-4-methylpentanamide hydrochloride (CAN 687-51-4) as starting materials. MS (EI): m/e = 395.5 [M+H] ⁺ .

Example 352

5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized in a similar manner to Example 1 using 5-cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid (Example 351b) and (S)-2-cyclopropyl-1-5-methyl-[1,2,4]oxadiazol-3-yl)-ethanamine (Example 38e) as starting materials. MS (EI): m/e = 433.2 [M+H] ⁺ .

Example 353

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-thiazol-2-yl)-ethyl]-amide

The title compound was synthesized in a similar manner to Example 1 using 6-cyclopropylmethyloxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69b) and α,α,5-trimethyl-2-thiazolidinemethanamine (CAN 1155530-59-8) as starting materials; LC-MS (UV peak area/ESI) 100%, 422.4588 (M+H) ⁺ .

Example 354

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((R)-3-methyl-1-pyridazin-3-yl-butyl)-amide

The title compound was synthesized in analogy to Example 1 using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69b) and 3-methyl-1-(pyridazin-3-yl)butan-1-amine (Example 321a) as starting materials. The product was separated by chiral chromatography on Reprosil Chiral NR using a mixture of heptane, ethanol, and 2-propanol as eluent. The (+)-enantiomer was separated. MS (EI): m/e = 432.5 [M+H] ⁺ .

Example 355

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-3-methyl-1-pyridazin-3-yl-butyl)-amide

The title compound was synthesized in analogy to Example 1 using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69b) and 3-methyl-1-(pyridazin-3-yl)butan-1-amine (Example 321a) as starting materials. The product was separated by chiral chromatography on Reprosil Chiral NR using a mixture of heptane, ethanol, and 2-propanol as eluent. The (-) enantiomer was separated. MS (EI): m/e = 432.5 [M+H] ⁺ .

Example 356

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-ethyl-1-(2-hydroxy-ethylcarbamoyl)-propyl]-amide

The title compound was synthesized in analogy to Example 1 using 2-(5-cyclopropyl-6-(cyclopropylmethoxy)picolinamido)-2-ethylbutanoic acid (Example 274a) and 2-(trimethylsilyloxy)ethylamine (CAN 5804-92-2) as starting materials. MS (EI): m/e = 390.5 [M+H] ⁺ .

Example 357

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(+)-2-cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

a) 2-Amino-3-cyclopropyl-2-methyl-propionitrile

To a solution of 1-cyclopropyl-propan-2-one (CAN 4160-75-2; 1.0 g, 10.2 mmol) and aqueous ammonia (25% in water, 10 mL) in ethanol (10 mL) was added ammonium chloride (1.63 g, 30.6 mmol). The reaction mixture was stirred at ambient temperature for 1 hour. Potassium cyanide (1 g, 15.30 mmol) was added portionwise and the reaction mixture was stirred at ambient temperature for 12 hours. Ice water (50 mL) was added and the mixture was extracted with ethyl acetate (3 x 50 mL). The organic phases were washed with ice-water, combined, dried _{over Na2SO4} and concentrated in vacuo to give the title compound (0.8 g, 62.99%) as a yellow oil; NMR (400 MHz, DMSO) δ = 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-cyano-2-cyclopropyl-1-methyl-ethyl)-carbamic acid tert-butyl ester

To a solution of 2-amino-3-cyclopropyl-2-methyl-propionitrile (1.0 g, 6.4 mmol) and triethylamine (3.36 mL, 19.8 mmol) in dichloromethane (20 mL) was added di-tert-butyl dicarbonate (CAN 24424-99-5, 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 _{over Na₂SO₄} , and concentrated in vacuo. The residue was purified by chromatography (silica gel, 50 g, 1:9 ethyl acetate/n-hexane) to afford the title compound (1.2 g, 66%) as a light yellow liquid; LC-MS (UV peak area, ESI) 83%, 225.14 (M+H).

c) [2-Cyclopropyl-1-(N-hydroxycarbamimidoyl)-1-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. To this was added a solution of (1-cyano-2-cyclopropyl-1-methyl-ethyl)-carbamic acid tert-butyl ester (600 mg, 2.69 mmol) in ethanol (10 mL) and the resulting reaction mixture was heated at 80° C. for 12 hours. After evaporation of the solvent, the residue was dissolved in ethyl 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 a white solid; LC-MS (UV peak area, ESI) 100%, 258.4 (M+H).

d) tert-Butyl 2-cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-carbamate

A solution of [2-cyclopropyl-1-(N-hydroxycarbamimidoyl)-1-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 the solvent, the residue was purified by column chromatography (silica gel, 20 g, eluted with 20% ethyl acetate in petroleum ether) to give the title compound (0.2 g; 61%) as a colorless viscous liquid; LC-MS (UV peak area, ESI) 90%, 282.2 (M+H).

e) 2-Cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine

To a solution of tert-butyl 2-cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-carbamate (0.2 g, 0.7 mmol) in methanol (5 mL) was added hydrochloric acid (4 N in dioxane, 0.87 mL, 3.5 mmol) and the reaction mixture was stirred at ambient temperature for 4 hours. Water (20 mL) was then added. The aqueous phase was washed with ethyl acetate (2 x 20 mL) and adjusted to pH 9-10 with 2 M sodium hydroxide solution. 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 the crude product as a white solid (0.1 g, 78%); LC-MS (UV peak area, ESI) 80%, 182.0 (M+H).

f) 5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(+)-2-cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized in analogy to Example 1 using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and 2-cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethanamine (Example 357e) as starting materials. The product was separated by chiral chromatography on Reprosil Chiral NR using heptane/10% 2-propanol as eluent. The (+)-enantiomer was separated. LC-MS (UV peak area/ESI) 100%, 397.2230 (M+H) ⁺ ,

Example 358

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(-)-2-cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized in analogy to Example 1 using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and 2-cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethanamine (Example 357e) as starting materials. The product was separated by chiral chromatography on Reprosil Chiral NR using heptane/10% 2-propanol as eluent. The (-)-enantiomer was separated. LC-MS (UV peak area/ESI) 100%, 397.2244 (M+H) ⁺ ,

Example 359

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid tert-butylamide

The title compound was synthesized similarly to Example 1 using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69b) and tert-butylamine (CAN 75-64-9) as starting materials. MS (EI): m/e=340.5 [M+H] ⁺ .

Example 360

2-{[5-cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carbonyl]-amino}-2-ethyl-butyric acid ethyl ester

The title compound was synthesized in analogy to Example 1 using 5-cyclopropyl-6-(isobutylsulfonyl)picolinic acid (Example 351b) and 2-amino-2-ethyl-butyric acid ethyl ester (CAN 189631-96-7) as starting materials. MS (EI): m/e = 425.4 [M+H] ⁺ .

Example 361

5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid ((S)-3,3-dimethyl-1-methylcarbamoyl-butyl)-amide

The title compound was synthesized in analogy to Example 1 using 5-cyclopropyl-6-(isobutylsulfonyl)picolinic acid (Example 351b) and (2S)-2-amino-N,4,4-trimethylpentanamide (CAN 1160161-70-5) as starting materials. MS (EI): m/e = 424.6 [M+H] ⁺ .

Example 362

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-2-oxo-tetrahydro-furan-3-yl)-amide

The title compound was synthesized in a similar manner to Example 1 using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and (3S)-3-aminodihydro-2(3H)-furanone (CAN 2185-02-6) as starting materials; LC-MS (UV peak area/ESI) 100%, 317.1500 (M+H) ⁺ .

Example 363

N′-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-N-cyclopropylmethyl-hydrazinecarboxylic acid tert-butyl ester

The title compound was synthesized similarly to Example 1 using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and 1-(cyclopropylmethyl)-hydrazinecarboxylic acid 1,1-dimethylethyl ester (CAN 1314973-05-1) as starting materials; LC-MS (UV peak area/ESI) 100%, 402.2375 (M+H) ⁺ .

Example 364

5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid ((S)-2,2-dimethyl-1-methylcarbamoyl-propyl)-amide

The title compound was synthesized similarly to Example 1 using 5-cyclopropyl-6-(isobutylsulfonyl)picolinic acid (Example 351b) and (2S)-2-amino-N,3,3-trimethyl-butyramide (CAN 89226-12-0 ) as starting materials. MS (EI): m/e = 410.6 [M+H] ⁺ .

Example 365

5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid ((S)-2,2,2-trifluoro-1-pyridin-3-yl-ethyl)-amide

The title compound was synthesized similarly to Example 1 using 5-cyclopropyl-6-(isobutylsulfonyl)picolinic acid (Example 351b) and (S)-2,2,2-trifluoro-1-(pyridin-3-yl)ethanamine hydrochloride (CAN 336105-46-5) as starting materials. MS (EI): m/e = 442.4 [M+H] ⁺ .

Example 366

(S)-2-[(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-amino]-4-methyl-pentanoic acid tert-butyl ester

The title compound was synthesized similarly to Example 1 using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and L-leucine 1,1-dimethylethyl ester hydrochloride (1:1) (CAN 2748-02-9) as starting materials; LC-MS (UV peak area/ESI) 98.7%, 403.2599 (M+H) ⁺ .

Example 367

5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide

The title compound was synthesized using 5-cyclopropyl-6-(isobutylsulfonyl)picolinic acid (Example 351b) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70b) as starting materials in a similar manner to Example 1. MS (EI): m/e = 410.21 [M+H] ⁺ .

Example 368

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid tert-butylamide

The title compound was synthesized in analogy to Example 1 using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and tert-butylamine (CAN 75-64-9) as starting materials. MS (EI): m/e = 289.4 [M+H] ⁺ .

Example 369

5-Cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid tert-butylamide

The title compound was synthesized similarly to Example 1 using 2-(5-cyclopropyl-6-((tetrahydrofuran-2-yl)methoxy)picolinamido)-2-ethylbutanoic acid (Example 166b) and tert-butylamine (CAN 75-64-9) as starting materials. MS (EI): m/e = 319.4 [M+H] ⁺ .

Example 370

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (3-methyl-oxetan-3-yl)-amide

The title compound was synthesized analogously to Example 1 using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69b) and (3-methyloxetan-3-yl)-amine (CAN 874473-14-0) as starting materials.

Example 371

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (2-oxo-[1,3]oxazin-3-yl)-amide

The title compound was synthesized similarly to Example 1 using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and 3-aminotetrahydro-2H-1,3-oxazin-2-one (CAN 54924-47-9) as starting materials; LC-MS (UV peak area/ESI) 98.7%, 332.1612 (M+H) ⁺ .

Example 372

5-Cyclopropyl-6-(2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide

a) 5-Bromo-6-(1,1,1-trifluoropropan-2-yloxy)picolinic acid

5-Bromo-6-chloropicolinic acid (5 g, 21.1 mmol; CAN 959958-25-9) was dissolved in DMSO (100 mL) to give a colorless solution. To this solution was added potassium hydroxide (4.75 g, 84.6 mmol). The reaction mixture became a white suspension and was stirred for 15 min. 1,1,1-trifluoropropan-2-ol (2.41 g, 1.92 mL, 21.1 mmol) was then added. The mixture was stirred at ambient temperature for 1 day, poured onto ice water/1N HCl (200 mL), and extracted with EtOAc (2 x 400 mL). The organic layers were washed with ice water/brine (200 _mL ), combined, dried over _Na₂SO₄ , and concentrated in vacuo to give the title compound (6.9 g, quantitative) as an orange solid. MS (EI): m/e = 312.3 [MH] ⁻ . b) 5-Cyclopropyl-6-(1,1,1-trifluoropropan-2-yloxy)picolinic acid

Under an argon atmosphere, 5-bromo-6-(1,1,1-trifluoropropan-2-yloxy)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). Butyl-1-adamantylphosphine (68.5 mg, 191 μmol) was added, and the reaction mixture was heated to 120° C. for 1 day, poured onto ice water/1N HCl (150 mL) and extracted with EtOAc (2×300 mL). The combined organic layers were washed with ice water/brine (150 mL), dried over Na ₂ SO ₄ 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] ⁺ c) 5-Cyclopropyl-6-(2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide

The title compound was synthesized similarly to Example 1 using 5-cyclopropyl-6-(1,1,1-trifluoropropan-2-yloxy)picolinic acid and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials. MS (EI): m/e = 388.4 [M+H] ⁺ .

Example 373

5-Cyclopropyl-6-(2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized similarly to Example 1 using 5-cyclopropyl-6-(1,1,1-trifluoropropan-2-yloxy)picolinic acid (Example 372b) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials. MS (EI): m/e = 399.5 [M+H] ⁺ .

Example 374

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((+)-carbamoyl-cyclopropyl-methyl)-amide

The title compound was synthesized similarly to Example 1 using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and α-amino-cyclopropaneacetamide (CAN 1100749-41-4) as starting materials. The product was separated by chiral chromatography on a Chiralpak AD using heptane/20% 2-propanol as eluent. The (+)-enantiomer was separated. LC-MS (UV peak area/ESI) 97.7%, 330.1804 (M+H) ⁺ ,

Example 375

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((-)-carbamoyl-cyclopropyl-methyl)-amide

The title compound was synthesized similarly to Example 1 using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and α-amino-cyclopropaneacetamide (CAN 1100749-41-4) as starting materials. The product was separated by chiral chromatography on a Chiralpak AD using heptane/20% 2-propanol as the eluent. The (-)-enantiomer was separated. LC-MS (UV peak area/ESI) 100%, 330.1806 (M+H) ⁺ ;

Example 376

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((+)-carbamoyl-cyclopropyl-methyl)-amide

The title compound was synthesized similarly to Example 1 using 6-cyclopropylmethyloxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69b) and α-amino-cyclopropaneacetamide (CAN 1100749-41-4) as starting materials. The product was separated by chiral chromatography on a Chiralpak AD using heptane/40% ethanol as eluent. The (+)-enantiomer was separated. LC-MS (UV peak area/ESI) 100%, 381.1739 (M+H) ⁺ ,

Example 377

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((-)-carbamoyl-cyclopropyl-methyl)-amide

The title compound was synthesized similarly to Example 1 using 6-cyclopropylmethyloxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69b) and α-amino-cyclopropaneacetamide (CAN 1100749-41-4) as starting materials. The product was separated by chiral chromatography on a Chiralpak AD using heptane/40% ethanol as eluent. The (-)-enantiomer was separated. LC-MS (UV peak area/ESI) 100%, 381.1734 (M+H) ⁺ ,

Example 378

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1-trifluoromethyl-cyclopropyl)-amide

The title compound was synthesized similarly to Example 1 using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69b) and 1-(trifluoromethyl)cyclopropylamine (CAN 112738-68-8) as starting materials. MS (EI): m/e=392.4 [M+H] ⁺ .

Example 379

(+)-5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(3-hydroxy-pyrrolidin-1-ylcarbamoyl)-ethyl]-amide

a) (S)-3-Cyclopropyl-2-[(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-amino]-propionic acid

(S)-3-Cyclopropyl-2-[(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-amino]-propionic acid methyl ester (Example 258, 42 mg, 117 μmol) was dissolved in THF (2 mL). After adding water (0.66 mL) and lithium hydroxide monohydrate (14.8 mg, 352 μmol), the mixture was heated at reflux temperature and stirred for 3 hours. The mixture was cooled to room temperature, water (7 mL) was added and the mixture was acidified with 1N HCl. The mixture was then extracted with ethyl acetate (14 and 7 mL), and the organic layers were washed with brine (10 mL), combined, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the title compound (36 mg, quantitative) as a white solid; LC-MS (UV peak area/ESI) 100%, 345.1814 (M+H) ⁺ .

b) 5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-((RS)-3-hydroxy-pyrrolidin-1-ylcarbamoyl)-ethyl]-amide

To a solution of (S)-3-cyclopropyl-2-[(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-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-amino-3-pyrrolidinol (CAN 887591-10-8, 30 mg, 0.29 mmol). The reaction mixture was stirred at room temperature for 16 h, concentrated in vacuo and purified by flash chromatography (silica gel, 10 g, 0% to 20% methanol in dichloromethane) to give the title compound as a mixture of epimers of the product (90 mg, 72%) as a white foam; LC-MS (UV peak area/ESI) 96%, 429.2493 (M+H) ⁺ .

c) (+)-5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(3-hydroxy-pyrrolidin-1-ylcarbamoyl)-ethyl]-amide

The title compound was isolated by chiral chromatography using Example 379b on a Chiralpak AD using heptane/20% ethanol as eluent. The (+)-enantiomer was separated. LC-MS (UV peak area/ESI) 100%, 429.2495 (M+H) ⁺ ,

Example 380

(-)-5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(3-hydroxy-pyrrolidin-1-ylcarbamoyl)-ethyl]-amide

The title compound was isolated by chiral chromatography using Example 379b on a Chiralpak AD using heptane/20% ethanol as eluent. The (-)-enantiomer was separated. LC-MS (UV peak area/ESI) 100%, 429.2503 (M+H) ⁺ ,

Example 381

(+)-5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid [1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

a) 5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid [(R,S)-1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was synthesized similarly to Example 1 using 5-cyclopropyl-6-(isobutylsulfonyl)picolinic acid (Example 351b) and α-cyclopropyl-α,5-dimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1155536-64-3) as starting materials. MS (EI): m/e = 433.4 [M+H] ⁺ .

b) (+)-5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid [1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was isolated by chiral chromatography according to Example 381a). The (+)-enantiomer was separated. MS (EI): m/e = 433.4 [M+H] ⁺ .

Example 382

(-)-5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid [1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

The title compound was isolated by chiral chromatography as in Example 381a). The (-)-enantiomer was separated. MS (EI): m/e = 433.4 [M+H] ⁺ .

Example 383

Pharmacological tests

The following tests were performed to determine the activity of the compounds of formula I:

Radioligand binding assay

The affinity of the compounds of the invention for the cannabinoid CB1 receptor was determined using the recommended amount of membrane preparations (PerkinElmer) from human embryonic kidney (HEK) cells expressing the human CNR1 or CNR2 receptor, respectively, bound to 1.5 or 2.6 nM [3H]-CP-55,940 (Perkin Elmer) as a radioligand. Binding was performed in a total volume of 0.2 ml of 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 the 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 the CB2 receptor) with shaking at 30°C for 1 hour. The reaction was terminated by rapid filtration through a microfiltration plate coated with 0.5% polyethyleneimine (UniFilter GF/B filter plate; Packard). Bound radioactivity was analyzed using nonlinear regression analysis (Activity Base, ID Business Solutions, Limited) for Ki and Kd values of 940 for [3H]CP55 were determined from saturation experiments. The compound of formula (I) showed excellent affinity for the CB2 receptor.

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

cAMP assay

CHO cells expressing human CB1 or CB2 receptors were seeded at 50,000 cells/well in black 96-well plates with clear flat bottoms (Corning Costar #3904) 17-24 hours prior to the experiment in DMEM (Invitrogen No. 31331), supplemented with 1x HT, with 10% fetal bovine serum, and incubated in a humidified incubator at 5% CO ₂ and 37° C. The medium was exchanged with Krebs Ringer Bicarbonate buffer with 1 mM IBMX and incubated at 30° C. for 30 minutes. Compounds were added to a final assay volume of 100 μl and incubated at 30° C. for 30 minutes. The cAMP-Nano-TRF detection kit (Roche Diagnostics) was used to terminate the assay by adding 50 μl of lysis reagent (Tris, NaCl, 1.5% Triton X100, 2.5% NP40, ₁₀ % NaN3) and 50 μl of detection solution (20 μM mAb Alexa700-cAMP 1:1 and 48 μM Ruthenium-2-AHA-cAMP) and shaking for 2 h at room temperature. Time-resolved energy transfer was measured using a TRF reader (Evotec Technologies GmbH) equipped with an Nd:YAG laser as the excitation source. The plate was measured in duplicate, with excitation at 355 nm and emission at either 730 (30 nm bandwidth) or 645 nm (75 nm bandwidth) with a 100 ns delay and a 100 ns gate, respectively, for a total exposure time of 10 s. The FRET signal was calculated as follows: FRET = T730-Alexa730-P (T645-B645), P = Ru730-B730/Ru645-B645, where T730 is the test well measured at 730 nM, T645 is the test well measured at 645 nm, and B730 and B645 are buffer controls at 730 nm and 645 nm, respectively. cAMP levels were determined using a standard curve spanning from 10 μM to 0.13 nM cAMP.

_EC50 values were determined using the Activity Base assay (ID Business Solution, Limited). The _EC50 values for a wide range of cannabinoid agonists generated from this assay for the reference compounds were consistent with values published in the scientific literature.

In the above assays, the compounds according to the invention have human CB2 _EC50s between 0.5 nM and 10 μM. Specific compounds according to the invention have human CB2 _EC50s between 0.5 nM and 1 μM. More specific compounds according to the invention have human CB2 _EC50s between 0.5 nM and 100 nM. They exhibit at least 10-fold selectivity over the human CB1 receptor in both the radioligand and cAMP assays, or in one of these two assays.

The results obtained for representative compounds of the invention are given in the following table.

β-Arrestin Translocation Assay - PathHunter ^™ (DiscoveRx)

PathHunter ^™ β-arrestin CHO-K1 CNR1 cell line (Catalog #93-0200C2) and β-arrestin CHO-K1 CNR2 cell line (Catalog #93-0706C2) were purchased from DiscoverRx Corporation. The cell lines were 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. The assay plates were seeded to contain 7500 (CNR1) and 10000 (CNR2) cells in 20 μL of Cell Plating Reagent 2 (Discoverx #93-0563R2A) in a 384-well plate (Corning Costar #3707, white, clear bottom). After incubation overnight at 37°C (5% CO ₂ , 95% relative humidity), 5 μl of test compound (1% final DMSO concentration) was added and incubation continued at 30°C for 90 min. Detection reagent (12 μl) was then added and incubation continued at room temperature for 60 min. The plate was then analyzed for chemiluminescent signals using a Victor ³ V reader (Perkin Elmer).

Example A

Film-coated tablets containing the following ingredients can be prepared in a conventional manner:

nuclear: Compound of formula (I) 10.0mg 200.0mg microcrystalline cellulose 23.5mg 43.5mg Lactose hydrate 60.0mg 70.0mg Polyvinylpyrrolidone (Povidone) K30 12.5mg 15.0mg Sodium starch glycolate 12.5mg 17.0mg magnesium stearate 1.5mg 4.5mg (Nuclear weight) 120.0mg 350.0mg Film coating: Hydroxypropyl methylcellulose 3.5mg 7.0mg Polyethylene glycol 6000 0.8mg 1.6mg talc 1.3mg 2.6mg Iron oxide (yellow) 0.8mg 1.6mg Titanium dioxide 0.8mg 1.6mg

The active ingredient is sieved and mixed with microcrystalline cellulose, and the mixture is granulated with an aqueous solution of polyvinylpyrrolidone. The granules are then mixed with sodium starch glycolate and magnesium stearate and compressed to obtain kernels of 120 or 350 mg, respectively. The kernels are coated with an aqueous solution/suspension of the above-mentioned film coating.

Example B

Capsules containing the following ingredients can be prepared in a conventional manner:

Compound of formula (I) 25.0mg lactose 150.0mg corn starch 20.0mg talc 5.0mg

The ingredients were sieved and mixed and filled into size 2 capsules.

Example C

The injection solution may have the following composition:

Compound of formula (I) 3.0mg polyethylene glycol 400 150.0mg Acetic acid Add enough water to obtain pH 5.0 Water for injection Add to 1.0ml

Dissolve the active ingredient in a mixture of polyethylene glycol 400 and water for injection (partial). Adjust the pH to 5.0 by adding acetic acid. Add the remainder of water to bring the volume to 1.0 ml. Filter the solution, fill into vials using an appropriate overdose, and sterilize.

Claims (6)

1. A compound, said compound being selected from: 2-(6-(3-chlorophenyl)pyridinecarboxamido)-2-methylpropionate; 2-(6-(2-chlorophenyl)pyridinecarboxamido)-2-methylpropionate; 6-(4-chloro-phenyl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide; 2-(5-cyclopropyl-6-(2,4-dichlorophenylamino)pyridinecarboxamido)-2-methylpropionate; 2-(6-(2,4-dichlorophenylamino)-5-methylpyridinecarboxamido)-2-methylpropionate methyl ester; 6-(3-chloro-phenyl)-pyridine-2-carboxylic acid (1-methyl-1-oxazol-2-yl-ethyl)-amide; 6-(3-chloro-phenyl)-pyridine-2-carboxylic acid piperidine-1-ylamide; 6-(3-chloro-phenyl)-pyridine-2-carboxylic acid (1-methyl-1-thiazolyl-2-yl-ethyl)-amide; 6-(3-chloro-phenyl)-pyridine-2-carboxylic acid (1-methyl-1-[1,3,4]oxadiazol-2-yl-ethyl)-amide; 6-(3-chloro-phenyl)-pyridine-2-carboxylic acid cyclohexylamide; 6-(3-chloro-phenyl)-pyridine-2-carboxylic acid phenylamide; 6-(3-chloro-phenyl)-pyridine-2-carboxylic acid pyridine-2-ylamide; 6-(3-chloro-phenyl)-pyridine-2-carboxylic acid (tetrahydro-pyran-4-yl)-amide; 6-(3-chloro-phenyl)-pyridine-2-carboxylic acid [1-methyl-1-(3-methyl-[1,2,4]thiadiazol-5-yl)-ethyl]-amide; 6-(3-chloro-phenyl)-pyridine-2-carboxylic acid (1-dimethylcarbamoyl-1-ethyl-propyl)-amide; 6-(3-chloro-phenyl)-pyridine-2-carboxylic acid (2-methyl-tetrahydro-pyran-4-yl)-amide; 6-(3-chloro-phenyl)-pyridine-2-carboxylic acid [1-methyl-1-(3-methyl-isoxazol-5-yl)-ethyl]-amide; 6-(3-chloro-phenyl)-pyridine-2-carboxylic acid (1-ethyl-1-hydroxymethyl-propyl)-amide; 6-(3-chloro-phenyl)-pyridine-2-carboxylic acid (tetrahydro-pyran-3-yl)-amide; 6-(3-chloro-phenyl)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide; 6-(3-chloro-phenyl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide; 6-(4-chloro-phenyl)-pyridine-2-carboxylic acid piperidine-1-ylamide; [6-(3-chloro-phenyl)-5-cyclopropyl-pyridin-2-yl]-(1,1-dioxtetrahydro-2H-thiaran-4-yl)-methyl ketone; 6-(3-chloro-phenyl)-5-methylpyridine-2-carboxylic acid (1-methyl-1-oxazol-2-yl-ethyl)-amide; 6-(3-chloro-phenyl)-5-methylpyridine-2-carboxylic acid (1-methyl-1-thiazolyl-2-yl-ethyl)-amide; 6-(3-chloro-phenyl)-5-methylpyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide; 6-(3-chloro-phenyl)-5-methyl-pyridine-2-carboxylic acid piperidine-1-ylamide; 6-(3-chloro-phenyl)-pyridine-2-carboxylic acid ((S)-3-methyl-1-thiazolyl-2-yl-butyl)-amide; 5-Chloro-6-(3-chloro-phenyl)pyridine-2-carboxylic acid (1-methyl-1-thiazolyl-2-yl-ethyl)-amide; 6-(3-chloro-phenyl)-pyridine-2-carboxylic acid ((S)-2-cyclopropyl-1-thiazolyl-2-yl-ethyl)-amide; 5-Chloro-6-(3-chloro-phenyl)-pyridine-2-carboxylic acid piperidine-1-ylamide; 6-(3-chloro-phenyl)-5-cyclopropylpyridine-2-carboxylic acid (1-methyl-1-methylcarbamoyl-ethyl)-amide; 6-(3-chloro-phenyl)-5-methylpyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide; 6-(3-chloro-phenyl)-5-cyclopropylpyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide; 6-(3-chloro-phenyl)-pyridine-2-carboxylic acid (1-methyl-1-[1,2,4]oxadiazol-3-yl-ethyl)-amide; 6-(4-chloro-phenyl)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide; 6-(3-chloro-phenyl)-5-methoxy-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide; 6-(3-chloro-phenyl)-5-methoxy-pyridine-2-carboxylic acid (1-methyl-1-thiazolyl-2-yl-ethyl)-amide; 5-Chloro-6-(3-chloro-phenyl)-pyridine-2-carboxylic acid (1-methyl-1-[1,2,4]oxadiazol-3-yl-ethyl)-amide; 6-(3-chloro-phenyl)-5-methoxy-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide; 6-(3-chloro-phenyl)-5-methoxy-pyridine-2-carboxylic acid (1-methyl-1-oxazol-2-yl-ethyl)-amide; 5-Chloro-6-(3-chloro-phenyl)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide; 6-(3-chloro-phenyl)-5-cyclopropylpyridine-2-carboxylic acid (1-methyl-1-oxazol-2-yl-ethyl)-amide; 6-(3-chloro-phenyl)-5-cyclopropylpyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide; 6-(3-chloro-phenyl)-5-cyclopropyl-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide; 6-(3-chloro-phenyl)-5-(tetrahydro-furan-3-yl)-pyridine-2-carboxylic acid (1-methyl-1-thiazolyl-2-yl-ethyl)-amide; 5-Chloro-6-(3-chloro-phenyl)-pyridine-2-carboxylic acid (1-methyl-1-oxazol-2-yl-ethyl)-amide; 5-Chloro-6-(3-chloro-phenyl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide; 6-(3-chloro-phenyl)-5-cyclopentylpyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide; 6-(3-chloro-phenyl)-5-cyclopropylpyridine-2-carboxylic acid (1-methyl-1-thiazolyl-2-yl-ethyl)-amide; 6-(3-chloro-phenyl)-5-(tetrahydro-furan-2-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide; 6-(3-chloro-phenyl)-5-(tetrahydro-furan-2-yl)-pyridine-2-carboxylic acid (1-methyl-1-oxazol-2-yl-ethyl)-amide; 6-(3-chloro-phenyl)-5-(tetrahydro-furan-2-yl)-pyridine-2-carboxylic acid (1-methyl-1-thiazolyl-2-yl-ethyl)-amide; 6-(3-chloro-phenyl)-5-cyclopentylpyridine-2-carboxylic acid (1-methyl-1-thiazolyl-2-yl-ethyl)-amide; 6-(3-chloro-phenyl)-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide; 6-(3-chloro-phenyl)-5-(tetrahydro-furan-3-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide; 6-(3-chloro-phenyl)-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridine-2-carboxylic acid [2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-amide; 6-(3-chloro-phenyl)-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridine-2-carboxylic acid (1-methyl-1-thiazolyl-2-yl-ethyl)-amide; 6-(3-chloro-phenyl)-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide; (S)-6-(3-chlorophenyl)-N-(3,3-dimethyl-1-(methylamino)-1-oxobut-2-yl)pyridinecarboxamide; (S)-6-(3-chlorophenyl)-N-(4,4-dimethyl-1-(methylamino)-1-oxopent-2-yl)pyridinecarboxamide; (S)-N-(3,3-dimethyl-1-(methylamino)-1-oxobut-2-yl)-6-phenylpyridinecarboxamide; (S)-N-(4-methyl-1-(methylamino)-1-oxopent-2-yl)-6-phenylpyridinecarboxamide; (S)-6-(3-fluorophenyl)-N-(4-methyl-1-(methylamino)-1-oxopent-2-yl)pyridinecarboxamide; (S)-6-(3-chloro-4-fluorophenyl)-N-(4-methyl-1-(methylamino)-1-oxopent-2-yl)pyridinecarboxamide; (S)-N-(3,3-dimethyl-1-(methylamino)-1-oxobut-2-yl)-6-(3-fluorophenyl)pyridinecarboxamide; (S)-N-(3,3-dimethyl-1-(methylamino)-1-oxobut-2-yl)-6-(3-methoxyphenyl)pyridinecarboxamide; (S)-6-(3-chloro-4-fluorophenyl)-N-(3,3-dimethyl-1-(methylamino)-1-oxobut-2-yl)pyridinecarboxamide; 6-(3-chloro-4-fluoro-phenyl)-pyridine-2-carboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide; 6-(3-chloro-4-fluoro-phenyl)-pyridine-2-carboxylic acid [(-)-cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide; 6-(3-chloro-4-fluoro-phenyl)-pyridine-2-carboxylic acid [(+)-cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide; 6-(4-chloro-3-fluoro-phenyl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide; 6-(3-chloro-4-fluoro-phenyl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide; 6-(3-chloro-4-fluoro-phenyl)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide; 6-(3-Fluoro-phenyl)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide. 2. The compound according to claim 1, wherein the compound is selected from: 6-(3-chloro-phenyl)-pyridine-2-carboxylic acid piperidine-1-ylamide; (S)-6-(3-chloro-4-fluorophenyl)-N-(3,3-dimethyl-1-(methylamino)-1-oxobut-2-yl)pyridinecarboxamide; 6-(3-chloro-4-fluoro-phenyl)-pyridine-2-carboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide; 6-(3-chloro-4-fluoro-phenyl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide; and 6-(3-chloro-4-fluoro-phenyl)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide. 3. The compound according to claim 1 or 2, which is used as a therapeutically active substance. 4. A pharmaceutical composition comprising a compound according to claim 1 or 2 and a therapeutically inert carrier. 5. Use of the compound according to claim 1 or 2 in the preparation of a medicament for the treatment or prevention of pain, atherosclerosis, bone regulation, inflammation, ischemia, reperfusion injury, systemic fibrosis, liver fibrosis, pulmonary fibrosis, renal fibrosis, chronic allogeneic transplant nephropathy, congestive heart failure, myocardial infarction, systemic sclerosis, glomerulonephropathy, thermal injury, burns, hypertrophic scars, keloids, gingivitis with fever, cirrhosis, or tumors. 6. The compound according to claim 1 or 2, for the treatment or prevention of pain, atherosclerosis, bone regulation, inflammation, ischemia, reperfusion injury, systemic fibrosis, liver fibrosis, pulmonary fibrosis, renal fibrosis, chronic allogeneic transplant nephropathy, congestive heart failure, myocardial infarction, systemic sclerosis, glomerulonephropathy, thermal injury, burns, hypertrophic scars, keloids, gingivitis with fever, cirrhosis, or tumors.