HK1208033B - Pyridine-2-amides useful as cb2 agonists - Google Patents

Description

Pyridine-2-amides as CB2 agonists

The present invention relates to organic compounds useful for treatment and/or prevention in mammals and in particular to compounds which are preferential agonists of the Cannabinoid Receptor 2.

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

in

^R1 is cycloalkylalkoxy, halophenyl, tetrahydrofuranylalkoxy, halophenylalkyl, haloalkyloxy, alkylsulfonyl, tetrahydropyranylalkoxy or halogen;

^R2 is alkyl, pyrrolidinyl, cycloalkyl, haloazetidinyl, haloalkyl, cycloalkylalkoxy, haloalkyloxy, halocycloalkyl, hydroxycycloalkyl or halooxetanyl;

one of ^R and ^R is alkyl, cycloalkyl, haloalkyl or hydroxyalkyl and the other is alkyl, alkyloxyalkyl, (haloazetidinyl)(cycloalkyloxy)pyridinylcarbonyloxyalkyl, haloalkylcycloalkyl, hydroxyalkyl, phenylalkyl, alkoxycarbonylalkyl, carboxyalkyl, alkylaminocarbonylalkyl, (alkyloxadiazolyl)(cycloalkylalkyl)alkyl, (alkyloxadiazolyl)(cycloalkyl)alkyl, pyridazinylalkyl, aminocarbonylalkyl, alkyloxadiazolylalkyl, alkyltetrazolylalkyl, formyl, phenyl, dialkylpyrazolyl, alkylcarbonylpiperidinyl or cycloalkylalkyl;

Alternatively, R ³ and R ⁴ together with the nitrogen atom to which they are attached form a heterocyclic group or a substituted heterocyclic group;

wherein heterocyclyl is 6-oxa-1-aza-spiro[3.3]heptyl, oxazolidinyl, morpholinyl, pyrrolidinyl, piperazinyl, 2-oxa-5-aza-spiro[3.4]octyl, piperidinyl, 6-aza-bicyclo[3.2.1.]octyl, imidazolidinyl, 4-aza-spiro[2.4]heptyl, 2-aza-bicyclo[2.2.1]heptyl, 2-thia-5-aza-bicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-oxa-5-aza-bicyclo[2.2.1]heptyl, hexahydro-furo[2,3-c]pyrrolyl, 2-thia-6-aza-spiro[3. 3]heptyl, 1,8-diaza-spiro[4.5]decyl, 1-oxa-7-aza-spiro[4.4]nonyl, 5-oxa-2-aza-spiro[3.4]octyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 3-oxa-8-aza-bicyclo[3.2.1]octyl, thiomorpholinyl, thiazolidinyl, 5-aza-spiro[3.4]octyl, azetidinyl, 5-aza-spiro[2.4]heptyl, 3-aza-bicyclo[3.1.0]hexyl or 5-aza-spiro[2.4]heptyl, 1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrolyl; and

wherein the substituted heterocyclyl is a heterocyclyl substituted with one to four substituents independently selected from the group consisting of alkyl, oxo, hydroxy, carboxyl, alkylcarbonylamino, alkyloxyalkyl, hydroxyalkyl, aminocarbonyl, halogen, phenylalkyl, phenyl, alkoxycarbonyl, cycloalkylalkyl, phenylalkoxycarbonyl, cycloalkyl, halohydroxyalkyl, and haloalkyl;

provided that R ³ and R ⁴ together with the carbon atom to which they are attached do not form an unsubstituted piperidinyl, an unsubstituted thiomorpholinyl or a hydroxyalkylpyrrolidinyl;

or a pharmaceutically acceptable salt or ester thereof.

The compounds of formula (I) are particularly useful for treating or preventing, for example, pain, atherosclerosis, age-related macular degeneration, diabetic retinopathy, glaucoma, retinal vein occlusion, retinopathy of prematurity, ocular ischemic syndrome, geographic atrophy, diabetes mellitus, inflammation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver failure, liver fibrosis, lung fibrosis, kidney fibrosis, systemic fibrosis, acute allograft rejection, and the like. rejection, chronic allograft nephropathy, diabetic nephropathy, glomerulonephropathy, cardiomyopathy, heart failure, myocardial ischemia, myocardial infarction, systemic sclerosis, thermal injury, burns, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumor, regulation of bone mass, neurodegeneration, amyotrophic lateral sclerosis, stroke, transient ischemic attack, or uveitis.

The compounds of formula (I) are particularly useful for treating or preventing diabetic retinopathy, retinal vein occlusion or uveitis.

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 PharmDes 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, 12(1), 139-140), and inflammatory bowel disease (Bab et al., Br J Pharmacol 2008, 12(2), 149-25). 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 has produced a condition in which restoration of circulation leads to further tissue damage. The cause of damage due to reperfusion injury is partly due to the inflammatory response of the damaged tissue. Leukocytes transported to the region by newly refluxed 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, 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 particularly 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 particularly methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl and isopentyl. Specific examples of alkyl groups are methyl, ethyl, isopropyl and tert-butyl, in particular methyl and tert-butyl.

The term "cycloalkyl", alone or in combination, 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 examples of "cycloalkyl" are cyclopropyl and cyclobutyl. A particular example of "cycloalkyl" is cyclopropyl.

The term "alkoxy", alone or in combination, 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, particular "alkoxy" being methoxy and tert-butoxy, and especially methoxy.

The term "oxy", alone or in combination, signifies an -O- group.

The term "oxa", alone or in combination, signifies an endocyclic -O- group.

The term "oxo", alone or in combination, signifies a =0 group.

The term "halogen" or "halo", alone or in combination, 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 one to four halogens (i.e. one, two, three or four halogens). Particular "halogen" is fluorine.

The term "haloalkyl", alone or in combination, denotes an alkyl group substituted by at least one halogen, particularly an alkyl group substituted by one to five halogens, especially one to three halogens. Particular "haloalkyl" is trifluoromethyl.

The term "haloalkoxy" or "haloalkyloxy", alone or in combination, means an alkoxy group substituted by at least one halogen, in particular an alkoxy group substituted by one to five halogens, in particular one to three halogens. Particular "haloalkoxy" groups are pentafluoropropoxy and trifluoropropoxy, fluoroethoxy, fluoropropoxy, difluoroethyloxy and difluoropropoxy. Particular "haloalkoxy" groups are pentafluoropropoxy and trifluoropropoxy.

The terms "hydroxyl" and "hydroxy", alone or in combination, mean an -OH group.

The term "carbonyl", alone or in combination, signifies a -C(O)- group.

The term "amino", alone or in combination, means a primary amino group (-NH ₂ ), a secondary amino group (-NH-), or a tertiary amino group (-N-).

The term "aminocarbonyl", alone or in combination, signifies a -C(O) _-NH2 group.

The term "sulfonyl", alone or in combination, signifies a -S(O) ₂ - 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.

"Pharmaceutically acceptable esters" means that the compounds of formula (I) can be derivatized at functional groups to provide derivatives that are capable of conversion back to the parent compound in vivo. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives, such as methoxymethyl ester, methylthiomethyl ester, and pivaloylmethyl ester. In addition, any physiologically acceptable equivalents of the compounds of formula (I), similar to the metabolically labile esters, which are capable of generating the parent compound of formula (I) in vivo, are within the scope of this invention.

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, 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.Wuts 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:

^R2 is alkyl, pyrrolidinyl, cycloalkyl, haloazetidinyl, haloalkyl, cycloalkylalkoxy or haloalkyloxy;

one of ^R and ^R is alkyl, cycloalkyl, haloalkyl or hydroxyalkyl and the other is alkyl, alkyloxyalkyl, (haloazetidinyl)(cycloalkyloxy)pyridinylcarbonyloxyalkyl, haloalkylcycloalkyl, hydroxyalkyl, phenylalkyl, alkoxycarbonylalkyl, carboxyalkyl, alkylaminocarbonylalkyl, (alkyloxadiazolyl)(cycloalkylalkyl)alkyl, (alkyloxadiazolyl)(cycloalkyl)alkyl, pyridazinylalkyl, aminocarbonylalkyl, alkyloxadiazolylalkyl, alkyltetrazolylalkyl, formyl, phenyl, dialkylpyrazolyl, alkylcarbonylpiperidinyl or cycloalkylalkyl;

Alternatively, R ³ and R ⁴ together with the nitrogen atom to which they are attached form a heterocyclic group or a substituted heterocyclic group;

wherein heterocyclyl is 6-oxa-1-aza-spiro[3.3]heptyl, oxazolidinyl, morpholinyl, pyrrolidinyl, piperazinyl, 2-oxa-5-aza-spiro[3.4]octyl, piperidinyl, 6-aza-bicyclo[3.2.1.]octyl, imidazolidinyl, 4-aza-spiro[2.4]heptyl, 2-aza-bicyclo[2.2.1]heptyl, 2-thia-5-aza-bicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-oxa-5-aza-bicyclo[2.2.1]heptyl, hexahydro-furo[2, 3-c] pyrrolyl, 2-thia-6-aza-spiro[3.3]heptyl, 1,8-diaza-spiro[4.5]decyl, 1-oxa-7-aza-spiro[4.4]nonyl, 5-oxa-2-aza-spiro[3.4]octyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 3-oxa-8-aza-bicyclo[3.2.1]octyl, thiomorpholinyl, thiazolidinyl, 5-aza-spiro[3.4]octyl, azetidinyl, 5-aza-spiro[2.4]heptyl or 3-aza-bicyclo[3.1.0]hexyl; and

wherein the substituted heterocyclyl is a heterocyclyl substituted with one to four substituents independently selected from the group consisting of alkyl, oxo, hydroxy, carboxyl, alkylcarbonylamino, alkyloxyalkyl, hydroxyalkyl, aminocarbonyl, halogen, phenylalkyl, phenyl, alkoxycarbonyl, cycloalkylalkyl, and phenylalkoxycarbonyl.

The present invention also particularly relates to:

A compound of formula (I), wherein R ¹ is cycloalkylalkoxy, tetrahydrofuranylalkoxy, alkylsulfonyl or halophenylalkyl;

A compound of formula (I), wherein R ¹ is cyclopropylmethoxy, tetrahydrofurylmethoxy, isobutylsulfonyl or fluorophenylmethyl;

A compound of formula (I), wherein R ² is a haloazetidinyl, cycloalkyl or halocycloalkyl group;

A compound of formula (I), wherein R ² is difluoroazetidinyl, cyclopropyl or fluorocyclobutyl;

A compound of formula (I), wherein R ² is a haloazetidinyl or cycloalkyl group;

A compound of formula (I), wherein R ² is difluoroazetidinyl or cyclopropyl;

A compound of formula (I) wherein one of R ³ and R ⁴ is alkyl and the other is alkyl or haloalkylcycloalkyl;

A compound of formula (I) wherein one of R ³ and R ⁴ is methyl and the other is tert-butyl or trifluoromethylcyclopropyl;

a compound of formula (I) wherein R and ^R together with the nitrogen atom to which they are attached form a heterocyclyl or substituted heterocyclyl, wherein heterocyclyl is oxazolidinyl, morpholinyl, pyrrolidinyl, 6-aza-bicyclo[3.2.1.]octyl, ⁴ -aza-spiro[2.4]heptyl, 2-thia-5-aza-bicyclo[2.2.1]heptyl, 5-aza-spiro[3.4]octyl, 5-aza-spiro[2.4]heptyl, 1,8-diaza-spiro[4.5]decyl, thiazolidinyl or 5-aza-spiro[2.4]heptyl, and wherein substituted heterocyclyl is heterocyclyl substituted with one to three substituents independently selected from the group consisting of alkyl, hydroxyalkyl, halogen, aminocarbonyl, alkoxycarbonyl, oxo or hydroxy;

a compound of formula (I) wherein R and ^R together with the nitrogen atom to which they are attached form a heterocyclyl or substituted heterocyclyl, wherein heterocyclyl is oxazolidinyl, morpholinyl, pyrrolidinyl, 6-aza-bicyclo[3.2.1.]octyl, ⁴ -aza-spiro[2.4]heptyl, 2-thia-5-aza-bicyclo[2.2.1]heptyl, 5-aza-spiro[3.4]octyl, 5-aza-spiro[2.4]heptyl, 1,8-diaza-spiro[4.5]decyl, thiazolidinyl or 5-aza-spiro[2.4]heptyl, and wherein substituted heterocyclyl is substituted with one to three substituents independently selected from the group consisting of methyl, hydroxymethyl, fluoro, aminocarbonyl, tert-butoxycarbonyl, oxo or hydroxy;

A compound of formula (I) wherein R ³ and R ⁴ together with the nitrogen atom to which they are attached form dimethyloxazolidinyl, dimethylmorpholinyl, dimethylpyrrolidinyl, trimethyl-6-aza-bicyclo[3.2.1.]octyl, (hydroxymethyl)(difluoro)pyrrolidinyl, 4-aza-spiro[2.4]heptyl, (aminocarbonyl)(difluoro)pyrrolidinyl, 2-thia-5-aza-bicyclo[2.2.1]heptyl, (aminocarbonyl)(dimethyl)pyrrolidinyl, 5-aza-spiro [3.4]octyl, difluoro-5-aza-spiro[2.4]heptyl, 5-aza-spiro[2.4]heptyl, tert-butoxycarbonyl-1,8-diaza-spiro[4.5]decyl, aminocarbonyl-1,1-dioxo-1λ6-thiazolidinyl, aminocarbonyl-1,1-dioxo-1,3-thiazolidinyl, (aminocarbonyl)(methyl)(hydroxy)pyrrolidinyl or (aminocarbonyl)-5-aza-spiro[2.4]heptyl;

a compound of formula (I) wherein R and ^R together with the nitrogen atom to which they are attached form a heterocyclyl or substituted heterocyclyl, wherein heterocyclyl is oxazolidinyl, morpholinyl, pyrrolidinyl, 6-aza-bicyclo[3.2.1.]octyl, ⁴ -aza-spiro[2.4]heptyl, 2-thia-5-aza-bicyclo[2.2.1]heptyl, 5-aza-spiro[3.4]octyl, 5-aza-spiro[2.4]heptyl, 1,8-diaza-spiro[4.5]decyl or thiazolidinyl, and wherein substituted heterocyclyl is heterocyclyl substituted with one to three substituents independently selected from the group consisting of alkyl, hydroxyalkyl, halogen, aminocarbonyl, alkoxycarbonyl and oxo;

a compound of formula (I) wherein R and ^R together with the nitrogen atom to which they are attached form a heterocyclyl or substituted heterocyclyl, wherein heterocyclyl is oxazolidinyl, morpholinyl, pyrrolidinyl, 6-aza-bicyclo[3.2.1.]octyl, ⁴ -aza-spiro[2.4]heptyl, 2-thia-5-aza-bicyclo[2.2.1]heptyl, 5-aza-spiro[3.4]octyl, 5-aza-spiro[2.4]heptyl, 1,8-diaza-spiro[4.5]decyl or thiazolidinyl, and wherein substituted heterocyclyl is heterocyclyl substituted with one to three substituents independently selected from the group consisting of methyl, hydroxymethyl, fluoro, aminocarbonyl, tert-butoxycarbonyl and oxo;

A compound of formula (I) wherein R and ^R together with the nitrogen atom to which they are attached form dimethyloxazolidinyl, dimethylmorpholinyl, dimethylpyrrolidinyl, trimethyl-6-aza-bicyclo[3.2.1.]octyl, (hydroxymethyl)(difluoro)pyrrolidinyl, ⁴ -aza-spiro[2.4]heptyl, (aminocarbonyl)(difluoro)pyrrolidinyl, 2-thia-5-aza-bicyclo[2.2.1]heptyl, (aminocarbonyl)(dimethyl)pyrrolidinyl, 5-aza-spiro[3.4]octyl, difluoro-5-aza-spiro[2.4]heptyl, 5-aza-spiro[2.4]heptyl, tert-butoxycarbonyl-1,8-diaza-spiro[4.5]decyl or aminocarbonyl-1,1-dioxo-1λ ⁶ -thiazolidinyl;

A compound of formula (I) wherein ^R3 and ^R4 together with the nitrogen atom to which they are attached form 6-oxa-1-aza-spiro[3.3]heptyl, dialkyloxazolidinyl, dialkylmorpholinyl, dialkylpyrrolidinyl, (dialkyl)(oxo)piperazinyl, (hydroxy)(alkyl)pyrrolidinyl, 2-oxa-5-aza-spiro[3.4]octyl, alkylcarbonylaminopyrrolidinyl, dialkylpiperidinyl, trialkyl-6-aza-bicyclo[3.2.1.]octyl, alkyloxyalkylpyrrolidinyl, (halo)(hydroxyalkyl)pyrrolidinyl, (dialkyl)(oxo)imidazolyl, 4-aza-spiro[2.4]heptyl, ( dialkyl)(oxo)pyrrolidinyl-piperidinyl, 2-aza-bicyclo[2.2.1]heptyl, (aminocarbonyl)(halo)pyrrolidinyl, (hydroxy)(alkyl)piperidinyl, 2-thia-5-aza-bicyclo[2.2.1]heptyl, phenylalkyl-2,5-diazabicyclo[2.2.1]heptyl, (phenyl)(alkyl)piperidinyl, 2-oxa-5-aza-bicyclo[2.2.1]heptyl, (hydroxy)(dialkyl)piperidinyl, (alkoxycarbonyl)(phenyl)piperidinyl, hexahydro-furo[2,3-c]pyrrolyl, 2,2-dioxo-2λ ⁶ -thia-6-aza-spiro[3.3]heptyl, (alkoxycarbonyl)-1,8-diaza-spiro[4.5]decyl, (aminocarbonyl)(dialkyl)pyrrolidinyl, (aminocarbonyl)(hydroxy)pyrrolidinyl, hydroxy-1-oxa-7-aza-spiro[4.4]nonyl, hydroxy-5-oxa-2-aza-spiro[3.4]octyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 3-oxa-8-aza-bicyclo[3.2.1]octyl, aminocarbonylpiperidinyl, aminocarbonylthiomorpholinyl, aminocarbonylthiazolidinyl, 5-oxa- 2-aza-spiro[3.4]octyl, 1-oxa-7-aza-spiro[4.4]nonyl, 5-aza-spiro[3.4]octyl, haloazetidinyl, halo-5-aza-spiro[2.4]heptyl, 5-aza-spiro[2.4]heptyl, cycloalkylalkylpiperazinyl, alkoxycarbonyl-3-aza-bicyclo[3.1.0]hexyl, phenylalkoxycarbonylpiperazinyl, carboxy-3-aza-bicyclo[3.1.0]hexyl, 1,8-diaza-spiro[4.5]decyl, aminocarbonylpyrrolidinyl, aminocarbonyl-1,1-dioxo-1λ ⁶ -thiazolidinyl, aminocarbonyl-1-oxo-1λ ^- thiazolidinyl, tetrafluoropyrrolidinyl, (dialkyl)(aminocarbonyl)thiazolidinyl, (aminocarbonyl)(halo)pyrrolidinyl, (aminocarbonyl)-1-oxo-1,3-thiazolidinyl, (aminocarbonyl)-1,1-dioxo-1,3-thiazolidinyl, (aminocarbonyl)(hydroxy)(alkyl)pyrrolidinyl, (aminocarbonyl)-5-aza-spiro[2.4]heptyl, (hydroxyhaloalkyl)pyrrolidinyl, (haloalkyl)(hydroxyalkyl)pyrrolidinyl, (haloalkyl)(hydroxy)pyrrolidinyl, (haloalkyl)(hydroxy)azetidinyl, 1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrolyl, (halo)(hydroxyalkyl)azetidinyl or (halo)(alkyl)azetidinyl; and

A compound of formula (I) wherein ^R3 and ^R4 together with the nitrogen atom to which they are attached form 6-oxa-1-aza-spiro[3.3]heptyl, dialkyloxazolidinyl, dialkylmorpholinyl, dialkylpyrrolidinyl, (dialkyl)(oxo)piperazinyl, (hydroxy)(alkyl)pyrrolidinyl, 2-oxa-5-aza-spiro[3.4]octyl, alkylcarbonylaminopyrrolidinyl, dialkylpiperidinyl, trialkyl-6-aza-bicyclo[3.2.1.]octyl, alkyloxyalkylpyrrolidinyl, (halo)(hydroxyalkyl)pyrrolidinyl, (dialkyl)(oxo)imidazolyl, 4-aza-spiro[2.4]heptyl, ( dialkyl)(oxo)pyrrolidinyl-piperidinyl, 2-aza-bicyclo[2.2.1]heptyl, (aminocarbonyl)(halo)pyrrolidinyl, (hydroxy)(alkyl)piperidinyl, 2-thia-5-aza-bicyclo[2.2.1]heptyl, phenylalkyl-2,5-diazabicyclo[2.2.1]heptyl, (phenyl)(alkyl)piperidinyl, 2-oxa-5-aza-bicyclo[2.2.1]heptyl, (hydroxy)(dialkyl)piperidinyl, (alkoxycarbonyl)(phenyl)piperidinyl, hexahydro-furo[2,3-c]pyrrolyl, 2,2-dioxo-2λ ⁶ -thia-6-aza-spiro[3.3]heptyl, (alkoxycarbonyl)-1,8-diaza-spiro[4.5]decyl, (aminocarbonyl)(dialkyl)pyrrolidinyl, (aminocarbonyl)(hydroxy)pyrrolidinyl, hydroxy-1-oxa-7-aza-spiro[4.4]nonyl, hydroxy-5-oxa-2-aza-spiro[3.4]octyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 3-oxa-8-aza-bicyclo[3.2.1]octyl, aminocarbonylpiperidinyl, aminocarbonylthiomorpholinyl, aminocarbonylthiazolidinyl, 5-oxa- ]octyl, 1-oxa-7-aza-spiro[4.4]nonyl, 5-aza-spiro[3.4]octyl, haloazetidinyl, halo-5-aza-spiro[2.4]heptyl, 5-aza-spiro[2.4]heptyl, cycloalkylalkylpiperazinyl, alkoxycarbonyl-3-aza-bicyclo[3.1.0]hexyl, phenylalkoxycarbonylpiperazinyl, carboxy-3-aza-bicyclo[3.1.0]hexyl, 1,8-diaza-spiro[4.5]decyl, aminocarbonylpyrrolidinyl, aminocarbonyl-1,1-dioxo-1λ ⁶ -thiazolidinyl, aminocarbonyl-1-oxo-1λ ⁴ -thiazolidinyl, tetrafluoropyrrolidinyl or (dialkyl)(aminocarbonyl)thiazolidinyl.

The present invention also relates to compounds selected from the group consisting of:

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

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

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid tert-butyl-methyl-amide;

5-Cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid tert-butyl-methyl-amide;

5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid tert-butyl-methyl-amide;

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

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

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

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

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-methanone;

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-methanone;

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

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

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(4,4-dimethyl-oxazolidin-3-yl)-methanone;

6-(Tetrahydro-furan-2-ylmethoxy)-5-trifluoromethyl-pyridine-2-carboxylic acid tert-butyl-methyl-amide;

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

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(3,3-dimethyl-morpholin-4-yl)-methanone;

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

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

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid tert-butyl-(2-methoxy-ethyl)-amide;

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

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

{tert-Butyl-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-amino}-acetic acid ethyl ester;

{tert-Butyl-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-amino}-acetic acid;

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

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

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

4-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-3,3-dimethyl-piperazin-2-one;

4-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-3,3-diethyl-piperazin-2-one;

[5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridin-2-yl]-(2,2-dimethyl-pyrrolidin-1-yl)-methanone;

[5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridin-2-yl]-(4,4-dimethyl-oxazolidin-3-yl)-methanone;

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]-methyl-amide;

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

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

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

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

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

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(2-oxa-5-aza-spiro[3.4]octan-5-yl)-methanone;

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

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

N-{1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-pyrrolidin-3-yl}-acetamide;

[5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridin-2-yl]-(4,4-dimethyl-piperidin-1-yl)-methanone;

[5-Cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridin-2-yl]-(4,4-dimethyl-piperidin-1-yl)-methanone;

[5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridin-2-yl]-(4,4-dimethyl-oxazolidin-3-yl)-methanone;

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-((1S,5R)-1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octan-6-yl)-methanone;

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

(6-Chloro-5-cyclopropylmethoxy-pyridin-2-yl)-(2,2-dimethyl-pyrrolidin-1-yl)-methanone;

(6-Cyclopropylmethoxy-5-trifluoromethoxy-pyridin-2-yl)-(4,4-dimethyl-oxazolidin-3-yl)-methanone;

(6-Chloro-5-cyclopropylmethoxy-pyridin-2-yl)-(4,4-dimethyl-oxazolidin-3-yl)-methanone;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1-acetyl-piperidin-4-yl)-cyclopropyl-amide;

6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-N-formyl-N-methylpyridine-2-carboxamide;

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

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-((S)-4,4-difluoro-2-hydroxymethyl-pyrrolidin-1-yl)-methanone;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1,4-dimethyl-1H-pyrazol-3-yl)-methyl-amide;

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(2,2-dimethyl-morpholin-4-yl)-methanone;

(R)-2-tert-Butyl-1-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-3-methyl-imidazolidin-4-one;

(4-Aza-spiro[2.4]hept-4-yl)-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-methanone;

3-{1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-piperidin-4-yl}-5,5-dimethyl-pyrrolidin-2-one;

(1S,4R)-2-Aza-bicyclo[2.2.1]hept-2-yl-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-methanone;

(S)-1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-4,4-difluoro-pyrrolidine-2-carboxylic acid amide;

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(4-hydroxy-4-methyl-piperidin-1-yl)-methanone;

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(1S,4S)-2-thia-5-aza-bicyclo[2.2.1]hept-5-yl-methanone;

((1S,4S)-5-Benzyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-methanone;

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(2-methyl-3-phenyl-piperidin-1-yl)-methanone;

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-methanone;

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(4-hydroxy-2,2-dimethyl-piperidin-1-yl)-methanone;

1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-2-phenyl-piperidine-3-carboxylic acid ethyl ester;

(S)-1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-4,4-difluoro-pyrrolidine-2-carboxylic acid amide;

(2S,4S)-1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-4-fluoro-pyrrolidine-2-carboxylic acid amide;

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(hexahydro-furo[2,3-c]pyrrol-5-yl)-methanone;

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(2,2-dioxo-2λ6-thia-6-aza-spiro[3.3]hept-6-yl)-methanone;

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

(S)-1-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-pyrrolidine-2-carboxylic acid amide;

1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-1,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester;

(S)-1-{5-Cyclopropyl-6-[(R,S)-1-(tetrahydro-furan-2-yl)methoxy]-pyridine-2-carbonyl}-4,4-difluoro-pyrrolidine-2-carboxylic acid amide;

(S)-1-[5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carbonyl]-4,4-difluoro-pyrrolidine-2-carboxylic acid amide;

(+)-1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-4,4-dimethyl-pyrrolidine-2-carboxylic acid amide;

(-)-1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-4,4-dimethyl-pyrrolidine-2-carboxylic acid amide;

(2S,4S)-1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-4-hydroxy-pyrrolidine-2-carboxylic acid amide;

(2S,4S)-1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-4-fluoro-pyrrolidine-2-carboxylic acid amide;

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

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(3-hydroxy-1-oxa-7-aza-spiro[4.4]nonan-7-yl)-methanone;

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(7-hydroxy-5-oxa-2-aza-spiro[3.4]octan-2-yl)-methanone;

[5-Cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridin-2-yl]-(2,2-dimethyl-pyrrolidin-1-yl)-methanone;

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(1S,5R)-8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl-methanone;

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(1R,5S)-3-oxa-8-aza-bicyclo[3.2.1]octan-8-yl-methanone;

(R)-1-[5-Cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carbonyl]-4,4-difluoro-pyrrolidine-2-carboxylic acid amide;

1-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-piperidine-2-carboxylic acid amide;

4-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-thiomorpholine-3-carboxylic acid amide;

1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-4,4-dimethyl-pyrrolidine-2-carboxylic acid amide;

(+)-1-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-piperidine-2-carboxylic acid amide;

(-)-1-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-piperidine-2-carboxylic acid amide;

(-)-4-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-thiomorpholine-3-carboxylic acid amide;

(+)-1-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-4,4-dimethyl-pyrrolidine-2-carboxylic acid amide;

(-)-1-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-4,4-dimethyl-pyrrolidine-2-carboxylic acid amide;

3-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-thiazolidine-4-carboxylic acid amide;

(-)-3-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-thiazolidine-4-carboxylic acid amide;

1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-4,4-dimethyl-pyrrolidine-2-carboxylic acid amide;

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(5-oxa-2-aza-spiro[3.4]octan-2-yl)-methanone;

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(1-oxa-7-aza-spiro[4.4]nonan-7-yl)-methanone;

(5-Aza-spiro[3.4]octan-5-yl)-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-methanone;

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

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(1,1-difluoro-5-aza-spiro[2.4]hept-5-yl)-methanone;

(5-Aza-spiro[2.4]hept-5-yl)-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-methanone;

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

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(4-cyclopropylmethyl-piperazin-1-yl)-methanone;

3-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-3-aza-bicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester;

1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-pyrrolidine-2-carboxylic acid methyl ester;

4-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-piperazine-1-carboxylic acid benzyl ester;

3-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-3-aza-bicyclo[3.1.0]hexane-6-carboxylic acid;

1-[5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carbonyl]-1,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester;

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

[5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridin-2-yl]-(1,8-diaza-spiro[4.5]dec-1-yl)-methanone;

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

(-)-3-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-1,1-dioxo-1λ6-thiazolidine-4-carboxylic acid amide;

(1S,4R)-3-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-1-oxo-1λ4-thiazolidine-4-carboxylic acid amide;

(1R,4S)-3-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-1-oxo-1λ4-thiazolidine-4-carboxylic acid amide;

(+)-3-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-1,1-dioxo-1λ6-thiazolidine-4-carboxylic acid amide;

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(3,3,4,4-tetrafluoro-pyrrolidin-1-yl)-methanone;

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(2,6-dimethyl-morpholin-4-yl)-methanone;

(R)-3-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-5,5-dimethyl-thiazolidine-4-carboxylic acid amide;

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

3-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-thiazolidine-4-carboxylic acid amide.

The present invention also particularly relates to compounds selected from the group consisting of:

(2S,4R)-1-[5-cyclopropyl-6-(cyclopropylmethoxy)pyridine-2-carbonyl]-4-fluoropyrrolidine-2-carboxamide;

3-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-1-oxo-1,3-thiazolidine-4-carboxamide;

3-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidine-4-carboxamide;

(2S,4R)-1-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-4-fluoropyrrolidine-2-carboxamide;

(-)-3-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidine-4-carboxamide;

3-[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidine-4-carboxamide;

(2S)-1-[6-(cyclopropylmethoxy)-5-(1-hydroxycyclobutyl)pyridine-2-carbonyl]-4,4-difluoropyrrolidine-2-carboxamide;

(2S)-1-[6-(cyclopropylmethoxy)-5-(1-fluorocyclobutyl)pyridine-2-carbonyl]-4,4-difluoropyrrolidine-2-carboxamide;

3-[6-(cyclopropylmethoxy)-5-(1-hydroxycyclobutyl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidine-4-carboxamide;

(2S)-1-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-4-hydroxy-4-methylpyrrolidine-2-carboxamide;

3-[6-(cyclopropylmethoxy)-5-(1-fluorocyclobutyl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidine-4-carboxamide;

(2S)-1-[6-(cyclopropylmethoxy)-5-(3-fluorooxetan-3-yl)pyridine-2-carbonyl]-4,4-difluoropyrrolidine-2-carboxamide;

5-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-5-azaspiro[2.4]heptane-6-carboxamide;

[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]-[3-(2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl]methanone;

[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]-[3-(hydroxymethyl)-3-(trifluoromethyl)pyrrolidin-1-yl]methanone;

[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]-[3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl]methanone;

[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone;

(+)-(2S)-1-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-4-hydroxy-4-methylpyrrolidine-2-carboxamide;

[5-Cyclopropyl-6-(cyclopropylmethoxy)pyridin-2-yl]-[3-(2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl]methanone;

[5-Cyclopropyl-6-(cyclopropylmethoxy)pyridin-2-yl]-[3-(hydroxymethyl)-3-(trifluoromethyl)pyrrolidin-1-yl]methanone;

[5-Cyclopropyl-6-(cyclopropylmethoxy)pyridin-2-yl]-[3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl]methanone;

[5-cyclopropyl-6-(cyclopropylmethoxy)pyridin-2-yl]-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone;

(6S)-5-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-5-azaspiro[2.4]heptane-6-carboxamide;

[(3aR,6aS)-1,3,3a,4,6,6a-Hexahydrofuro[3,4-c]pyrrol-5-yl]-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]methanone;

(2S)-1-[5-(3,3-Difluoroazetidin-1-yl)-6-(2-fluoroethoxy)pyridine-2-carbonyl]-4,4-difluoro-pyrrolidine-2-carboxamide;

[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-2-pyridyl]-[3-fluoro-3-(hydroxymethyl)azetidin-1-yl]methanone;

[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-2-pyridyl]-(3-fluoro-3-methyl-azetidin-1-yl)methanone;

(3-Cyclopropyl-3-fluoroazetidin-1-yl)-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]methanone;

(-)-5-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-5-azaspiro[2.4]heptane-4-carboxamide; and

(+)-5-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-5-azaspiro[2.4]heptane-4-carboxamide.

The present invention also particularly relates to compounds selected from the group consisting of:

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

5-Cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid tert-butyl-methyl-amide;

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(4,4-dimethyl-oxazolidin-3-yl)-methanone;

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

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(3,3-dimethyl-morpholin-4-yl)-methanone;

[5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridin-2-yl]-(2,2-dimethyl-pyrrolidin-1-yl)-methanone;

[5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridin-2-yl]-(4,4-dimethyl-oxazolidin-3-yl)-methanone;

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-((1S,5R)-1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octan-6-yl)-methanone;

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-((S)-4,4-difluoro-2-hydroxymethyl-pyrrolidin-1-yl)-methanone;

(4-Aza-spiro[2.4]hept-4-yl)-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-methanone;

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(1S,4S)-2-thia-5-aza-bicyclo[2.2.1]hept-5-yl-methanone;

(S)-1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-4,4-difluoro-pyrrolidine-2-carboxylic acid amide;

(-)-1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-4,4-dimethyl-pyrrolidine-2-carboxylic acid amide;

(5-Aza-spiro[3.4]octan-5-yl)-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-methanone;

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(1,1-difluoro-5-aza-spiro[2.4]hept-5-yl)-methanone;

(5-Aza-spiro[2.4]hept-5-yl)-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-methanone;

1-[5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carbonyl]-1,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester; and

(-)-3-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-1,1-dioxo-1λ6-thiazolidine-4-carboxylic acid amide.

The present invention also particularly relates to compounds selected from the group consisting of:

3-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidine-4-carboxamide;

(-)-3-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidine-4-carboxamide;

(2S)-1-[6-(cyclopropylmethoxy)-5-(1-hydroxycyclobutyl)pyridine-2-carbonyl]-4,4-difluoropyrrolidine-2-carboxamide;

(2S)-1-[6-(cyclopropylmethoxy)-5-(1-fluorocyclobutyl)pyridine-2-carbonyl]-4,4-difluoropyrrolidine-2-carboxamide;

(2S)-1-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-4-hydroxy-4-methylpyrrolidine-2-carboxamide;

3-[6-(cyclopropylmethoxy)-5-(1-fluorocyclobutyl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidine-4-carboxamide; and

5-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-5-azaspiro[2.4]heptane-6-carboxamide.

(S)-1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-4,4-difluoro-pyrrolidine-2-carboxylic acid amide is a particular compound of formula (I).

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.

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 5 or as described in the experimental section.

Compounds AC can be prepared from AA by coupling an appropriately substituted aryl, heteroaryl or alkenyl metal species of formula AB (M is, for example, boronic acid B(OH) 2 or boronic acid pinacol ester) (step a), in particular an aryl boronic acid or aryl boronic ester, in the presence of a suitable catalyst, in particular a palladium catalyst and more particularly a palladium(II) acetate/triphenylphosphine mixture or 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 ¹ residues can be converted to the corresponding alkyl analogs AC using conditions described in the literature, such as, for example, 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.

Esters of general formula AC (R'≠H) are saponified by methods 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 the amine 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 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 (M is, for example, boronic acid B(OH) 2 or boronic acid pinacol ester) in the presence of a suitable catalyst, in particular a palladium catalyst and more in particular a palladium(II) acetate/triphenylphosphine mixture or 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 (step a′), in particular an arylboronic acid or an arylboronic acid ester. Optionally, the alkenyl-containing R ¹ 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.

If one of ^R and ^R in the amide AE or I is equal to hydrogen, alkylation towards the corresponding tertiary amide AE or I can be accomplished, for example, by converting the secondary amide AE or I into its conjugate base by treatment with, for example, sodium hydroxide in a solvent such as DMF and subsequent alkylation, for example, with an alkyl halide preferentially at ambient temperature, or by applying any other suitable method known to those skilled in the art.

Amines 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, AE (wherein one of R ³ and R ⁴ is equal to hydrogen), III or I (wherein one of R ³ and R ⁴ is equal to hydrogen), 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 before the key step using methods well known in the art (as described, for example, in TW 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.

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 into compound BD by reaction with a suitably 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).

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 by treatment with amine III as described in step c of Scheme 1; and iii) reacted with alcohol BC as described in step c to provide compound I.

If one of ^R and ^R in the amide I is equal to hydrogen, alkylation towards the corresponding tertiary amide I can be accomplished, for example, by converting the secondary amide I into its conjugate base by treatment with, for example, sodium hydride in a solvent such as DMF followed by, for example, alkylation with an alkyl halide preferentially at ambient temperature, or by applying any other suitable method known to those skilled in the art.

If one of the starting materials, i.e., compounds of formula BA, BC, III or I (wherein one of R ³ and R ⁴ is equal to hydrogen), 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 before the key step using methods well known in the art (as described, for example, in TW 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.

Compound AA" can be prepared from CA by coupling an appropriately substituted aryl, heteroaryl or alkenyl metal species of formula CB (M is, for example, trifluoroborate [BF ₃ ] ^{-K +} , boric acid B(OH) ₂ or boric acid pinacol ester) (step a), for example an organic potassium trifluoroborate, 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 or In 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, in particular 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 CD by treatment with amine III as described in step c of Scheme 1; and iii) reacted with CB as described in step a to provide compound I.

Alternatively, compounds of formula I wherein R ¹ is an alkylsulfonyl residue can be synthesized using the following reaction sequence: i) reaction of compound CA (e.g., for R′═H: 5-bromo-6-chloro-pyridine-2-carboxylic acid; CAN959958-25-9) with a thiol BC to form a thioether CC, e.g., in the presence of a base such as cesium carbonate in a solvent such as DMSO, preferably at a temperature of 100 to 150° C.; ii) conversion of the thioether CC (R ¹ ═S-alkyl) to its corresponding sulfonyl congener CC (R ¹ ═S(O) ₂ -alkyl), for example, by using an oxidizing agent such as 3-chloroperoxybenzoic acid in a solvent such as dichloromethane, preferably at ambient temperature; iii) conversion of the sulfonyl derivative CC to compound BD, as discussed for the conversion of CA to AA (step a); and iv) further modification to the sulfonyl derivative I via saponification as described in step b of Scheme 1, followed by amide bond formation as described in step c of Scheme 1. Optionally, the order of the reactions can be interchanged.

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 by treatment with amine 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 ^R and ^R in the amide CD or I is equal to hydrogen, alkylation towards the corresponding tertiary amide CD or I can be accomplished, for example, by converting the secondary amide CD or I into its conjugate base by treatment with, for example, sodium hydride in a solvent such as DMF followed by, for example, alkylation with an alkyl halide preferentially at ambient temperature, or by applying any other suitable method known to those skilled in the art.

If the starting material, i.e., one of the compounds of formula CA, CB, CD (wherein one of R ³ and R ⁴ is equal to hydrogen), BC, III or I (wherein one of R ³ and R ⁴ is equal to hydrogen), 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 before the key step using methods well known in the art (as described, for example, in TW 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, BC or III contain a chiral center, the picolinyls of formula AA', BD and I 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.

Compounds BD can be prepared from CC by coupling an appropriately substituted aryl, heteroaryl or alkenyl metal species of formula CB (M is, for example, trifluoroborate [BF ₃ ] ^{-K +} , boronic acid B(OH) ₂ or boronic acid pinacol ester) (step a), for example, an organic potassium trifluoroborate salt 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, 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 to the amino derivative BD by treatment with an amine BC (step b) using methods well known in the art, 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.

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.

Compound GA (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 5. GA is commercially available, described in the literature or can be synthesized by a person skilled in the art.

Compound BA can be prepared from EA by coupling an appropriately substituted aryl, heteroaryl or alkenyl metal species of formula CB (M is, for example, trifluoroborate [BF ₃ ] ^{-K +} , boronic acid B(OH) ₂ or boronic acid pinacol ester) (step a), for example, an organic potassium trifluoroborate salt 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 with EA 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 into 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 (M is, for example, boronic acid B(OH) ₂ or boronic acid pinacol ester) (step d), in particular an aryl boronic acid or aryl boronic acid 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 ¹ 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 one of ^R and ^R in the amide I is equal to hydrogen, alkylation towards the corresponding tertiary amide I can be accomplished, for example, by converting the secondary amide I into its conjugate base by treatment with, for example, sodium hydride in a solvent such as DMF followed by, for example, alkylation with an alkyl halide preferentially at ambient temperature, or by applying any other suitable method known to those skilled in the art.

If the starting material, i.e. one of the compounds of formula EA, CB, AB, III or I (wherein one of R ³ and R ⁴ is equal to hydrogen) 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 before the key step using methods well known in the art (as described, for example, in TW 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 EA, 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 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 can be used as starting material following 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.

Compound FB can be prepared from FA 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 FB to 6-chloro or 6-bromo compound FC (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.

The hydrolysis of compound FC gives the picoline FD 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 FD by coupling an appropriately substituted aryl, heteroaryl or alkenyl metal species of formula AB (M is, for example, boronic acid B(OH) ₂ or boronic acid pinacol ester) (step d), as described in step d of Scheme 6. Optionally, the alkenyl-containing R ¹ 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 FD is incompatible with the conditions for introducing the R ¹ 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 ^R and ^R in the amide I is equal to hydrogen, alkylation towards the corresponding tertiary amide I can be accomplished, for example, by converting the secondary amide I into its conjugate base by treatment with, for example, sodium hydride in a solvent such as DMF followed by, for example, alkylation with an alkyl halide preferentially at ambient temperature, or by applying any other suitable method known to those skilled in the art.

If one of the starting materials, i.e., compounds of formula FA, AB, III or I (wherein one of R ³ and R ⁴ is equal to hydrogen), 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 before the key step using methods well known in the art (as described, for example, in TW 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 to FD, 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 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 GA (CAN1173897-86-3) can be used as a starting material according to the procedure according to Scheme 7. In Scheme 7, R ¹ is benzyl or halogenated benzyl; R ^1′ is phenyl or halogenated phenyl.

Compound GB can be prepared from GA by treatment with compound CB (M is, for example, trifluoroborate [BF ₃ ] ⁻ K ⁺ , boronic acid B(OH) ₂ or boronic acid pinacol ester) as described in step a of Scheme 5 (step a).

Further conversion of GB to GC can be achieved by oxidation with a suitable oxidizing agent as described in step a of Scheme 6 (step b).

The conversion of the N-oxide GC to the alcohol GD 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 how to convert alcohol GD into a compound GE containing a leaving group (Y═Cl, Br or another suitable leaving group) is described in detail in the literature and is known to those skilled in the art (step d). For example, alcohol GD can be converted into compound GE in which Y═Br by reacting it 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 GE to compound GF can be accomplished, for example, by coupling an appropriately substituted aryl metal species of formula AB' (M is, for example, boronic acid B(OH) ₂ or boronic acid pinacol ester), in particular an aryl boronic acid or an aryl boronic 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, cesium carbonate or potassium phosphate, in an inert solvent such as dimethylformamide, toluene, tetrahydrofuran and 1,4-dioxane (step e).

Nitrile GF can be hydrolyzed to acid II using the method described in step c of Scheme 6 (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 one of ^R and ^R in the amide I is equal to hydrogen, alkylation towards the corresponding tertiary amide I can be accomplished, for example, by converting the secondary amide I into its conjugate base by treatment with, for example, sodium hydride in a solvent such as DMF followed by, for example, alkylation with an alkyl halide preferentially at ambient temperature, or by applying any other suitable method known to those skilled in the art.

If one of the starting materials, i.e., compounds of formula GA, CB, AB', III or I (wherein one of R ³ and R ⁴ is equal to hydrogen), 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 TW 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 GF, 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 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.

The present invention also relates to a process for preparing a compound of formula (I), said process comprising one of the following steps:

(a) reacting a compound of formula (A) in the presence of NHR ³ R ⁴ , an amide bond-forming coupling agent, and a base;

or

(b) Compounds of formula (B)

reacting with a compound of formula R ⁴ -X;

wherein R ¹ to R ⁴ are as defined above and X is a leaving group.

X is, for example, Cl, Br or I. X may be any other suitable leaving group known to those skilled in the art.

The compound of formula (A) or NHR ³ R ⁴ may contain functional groups that will interfere with the coupling procedure described for the amide coupling step. In this case, it will be understood that (A) or NHR ³ R ⁴ needs to be suitably protected by methods known in the art before carrying out the amide coupling procedure and that the compound needs to be deprotected by methods known in the art after the coupling step to provide the compound of formula (I).

Suitable coupling agents are, 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-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) or O-benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro-phosphate (HBTU). A particular coupling agent is HBTU.

Examples of suitable bases include triethylamine, diisopropylethylamine and in particular N-methylmorpholine.

The reaction temperature is, for example, room temperature.

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

The present invention also particularly relates to:

Use of a compound of formula (I) for treating or preventing pain, atherosclerosis, age-related macular degeneration, diabetic retinopathy, glaucoma, retinal vein occlusion, retinopathy of prematurity, ocular ischemic syndrome, geographic atrophy, diabetes, inflammation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver failure, liver fibrosis, pulmonary fibrosis, renal fibrosis, systemic fibrosis, acute allograft rejection, chronic allograft nephropathy, diabetic nephropathy, glomerular nephropathy, cardiomyopathy, heart failure, myocardial ischemia, myocardial infarction, systemic sclerosis, thermal injury, burns, hypertrophic scars, keloids, gingivitis, liver cirrhosis or tumors, bone modulation, neurodegeneration, amyotrophic lateral sclerosis, stroke, transient ischemic attack or uveitis;

Use of a compound of formula (I) for the preparation of a medicament for the treatment or prevention of pain, atherosclerosis, age-related macular degeneration, diabetic retinopathy, glaucoma, retinal vein occlusion, retinopathy of prematurity, ocular ischemic syndrome, geographic atrophy, diabetes, inflammation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver failure, liver fibrosis, pulmonary fibrosis, renal fibrosis, systemic fibrosis, acute allograft rejection, chronic allograft nephropathy, diabetic nephropathy, glomerular nephropathy, cardiomyopathy, heart failure, myocardial ischemia, myocardial infarction, systemic sclerosis, thermal injury, burns, hypertrophic scars, keloids, gingivitis fever, cirrhosis or tumors, bone modulation, neurodegeneration, amyotrophic lateral sclerosis, stroke, transient ischemic attack or uveitis;

A compound of formula (I) for use in the treatment or prevention of pain, atherosclerosis, age-related macular degeneration, diabetic retinopathy, glaucoma, retinal vein occlusion, retinopathy of prematurity, ocular ischemic syndrome, geographic atrophy, diabetes, inflammation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver failure, liver fibrosis, pulmonary fibrosis, renal fibrosis, systemic fibrosis, acute allograft rejection, chronic allograft nephropathy, diabetic nephropathy, glomerular nephropathy, cardiomyopathy, heart failure, myocardial ischemia, myocardial infarction, systemic sclerosis, thermal injury, burns, hypertrophic scars, keloids, gingivitis fever, cirrhosis or tumors, bone modulation, neurodegeneration, amyotrophic lateral sclerosis, stroke, transient ischemic attack or uveitis; and

A method for treating or preventing pain, atherosclerosis, age-related macular degeneration, diabetic retinopathy, glaucoma, retinal vein occlusion, retinopathy of prematurity, ocular ischemic syndrome, geographic atrophy, diabetes, inflammation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver failure, liver fibrosis, pulmonary fibrosis, renal fibrosis, systemic fibrosis, acute allograft rejection, chronic allograft nephropathy, diabetic nephropathy, glomerular nephropathy, cardiomyopathy, heart failure, myocardial ischemia, myocardial infarction, systemic sclerosis, thermal injury, burns, hypertrophic scars, keloids, gingivitis, cirrhosis or tumors, bone modulation, neurodegeneration, amyotrophic lateral sclerosis, stroke, transient ischemic attack or uveitis, the method comprising administering to a patient in need thereof an effective amount of a compound of formula (I).

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 also particularly relates to compounds of formula (I) for use in the treatment or prevention of diabetic retinopathy, retinal vein occlusion or uveitis.

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

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 compound 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 infusion includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. The compound of the present invention can be used especially by intravitreal 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

BINAP = 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; CAN = CAS registry number; DCM = dichloromethane; DIEA = N-ethyl-N-isopropylpropane-2-amine; DMF = dimethylformamide; DMSO = dimethyl sulfoxide; dppf = 1,1′-bis(diphenylphosphino)ferrocene; EI = electron ionization; ESI = electrospray; EtOAc = ethyl acetate; HPLC = LC = high performance liquid chromatography; m-CPBA = meta-chloroperbenzoic acid; MS = mass spectrometry; NMR = nuclear magnetic resonance; TBTU = O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyl-urea-tetrafluoroborate; TBME = methyl tert-butyl ether, TEMPO = (2,2,6,6-tetramethylpiperidin-1-yl)oxyl; THF = tetrahydrofuran; tlc = thin layer chromatography.

Example 1

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

a) 6-Chloro-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid methyl ester

Under nitrogen atmosphere, a mixture of methyl 5-bromo-6-chloro-pyridine-2-carboxylate (Example 3a, 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. 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 give a residue. The residue was purified by column chromatography (silica gel, 20 g, 10% ethyl acetate in petroleum ether) to give the title compound (0.44 g, 21%) as a light yellow solid; MS (EI): m/e = 263.0 [MH ⁺ ].

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

In the 4-thiazolinone (5-nitro-1-yl)-2-nitro-1-propanediol (5-nitro-2-oxo-1-pyridine) of 1-nitro-2-oxo-1-propanediol (6 ... 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 [MH ⁺ ].

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

A solution of 6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidine-1-yl)picolinic acid (10 mg, 35 μmol), N, 2-dimethylpropane-2-amine (CAN 94896-77-2, 3.68 mg, 42.2 μmol), 1-hydroxybenzotriazole hydrate (11 mg, 70 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (12 mg, 70 μmol) and DIEA (18.2 mg, 24 μl, 141 μmol) in DMF (157 μL) was stirred at ambient temperature for 2 days. The reaction mixture was poured onto ice-water/1N HCl (20 mL), extracted with EtOAc (2x 30 mL) and washed with ice-water/brine (20 mL). The combined organic layers were dried _{over Na2SO4} and concentrated in vacuo to give 24 mg of a yellow oil which was purified by TLC (silica gel, heptane/EtOAc 1:1, eluted with DCM/EtOAc 1:1) to give the title compound (11 mg, 89%) as a light yellow oil; MS (EI): m/e = 354.5 [MH ⁺ ].

Example 2

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

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with dimethylamine hydrochloride (CAN506-59-2) in the presence of TBTU and DIEA to give the title compound as a light yellow oil; MS (EI): m/e=312.4 [MH ⁺ ].

Example 3

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid tert-butyl-methyl-amide

a) 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 anhydrous dichloromethane is heated to 60 ℃ and reaches 20h.Afterwards, mixture is quenched with saturated sodium sulfite solution and extracted with ethyl acetate (2x 200mL).Organic layer is washed with salt water (2x 200mL) and evaporated to dryness.Residue obtains brown oil by column chromatography (silica gel, 300g, eluted with 15% ethyl acetate in petroleum ether) purifying.At 0 ℃, this brown oil 5-bromo-2-(methoxycarbonyl) pyridine 1-oxide (30g, 0.13mol) is added in phosphorus oxychloride (CAN 10025-87-3,80mL) in 1h, then mixture is heated to 95 ℃ and reaches 1h. After that time, the mixture was evaporated to dryness, the residue was dissolved in water (50 mL), extracted with ethyl acetate (3 x 50 mL) and the organic layer was evaporated to dryness to afford the product as a white solid (19 g, 59%); MS (EI): m/e = 249.9 [MH ⁺ ].

b) 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 [MH ⁺ ].

c) 5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid

A mixture of 5-bromo-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid (1.5 g, 5.5 mmol), cyclopropylboronic acid (CAN411235-57-9, 0.57 g, 7 mmol), palladium diacetate (CAN 3375-31-3, 62 mg, 0.28 mmol), tricyclohexylphosphine (CAN2622-14-2, 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. The mixture was then evaporated to dryness, dissolved in 30 mL of water, extracted with ethyl acetate (30 mL) and the organic layer was dropped. 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 [MH ⁺ ].

d) 5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid tert-butyl-methyl-amide

In analogy to the procedure described in Example 47b), 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid was reacted with N,2-dimethylpropan-2-amine (CAN 94896-77-2) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e = 303.4 [MH ⁺ ].

Example 4

5-Cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid tert-butyl-methyl-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 mixed with DMSO (1.93mL) to obtain a colorless solution, which is stirred at ambient temperature for 15min. Then tetrahydro-2-furanmethanol (130mg, 123 μl, 1.27mmol, CAN 97-99-4) is added, 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 (2x 25mL) and washed with ice-water/salt water. Combine aqueous phases and acidify with ice/1N HCl and extract with isopropyl acetate (2x 30mL). 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

Palladium (II) acetate (1.19 mg, 5.3 μmol), butylbis(tricyclo[3.3.1.13,7]dec-1-yl)-phosphine (2.85 mg, 7.94 μmol, CAN 321921-71-5), potassium cyclopropyltrifluoroborate (39.6 mg, 267 μmol) and cesium carbonate (259 mg, 794 μmol) were mixed to give a white solid. To this solid, 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) was added through a septum cap. The reaction mixture was heated to 120° C. and stirred for 20 h. After cooling to ambient temperature, the reaction mixture was diluted with water (2 mL), poured onto 20 mL 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] ⁻ .

c) 5-Cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid tert-butyl-methyl-amide

In analogy to the procedure described in Example 47b), 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid was reacted with N,2-dimethylpropan-2-amine (CAN 94896-77-2) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e = 333.5 [MH ⁺ ].

Example 5

5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid tert-butyl-methyl-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 H ₂ O (100 mL), and extracted with ethyl acetate (2 x 100 mL). The organic layer was dried over Na ₂ SO ₄ , 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

5-Bromo-6-methyl-pyridine-2-carbonitrile (0.5 g, 2.5 mmol), cyclopropylboronic acid (CAN411235-57-9, 0.36 g, 4 mmol), _Pd2 (dba) ₃ (CAN 411235-57-9, 0.1 g, 0.2 mmol), xantphos (CAN161265-03-8, 0.15 g, 0.26 mmol) and _Cs2CO3 (1.1 g, 3 mmol) were suspended in 1,4- _dioxane (30 mL) under a nitrogen atmosphere. 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 under reduced pressure, concentrated 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 NaOH aq. (10 mL) and _CH₂Cl₂ (10 _mL ). The aqueous phase was washed several times _{with CH₂Cl₂} and the combined organic fractions were dried _{over Na₂SO₄} and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 3 g, 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. for 12 h under a nitrogen atmosphere. 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 tert-butyl-methyl-amide

In analogy to the procedure described in Example 47b), 5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid was reacted with N,2-dimethylpropan-2-amine (CAN 94896-77-2) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e = 341.1 [MH ⁺ ].

Example 6

5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid tert-butyl-methyl-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 directly in the next reaction 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 _Na2SO4 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) Methyl 5-bromo-6-(isobutylsulfonyl)picolinate

Methyl 5-bromo-6-(isobutylthio)picolinate (30 mg, 98.6 μmol) 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 (2 _x 30 mL). The extract was washed with a 10% aqueous solution _{of Na₂S₂O₃} (15 mL). The aqueous layer was back-extracted with dichloromethane (30 mL). The combined organic layers were washed with a 10% aqueous sodium bicarbonate solution, dried _{over Na₂SO₄} and concentrated in vacuo to give the crude product as a white solid. Filtered through silica gel (3 g, heptane/EtOAc 1:1) to give the title compound (19 mg, 70%) as a white oil. MS(EI): m/e=338.3[M+H] ⁺ .

d) 5-cyclopropyl-6-(isobutylsulfonyl)picolinic acid

The title compound was prepared in analogy to the procedure described in Example 3c) using methyl 5-bromo-6-(isobutylsulfonyl)picolinate as starting material. MS (EI): m/e = 284.3 [M+H] ⁺ .

e) 5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid tert-butyl-methyl-amide

In analogy to the procedure described in Example 47b), 5-cyclopropyl-6-(isobutylsulfonyl)picolinic acid was reacted with N,2-dimethylpropan-2-amine (CAN 94896-77-2) in the presence of TBTU and DIEA to give the title compound as a white solid; MS (EI): m/e = 353.5 [MH ⁺ ].

Example 7

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid tert-butyl-ethyl-amide

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with N-ethyl-2-methylpropane-2-amine (CAN 4432-77-3) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=368.5 [MH ⁺ ].

Example 8

Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid diisopropylamide

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with (3-methyloxetane-3-yl)methanamine (CAN 153209-97-3) in the presence of TBTU and DIEA to give the title compound as a colorless oil as a by-product; MS (EI): m/e=368.5 [MH ⁺ ].

Example 9

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

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with 3-methoxy-2,2-dimethylpropan-1-amine (CAN 1177316-77-6) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=384.5 [MH ⁺ ].

Example 10

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-methanone

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with 6-oxa-1-azaspiro[3.3]heptane oxalate (CAN 1359655-43-8) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=366.4 [MH ⁺ ].

Example 11

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-methanone

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with 2-oxa-6-azaspiro[3.3]heptane oxalate (CAN 1159599-99-1) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=366.4 [MH ⁺ ].

Example 12

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid 2-{[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-methyl-amino}-2-methyl-propyl ester

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with 2-methyl-2-(methylamino)propan-1-ol (CAN 27646-80-6) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e = 636.3 [MH ⁺ ].

Example 13

5-Cyclopropyl-6-(2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid tert-butyl-methyl-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-trifluoropropane-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 tert-butyl-methyl-amide

In analogy to the procedure described in Example 47b), 5-cyclopropyl-6-(1,1,1-trifluoropropan-2-yloxy)picolinic acid was reacted with 2-methyl-2-(methylamino)propan-1-ol (CAN 27646-80-6) in the presence of TBTU and DIEA to give the title compound as a white solid; MS (EI): m/e = 345.4 [MH ⁺ ].

Example 14

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(4,4-dimethyl-oxazolidin-3-yl)-methanone

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with 4,4-dimethyloxazolidine (CAN51200-87-4) in the presence of TBTU and DIEA to give the title compound as a white solid; MS (EI): m/e=368.5 [MH ⁺ ].

Example 15

6-(Tetrahydro-furan-2-ylmethoxy)-5-trifluoromethyl-pyridine-2-carboxylic acid tert-butyl-methyl-amide

a) 6-(Tetrahydro-furan-2-ylmethoxy)-5-trifluoromethyl-pyridine-2-carboxylic acid

In analogy to the procedure described in Example 4a), 6-chloro-5-(trifluoromethyl)picolinic acid (CAN 855915-21-8) was reacted with (tetrahydrofuran-2-yl)methanol (CAN 97-99-4) in the presence of potassium hydroxide to give the title compound as a yellow solid; MS (EI): m/e = 290.0 [MH ⁺ ].

b) 6-(Tetrahydro-furan-2-ylmethoxy)-5-trifluoromethyl-pyridine-2-carboxylic acid tert-butyl-methyl-amide

In analogy to the procedure described in Example 47b), 6-((tetrahydrofuran-2-yl)methoxy)-5-(trifluoromethyl)picolinic acid was reacted with N,2-dimethylpropan-2-amine (CAN 94896-77-2) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e = 361.5 [MH ⁺ ].

Example 16

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

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

The title compound was synthesized similarly to the procedure described in Example 47b) using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) and 1-(trifluoromethyl)cyclopropylamine (CAN112738-68-8) as starting materials. MS (EI): m/e = 392.4 [M+H] ⁺ .

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

A solution of 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1-trifluoromethyl-cyclopropyl)-amide (20 mg, 51.1 μmol) and sodium hydride (3.3 mg, 76.7 μmol) in DMF (0.2 mL) was stirred at ambient temperature for 15 min. Iodomethane (14.5 mg, 6.38 μL, 102 μmol) was added and stirring was continued for 1 h. The reaction mixture was poured onto ice/saturated NaHCO ₃ aqueous solution (15 mL) and extracted with EtOAc (2x25 mL). The combined extracts were washed with ice water/brine (2x20 mL), dried over Na ₂ SO ₄ and dried to dryness. The crude brown oil was purified by preparative TLC (silica gel, 1 mm, heptane/EtOAc 4:1, eluting with EtOAc) to give the title compound (13 mg, 63%) as a colorless oil; MS (EI): m/e = 406.4 [MH] ⁺ .

Example 17

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(3,3-dimethyl-morpholin-4-yl)-methanone

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with 3,3-dimethylmorpholine (CAN59229-63-9) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=382.4 [MH ⁺ ].

Example 18

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

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with 2,2-dimethylpyrrolidine (CAN35018-15-6) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=366.4 [MH ⁺ ].

Example 19

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

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with 2-(2-methoxyethylamino)-2-methylpropan-1-ol (CAN1156380-97-0) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=414.4 [MH ⁺ ].

Example 20

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid tert-butyl-(2-methoxy-ethyl)-amide

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with N-(2-methoxyethyl)-2-methylpropan-2-amine (CAN 22687-22-5) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=398.4 [MH ⁺ ].

Example 21

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

By 6- (cyclopropylmethoxy) -5- (3,3- difluoroazetidine -1- bases) -N- (1- (trifluoromethyl) cyclopropyl) picolinamide (Example 16a), 15mg, 38μmol) and 2- methylbutane -2- sodium oleate (5mg, 46μmol) in DMF (150μL) solution was stirred at ambient temperature for 15 minutes. Iodoethane (9mg, 7μL, 58μmol) was added and stirring was continued for 1h. The reaction mixture was poured onto ice / saturated NaHCO ₃ aqueous solution (15mL) and extracted with EtOAc (2x25mL). The combined extracts were washed with ice / brine (2x20mL), dried over Na ₂ SO ₄ and dried to dryness. The crude product was purified by preparative TLC (silica gel, 1 mm, heptane/EtOAc 2:1, eluting with EtOAc) to give the title compound (12 mg, 75%) as a colorless oil; MS (EI): m/e = 420.2 [MH] ⁺ .

Example 22

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

In analogy to the procedure described in Example 16b), 6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-N-(1-(trifluoromethyl)cyclopropyl)picolinamide (Example 16a) was reacted with (chloromethyl)benzene (CAN 27987-13-9) in the presence of sodium hydride to give the title compound as a colorless oil; MS (EI): m/e = 482.4 [MH] ⁺ .

Example 23

{tert-Butyl-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-amino}-ethyl acetate

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with ethyl 2-(tert-butylamino)acetate (CAN 37885-76-0) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e = 426.5 [MH ⁺ ].

Example 24

{tert-Butyl-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-amino}-acetic acid

A solution of 2-(N-tert-butyl-6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinamido)acetate (Example 23, 58 mg, 136 μmol) in a mixture of 1N aqueous NaOH (164 μL, 164 μmol), THF (0.5 mL), MeOH (0.2 mL) and water (0.05 mL) was stirred at ambient temperature for 24 h and evaporated to dryness. The residue was partitioned between ice water/0.1N aqueous HCl (25 mL) and EtOAc (25 mL). The aqueous layer was extracted once more with EtOAc (25 mL). The combined extracts were washed with ice/brine (25 mL), dried over Na ₂ SO ₄ and dried to dryness to give the title compound (51 mg, 128 μmol, 94%) as a light yellow solid; MS (EI): m/e = 398.4 [MH ⁺ ].

Example 25

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid benzyl-tert-butyl-amide

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with N-benzyl-2-methylpropane-2-amine (CAN 3378-72-1) in the presence of TBTU and DIEA to give the title compound as a colorless solid; MS (EI): m/e=430.5 [MH ⁺ ].

Example 26

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid tert-butyl-methylcarbamoylmethyl-amide

In analogy to the procedure described in Example 47b), {tert-butyl-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-amino}-acetic acid (Example 24) was reacted with a 2M solution of methylamine (CAN 74-89-5) in MeOH in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=411.5 [MH ⁺ ].

Example 27

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid tert-butyl-dimethylcarbamoylmethyl-amide

In analogy to the procedure described in Example 47b), {tert-butyl-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-amino}-acetic acid (Example 24) was reacted with dimethylamine hydrochloride (CAN 506-59-2) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e = 425.5 [MH ⁺ ].

Example 28

4-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-3,3-dimethyl-piperazin-2-one

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with 3,3-dimethylpiperazin-2-one hydrochloride (CAN 1104383-07-4) in the presence of TBTU and DIEA to give the title compound as a white solid; MS (EI): m/e = 395.4 [MH ⁺ ].

Example 29

4-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-3,3-diethyl-piperazin-2-one

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with 3,3-dimethylpiperazin-2-one hydrochloride (CAN 907973-05-1) in the presence of TBTU and DIEA to give the title compound as a colorless solid; MS (EI): m/e=423.4 [MH ⁺ ].

Example 30

[5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridin-2-yl]-(2,2-dimethyl-pyrrolidin-1-yl)-methanone

In analogy to the procedure described in Example 47b), 5-cyclopropyl-6-(isobutylsulfonyl)picolinic acid (Example 6d)) was reacted with 2,2-dimethylpyrrolidine (CAN 35018-15-6) in the presence of TBTU and DIEA to give the title compound as a colorless solid; MS (EI): m/e=365.5 [MH ⁺ ].

Example 31

[5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridin-2-yl]-(4,4-dimethyl-oxazolidin-3-yl)-methanone

In analogy to the procedure described in Example 47b), 5-cyclopropyl-6-(isobutylsulfonyl)picolinic acid (Example 6d)) was reacted with 4,4-dimethyloxazolidine (CAN 51200-87-4) in the presence of TBTU and DIEA to give the title compound as a colorless solid; MS (EI): m/e=367.4 [MH ⁺ ].

Example 32

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]-methyl-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. Aqueous 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 off 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 (S)-tert-butyl 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 give 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. A solution of (S)-tert-butyl 1-cyano-2-cyclopropylethylcarbamate (3.31 g, 16 mmol) in ethanol (24 mL) was added 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-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

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with (S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine in the presence of TBTU and DIEA to give the title compound; MS (EI): m/e=434.2 [MH ⁺ ].

g) 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]-methyl-amide

In analogy to the procedure described in Example 16b), 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 was reacted with iodomethane (CAN 74-88-4) in the presence of sodium hydride to give the title compound as a colorless oil; MS (EI): m/e = 448.2 [MH] ⁺ .

Example 33

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

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

In analogy to the procedure described in Example 47b), 5-cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carboxylic acid (which can be prepared, for example, in an analogous manner to 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 4b)) is reacted with cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methylamine (which can be prepared, for example, in an analogous manner to (S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 32e)) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e = 413.1 [MH ⁺ ].

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

In analogy to the procedure described in Example 16b), 5-cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide was reacted with iodomethane (CAN 74-88-4) in the presence of sodium hydride to give the title compound as a colorless oil; MS (EI): m/e = 427.2 [MH] ⁺ .

Example 34

(+)-6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid methyl-(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 remaining 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 _Na₂SO₄ . Filtration and evaporation gave the title compound (233 mg, 27%) as a brown oil sufficiently pure for use in the next reaction 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 compound was synthesized using a procedure analogous to that described in Example 47b) using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) and 3-methyl-1-(pyridazin-3-yl)butan-1-amine as starting materials. The product was separated by chiral chromatography on Reprosil Chiral NR using heptane, ethanol, and 2-propanol as eluents. The (+)-enantiomer was separated. MS (EI): m/e = 432.5 [MH ⁺ ].

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

In analogy to the procedure described in Example 16b), (+)-6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (3-methyl-1-pyridazin-3-yl-butyl)-amide was reacted with iodomethane (CAN 74-88-4) in the presence of sodium hydride to give the title compound as a colorless oil; MS (EI): m/e = 446.2 [MH] ⁺ .

Example 35

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid tert-butyl-carbamoylmethyl-amide

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with 2-(tert-butylamino)acetamide (207925-15-3) in the presence of TBTU and DIEA to give the title compound as a white solid; MS (EI): m/e=397.5 [MH ⁺ ].

Example 36

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

a) 2-Methyl-N-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)propan-2-amine

A suspension of 2-methylpropane-2-amine (75-64-9, 141 mg, 202 μL, 1.92 mmol) and 2-(chloromethyl)-5-methyl-1,3,4-oxadiazole (3914-42-9, 50 mg, 377 μmol) in DMF (200 μL) was stirred at ambient temperature for 16 h. The mixture was poured onto ice-water (20 mL) and extracted with _CH₂Cl₂ ( ₂ x 30 mL). The combined extracts were washed with ice-water (20 mL), dried _{over Na₂SO₄} , and concentrated in vacuo to afford a yellow oil. The crude product was purified by preparative TLC (silica gel 1 mm, EtOAc/diethylamine 95:5, eluted with DCM/EtOAc 1:1) to afford the title compound (45 mg, 71%) as a yellow oil; MS (EI): m/e = 170.2 [ ^MH⁺ ].

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

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with 2-methyl-N-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)propan-2-amine in the presence of TBTU and DIEA to give the title compound as a yellow solid; MS (EI): m/e=436.4 [MH ⁺ ].

Example 37

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(3-hydroxy-3-methyl-pyrrolidin-1-yl)-methanone

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with 3-methylpyrrolidin-3-ol (125032-87-3) in the presence of TBTU and DIEA to give the title compound as a yellow solid; MS (EI): m/e=368.5 [MH ⁺ ].

Example 38

5-Chloro-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (2,2-dimethyl-1-thiazol-2-yl-propyl)-amide

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with 2-oxa-5-azaspiro[3.4]octane oxalate (90207-55-9) in the presence of TBTU and DIEA to give the title compound as a yellow solid; MS (EI): m/e=380.3 [MH ⁺ ].

Example 39

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

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with N-ethyl-2-methoxyethanamine (34322-82-2) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=370.6 [MH ⁺ ].

Example 40

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid tert-butyl-(1-methyl-1H-tetrazol-5-ylmethyl)-amide

a) 2-Methyl-N-((1-methyl-1H-tetrazol-5-yl)methyl)propan-2-amine hydrochloride

A mixture of 2-methylpropan-2-amine (75-64-9, 281 mg, 404 μL, 3.85 mmol) and 5-(chloromethyl)-1-methyl-1H-tetrazole (57235-84-4, 100 mg, 754 μmol) was stirred at ambient temperature for 16 h and concentrated in vacuo to give the title compound (112 mg, 72%) as a yellow solid; MS (EI): m/e = 169 [M ⁺ ].

b) 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid tert-butyl-(1-methyl-1H-tetrazol-5-ylmethyl)-amide

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with 2-methyl-N-((1-methyl-1H-tetrazol-5-yl)methyl)propan-2-amine hydrochloride in the presence of TBTU and DIEA to give the title compound as a yellow solid; MS (EI): m/e=436.5 [MH ⁺ ].

Example 41

N-{1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-pyrrolidin-3-yl}-acetamide

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with N-(pyrrolidin-3-yl)acetamide (79286-74-1) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=395.5 [MH ⁺ ].

Example 42

[5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridin-2-yl]-(4,4-dimethyl-piperidin-1-yl)-methanone

In analogy to the procedure described in Example 47b), 5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid (Example 5g)) was reacted with 4,4-dimethyl-piperidine (4045-30-1) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=367.5 [MH ⁺ ].

Example 43

[5-Cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridin-2-yl]-(4,4-dimethyl-piperidin-1-yl)-methanone

In analogy to the procedure described in Example 47b), 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 4b)) was reacted with 4,4-dimethyl-piperidine (4045-30-1) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=359.6 [MH ⁺ ].

Example 44

[5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridin-2-yl]-(4,4-dimethyl-oxazolidin-3-yl)-methanone

In analogy to the procedure described in Example 47b), 5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid (Example 5g)) was reacted with 4,4-dimethyloxazolidine (CAN 51200-87-4) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e = 355.5 [MH ⁺ ].

Example 45

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-((1S,5R)-1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octan-6-yl)-methanone

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with (1S,5R)-1,3,3-trimethyl-6-azabicyclo[3.2.1]octane hydrochloride (380228-03-5) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=420.2 [MH ⁺ ].

Example 46

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-((R)-2-methoxymethyl-pyrrolidin-1-yl)-methanone

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with (R)-2-(methoxymethyl)pyrrolidine (84025-81-0) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e = 382.5 [MH ⁺ ].

Example 47

(6-Chloro-5-cyclopropylmethoxy-pyridin-2-yl)-(2,2-dimethyl-pyrrolidin-1-yl)-methanone

a) A mixture of 6-cyclopropylmethoxy-5-trifluoromethoxy-pyridine-2-carboxylic acid and 6-chloro-5-cyclopropylmethoxy-pyridine-2-carboxylic acid

To a solution of 6-chloro-5-trifluoromethoxy-pyridine-2-carboxylic acid (CAN 1221171-90-9, 1.0 g, 4.14 mmol) in DMSO (16 mL) was added potassium hydroxide (0.93 g, 16.6 mmol) and the reaction mixture was stirred at room temperature for 15 minutes. To this suspension was added cyclopropylmethanol (335 μL, 4.14 mmol) and the mixture was stirred at ambient temperature for 16 hours. More cyclopropylmethanol (335 μL, 4.14 mmol) was added and stirring was continued at 50° C. for 4 hours. The mixture was cooled, added to 2N sodium hydroxide solution (50 mL) while cooling and partitioned between TBME and 1N sodium hydroxide solution. The organic phase was poured off; the aqueous phases were combined, acidified with 2N hydrochloric acid and extracted with TBME. The organic phases were combined, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude material (1.05 g) as a light brown solid was used without purification and contained a mixture of 6-cyclopropylmethoxy-5-trifluoromethoxy-pyridine-2-carboxylic acid and 6-chloro-5-cyclopropylmethoxy-pyridine-2-carboxylic acid (~7/3 by NMR); LC-MS (UV peak area, ESI) 48.8%, 228.0425 [MH ⁺ ], 51.2%, 278.0628 [MH ⁺ ].

b) (6-Chloro-5-cyclopropylmethoxy-pyridin-2-yl)-(2,2-dimethyl-pyrrolidin-1-yl)-methanone

A mixture of 6-cyclopropylmethoxy-5-trifluoromethoxy-pyridine-2-carboxylic acid and 6-chloro-5-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 47a, 50 mg, 180 μmol) was dissolved in DMF (2 mL). TBTU (63.7 mg, 198 μmol), DIEA (154 μl, 902 μmol) and 2,2-dimethylpyrrolidine (CAN 35018-15-6, 24 μl, 198 μmol) were added and the reaction mixture was stirred at room temperature for 16 hours. Ethyl acetate (3 mL) and 1N sodium hydroxide solution (2 mL) were added; the mixture was dried and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, ethyl acetate/n-heptane gradient) to give the title compound (17 mg, 31%) as a light white wax; LC-MS (UV peak area, ESI) 97%, 309.1367 [MH ⁺ ].

Example 48

(6-Cyclopropylmethoxy-5-trifluoromethoxy-pyridin-2-yl)-(4,4-dimethyl-oxazolidin-3-yl)-methanone

The title compound was synthesized in analogy to the procedure described in Example 47b using 6-cyclopropylmethoxy-5-trifluoromethoxy-pyridine-2-carboxylic acid and 6-chloro-5-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 47a, 50 mg, 180 μmol) and 4,4-dimethyl-oxazolidine (CAN 51200-87-4; 28.4 μl (75%), 198 μmol) as starting materials and isolated (24 mg, 37%) as a colorless oil; LC-MS (UV peak area, ESI) 100%, 361.1370 [MH ⁺ ].

Example 49

(6-Chloro-5-cyclopropylmethoxy-pyridin-2-yl)-(4,4-dimethyl-oxazolidin-3-yl)-methanone

The title compound was synthesized in analogy to the procedure described in Example 47b using a mixture of 6-cyclopropylmethoxy-5-trifluoromethoxy-pyridine-2-carboxylic acid and 6-chloro-5-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 47a, 50 mg, 180 μmol) and 4,4-dimethyl-oxazolidine (CAN 51200-87-4; 28.4 μl (75%), 198 μmol) as starting materials and isolated (13 mg, 23%) as a colorless oil; LC-MS (UV peak area, ESI) 100%, 311.1158 [MH ⁺ ].

Example 50

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1-acetyl-piperidin-4-yl)-cyclopropyl-amide

The title compound was synthesized by a procedure analogous to that described in Example 47b) using 6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinic acid and 1-(4-(cyclopropylamino)piperidin-1-yl)ethanone (CAS 387358-46-5) as starting materials and isolated as a colorless oil. MS (EI): m/e = 449.6 [MH ⁺ ].

Example 51

6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-N-formyl-N-methylpyridine-2-carboxamide

a) 6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)picolinamide

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b) was reacted with C-(3-trifluoromethyl-[1,2,4]oxadiazol-5-yl)-methylamine hydrochloride (CAS 944905-93-5) in the presence of TBTU and DIEA to give the title compound as a white solid; MS (EI): m/e=434.5 [MH ⁺ ].

b) 6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-N-formyl-N-methylpyridine-2-carboxamide

The title compound was synthesized in a manner analogous to that described in Example 47b) using 6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)picolinamide as the starting material. MS (EI): m/e = 326.1 [M+H] ⁺ .

Example 52

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

The title compound was synthesized similarly to the procedure described in Example 47b) using 6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinic acid (Example 1b) and N-methylaniline 2,2,2-trifluoroacetate (CAS 29885-95-8) as starting materials and isolated as a colorless oil. MS (EI): m/e = 374.5 [MH ⁺ ].

Example 53

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-((S)-4,4-difluoro-2-hydroxymethyl-pyrrolidin-1-yl)-methanone

The title compound was synthesized in a manner analogous to that described in Example 47b) using 6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinic acid (Example 1b) and (S)-(4,4-difluoropyrrolidin-2-yl)methanol hydrochloride (CAS 623583-10-8) as starting materials and isolated as a colorless oil. MS (EI): m/e = 404.5 [MH ⁺ ].

Example 54

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1,4-dimethyl-1H-pyrazol-3-yl)-methyl-amide

The title compound was synthesized in a manner similar to that described in Example 47b) using 6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinic acid (Example 1b) and N,1,4-trimethyl-1H-pyrazol-3-amine (which can be prepared from ethyl 3-formylamino-1-methyl-1H-pyrazole-4-carboxylate CAN 114936-04-8 via reduction with lithium aluminum hydride in diethyl ether at ambient temperature) as starting materials and isolated as a colorless oil. MS (EI): m/e = 392.5 [MH ⁺ ].

Example 55

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(2,2-dimethyl-morpholin-4-yl)-methanone

The title compound was synthesized in a manner analogous to that described in Example 47b) using 6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinic acid (Example 1b) and 2,2-dimethylmorpholine (CAS 147688-58-2) as starting materials and isolated as a colorless oil. MS (EI): m/e = 382.5 [MH ⁺ ].

Example 56

(R)-2-tert-Butyl-1-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-3-methyl-imidazolidin-4-one

The title compound was synthesized similarly to the procedure described in Example 47b) using 6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinic acid (Example 1b) and N-methylaniline 2,2,2-trifluoroacetate (CAS 101143-57-1) as starting materials and isolated as a colorless oil. MS (EI): m/e = 423.5 [MH ⁺ ].

Example 57

(4-Aza-spiro[2.4]hept-4-yl)-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-methanone

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with 4-azaspiro[2.4]heptane (95442-76-5) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=364.5 [MH ⁺ ].

Example 58

3-{1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-piperidin-4-yl}-5,5-dimethyl-pyrrolidin-2-one

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with 5,5-dimethyl-3-(piperidin-4-yl)pyrrolidin-2-one hydrochloride in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=463.6 [MH ⁺ ].

Example 59

(1S,4R)-2-Aza-bicyclo[2.2.1]hept-2-yl-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-methanone

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with (1S,4R)-2-azabicyclo[2.2.1]heptane hydrochloride (175275-72-6) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=364.5 [MH ⁺ ].

Example 60

(S)-1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-4,4-difluoro-pyrrolidine-2-carboxylic acid amide

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with (S)-4,4-difluoropyrrolidine-2-carboxamide hydrochloride (426844-51-1) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=417.5 [MH ⁺ ].

Example 61

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(4-hydroxy-4-methyl-piperidin-1-yl)-methanone

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with 4-methylpiperidin-4-ol hydrochloride (586375-35-1) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=382.6 [MH ⁺ ].

Example 62

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(1S,4S)-2-thia-5-aza-bicyclo[2.2.1]hept-5-yl-methanone

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with (1S,4S)-2-thia-5-azabicyclo[2.2.1]heptane hydrochloride (125136-43-8) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=382.5 [MH ⁺ ].

Example 63

((1S,4S)-5-Benzyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-methanone

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with (1S,4S)-2-benzyl-2,5-diazabicyclo[2.2.1]heptane dihydrobromide (116258-17-4) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=455.7 [MH ⁺ ].

Example 64

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(2-methyl-3-phenyl-piperidin-1-yl)-methanone

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with 2-methyl-3-phenylpiperidine (70769-67-4) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=442.5 [MH ⁺ ].

Example 65

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-methanone

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (31560-06-2) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=366.5 [MH ⁺ ].

Example 66

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(4-hydroxy-2,2-dimethyl-piperidin-1-yl)-methanone

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with 2,2-dimethylpiperidin-4-ol (937681-12-4) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=396.6 [MH ⁺ ].

Example 67

1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-2-phenyl-piperidine-3-carboxylic acid ethyl ester

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with ethyl 2-phenylpiperidine-3-carboxylate (54529-38-3) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=500.2 [MH ⁺ ].

Example 68

(S)-1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-4,4-difluoro-pyrrolidine-2-carboxylic acid amide

The title compound was synthesized in a similar manner to the procedure described in Example 47b using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3c, 50 mg, 214 μmol) and (2S)-4,4-difluoro-2-pyrrolidinecarboxamide hydrochloride (CAN426844-51-1; 44 mg, 236 μmol) as starting materials and isolated (63 mg, 80%) as a light white solid; LC-MS (UV peak area, ESI) 100%, 366.1629 [MH ⁺ ].

Example 69

(2S,4S)-1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-4-fluoro-pyrrolidine-2-carboxylic acid amide

The title compound was synthesized in analogy to the procedure described in Example 47b using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3c, 50 mg, 214 μmol) and (2S,4S)-4-fluoro-2-pyrrolidinecarboxamide hydrochloride (1:1) (CAN 426844-23-7; 40 mg, 236 μmol) as starting materials and isolated (68 mg, 91%) as a light white solid; LC-MS (UV peak area, ESI) 100%, 348.1721 [MH ⁺ ].

Example 70

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(hexahydro-furo[2,3-c]pyrrol-5-yl)-methanone

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with hexahydro-2H-furo[3,2-c]pyrrole (1214875-23-6) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=380.5 [MH ⁺ ].

Example 71

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(2,2-dioxo-2λ6-thia-6-aza-spiro[3.3]hept-6-yl)-methanone

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with 2-thia-6-azaspiro[3.3]heptane, 2,2-dioxide (1263182-09-7) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=414.5 [MH ⁺ ].

Example 72

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid tert-butyl-(2-carbamoyl-ethyl)-amide

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with 3-(tert-butylamino)propionamide (289656-97-9) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=411.6 [MH ⁺ ].

Example 73

(S)-1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-pyrrolidine-2-carboxylic acid amide

The title compound was synthesized in analogy to the procedure described in Example 47b using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3c, 40 mg, 171 μmol) and (2S)-2-pyrrolidinecarboxamide (CAN 7531-52-4; 21.5 mg, 189 μmol) as starting materials and isolated (49 mg, 87%) as a white solid; LC-MS (UV peak area, ESI) 100%, 330.1818 [MH ⁺ ].

Example 74

1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-1,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with tert-butyl 1,8-diazaspiro[4.5]decane-8-carboxylate hydrochloride (851325-42-3) in the presence of TBTU and DIEA to give the title compound as a yellow oil; MS (EI): m/e=507.6 [MH ⁺ ].

Example 75

(S)-1-{5-Cyclopropyl-6-[(R,S)-1-(tetrahydro-furan-2-yl)methoxy]-pyridine-2-carbonyl(arbonyl)}-4,4-difluoro-pyrrolidine-2-carboxylic acid amide

In analogy to the procedure described in Example 47b), 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 4b)) was reacted with (S)-4,4-difluoropyrrolidine-2-carboxamide hydrochloride (CAN 426844-51-1) in the presence of TBTU and DIEA to give the title compound as a white solid; MS (EI): m/e = 396.5 [MH ⁺ ].

Example 76

(S)-1-[5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carbonyl]-4,4-difluoro-pyrrolidine-2-carboxylic acid amide

In analogy to the procedure described in Example 47b), 5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid (Example 5g)) was reacted with (S)-4,4-difluoropyrrolidine-2-carboxamide hydrochloride (CAN 426844-51-1) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e = 404.5 [MH ⁺ ].

Example 77

(+)-1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-4,4-dimethyl-pyrrolidine-2-carboxylic acid amide

In a manner analogous to that described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with 4,4-dimethylpyrrolidine-2-carboxamide hydrochloride (Example 90d) in the presence of TBTU and DIEA. The enantiomeric mixture was separated by chiral HPLC (Reprosil Chiral NR). The (+) enantiomer was isolated as a yellow solid; MS (EI): m/e = 409.6 [MH ⁺ ];

Example 78

(-)-1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-4,4-dimethyl-pyrrolidine-2-carboxylic acid amide

In a manner analogous to that described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with 4,4-dimethylpyrrolidine-2-carboxamide hydrochloride (Example 90d) in the presence of TBTU and DIEA. The enantiomeric mixture was separated by chiral HPLC (Reprosil Chiral NR). The (-) enantiomer was isolated as a yellow solid; MS (EI): m/e = 409.6 [MH ⁺ ];

Example 79

(2S,4S)-1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-4-hydroxy-pyrrolidine-2-carboxylic acid amide

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with (2S,4S)-4-hydroxypyrrolidine-2-carboxamide hydrochloride (851233-67-5) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=397.5 [MH ⁺ ].

Example 80

(2S,4S)-1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-4-fluoro-pyrrolidine-2-carboxylic acid amide

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with (2S,4S)-4-fluoropyrrolidine-2-carboxamide hydrochloride (426844-23-7) in the presence of TBTU and DIEA to give the title compound as a white solid; MS (EI): m/e=399.4 [MH ⁺ ].

Example 81

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

a) Cyclopropyl-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amine

A mixture of cyclopropylamine (765-30-0, 194 mg, 236 μL, 3.39 mmol) and 2-(chloromethyl)-5-methyl-1,3,4-oxadiazole (3914-42-9, 90 mg, 679 μmol) was stirred at ambient temperature for 16 h. The mixture was concentrated under reduced pressure and the residue was taken up in ice-water/saturated _{aqueous Na₂CO₃} (1/1) (20 mL) and EtOAc (30 mL). The layers were separated and the aqueous layer was extracted once more with EtOAc (30 mL). The combined extracts were washed with ice-water/brine (1/1) (15 mL), _dried over _Na₂SO₄ , and dried to dryness to give the title compound (36 mg, 35%) as a yellow oil sufficiently pure for use in the next reaction step; MS (EI): m/e = 154.2 [ ^MH⁺ ].

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

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with cyclopropyl-(5-methyl-[1,3,4]diazol-2-ylmethyl)-amine in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=420.6 [MH ⁺ ].

Example 82

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(3-hydroxy-1-oxa-7-aza-spiro[4.4]nonan-7-yl)-methanone

a) 1-Oxa-7-azaspiro[4.4]nonan-3-ol hydrochloride

A mixture of tert-butyl 3-hydroxy-1-oxa-7-azaspiro[4.4]nonane-7-carboxylate (CAN 1331825-50-3, 33 mg, 136 μmol) and 4 M HCl in dioxane (339 μL, 1.36 mmol) in dioxane (0.3 mL) was stirred at ambient temperature for 3 h to give the title compound (14 mg, 58%) as a light brown oil, which was sufficiently pure for use in the next step; MS (EI): m/e = 144.2 [(M-Cl)H ⁺ ].

b) [6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(3-hydroxy-1-oxa-7-aza-spiro[4.4]nonan-7-yl)-methanone

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with 1-oxa-7-azaspiro[4.4]nonan-3-ol hydrochloride in the presence of TBTU and DIEA to give the title compound as a yellow oil; MS (EI): m/e=410.5 [MH ⁺ ].

Example 83

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(7-hydroxy-5-oxa-2-aza-spiro[3.4]octan-2-yl)-methanone

a) 7-Hydroxy-5-oxa-2-azonia-spiro[3.4]octane hydrochloride

In analogy to the procedure described in Example 82a), tert-butyl 7-hydroxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (which can be prepared analogously to tert-butyl 3-hydroxy-1-oxa-7-azaspiro[4.4]nonane-7-carboxylate (CAN 1331825-50-3) starting from tert-butyl 3-oxoazetidine-1-carboxylate (CAN 398489-26-4) as described in AI Moskalenko et al., Russian Journal of Organic Chemistry, 47(7), 1091-1096; 2011) was treated with 4M HCl in dioxane to give the title compound as a colorless solid, which was sufficiently pure for the next step; MS (EI): m/e = 130.2 [(M-Cl)H ⁺ ].

b) [6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(7-hydroxy-5-oxa-2-aza-spiro[3.4]octan-2-yl)-methanone

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with 5-oxa-2-azaspiro[3.4]octan-7-ol hydrochloride in the presence of TBTU and DIEA to give the title compound as a yellow oil; MS (EI): m/e=396.5 [MH ⁺ ].

Example 84

[5-Cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridin-2-yl]-(2,2-dimethyl-pyrrolidin-1-yl)-methanone

a) 5-Bromo-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid

To a solution of 6-chloro-5-bromo-pyridine-2-carboxylic acid (CAN 959958-25-9, 1.7 g, 7.19 mmol) in DMF (90 mL) and THF (30 mL) was added potassium tert-butoxide (2.02 g, 18.0 mmol) and 2,2,3,3,3-pentafluoropropan-1-ol (5.73 mL, 57.5 mmol). The mixture was stirred at 140° C. for 4 days, cooled and poured into ice-water (100 mL). 2M hydrochloric acid (15 mL) was added to adjust the pH to 2-3 and the mixture was extracted with TBME. The organic layers were washed twice with water, combined, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, ethyl acetate/n-heptane gradient) to give the title compound (548 mg, 22%) as a light brown solid; LC-MS (UV peak area, ESI) 100%, 347.9306 [MH ⁻ ].

b) 5-Cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid

A mixture of 5-bromo-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid (501 mg, 1.43 mmol), cyclopropylboronic acid (CAN 411235-57-9, 184 mg, 2.15 mmol), palladium diacetate (CAN 3375-31-3, 16.1 mg, 71.6 μmol), tricyclohexylphosphine (CAN 2622-14-2, 8.03 mg, 28.6 μmol) and potassium phosphate (1.06 g, 5.01 mmol) in toluene/water (20/1 v/v, 10.5 mL) was stirred at 100° C. for 22 hours. After cooling, the mixture was poured into ice-water (80 mL). 2M hydrochloric acid (25 mL) was added and the mixture was extracted with TBME. The organic layers were washed twice with water, combined, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, ethyl acetate/n-heptane gradient) to give the title compound (340 mg, 76%) as a pale white solid; LC-MS (UV peak area, ESI) 96.6%, 310.0513 [MH ⁻ ].

c) [5-Cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridin-2-yl]-(2,2-dimethyl-pyrrolidin-1-yl)-methanone

The title compound was synthesized in analogy to the procedure described in Example 47b using 5-cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid (40 mg, 129 μmol) and 2,2-dimethylpyrrolidine (CAN 35018-15-6; 18 μL, 141 μmol) as starting materials and isolated (41 mg, 81%) as a light brown oil; LC-MS (UV peak area, ESI) 100%, 393.1611 [MH ⁺ ].

Example 85

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(1S,5R)-8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl-methanone

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with (1R,5S)-8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (54745-74-3) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=380.5 [MH ⁺ ].

Example 86

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(1R,5S)-3-oxa-8-aza-bicyclo[3.2.1]octan-8-yl-methanone

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with (1R,5S)-3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (904316-92-3) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=380.6 [MH ⁺ ].

Example 87

(R)-1-[5-Cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carbonyl]-4,4-difluoro-pyrrolidine-2-carboxylic acid amide

The title compound was synthesized in analogy to the procedure described in Example 47b using 5-cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid (30 mg, 96 μmol) and (2R)-4,4-difluoropyrrolidine-2-carboxamide hydrochloride (CAN 1315053-41-8; 19.8 mg, 106 μmol) as starting materials and isolated (38 mg, 89%) as a white solid; LC-MS (UV peak area, ESI) 97%, 444.1155 [MH ⁺ ].

Example 88

1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-piperidine-2-carboxylic acid amide

The title compound was synthesized in a similar manner to the procedure described in Example 47b using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3c, 100 mg, 429 μmol) and 2-piperidinecarboxamide (CAN 19889-77-1, 60.4 mg, 472 μmol) as starting materials and isolated (135 mg, 92%) as a white solid; LC-MS (UV peak area, ESI) 100%, 344.1972 [MH ⁺ ].

Example 89

4-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-thiomorpholine-3-carboxylic acid amide

The title compound was synthesized in analogy to the procedure described in Example 47b using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3c, 100 mg, 429 μmol) and 3-thiomorpholinecarboxamide (CAN 103742-31-0, 68.9 mg, 472 μmol) as starting materials and isolated (119 mg, 77%) as a white solid; LC-MS (UV peak area, ESI) 100%, 362.1540 [MH ⁺ ].

Example 90

1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-4,4-dimethyl-pyrrolidine-2-carboxylic acid amide

a) 4,4-Dimethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester

To a solution of 4,4-dimethyl-proline (1.7 g, 11.8 mmol) in anhydrous dioxane (29 mL) and water (24 mL) was added 1 N sodium hydroxide solution (9 mL), followed by the slow addition of di-tert-butyl dicarbonate (1.80 g, 8.2 mmol) dissolved in dioxane (5 mL) at ambient temperature. Additional 1 N sodium hydroxide solution (3 mL) was added and the mixture was stirred overnight. Additional di-tert-butyl dicarbonate (1.80 g, 8.2 mmol) dissolved in dioxane (5 mL) was added and stirring continued for 3 hours. The mixture was concentrated, 1 N sodium bisulfite solution (22 mL) was added and the suspension was extracted with ethyl acetate. The organic phases were washed with water and brine, combined, dried over _MgSO₄ , filtered and concentrated. The solid was crystallized from diethyl ether by adding heptane and dried in vacuo to give the title compound (2.54 g, 89%) as a white crystalline solid; MS (ESI) 242.0 [MH-].

b) 4,4-Dimethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl 2-(2,5-dioxo-pyrrolidin-1-yl) ester

A solution of 1-tert-butyl 4,4-dimethyl-pyrrolidine-1,2-dicarboxylate (2.0 g, 8.22 mmol) in THF (20 mL) was cooled to 0°C. To the cold solution was added N-hydroxysuccinimide (1.2 g, 10.4 mmol) and diisopropylcarbodiimide (1.32 g, 10.4 mmol). The cooling was removed and the mixture was stirred at room temperature for 3 hours. The urea was filtered off, washed with diethyl ether and the filtrate was concentrated. The residue was partitioned between ethyl acetate and cold water; the organic phases were washed with cold brine, combined, dried over _MgSO4 , filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, heptane/ethyl acetate 9:1) to give the title compound (1.95 g, 70%) as a colorless oil; MS (ESI) 341.1 [MH ⁺ ].

b) 2-Carbamoyl-4,4-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

A solution of 1-tert-butyl 4,4-dimethyl-pyrrolidine-1,2-dicarboxylate 2-(2,5-dioxo-pyrrolidin-1-yl) ester (1.9 g, 5.58 mmol) in DCM (20 mL) was cooled to 0°C. Gaseous ammonia was bubbled through the cold solution for 15 minutes, and stirring was continued under cooling for 1 hour. The succinimide was filtered off, washed with DCM, and the filtrate was partitioned between ethyl acetate and cold brine; _the organic phases were combined, dried over _Na2SO4 , filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica, ethyl acetate) to give the title compound (1.33 g, 98%) as a colorless foam; MS (ESI) 243.1 [MH ⁺ ].

d) 4,4-Dimethyl-pyrrolidine-2-carboxamide hydrochloride

A solution of tert-butyl 2-carbamoyl-4,4-dimethyl-pyrrolidine-1-carboxylate (1.2 g, 4.95 mmol) in dioxane (5 mL) was cooled to 10° C. Hydrogen chloride dissolved in dioxane (10 mL, 6.4 N) was added and the mixture was stirred for 1.5 hours. Diethyl ether (50 mL) was added to completely precipitate the product, which was filtered and dried to give the title compound (0.84 g, 95%) as a colorless solid; MS (ESI) 143.0 [MH ⁺ ].

e) 1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-4,4-dimethyl-pyrrolidine-2-carboxylic acid amide

The title compound was synthesized in a similar manner to the procedure described in Example 47b using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3c, 100 mg, 429 μmol) and 4,4-dimethyl-pyrrolidine-2-carboxylic acid amide hydrochloride (84.3 mg, 472 μmol) as starting materials and isolated (145 mg, 95%) as a white foam; LC-MS (UV peak area, ESI) 100%, 358.2124 [MH ⁺ ].

Example 91

(+)-1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-piperidine-2-carboxamide

The enantiomers of 1-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-piperidine-2-carboxylic acid amide (Example 88) were separated by chiral HPLC (Reprosil Chiral NR, 25% ethanol in n-heptane). The (+) enantiomer (47 mg, 40%) was isolated as a white solid; LC-MS (UV peak area/ESI) 100%, 344.1976 [ ^{MH +} ]; (+) enantiomer, ∼100% ee;

Example 92

(-)-1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-piperidine-2-carboxylic acid amide

The enantiomers of 1-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-piperidine-2-carboxylic acid amide (Example 88) were separated by chiral HPLC (Reprosil Chiral NR, 25% ethanol in n-heptane). The (-) enantiomer (47 mg, 40%) was isolated as a white solid; LC-MS (UV peak area/ESI) 100%, 344.1966 [ ^{MH +} ]; (-) enantiomer, ∼100% ee;

Example 93

(-)-4-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-thiomorpholine-3-carboxylic acid amide

The enantiomers of 4-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-thiomorpholine-3-carboxylic acid amide (Example 89) were separated by chiral HPLC (Reprosil Chiral NR, 30% ethanol in n-heptane). The (-) enantiomer (49 mg, 47%) was isolated as a white solid; LC-MS (UV peak area/ESI) 100%, 362.1541 [MH ⁺ ]; (-) enantiomer, ˜100% ee.

Example 94

(+)-1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-4,4-dimethyl-pyrrolidine-2-carboxylic acid amide

The enantiomers of 1-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-4,4-dimethyl-pyrrolidine-2-carboxylic acid amide (Example 90e) were separated by chiral HPLC (Reprosil Chiral NR, 20% ethanol in n-heptane). The (+) enantiomer (65 mg, 49%) was isolated as a white foam; LC-MS (UV peak area/ESI) 100%, 358.2125 [ ^{MH +} ]; (+) enantiomer, ∼79% ee;

Example 95

(-)-1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-4,4-dimethyl-pyrrolidine-2-carboxylic acid amide

The enantiomers of 1-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-4,4-dimethyl-pyrrolidine-2-carboxylic acid amide (Example 90e) were separated by chiral HPLC (Reprosil Chiral NR, 20% ethanol in n-heptane). The (-) enantiomer (50 mg, 38%) was isolated as a white foam; LC-MS (UV peak area/ESI) 100%, 358.2133 [MH ⁺ ]; (-) enantiomer, ∼99.5% ee;

Example 96

3-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-thiazolidine-4-carboxylic acid amide

The title compound was synthesized in a similar manner to the procedure described in Example 47b using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3c, 100 mg, 429 μmol) and 4-thiazolidinecarboxamide (CAN 103749-87-7, 62.3 mg, 472 μmol) as starting materials and isolated (114 mg, 77%) as a white solid; LC-MS (UV peak area, ESI) 100%, 348.1377 [MH ⁺ ].

Example 97

(-)-3-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-thiazolidine-4-carboxylic acid amide

The enantiomers of 3-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-thiazolidine-4-carboxylic acid amide (Example 96) were separated by chiral HPLC (Reprosil Chiral NR, 40% ethanol in n-heptane). The (-) enantiomer (48 mg, 48%) was isolated as a white solid; LC-MS (UV peak area/ESI) 97.9%, 348.1378 [MH ⁺ ]; (-) enantiomer, ˜100% ee.

Example 98

1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-4,4-dimethyl-pyrrolidine-2-carboxylic acid amide

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with 4,4-dimethyl-pyrrolidine-2-carboxylic acid amide hydrochloride (Example 90d)) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=380.6 [MH ⁺ ].

Example 99

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(5-oxa-2-aza-spiro[3.4]octan-2-yl)-methanone

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with 5-oxa-2-azaspiro[3.4]octane hydrochloride (1359656-11-3) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=380.5 [MH ⁺ ].

Example 100

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(1-oxa-7-aza-spiro[4.4]nonan-7-yl)-methanone

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with 1-oxa-7-azaspiro[4.4]nonane (176-12-5) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=394.5 [MH ⁺ ].

Example 101

(5-Aza-spiro[3.4]octan-5-yl)-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-methanone

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with 5-azaspiro[3.4]octane (52876-78-5) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=378.5 [MH ⁺ ].

Example 102

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

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with 3,3-difluoroazetidine hydrochloride (CAN 288315-03-7) in the presence of TBTU and DIEA to give the title compound as a colorless solid; MS (EI): m/e=360.4 [MH ⁺ ].

Example 103

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(1,1-difluoro-5-aza-spiro[2.4]hept-5-yl)-methanone

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with 1,1-difluoro-5-azaspiro[2.4]heptane hydrochloride (1215071-12-7) in the presence of TBTU and DIEA to give the title compound as a colorless solid; MS (EI): m/e=400.5 [MH ⁺ ].

Example 104

(5-Aza-spiro[2.4]hept-5-yl)-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-methanone

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with 5-azaspiro[2.4]heptane hydrochloride (3659-21-0) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=364.5 [MH ⁺ ].

Example 105

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

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with 1-cyclopropyl-N-methylmethanamine hydrochloride (77335-18-3) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=352.4 [MH ⁺ ].

Example 106

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(4-cyclopropylmethyl-piperazin-1-yl)-methanone

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with 1-(cyclopropylmethyl)piperazine (57184-25-5) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=407.6 [MH ⁺ ].

Example 107

3-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-3-aza-bicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with 3-azabicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester (179236-79-4) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=422.5 [MH ⁺ ].

Example 108

1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-pyrrolidine-2-carboxylic acid methyl ester

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with pyrrolidine-2-carboxylic acid methyl ester hydrochloride (79397-50-5) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=396.5 [MH ⁺ ].

Example 109

4-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-piperazine-1-carboxylic acid benzyl ester

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with piperazine-1-carboxylic acid benzyl ester (31166-44-6) in the presence of TBTU and DIEA to give the title compound as a light brown oil; MS (EI): m/e=487.5 [MH ⁺ ].

Example 110

3-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-3-aza-bicyclo[3.1.0]hexane-6-carboxylic acid

Following a procedure analogous to that described in Example 24, 3-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-3-aza-bicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester (Example 107) was saponified to give the title compound as a colorless solid; MS (EI): m/e = 394.5 [MH ⁺ ].

Example 111

1-[5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carbonyl]-1,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester

In analogy to the procedure described in Example 47b), 5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid (Example 5g)) was reacted with tert-butyl 1,8-diazaspiro[4.5]decane-8-carboxylate (937729-06-1) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=494.6 [MH ⁺ ].

Example 112

(-)-3-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-thiazolidine-4-carboxylic acid amide

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with 4-thiazolidinecarboxamide (CAN103749-87-7) in the presence of TBTU and DIEA in a procedure analogous to that described in Example 47b). The enantiomer mixture was separated by chiral HPLC (Reprosil Chiral NR). The (-) enantiomer was isolated as a white solid; MS (EI): m/e = 399.4 [MH ⁺ ];

Example 113

[5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridin-2-yl]-(1,8-diaza-spiro[4.5]dec-1-yl)-methanone

A solution of tert-butyl 1-(5-cyclopropyl-6-(4-fluorobenzyl)picolinyl)-1,8-diazaspiro[4.5]decane-8-carboxylate (Example 111, 19 mg, 38.5 μmol) and 2,2,2-trifluoroacetic acid (43.9 mg, 29.5 μL, 385 μmol) in DCM (0.4 mL) was stirred at ambient temperature for 12 h. The reaction mixture was poured onto 20 mL of saturated aqueous _NaHCO₃ /ice and extracted with EtOAc (2 x 20 mL). The combined extracts were washed with ice-water/brine (20 mL), _dried over _Na₂SO₄ , and dried to dryness to afford the title compound (14 mg, 92%) as a colorless oil; MS (EI): m/e = 394.5 [ ^MH⁺ ].

Example 114

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

a) 1-(6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinoyl)pyrrolidine-2-carboxylic acid

Following a procedure analogous to that described in Example 24, 1-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-pyrrolidine-2-carboxylic acid methyl ester (Example 108) was saponified to give the title compound as a colorless solid; MS (EI): m/e = 382.5 [MH ⁺ ].

b) 1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-pyrrolidine-2-carboxylic acid amide

To an ice-cold solution of 1-(6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinyl)pyrrolidine-2-carboxylic acid (8.6 mg, 22.6 μmol) in DMF (2 mL) was added carbonyldiimidazole (10.2 mg, 63.1 μmol). After 5 minutes, the reaction mixture was warmed to ambient temperature and stirred for 2 hours. NH ₃ gas was bubbled through the solution for 10 minutes and stirring was continued for 12 hours. The reaction mixture was poured onto ice-water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined extracts were dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound (9 mg, quantitative) as a colorless wax; MS (EI): m/e = 381.5 [MH ⁺ ].

Example 115

(-)-3-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-1,1-dioxo-1λ ⁶ -thiazolidine-4-carboxylic acid amide

To a suspension of (-)-3-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-thiazolidine-4-carboxylic acid amide (Example 97, 60 mg, 173 μmol) in DCM (6 mL) was added m-CPBA (65.6 mg, 380 μmol) and the reaction mixture was stirred at room temperature for 3 hours. 1N sodium hydroxide solution (3 mL) was added and the mixture was dried by filtration over Celite® and concentrated in vacuo. The residue was purified by flash chromatography (silica, DCM/methanol 0-5%) to give the title compound (21 mg, 32%) as a white solid; LC-MS (UV peak area/ESI) 100%, 380.1286 [MH ⁺ ].

Example 116

(1S,4R)-3-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-1-oxo-1λ ⁴ -thiazolidine-4-carboxylic acid amide or (1R,4S)-3-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-1-oxo-1λ ⁴ -thiazolidine-4-carboxylic acid amide

To a suspension of (-)-3-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-thiazolidine-4-carboxylic acid amide (Example 97, 60 mg, 173 μmol) in DCM (6 mL) was added m-CPBA (65.6 mg, 380 μmol) and the reaction mixture was stirred at room temperature for 3 hours. 1N sodium hydroxide solution (3 mL) was added and the mixture was dried by filtration over Celite® and concentrated in vacuo. The residue was purified by flash chromatography (silica, DCM/methanol 0-5%) to give the title compound (30 mg, 48%) as a white solid; LC-MS (UV peak area/ESI) 95.8%, 364.1335 [MH ⁺ ].

Example 117

(+)-3-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-1,1-dioxo-1λ ⁶ -thiazolidine-4-carboxylic acid amide

a)(+)-3-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-thiazolidine-4-carboxylic acid amide

The enantiomers of 3-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-thiazolidine-4-carboxylic acid amide (Example 96) were separated by chiral HPLC (Reprosil Chiral NR, 40% ethanol in n-heptane). The (+) enantiomer (34 mg, 34%) was isolated as a white solid; LC-MS (UV peak area/ESI) 100%, 348.1380 [ ^{MH +} ]; (+) enantiomer, ˜100% ee.

b) (+)-3-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-1,1-dioxo-1λ ⁶ -thiazolidine-4-carboxylic acid amide

To a suspension of (+)-3-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-thiazolidine-4-carboxylic acid amide (60 mg, 173 μmol) in DCM (6 mL) was added m-CPBA (65.6 mg, 380 μmol) and the reaction mixture was stirred at room temperature overnight. 1N sodium hydroxide solution (3 mL) was added and the mixture was dried by filtration over Celite® and concentrated in vacuo. The residue was purified by flash chromatography (silica, DCM/methanol 0-5%) to give the title compound (31 mg, 47%) as a white solid; LC-MS (UV peak area/ESI) 99.0%, 380.1279 [MH ⁺ ].

Example 118

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(3,3,4,4-tetrafluoro-pyrrolidin-1-yl)-methanone

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with 3,3,4,4-tetrafluoropyrrolidine hydrochloride (1810-13-5) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=410.5 [MH ⁺ ].

Example 119

[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(2,6-dimethyl-morpholin-4-yl)-methanone

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with 2,6-dimethylmorpholine (141-91-3) in the presence of TBTU and DIEA to give the title compound as a colorless oil; MS (EI): m/e=382.5 [MH ⁺ ].

Example 120

(R)-3-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-5,5-dimethyl-thiazolidine-4-carboxylic acid amide

a) (R)-5,5-Dimethylthiazolidine-4-carboxamide hydrochloride

In analogy to the procedure described in Example 114b), (R)-3-(tert-butoxycarbonyl)-5,5-dimethylthiazolidine-4-carboxylic acid (CAN 117918-23-7) was converted into the title compound in the form of a colorless solid; MS (EI): m/e=260 [M ⁺ ].

b) (R)-5,5-Dimethylthiazolidine-4-carboxamide hydrochloride

In analogy to the procedure described in Example 82a), (R)-tert-butyl 4-carbamoyl-5,5-dimethylthiazolidine-3-carboxylate was treated with 4M HCl in dioxane to give the title compound as a yellow solid, sufficiently pure for the next step; MS (EI): m/e = 161.2 [(M-Cl)H ⁺ ].

c) (R)-3-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-5,5-dimethyl-thiazolidine-4-carboxylic acid amide

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with (R)-5,5-dimethylthiazolidine-4-carboxamide hydrochloride in the presence of TBTU and DIEA to give the title compound as a light yellow solid; MS (EI): m/e = 427.4 [MH ⁺ ].

Example 121

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

a) (S)-5,5-Dimethylpyrrolidine-2-carboxamide hydrochloride

In analogy to the procedure described in Example 82a), (S)-tert-butyl 5-carbamoyl-2,2-dimethylpyrrolidine-1-carboxylate (CAN 1292838-05-1) was treated with 4M HCl in dioxane to give the title compound as a colorless solid sufficiently pure for the next step; MS (EI): m/e = 143.2 [(M-Cl)H ⁺ ].

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

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with (S)-5,5-dimethylpyrrolidine-2-carboxamide hydrochloride in the presence of TBTU and DIEA to give the title compound as a colorless foam; MS (EI): m/e=409.5 [MH ⁺ ].

Example 122

3-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-thiazolidine-4-carboxylic acid amide

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b)) was reacted with 4-thiazolidinecarboxamide (CAN103749-87-7) in the presence of TBTU and DIEA to give the title compound as a white solid; MS (EI): m/e=399.5 [MH ⁺ ].

Example 123

(2S,4R)-1-[5-Cyclopropyl-6-(cyclopropylmethoxy)pyridine-2-carbonyl]-4-fluoropyrrolidine-2-carboxamide

In analogy to the procedure described in Example 47b), 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3c, 50 mg, 214 μmol) was reacted with (2S,4R)-4-fluoropyrrolidine-2-carboxamide hydrochloride (CAN 796884-06-5, 39.8 mg, 236 μmol) to give the title compound (54 mg, 73%) as a white solid; LC-MS (UV peak area, ESI) 100%, 348.1727 [MH ⁺ ].

Example 124

3-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-1-oxo-1,3-thiazolidine-4-carboxamide

3-Chloroperbenzoic acid (172 mg, 994 μmol) was added to a solution of 3-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-thiazolidine-4-carboxylic acid amide (Example 122, 180 mg, 452 μmol) in dichloromethane (1.8 mL). The reaction mixture was stirred at ambient temperature for 12 h, poured onto sodium thiosulfate/ice water (1 x 15 mL) and extracted with EtOAc (2 x 20 mL). The combined extracts were washed with ice/brine (1 x 25 mL), dried over Na ₂ SO ₄ and filtered. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC (methanol/formic acid 95/5) to give the title compound (9 mg, 5%) as a light yellow solid; MS (EI): m/e = 415.4 [MH ⁺ ].

Example 125

3-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidine-4-carboxamide

3-Chloroperbenzoic acid (172 mg, 994 μmol) was added to a solution of 3-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-thiazolidine-4-carboxylic acid amide (Example 122, 180 mg, 452 μmol) in dichloromethane (1.8 mL). The reaction mixture was stirred at ambient temperature for 12 h, poured onto sodium thiosulfate/ice water (1 x 15 mL) and extracted with EtOAc (2 x 20 mL). The combined extracts were washed with ice/brine (1 x 25 mL), dried over Na ₂ SO ₄ and filtered. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC (methanol/formic acid 95/5) to give the title compound (9 mg, 5%) as a light yellow solid; MS (EI): m/e = 431.4 [MH ⁺ ].

Example 126

(2S,4R)-1-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-4-fluoropyrrolidine-2-carboxamide

In analogy to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b, 25 mg, 87.9 μmol) was reacted with (2S,4R)-4-fluoropyrrolidine-2-carboxamide hydrochloride (CAN 796884-06-5, 17.8 mg, 106 μmol) to give the title compound (17 mg, 49%) as a white solid; MS (EI): m/e = 399.4 [MH ⁺ ].

Example 127

(-)-3-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidine-4-carboxamide

a) 1,1-dioxo-1,3-thiazolidine-3,4-dicarboxylic acid O3-tert-butyl ester O4-methyl ester

3-Chloroperbenzoic acid (698 mg, 4.04 mmol) was added to an ice-cold solution of 3-tert-butyl 4-methyl thiazolidine-3,4-dicarboxylate (CAN 63664-10-8, 0.5 g, 2.02 mmol) in dichloromethane (4 mL). The suspension was stirred at ambient temperature for 2 h. Further 3-chloroperbenzoic acid (349 mg, 2.02 mmol) was added and stirring was continued at ambient temperature for 12 h. The reaction mixture was poured onto ice water/saturated _NaHCO₃ solution (50 mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (2 x 50 mL). The combined organic layers were washed with ice water/brine (30 mL), _dried over _Na2SO4 and concentrated in vacuo to give a yellow oil, which was purified by column chromatography (20 g silica gel, heptane/AcOEt 0-20% in 120 min) to obtain the title compound (362 mg, 64%) as a colorless liquid, MS (ESI) m/e = 180.1 [MH-Boc ⁺ ].

b) 3-tert-Butoxycarbonyl-1,1-dioxo-1,3-thiazolidine-4-carboxylic acid

A solution of 03-tert-butyl 04-methyl 1,1-dioxo-1,3-thiazolidine-3,4-dicarboxylate (Example 127a, 0.35 g, 1.25 mmol) and lithium hydroxide hydrate (63.1 mg, 1.5 mmol) in THF (3.5 mL) and water (1.05 mL) was stirred at ambient temperature for 20 h. The reaction mixture was poured onto ice/0.1 N HCl (25 mL) and extracted with EtOAc (2 x 25 mL). The combined extracts were washed with ice/brine (1 x 25 _mL ), dried over _Na2SO4 , and filtered. The solvent was removed under reduced pressure and purified to afford the title compound (306 mg, 92%) as a colorless foam, MS (ESI) m/e = 264.05 [ ^MH- ].

c) tert-Butyl 4-carbamoyl-1,1-dioxo-1,3-thiazolidine-3-carboxylate

Carbonyldiimidazole (520 mg, 3.21 mmol) was added to an ice-cold solution of 3-tert-butoxycarbonyl-1,1-dioxo-1,3-thiazolidine-4-carboxylic acid (Example 127b, 304 mg, 1.15 mmol) in DMF (1 mL). After 5 min, the mixture was warmed to ambient temperature and stirred for 2 h. Gaseous NH ₃ was bubbled through the solution for 10 min while maintaining the temperature below 20° C. Stirring was continued at ambient temperature for 12 h. The reaction mixture was poured into 30 mL of ice/water/1N HCl and extracted with EtOAc (2 x 30 mL). The combined extracts were washed with ice/brine (20 mL). Dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound (197 mg, 65%) as a white solid, MS (ESI) m/e=263.1 [MH ⁻ ].

d) 1,1-Dioxo-1,3-thiazolidine-4-carboxamide hydrochloride

An ice-cold 4M solution of HCl in dioxane (4.73 mL, 18.9 mmol) was added to a solution of tert-butyl 4-carbamoyl-1,1-dioxo-1,3-thiazolidine-3-carboxylate (Example 127c, 500 mg, 1.89 mmol) in dichloromethane (10.2 mL). The mixture was stirred at ambient temperature for 4 days. The solvent was removed in vacuo to give the title compound (388 mg, quantitative) as a white solid, which was used directly in the next reaction step without further purification, MS (ESI) m/e=198.99 [MH ⁻ ].

e) (-)-3-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidine-4-carboxamide

By 6- cyclopropylmethoxy -5- (3,3- bis-fluoro- azetidine -1- bases) -pyridine -2- carboxylic acid (embodiment 1b, 200mg, 704μmol), 1,1- dioxo -1,3- thiazolidine -4- carboxamide hydrochloride (embodiment 127d, 169mg, 844μmol), 2- bromo -1- ethylpyridine tetrafluoroborate (212mg, 774μmol) and DIEA (273mg, 361μL, 2.11mmol) solution in THF (20mL) is stirred 24h in environment temperature.Solvent is removed under reduced pressure, ice/saturated NaHCO _The aqueous solution (75mL) and EtOAc (75mL) are added and each layer is separated.Water layer is extracted (75mL) with EtOAc. The combined extracts were washed with ice/0.1N HCl (75 mL) and ice/brine (75 mL), dried over _Na₂SO₄ , and filtered. The solvent was removed under reduced pressure to give _a yellow solid, which was recrystallized from EtOAc (3 mL). The crude product was purified (Reprosil Chiral NR, EtOH/heptane 40%/60%) to give the title compound (63 mg, 21%) as a colorless oil. MS (EI): m/e = 431.3 [ ^MH⁺ ].

Example 128

3-[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidine-4-carboxamide

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

Under nitrogen atmosphere, 3-methoxyazetidine (38 mg, 0.44 mmol), BINAP (23 mg, 0.037 mmol), Pd ₂ (dba) ₃ (17 mg, 0.02 mmol) and Cs ₂ CO ₃ (240 mg, 0.735 mmol) were added to a solution of 5-bromo-6-(cyclopropylmethoxy)pyridine-2-carboxylic acid (CAN 1415898-37-1, 100 mg, 0.37 mmol) in toluene (4 mL). The reaction mixture was stirred at 110 ° C overnight and then concentrated under reduced pressure. The residue was dissolved in water and extracted with ethyl acetate (30 mL). The aqueous layer was adjusted to pH 2 by adding 1N HCl. The resulting precipitate was collected by filtration and dried under vacuum. Purification by chromatography on silica gel using petroleum ether/ethyl acetate = 1/2 gave the title compound (35 mg, 34%) as a yellow solid, LC-MS: 265.2 [MH ⁺ ].

b) 3-[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidine-4-carboxamide

In a manner analogous to the procedure described in Example 127e), 6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxylic acid (Example 128a, 30 mg, 108 μmol) was reacted with 1,1-dioxo-1,3-thiazolidine-4-carboxamide hydrochloride (Example 127d, 26.0 mg, 129 μmol) to give the title compound (15 mg, 33%) as a pale white solid, MS (EI): m/e = 425.5 [MH ⁺ ].

Example 129

(2S)-1-[6-(Cyclopropylmethoxy)-5-(1-hydroxycyclobutyl)pyridine-2-carbonyl]-4,4-difluoropyrrolidine-2-carboxamide

In analogy to the procedure described in Example 127e), 6-(cyclopropylmethoxy)-5-(1-hydroxycyclobutyl)picolinic acid (CAN 1415899-53-4, 15 mg, 57 μmol) was reacted with (S)-4,4-difluoropyrrolidine-2-carboxamide hydrochloride (CAN 426844-51-1, 10.6 mg, 57 μmol) to give the title compound (6 mg, 21%) as a light yellow oil, LC-MS (UV peak area, ESI) 100%, 396.1740 [MH ⁺ ].

Example 130

(2S)-1-[6-(Cyclopropylmethoxy)-5-(1-fluorocyclobutyl)pyridine-2-carbonyl]-4,4-difluoropyrrolidine-2-carboxamide

a) 1-(2-chloro-6-methylpyridin-3-yl)cyclobutanol

A suspension of molecular sieves and 3-bromo-2-chloro-6-methylpyridine (CAN 185017-72-5, 5 g, 24.2 mmol) in THF (50 mL) was cooled to -15°C. A 1.3 M isopropylmagnesium chloride lithium chloride complex solution (19.6 mL, 25.4 mmol) in THF was added over 30 min. Stirring was continued at -15°C for 1 h. Cyclobutanone (1.87 g, 2.00 mL, 26.6 mmol) was slowly added. Stirring was continued at -15°C for 2 h and at 0°C for an additional 2 h. Water (2.5 mL) was added, and the mixture was concentrated under vacuum and poured onto a saturated NH ₄ Cl aqueous solution. The mixture was extracted with EtOAc (2 x 100 mL). The combined extracts were washed with ice water (50 mL). Dried over Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 140 g, heptane/EtOAc 0-40% in 120 min) to give the title compound (3.33 g, 70%) as a white solid, MS (ESI): m/e = 198.1 [MH ⁺ ].

b) 2-Chloro-3-(1-fluorocyclobutyl)-6-methylpyridine

Diethylaminosulfur trifluoride (1.22 g, 1.00 mL, 7.57 mmol) was added to an ice-cold solution of 1-(2-chloro-6-methylpyridin-3-yl)cyclobutanol (Example 130a, 1 g, 5.06 mmol) in dichloromethane (10 mL) while maintaining the temperature below 5°C. The reaction mixture was stirred at 0°C for 30 min, poured onto ice water/saturated _{aqueous Na2CO3} solution (35 mL) and extracted with dichloromethane (2 x 50 mL). The organic layers were combined, washed with ice water/brine (30 _mL ), dried over _Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 50 g, heptane/EtOAc 0-10% over 75 min) to give the title compound (939 mg, 93%) as a colorless oil, MS (ESI): m/e = 200.3 [MH ⁺ ].

c) 2-Chloro-3-(1-fluorocyclobutyl)-6-methylpyridine 1-oxide

3-Chloroperoxybenzoic acid (173 mg, 1.00 mmol) was added to a solution of 2-chloro-3-(1-fluorocyclobutyl)-6-methylpyridine (Example 130b, 100 mg, 501 μmol) in dichloromethane (2 mL) in two portions. The reaction mixture was stirred at ambient temperature for 72 h, poured onto _a 10% _{aqueous Na₂S₂O₃} solution (30 mL) and extracted with dichloromethane (2 _x 40 mL). The combined organic layers were washed with ice water/brine (30 mL), dried over _Na₂SO₄ and concentrated in vacuo. The residue was dissolved in dichloromethane, washed with a saturated aqueous _NaHCO₃ solution (30 mL) and ice water (30 mL), _dried over _Na₂SO₄ and concentrated in vacuo to afford the title compound (81 mg, 74%) as a yellow oil, MS (ESI): m/e = 216.3 [ ^MH⁺ ].

d)(6-chloro-5-(1-fluorocyclobutyl)pyridin-2-yl)methanol

Trifluoroacetic anhydride (1.27 g, 840 μL, 6.04 mmol) was added to a solution of 2-chloro-3-(1-fluorocyclobutyl)-6-methylpyridine 1-oxide (Example 130c, 869 mg, 4.03 mmol) in dichloromethane (10.9 mL) under ice-cooling. The mixture was stirred at ambient temperature for 72 h. After cooling in an ice bath, 5N NaOH solution (1 mL) and then ice water (20 mL) were added. The mixture was extracted with dichloromethane (2 x 40 mL). The combined organic layers were washed with ice water/brine (20 mL), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 50 g, heptane/EtOAc 0-40% in 120 min) to give the title compound (279 mg, 32%) as a light yellow oil, MS (ESI): m/e=216.3 [MH ⁺ ].

e) 6-Chloro-5-(1-fluorocyclobutyl)pyridine-2-carboxylic acid

Under an argon atmosphere, aqueous phosphate buffer (pH = 6.7, 0.7 mL) and TEMPO (2.54 mg, 16.2 μmol) were added to a solution of (6-chloro-5-(1-fluorocyclobutyl)pyridin-2-yl)methanol (Example 130d, 50 mg, 232 μmol) in acetonitrile (1 mL). The reaction mixture was warmed to 35° C. A solution of sodium chlorite (52.4 mg, 464 μmol) in 150 μL of water and a solution of sodium hypochlorite (2.66 mg, 2.19 μL, 4.64 μmol) in 100 μL of water were added simultaneously over a 30-min period. Stirring was continued at 35° C. for 20 h. Water (40 mL) and 2N NaOH solution (8 mL) were added. The mixture was poured into an ice-cold Na ₂ SO ₃ solution (1.62 _{Na 2} SO ₃ g in 30 mL of water) and stirred at ambient temperature for 30 min. Under ice cooling, the mixture was acidified with 25 mL of 2N HCl solution and extracted with a mixture of 100 mL of EtOAc and ₂₀ mL of THF. The organic layer was dried over _Na2SO4 , filtered and the solvent was concentrated in vacuo to give the title compound (66 mg, 90%) as a yellow oil, MS (ESI): m/e = 230.4 [MH ⁺ ].

f) 6-(Cyclopropylmethoxy)-5-(1-fluorocyclobutyl)pyridine-2-carboxylic acid

Powdered potassium hydroxide (240mg, 4.28mmol) is added to a solution of 6-chloro-5-(1-fluorocyclobutyl)pyridine-2-carboxylic acid (Example 130e, 393mg, 1.71mmol) in DMSO (7.86mL). The mixture is stirred at ambient temperature for 15 minutes. Cyclopropylmethanol (136mg, 153 μL, 1.88mmol) is added and continued to stir for 5h at 60°C. Other cyclopropylmethanol (68mg, 76 μL, 94mmol) is added and the mixture is stirred at ambient temperature for 14h, poured onto ice/brine (100mL) and extracted with TBME (2x100mL). The water layer is acidified with 1N HCl and extracted with EtOAc (2x150mL). The combined organic layer is washed with ice/brine (50mL), used _Na SO _dried and filtered. The solvent was removed under reduced pressure and the residue was flash chromatographed (20 g SiO ₂ , dichloromethane/MeOH 0-3% in 75 min) to give the title compound (65 mg, 31%) as a colorless oil, MS (ESI) m/e = 264.5 [MH ⁻ ].

g) (2S)-1-[6-(cyclopropylmethoxy)-5-(1-fluorocyclobutyl)pyridine-2-carbonyl]-4,4-difluoropyrrolidine-2-carboxamide

In analogy to the procedure described in Example 127e), 6-(cyclopropylmethoxy)-5-(1-fluorocyclobutyl)picolinic acid (Example 130f, 20 mg, 49.8 μmol) was reacted with (S)-4,4-difluoropyrrolidine-2-carboxamide hydrochloride (CAN426844-51-1, 11.1 mg, 59.7 μmol) to give the title compound (18 mg, 91%) as a pale white solid, MS (EI): m/e = 398.4 [MH ⁺ ].

Example 131

3-[6-(cyclopropylmethoxy)-5-(1-hydroxycyclobutyl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidine-4-carboxamide

In analogy to the procedure described in Example 127e), 6-(cyclopropylmethoxy)-5-(1-hydroxycyclobutyl)pyridine-2-carboxylic acid (CAN 1415899-53-4, 50 mg, 190 μmol) was reacted with 1,1-dioxo-1,3-thiazolidine-4-carboxamide hydrochloride (Example 127d, 45.7 mg, 228 μmol) to give the title compound (7 mg, 8%) as a colorless oil, MS (EI): m/e = 410.5 [MH ⁺ ].

Example 132

(2S)-1-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-4-hydroxy-4-methylpyrrolidine-2-carboxamide

a) (2S)-tert-Butyl 2-carbamoyl-4-hydroxy-4-methylpyrrolidine-1-carboxylate

A solution of 1-tert-butyl 2-methyl (2S)-4-hydroxy-4-methylpyrrolidine-1,2-dicarboxylate (CAN 1430105-48-8, 50 mg, 193 μmol) in 7M NH ₃ in methanol (551 μL, 3.86 mmol) was stirred at ambient temperature for 72 h. The solvent was removed in vacuo to give the title compound (48 mg, quantitative) as a colorless oil, MS (ESI) m/e=145.2 [MH-Boc ⁺ ].

b) (2S)-4-Hydroxy-4-methylpyrrolidine-2-carboxamide hydrochloride

A solution of (2S)-tert-butyl 2-carbamoyl-4-hydroxy-4-methylpyrrolidine-1-carboxylate (Example 132a, 46 mg, 188 μmol) in 4M HCl in dioxane (942 μL, 3.8 mmol) was stirred at ambient temperature for 5 h. The solvent was removed in vacuo to afford the title compound (36 mg, quantitative) as a light brown solid, MS (ESI) m/e = 145.2 [MH ⁺ ].

c) (2S)-1-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-4-hydroxy-4-methylpyrrolidine-2-carboxamide

In a similar manner to the procedure described in Example 47b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b, 20 mg, 70.4 μmol) was reacted with (2S)-4-hydroxy-4-methylpyrrolidine-2-carboxamide hydrochloride (Example 132b, 15.3 mg, 84.4 μmol) to give the title compound (22 mg, 76%) as a pale white solid; MS (EI): m/e = 411.5 [MH ⁺ ].

Example 133

3-[6-(Cyclopropylmethoxy)-5-(1-fluorocyclobutyl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidine-4-carboxamide

In analogy to the procedure described in Example 127e), 6-(cyclopropylmethoxy)-5-(1-fluorocyclobutyl)pyridine-2-carboxylic acid (Example 130f) was reacted with 1,1-dioxo-1,3-thiazolidine-4-carboxamide hydrochloride (Example 127d) to give the title compound as a yellow oil, MS (EI): m/e = 412.13 [MH ⁺ ].

Example 134

(2S)-1-[6-(cyclopropylmethoxy)-5-(3-fluorooxetan-3-yl)pyridine-2-carbonyl]-4,4-difluoropyrrolidine-2-carboxamide

a) 3-(2-chloro-6-methylpyridin-3-yl)oxetane-3-ol

In analogy to the procedure described in Example 130a), 3-bromo-2-chloro-6-methylpyridine (CAN 185017-72-5, 5 g, 24.2 mmol) was reacted with oxetan-3-one (CAN 6704-31-0, 1.75 g, 1.42 mL, 24.2 mmol) to give the title compound (3.42 g, 71%) as a light white solid, MS (ESI): m/e = 200.5 [MH ⁺ ].

b) 2-Chloro-3-(3-fluorooxetan-3-yl)-6-methylpyridine

In analogy to the procedure described in Example 130b), 3-(2-chloro-6-methylpyridin-3-yl)oxetane-3-ol (Example 134a, 1.5 g, 7.51 mmol) was reacted with diethylaminosulfur trifluoride to give the title compound (850 mg, 56%) as a colorless liquid, MS (ESI): m/e = 202.1 [MH ⁺ ].

c) 2-Chloro-3-(3-fluorooxetan-3-yl)-6-methylpyridine 1-oxide

In analogy to the procedure described in Example 130c), 2-chloro-3-(3-fluorooxetan-3-yl)-6-methylpyridine (Example 134b, 850 mg, 4.22 mmol) was oxidized to give the title compound (875 mg, 95%) as a light brown solid, MS (ESI): m/e = 218.4 [MH ⁺ ].

d)(6-chloro-5-(3-fluorooxetane-3-yl)pyridin-2-yl)methanol

Following the procedure analogously to that described in Example 130d), 2-chloro-3-(3-fluorooxetan-3-yl)-6-methylpyridine 1-oxide (Example 134c, 870 mg, 4 mmol) was rearranged to give the title compound (154 mg, 18%) as a colorless liquid, MS (ESI): m/e = 218.4 [MH ⁺ ].

e) 6-Chloro-5-(3-fluorooxetan-3-yl)pyridine-2-carboxylic acid

In a similar manner to the procedure described in Example 130e), (6-chloro-5-(3-fluorooxetan-3-yl)pyridin-2-yl)methanol (Example 134d, 154 mg, 708 μmol) was oxidized to give the title compound (66 mg, 40%) as a pale white solid, MS (ESI): m/e = 232.1 [MH ⁺ ].

f) 6-(Cyclopropylmethoxy)-5-(3-fluorooxetan-3-yl)pyridine-2-carboxylic acid

6-Chloro-5-(3-fluorooxetane-3-yl)pyridine-2-carboxylic acid (Example 134e, 44 mg, 190 μmol) and cyclopropylmethanol (CAN 2516-33-8, 17.8 mg, 20.0 μL, 247 μmol) are dissolved in DMF (1.32 mL). A solution of 2-methylpropane-2-sodium oleate (42.0 mg, 437 μmol) in THF (800 μL) is added and the mixture is heated to 50° C. for 3 h and to 70° C. for another 3 h. After cooling to ambient temperature, the reaction mixture is poured onto ice/0.1N HCl (25 mL) and extracted with EtOAc (2x 25 mL). The combined extracts are washed with ice/brine (20 mL), _dried over _Na SO , filtered and evaporated to dryness. The residue was purified by thin layer chromatography (2 mm _SiO2 , dichloromethane/MeOH 19:1, elution with EtOAc) to give the title compound (11 mg, 22 mg) as a colorless oil, MS (ESI) m/e = 268.2 [MH ⁺ ].

g) (2S)-1-[6-(cyclopropylmethoxy)-5-(3-fluorooxetan-3-yl)pyridine-2-carbonyl]-4,4-difluoropyrrolidine-2-carboxamide

In analogy to the procedure described in Example 127e), 6-(cyclopropylmethoxy)-5-(3-fluorooxetan-3-yl)picolinic acid (Example 134f, 25 mg, 93.5 μmol) was reacted with (S)-4,4-difluoropyrrolidine-2-carboxamide hydrochloride (CAN 426844-51-1, 20.9 mg, 112 μmol) to give the title compound (20 mg, 54%) as a colorless oil, MS (EI): m/e = 400.2 [MH ⁺ ].

Example 135

5-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-5-azaspiro[2.4]heptane-6-carboxamide

a) tert-Butyl 6-carbamoyl-5-azaspiro[2.4]heptane-5-carboxylate

In analogy to the procedure described in Example 127c), 5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (CAN 1454843-77-6, 112 mg, 464 μmol) was condensed with aqueous ammonia to give the title compound (87 mg, 78%) as a colorless liquid, MS (EI): m/e = 240.0 [M ⁺ ].

b) 5-Azaspiro[2.4]heptane-6-carboxamide hydrochloride

In a similar manner to the procedure described in Example 132b), tert-butyl 6-carbamoyl-5-azaspiro[2.4]heptane-5-carboxylate (Example 135a, 65 mg, 270 μmol) was deprotected to give the title compound (55 mg, quantitative) as a light yellow solid, LC-MS (UV peak area/ESI) 100%, 141.1023 [MH ⁺ ].

c) 5-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-5-azaspiro[2.4]heptane-6-carboxamide

In analogy to the procedure described in Example 127e), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b, 18.6 mg, 106 μmol) was reacted with 5-azaspiro[2.4]heptane-6-carboxamide hydrochloride (Example 135b, 18.6 mg, 106 μmol) to give the title compound (16 mg, 56%) as a colorless liquid, MS (EI): m/e = 407.3 [MH ⁺ ].

Example 136

[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]-[3-(2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl]methanone

In analogy to the procedure described in Example 127e), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b, 20 mg, 70.4 μmol) was reacted with 2,2,2-trifluoro-1-(pyrrolidin-3-yl)ethanol hydrochloride (CAN corresponding to the free base: 943906-23-8, 14.5 mg, 70.4 μmol) to give the title compound (14 mg, 46%) as a colorless liquid, MS (EI): m/e = 436.4 [MH ⁺ ].

Example 137

[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]-[3-(hydroxymethyl)-3-(trifluoromethyl)pyrrolidin-1-yl]methanone

In analogy to the procedure described in Example 127e), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b, 20 mg, 70.4 μmol) was reacted with (3-(trifluoromethyl)pyrrolidin-3-yl)methanol hydrochloride (CAN 1260812-78-9, 17.4 mg, 84.4 μmol) to give the title compound (11 mg, 36%) as a colorless liquid, MS (EI): m/e = 436.4 [MH ⁺ ].

Example 138

[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]-[3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl]methanone

In analogy to the procedure described in Example 127e), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b, 40 mg, 141 μmol) was reacted with 3-(trifluoromethyl)pyrrolidin-3-ol hydrochloride (CAN 1334147-81-7, 32.4 mg, 169 μmol) to give the title compound (28 mg, 47%) as a light white solid, MS (EI): m/e = 422.3 [MH ⁺ ].

Example 139

[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone

In analogy to the procedure described in Example 127e), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b, 40 mg, 141 μmol) was reacted with 3-(trifluoromethyl)azetidin-3-ol hydrochloride (CAN 848192-96-1, 30.0 mg, 169 μmol) to give the title compound (32 mg, 56%) as a light white solid, MS (EI): m/e = 408.3 [MH ⁺ ].

Example 140

(+)-(2S)-1-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-4-hydroxy-4-methylpyrrolidine-2-carboxamide

In analogy to the procedure described in Example 127e), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b, 50 mg, 176 μmol) was reacted with (2S)-4-hydroxy-4-methylpyrrolidine-2-carboxamide hydrochloride (Example 132b, 39.7 mg, 176 μmol) and purified by chiral HPLC to give the title compound (8 mg, 10%) as a white solid, LC-MS (UV peak area, ESI) 93%, 411.1854 [MH ⁺ ].

Example 141

[5-Cyclopropyl-6-(cyclopropylmethoxy)pyridin-2-yl]-[3-(2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl]methanone

In a similar manner to the procedure described in Example 127e), 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3c, 20 mg, 85.7 μmol) and 2,2,2-trifluoro-1-(pyrrolidin-3-yl)ethanol hydrochloride (CAN corresponding to the free base: 943906-23-8, 21.2 mg, 103 μmol) were purified to give the title compound (16 mg, 49%) as a colorless liquid, MS (EI): m/e = 385.3 [MH ⁺ ].

Example 142

[5-Cyclopropyl-6-(cyclopropylmethoxy)pyridin-2-yl]-[3-(hydroxymethyl)-3-(trifluoromethyl)pyrrolidin-1-yl]methanone

In analogy to the procedure described in Example 127e), 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3c, 20 mg, 85.7 μmol) was reacted with (3-(trifluoromethyl)pyrrolidin-3-yl)methanol hydrochloride (CAN 1260812-78-9, 21.2 mg, 103 μmol) to give the title compound (12 mg, 36%) as a colorless liquid, MS (EI): m/e = 385.3 [MH ⁺ ].

Example 143

[5-Cyclopropyl-6-(cyclopropylmethoxy)pyridin-2-yl]-[3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl]methanone

In analogy to the procedure described in Example 127e), 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3c, 20 mg, 85.7 μmol) was reacted with 3-(trifluoromethyl)pyrrolidin-3-ol hydrochloride (CAN 1334147-81-7, 19.7 mg, 103 μmol) to obtain the title compound (15 mg, 47%) as a colorless liquid, MS (EI): m/e = 371.3 [MH ⁺ ].

Example 144

[5-Cyclopropyl-6-(cyclopropylmethoxy)pyridin-2-yl]-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone

In analogy to the procedure described in Example 127e), 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3c, 20 mg, 85.7 μmol) was reacted with 3-(trifluoromethyl)azetidin-3-ol hydrochloride (CAN 848192-96-1, 18.3 mg, 103 μmol) to give the title compound (7 mg, 23%) as a colorless oil, MS (EI): m/e = 357.3 [MH ⁺ ].

Example 145

(6S)-5-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-5-azaspiro[2.4]heptane-6-carboxamide

In analogy to the procedure described in Example 127e), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b, 50 mg, 176 μmol) was reacted with 5-azaspiro[2.4]heptane-6-carboxamide hydrochloride (Example 135b, 37.3 mg, 211 μmol) and purified by chiral HPLC to give the title compound (12 mg, 17%) as a colorless oil, MS (EI): m/e = 407.3 [MH ⁺ ].

Example 146

[(3aR,6aS)-1,3,3a,4,6,6a-Hexahydrofuro[3,4-c]pyrrol-5-yl]-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]methanone

In analogy to the procedure described in Example 127e), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b, 30 mg, 106 μmol) was reacted with (3aR,6aS)-hexahydro-1H-furo[3,4-c]pyrrole hydrochloride (CAN 57710-36-8, 15.8 mg, 106 μmol) to give the title compound (22 mg, 55%) as a white solid, MS (EI): m/e = 380.3 [MH ⁺ ].

Example 147

(2S)-1-[5-(3,3-Difluoroazetidin-1-yl)-6-(2-fluoroethoxy)pyridine-2-carbonyl]-4,4-difluoro-pyrrolidine-2-carboxamide

a) Methyl 5-bromo-6-(2-fluoroethoxy)pyridine-2-carboxylate

Over 30 minutes, 2-methylpropane-2-oleate lithium (4.17 mL, 9.18 mmol) was added to a solution of 5-bromo-6-chloro-pyridine-2-formic acid methyl ester (CAN 1214353-79-3, 1 g, 3.99 mmol) and 2-fluoroethanol (CAN 371-62-0, 332 mg, 300 μ L, 5.19 mmol) in DMF (6.67 mL) at ambient temperature. The reaction mixture was heated to 70° C. and stirred for 6 h. After cooling to ambient temperature, water (5 mL) and 2N HCl (5 mL) were added. The mixture was poured onto ice/brine (50 mL) and extracted with EtOAc (2 x 50 mL). The combined extracts were washed with ice/brine (50 mL), dried over _Na SO _, filtered, and evaporated to dryness. The crude product was purified by flash chromatography (50 g _SiO2 , heptane/0-30% EtOAc in 120 min) to afford the title compound (132 mg, 12%) as a light brown solid, MS (ESI) m/e = 278.0 [MH ⁺ ]

b) Methyl 5-(3,3-difluoroazetidin-1-yl)-6-(2-fluoroethoxy)pyridine-2-carboxylate

In analogy to the procedure described in Example 1a), methyl 5-bromo-6-(2-fluoroethoxy)picolinate (Example 147a, 130 mg, 467 μmol) was reacted with 3,3-difluoroazetidine hydrochloride (CAN 288315-03-7, 66.6 mg, 514 μmol) in the presence of palladium(II) acetate, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and cesium carbonate to give the title compound (73 mg, 54%) as a light yellow solid, MS (ESI) m/e=291.1 [MH ⁺ ].

c) 5-(3,3-Difluoroazetidin-1-yl)-6-(2-fluoroethoxy)pyridine-2-carboxylic acid

A solution of methyl 5-(3,3-difluoroazetidin-1-yl)-6-(2-fluoroethoxy)picolinate (Example 147b, 73 mg, 252 μmol) and lithium hydroxide hydrate (12.7 mg, 302 μmol) in tetrahydrofuran (500 μL) and water (50.0 μL) was stirred at ambient temperature for 12 h. The reaction mixture was poured onto ice/0.1 N HCl (25 mL) and extracted with EtOAc (2 x 25 mL). The combined extracts were washed with ice/brine (25 mL), dried over Na ₂ SO ₄ , filtered, and evaporated to dryness to afford the title compound (69 mg, quantitative) as a light white solid, MS (ESI) m/e=277.1 [MH ⁺ ].

d) (2S)-1-[5-(3,3-difluoroazetidin-1-yl)-6-(2-fluoroethoxy)pyridine-2-carbonyl]-4,4-difluoro-pyrrolidine-2-carboxamide

In analogy to the procedure described in Example 127e), 5-(3,3-difluoroazetidin-1-yl)-6-(2-fluoroethoxy)picolinic acid (Example 147c, 25 mg, 90.5 μmol) was reacted with (S)-4,4-difluoropyrrolidine-2-carboxamide hydrochloride (CAN 426844-51-1, 20.3 mg, 109 μmol) to give the title compound (16 mg, 43%) as a light white solid, MS (ESI): m/e = 409.1304 [MH ⁺ ].

Example 148

[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-2-pyridyl]-[3-fluoro-3-(hydroxymethyl)azetidin-1-yl]methanone

In analogy to the procedure described in Example 127e), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b, 20 mg, 70.4 μmol) was reacted with (3-fluoroazetidin-3-yl)methanol (CAN1268520-93-9, 8.87 mg, 84.4 μmol) to give the title compound (11 mg, 42%) as a colorless liquid, MS (ESI): m/e = 372.2 [MH ⁺ ].

Example 149

[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-2-pyridyl]-(3-fluoro-3-methyl-azetidin-1-yl)methanone

In analogy to the procedure described in Example 127e), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b, 20 mg, 70.4 μmol) was reacted with 3-fluoro-3-methylazetidine hydrochloride (CAN1427379-42-7, 10.6 mg, 84.4 μmol) to give the title compound (6 mg, 24%) as a light white solid, MS (ESI): m/e = 356.2 [MH ⁺ ].

Example 150

(3-Cyclopropyl-3-fluoroazetidin-1-yl)-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]methanone

In analogy to the procedure described in Example 127e), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b, 20 mg, 70.4 μmol) was reacted with 3-cyclopropyl-3-fluoroazetidine hydrochloride (CAN 936548-77-5, 12.8 mg, 84.4 μmol) to give the title compound (8 mg, 30%) as a colorless liquid, MS (ESI): m/e = 382.3 [MH ⁺ ].

Example 151

(-)-5-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-5-azaspiro[2.4]heptane-4-carboxamide

a) tert-Butyl 4-formyl-5-azaspiro[2.4]heptane-5-carboxylate and tert-Butyl 4-ethyl-2-formyl-4-methyl-pyrrolidine-1-carboxylate

A solution of sec-butyllithium in cyclohexane (1.13 mL, 1.58 mmol) was added to a solution of tert-butyl 5-azaspiro[2.4]heptane-5-carboxylate (CAN 1026796-26-8, 240 mg, 1.22 mmol) in THF (9.6 mL) at -30°C over 5 min. After stirring for 5 min, DMF (177 mg, 188 μL, 2.43 mmol) was added and stirring was continued at -30°C for 10 min. The mixture was allowed to warm to ambient temperature and stirring was continued for ₁₅ min. The reaction mixture was poured onto ice/saturated _NH₄Cl₃ solution (25 mL) and extracted with EtOAc (2 x 25 mL). The combined extracts were washed with ice/brine (25 mL), dried over _Na₂SO₄ , filtered and evaporated to dryness. The crude product was purified by preparative TLC (2 mm _SiO2 , heptane/EtOAc 4:1, eluting with EtOAc) to give the title compound (145 mg, 53%) as a colorless liquid, MS (ESI) m/e = 126.1 [MH-Boc ⁺ ].

b) 5-tert-Butoxycarbonyl-5-azaspiro[2.4]heptane-4-carboxylic acid and 1-tert-Butoxycarbonyl-4-ethyl-4-methyl-pyrrolidine-2-carboxylic acid

The mixture of 4-formyl-5-azaspiro [2.4] heptane-5-tert-butyl formates and 4-ethyl-2-formyl-4-methyl-pyrrolidine-1-tert-butyl formates (embodiment 151a, 142 mg, 630 μmol) is dissolved in t-BuOH (3.69 mL) and 2-methyl-2-butene (1.99 mL). Add sodium chlorite (114 mg, 1.26 mmol) and sodium dihydrogen phosphate dihydrate (151 mg, 1.26 mmol) in water (568 μL). The mixture is stirred at ambient temperature for 90 minutes and concentrated in vacuo. The residue is dissolved in water (10 mL). By dropwise addition of 2N HCl, the pH is adjusted to 3-4. The mixture is extracted with EtOAc (2x25 mL) and the combined extract is washed with ice/salt water (25 mL), and Na _{SO is} dried and evaporated to dryness. The crude product is poured onto ice/brine/1M NaOH (20 mL) and extracted with tBuOMe (2x25 mL). The aqueous layer is acidified with ice water/1M HCl (20 mL) and extracted with EtOAc (2x 25 mL). The combined extracts are washed with ice/brine (25 mL) and dried over Na ₂ SO ₄ , filtered and evaporated to dryness to obtain the title compound (155 mg, quantitative) as a colorless oil.

c) tert-Butyl 4-carbamoyl-5-azaspiro[2.4]heptane-5-carboxylate and tert-Butyl 2-carbamoyl-4-ethyl-4-methyl-pyrrolidine-1-carboxylate

In a similar manner to the procedure described in Example 127c), 5-tert-butoxycarbonyl-5-azaspiro[2.4]heptane-4-carboxylic acid and 1-tert-butoxycarbonyl-4-ethyl-4-methyl-pyrrolidine-2-carboxylic acid (Example 151b, 152 mg, 630 μmol) were condensed with aqueous ammonia to give the title compound (118 mg, 78%) as light white amorphous solids, MS (EI): m/e=141.1 [MH-Boc ⁺ ].

d) 5-Azaspiro[2.4]heptane-4-carboxamide hydrochloride and 5-Azaspiro[2.4]heptane-6-carboxamide hydrochloride

tert-Butyl 4-carbamoyl-5-azaspiro[2.4]heptane-5-carboxylate and tert-butyl 2-carbamoyl-4-ethyl-4-methyl-pyrrolidine-1-carboxylate (Example 151c, 115 mg, 479 μmol) were dissolved in a solution of 4M HCl in dioxane (2.39 mL, 9.55 mmol) and stirred at ambient temperature for 4 h. The solvent was removed in vacuo to give the title compound (115 mg, quantitative) as a light yellow oil.

e) (-)-5-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-5-azaspiro[2.4]heptane-4-carboxamide

In analogy to the procedure described in Example 127e), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b, 80 mg, 281 μmol) was reacted with a mixture of 5-azaspiro[2.4]heptane-4-carboxamide hydrochloride and 5-azaspiro[2.4]heptane-6-carboxamide hydrochloride (Example 151d, 59.7 mg, 338 μmol) to give the title compound (10 mg, 9%) as an off-white solid after preparative chiral HPLC, MS (ESI): m/e=407.3 [MH ⁺ ].

Example 152

(+)-5-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-5-azaspiro[2.4]heptane-4-carboxamide

In analogy to the procedure described in Example 127e), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1b, 80 mg, 281 μmol) was reacted with a mixture of 5-azaspiro[2.4]heptane-4-carboxamide hydrochloride and 5-azaspiro[2.4]heptane-6-carboxamide hydrochloride (Example 151d, 59.7 mg, 338 μmol) to give the title compound (22 mg, 19%) as an off-white solid after preparative chiral HPLC, MS (ESI): m/e=407.3 [MH ⁺ ].

Example 153

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, combined with 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 for [3H]CP55,940 were determined from saturation experiments. The compounds of formula (I) exhibited excellent affinity for the CB2 receptor, with affinities below 10 μM, more particularly between 1 nM and 3 μM, and most particularly between 1 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% _CO2 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 at room temperature for 2 h. 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 generated from this assay for a wide range of cannabinoid agonists were consistent with those published in the scientific literature.

The compounds of the invention are CB2 agonists with _EC50 below 0.5 μM and are at least 10-fold selective for CB1 in corresponding assays. Particular compounds of the invention are CB2 agonists with _EC50 below 0.05 μM and are at least 100-fold selective for CB1 in corresponding assays.

For example, the following compounds exhibited the following human _EC50 values in the functional cAMP assay described above:

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 (16)

1. A compound of formula (I), in ^R1 is a _C3-8 cycloalkyl _C1-8 alkoxy, halophenyl, tetrahydrofuranyl _C1-8 alkoxy, halophenyl _C1-8 alkyl, _haloC1-8 alkyloxy, _C1-8 alkylsulfonyl, tetrahydropyranyl _C1-8 alkoxy, or halogen. ^R2 is a _C1-8 alkyl, pyrrolidinyl, _C3-8 cycloalkyl, haloazacyclobutyl, _haloC1-8 alkyl, _{C3-8 cycloalkylC1-8} alkoxy, _haloC1-8 alkyloxy, _haloC3-8 cycloalkyl, _hydroxyC3-8 cycloalkyl, or halooxacyclobutyl. One of ^R3 and ^R4 is a _C1-8 alkyl, _C3-8 cycloalkyl, halo- _C1-8 alkyl, or hydroxy- _C1-8 alkyl, and the other is a _C1-8 alkyl, _C1-8 alkyloxy- _C1-8 alkyl, (haloazacyclobutyl)( _C3-8 cycloalkyloxy)pyridylcarbonyloxy-C1-8 alkyl, halo- _C1-8 alkyl- _C3-8 cycloalkyl, hydroxy _{-C1-8 alkyl, phenyl-C1-8 alkyl , C1-8} alkoxycarbonyl- _C1-8 alkyl, carboxyl- _C1-8 alkyl, _C1-8 alkylaminocarbonyl- _C1-8 alkyl, (C1-8 alkyldiazolyl)( _{C3-8 cycloalkyl-C1-8 alkyl)C1-8 alkyl ,} ( _C1-8 alkyldiazolyl)( _C3-8 cycloalkyl)C1-8 alkyl, pyridazinyl _-C1-8 alkyl, aminocarbonyl- _C1-8 alkyl, etc. _1-8 alkyl, _C1-8 alkyl diazolyl _C1-8 alkyl, _C1-8 alkyl tetrazolyl _C1-8 alkyl, formyl, phenyl, di( _C1-8 alkyl)pyrazolyl, _C1-8 alkyl carbonyl piperidinyl or _C3-8 cycloalkyl _C1-8 alkyl; Alternatively, ^R3 and ^R4, together with the nitrogen atom to which they are attached, form a heterocyclic group or a substituted heterocyclic group; The heterocyclic groups are 6-oxa-1-aza-spiro[3.3]heptyl, zolyl, morpholinyl, pyrrolyl, piperazine, 2-oxa-5-aza-spiro[3.4]octyl, piperidinyl, 6-aza-bicyclo[3.2.1.]octyl, imidazolyl, 4-aza-spiro[2.4]heptyl, 2-aza-bicyclo[2.2.1]heptyl, 2-thia-5-aza-bicyclo[2.2.1]heptyl, 2,5-diaza-bicyclo[2.2.1]heptyl, 2-oxa-5-aza-bicyclo[2.2.1]heptyl, hexahydro-furano[2,3-c]pyrrole, 2-thia-6-aza-spiro[3. 3] Heptyl, 1,8-diazaspiro[4.5]decyl, 1-oxa-7-azaspiro[4.4]nonyl, 5-oxa-2-azaspiro[3.4]octyl, 8-oxa-3-azabicyclo[3.2.1]octyl, 3-oxa-8-azabicyclo[3.2.1]octyl, thiomorpholinyl, thiazolyl, 5-azaspiro[3.4]octyl, azacyclobutyl, 5-azaspiro[2.4]heptyl, 3-azabicyclo[3.1.0]hexyl or 5-azaspiro[2.4]heptyl, 1,3,3a,4,6,6a-hexahydrofuran[3,4-c]pyrrole; and The substituted heterocyclic group is a heterocyclic group that is substituted by one to four substituents independently selected from the following: _C1-8 alkyl, oxo, hydroxy, carboxyl, _C1-8 alkylcarbonylamino, _C1-8 alkyloxyC1-8 alkyl, hydroxyC1-8 alkyl, aminocarbonyl, halogen, _phenylC1-8 alkyl, _{phenyl, C1-8 alkoxycarbonyl} , _{C3-8 cycloalkylC1-8} alkyl, _phenylC1-8 alkoxycarbonyl, _C3-8 cycloalkyl, _{halohydroxyC1-8} alkyl and _{haloC1-8 alkyl} ; The condition is that ^R3 and ^R4 , together with the nitrogen atom to which they are attached, do not form an unsubstituted piperidinyl group, an unsubstituted thiomorpholinyl group, or a hydroxy _C1-8 alkylpyrroleyl group; Or its medicinal salt. 2. The compound according to claim 1, wherein ^R1 is a _C3-8 cycloalkyl _C1-8 alkoxy, tetrahydrofuranyl _C1-8 alkoxy, _C1-8 alkylsulfonyl, or halophenyl _C1-8 alkyl. 3. The compound according to claim 1 or 2, wherein ^R1 is cyclopropylmethoxy, tetrahydrofuranylmethoxy, isobutylsulfonyl or fluorophenylmethyl. 4. The compound according to claim 1 or 2, wherein ^R2 is a haloazacyclobutane, _C3-8 cycloalkyl, or _haloC3-8 cycloalkyl. 5. The compound according to claim 1 or 2, wherein ^R2 is a difluoroazacyclobutane, cyclopropyl, or fluorocyclobutyl. 6. The compound according to claim 1 or 2, wherein one of ^R3 and ^R4 is a _C1-8 alkyl and the other is a _C1-8 alkyl or a halogenated _C1-8 alkyl- _C3-8 cycloalkyl. 7. The compound according to claim 1 or 2, wherein one of ^R3 and ^R4 is methyl and the other is tert-butyl or trifluoromethylcyclopropyl. 8. The compound according to claim 1 or 2, wherein ^R3 and ^R4 together with the nitrogen atom to which they are attached form a heterocyclic group or a substituted heterocyclic group, wherein the heterocyclic group is azole alkyl, morpholino, pyrrolidinyl, 6-aza-bicyclo[3.2.1.]octyl, 4-aza-spiro[2.4]heptyl, 2-thia-5-aza-bicyclo[2.2.1]heptyl, 5-aza-spiro[3.4]octyl, 5-aza-spiro[2.4]heptyl, 1,8-diaza-spiro[4.5]decyl, thiazolyl or 5-aza-spiro[2.4]heptyl, and wherein the substituted heterocyclic group is a heterocyclic group substituted by one to three substituents independently selected from: _C1-8 alkyl, hydroxy _C1-8 alkyl, halogen, aminocarbonyl, _C1-8 alkoxycarbonyl, oxo or hydroxy. 9. The compound according to claim 1 or 2, wherein ^R3 and ^R4 together with the nitrogen atom to which they are attached form a heterocyclic group or a substituted heterocyclic group, wherein the heterocyclic group is azolealkyl, morpholinyl, pyrrolidinyl, 6-aza-bicyclo[3.2.1.]octyl, 4-aza-spiro[2.4]heptyl, 2-thia-5-aza-bicyclo[2.2.1]heptyl, 5-aza-spiro[3.4]octyl, 5-aza-spiro[2.4]heptyl, 1,8-diaza-spiro[4.5]decyl, thiazoalkyl or 5-aza-spiro[2.4]heptyl, and wherein the substituted heterocyclic group is a heterocyclic group substituted by one to three substituents independently selected from: methyl, hydroxymethyl, fluorine, aminocarbonyl, tert-butoxycarbonyl, oxo or hydroxy. 10. The compound according to claim 1 or 2, wherein ^R3 and ^R4, together with the nitrogen atom to which they are attached, form dimethylazolanic, dimethylmorpholino, dimethylpyrrolinic, trimethyl-6-azabicyclo[3.2.1.]octyl, (hydroxymethyl)(difluoro)pyrrolinic, 4-azaspiro[2.4]heptyl, (aminocarbonyl)(difluoro)pyrrolinic, 2-thia-5-azabicyclo[2.2.1]heptyl, (aminocarbonyl)(dimethyl)pyrrolinic, 5-azaspiro [3.4]Octoyl, difluoro-5-azaspiro[2.4]Heptyl, 5-azaspiro[2.4]Heptyl, tert-butoxycarbonyl-1,8-diazaspiro[4.5]Decyl, aminocarbonyl-1,1-dioxo-1λ6-thiazolyl, aminocarbonyl-1,1-dioxo-1,3-thiazolyl, (aminocarbonyl)(methyl)(hydroxy)pyrrolidinyl or (aminocarbonyl)-5-azaspiro[2.4]Heptyl. 11. The compound according to claim 1 or 2, wherein the compound is selected from: 6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridine-2-carboxylic acid tert-butyl-methyl-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridine-2-carboxylic acid dimethylamide; 5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid tert-butyl-methyl-amide; 5-Cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)pyridine-2-carboxylic acid tert-butyl-methyl-amide; 5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid tert-butyl-methyl-amide; 5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid tert-butyl-methyl-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)pyridine-2-carboxylic acid tert-butyl-ethyl-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridine-2-carboxylic acid diisopropylamide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridine-2-carboxylic acid (2-methoxy-1,1-dimethyl-ethyl)-methyl-amide; [6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridin-2-yl]-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-methyl ketone; [6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridin-2-yl]-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-methyl ketone; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)pyridine-2-carboxylic acid 2-{[6-cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)pyridine-2-carbonyl]-methyl-amino}-2-methyl-propyl ester; 5-Cyclopropyl-6-(2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid tert-butyl-methyl-amide; [6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)pyridin-2-yl]-(4,4-dimethyl-azolidin-3-yl)-methyl ketone; 6-(tetrahydro-furan-2-ylmethoxy)-5-trifluoromethyl-pyridine-2-carboxylic acid tert-butyl-methyl-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)pyridine-2-carboxylic acid methyl-(1-trifluoromethyl-cyclopropyl)-amide; [6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)pyridin-2-yl]-(3,3-dimethylmorpholin-4-yl)-methyl ketone; [6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridin-2-yl]-(2,2-dimethyl-pyrrolidone-1-yl)-methyl ketone; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridine-2-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-(2-methoxy-ethyl)-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)pyridine-2-carboxylic acid tert-butyl-(2-methoxy-ethyl)-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridine-2-carboxylic acid ethyl-(1-trifluoromethyl-cyclopropyl)-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)pyridine-2-carboxylic acid benzyl-(1-trifluoromethyl-cyclopropyl)-amide; {tert-butyl-[6-cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)pyridine-2-carbonyl]amino}-ethyl acetate; {tert-butyl-[6-cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridin-2-carbonyl]-amino}-acetic acid; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)pyridine-2-carboxylic acid benzyl-tert-butyl-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridine-2-carboxylic acid tert-butyl-methylcarbamoylmethyl-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridine-2-carboxylic acid tert-butyl-dimethylcarbamoylmethyl-amide; 4-[6-cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridin-2-carbonyl]-3,3-dimethyl-piperazin-2-one; 4-[6-cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridin-2-carbonyl]-3,3-diethyl-piperazin-2-one; [5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridin-2-yl]-(2,2-dimethyl-pyrrolidin-1-yl)-methyl ketone; [5-Cyclopropyl-6-(2-Methyl-propane-1-sulfonyl)-pyridin-2-yl]-(4,4-dimethyl-azolidine-3-yl)-methyl ketone; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]diazol-3-yl)-ethyl]-methyl-amide; 5-Cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carboxylic acid [cyclopropyl-(5-methyl-[1,2,4]diazol-3-yl)-methyl]-methyl-amide; (+)-6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridine-2-carboxylic acid methyl-(3-methyl-1-pyridazin-3-yl-butyl)-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridine-2-carboxylic acid tert-butyl-carbamoylmethyl-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridine-2-carboxylic acid tert-butyl-(5-methyl-[1,3,4]diazol-2-ylmethyl)-amide; [6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridin-2-yl]-(3-hydroxy-3-methyl-pyrrolidine-1-yl)-methyl ketone; [6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridin-2-yl]-(2-oxa-5-aza-spiro[3.4]oct-5-yl)-methyl ketone; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)pyridine-2-carboxylic acid ethyl-(2-methoxy-ethyl)-amide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)pyridine-2-carboxylic acid tert-butyl-(1-methyl-1H-tetrazole-5-ylmethyl)-amide; N-{1-[6-cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)pyridin-2-carbonyl]pyrrolidine-3-yl}-acetamide; [5-Cyclopropyl-6-(4-Fluorobenzyl)pyridin-2-yl]-(4,4-Dimethylpiperidin-1-yl)-methyl ketone; [5-Cyclopropyl-6-(Tetrahydro-furan-2-ylmethoxy)pyridin-2-yl]-(4,4-dimethyl-piperidin-1-yl)-methyl ketone; [5-Cyclopropyl-6-(4-Fluoro-benzyl)-pyridin-2-yl]-(4,4-Dimethyl-azolidin-3-yl)-methyl ketone; [6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridin-2-yl]-((1S,5R)-1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methyl ketone; [6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridin-2-yl]-((R)-2-methoxymethyl-pyrrolidine-1-yl)-methyl ketone; (6-Chloro-5-cyclopropylmethoxy-pyridin-2-yl)-(2,2-dimethyl-pyrrolidone-1-yl)-methyl ketone; (6-Cyclopropylmethoxy-5-trifluoromethoxy-pyridin-2-yl)-(4,4-dimethyl-azolidin-3-yl)-methyl ketone; (6-Chloro-5-cyclopropylmethoxypyridin-2-yl)-(4,4-dimethyl-azolidin-3-yl)-methyl ketone; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)pyridine-2-carboxylic acid (1-acetyl-piperidin-4-yl)-cyclopropyl-amide; 6-(cyclopropylmethoxy)-5-(3,3-difluoroazacyclobutan-1-yl)-N-formyl-N-methylpyridine-2-carboxamide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridine-2-carboxylic acid methyl-phenyl-amide; [6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridin-2-yl]-((S)-4,4-difluoro-2-hydroxymethyl-pyrrolidine-1-yl)-methyl ketone; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridine-2-carboxylic acid (1,4-dimethyl-1H-pyrazol-3-yl)-methyl-amide; [6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)pyridin-2-yl]-(2,2-dimethyl-morpholin-4-yl)-methyl ketone; (R)-2-tert-butyl-1-[6-cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridin-2-carbonyl]-3-methyl-imidazolidine-4-one; (4-aza-spiro[2.4]hept-4-yl)-[6-cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)pyridin-2-yl]-methyl ketone; 3-{1-[6-cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridin-2-carbonyl]-piperidin-4-yl}-5,5-dimethyl-pyrrolidone-2-one; (1S,4R)-2-aza-bicyclo[2.2.1]hept-2-yl-[6-cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)pyridin-2-yl]-methyl ketone; (S)-1-[6-cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridin-2-carbonyl]-4,4-difluoro-pyrrolidine-2-carboxamide; [6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)pyridin-2-yl]-(4-hydroxy-4-methyl-piperidin-1-yl)-methyl ketone; [6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridin-2-yl]-(1S,4S)-2-thia-5-aza-bicyclo[2.2.1]hept-5-yl methyl ketone; ((1S,4S)-5-benzyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-[6-cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)pyridin-2-yl]-methyl ketone; [6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)pyridin-2-yl]-(2-methyl-3-phenyl-piperidin-1-yl)-methyl ketone; [6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridin-2-yl]-(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl methyl ketone; [6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridin-2-yl]-(4-hydroxy-2,2-dimethyl-piperidin-1-yl)-methyl ketone; 1-[6-cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridine-2-carbonyl]-2-phenyl-piperidine-3-carboxylic acid ethyl ester; (S)-1-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-4,4-difluoro-pyrrolidine-2-carboxamide; (2S,4S)-1-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-4-fluoro-pyrrolidine-2-carboxamide; [6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridin-2-yl]-(hexahydro-furano[2,3-c]pyrrolo-5-yl)-methyl ketone; [6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridin-2-yl]-(2,2-dioxo-2λ6-thia-6-aza-spiro[3.3]hept-6-yl)-methyl ketone; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridine-2-carboxylic acid tert-butyl-(2-carbamoyl-ethyl)-amide; (S)-1-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-pyrrolidine-2-carboxamide; 1-[6-cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridine-2-carbonyl]-1,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester; (S)-1-{5-cyclopropyl-6-[(R,S)-1-(tetrahydro-furan-2-yl)methoxy]-pyridine-2-carbonyl}-4,4-difluoro-pyrrolidine-2-carboxamide; (S)-1-[5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carbonyl]-4,4-difluoro-pyrrolidine-2-carboxamide; (+)-1-[6-cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridin-2-carbonyl]-4,4-dimethyl-pyrrolidine-2-carboxamide; (-)-1-[6-cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridine-2-carbonyl]-4,4-dimethyl-pyrrolidine-2-carboxamide; (2S,4S)-1-[6-cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)pyridine-2-carbonyl]-4-hydroxy-pyrrolidine-2-carboxamide; (2S,4S)-1-[6-cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)pyridine-2-carbonyl]-4-fluoro-pyrrolidine-2-carboxamide; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)pyridine-2-carboxylic acid cyclopropyl-(5-methyl-[1,3,4]diazol-2-ylmethyl)-amide; [6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridin-2-yl]-(3-hydroxy-1-oxa-7-aza-spiro[4.4]non-7-yl)-methyl ketone; [6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridin-2-yl]-(7-hydroxy-5-oxa-2-aza-spiro[3.4]oct-2-yl)-methyl ketone; [5-Cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridin-2-yl]-(2,2-dimethyl-pyrrolidone-1-yl)-methyl ketone; [6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridin-2-yl]-(1S,5R)-8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl-methyl ketone; [6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridin-2-yl]-(1R,5S)-3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl methyl ketone; (R)-1-[5-cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carbonyl]-4,4-difluoro-pyrrolidine-2-carboxamide; 1-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-piperidine-2-carboxamide; 4-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-thiomorpholine-3-carboxamide; 1-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-4,4-dimethyl-pyrrolidine-2-carboxamide; (+)-1-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-piperidine-2-carboxamide; (-)-1-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-piperidine-2-carboxamide; (-)-4-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-thiomorpholine-3-carboxamide; (+)-1-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-4,4-dimethyl-pyrrolidine-2-carboxamide; (-)-1-(5-Cyclopropyl-6-Cyclopropylmethoxy-pyridine-2-carbonyl)-4,4-Dimethyl-pyrrolidine-2-carboxamide; 3-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-thiazolidin-4-carboxamide; (-)-3-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-thiazolidin-4-carboxamide; 1-[6-cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridin-2-carbonyl]-4,4-dimethyl-pyrrolidine-2-carboxamide; [6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridin-2-yl]-(5-oxa-2-aza-spiro[3.4]oct-2-yl)-methyl ketone; [6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridin-2-yl]-(1-oxa-7-aza-spiro[4.4]non-7-yl)-methyl ketone; (5-aza-spiro[3.4]oct-5-yl)-[6-cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)pyridin-2-yl]-methyl ketone; [6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridin-2-yl]-(3,3-difluoro-azacyclobutane-1-yl)-methyl ketone; [6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridin-2-yl]-(1,1-difluoro-5-aza-spiro[2,4]hept-5-yl)-methyl ketone; (5-aza-spiro[2.4]hept-5-yl)-[6-cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)pyridin-2-yl]-methyl ketone; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)pyridine-2-carboxylic acid cyclopropylmethyl-methyl-amide; [6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridin-2-yl]-(4-cyclopropylmethyl-piperazin-1-yl)-methyl ketone; 3-[6-cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridin-2-carbonyl]-3-aza-bicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester; 1-[6-cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)pyridine-2-carbonyl]-pyrrolidine-2-carboxylic acid methyl ester; 4-[6-cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)pyridin-2-carbonyl]-piperazine-1-carboxylic acid benzyl ester; 3-[6-cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridin-2-carbonyl]-3-aza-bicyclo[3.1.0]hexane-6-carboxylic acid; 1-[5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carbonyl]-1,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester; (-)-3-[6-cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)pyridine-2-carbonyl]-thiazolidin-4-carboxamide; [5-Cyclopropyl-6-(4-Fluorobenzyl)pyridin-2-yl]-(1,8-diaza-spiro[4.5]dec-1-yl)-methyl ketone; 1-[6-cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridine-2-carbonyl]-pyrrolidine-2-carboxamide; (-)-3-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-1,1-dioxo-1λ6-thiazolidin-4-carboxamide; (1S,4R)-3-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-1-oxo-1λ4-thiazolidin-4-carboxamide; (1R,4S)-3-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-1-oxo-1λ4-thiazolidin-4-carboxamide; (+)-3-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-1,1-dioxo-1λ6-thiazolidin-4-carboxamide; [6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridin-2-yl]-(3,3,4,4-tetrafluoro-pyrrolidine-1-yl)-methyl ketone; [6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)pyridin-2-yl]-(2,6-dimethyl-morpholin-4-yl)-methyl ketone; (R)-3-[6-cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridin-2-carbonyl]-5,5-dimethyl-thiazolidin-4-carboxamide; (S)-1-[6-cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridin-2-carbonyl]-5,5-dimethyl-pyrrolidine-2-carboxamide; 3-[6-cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)pyridine-2-carbonyl]-thiazolidin-4-carboxamide; (2S,4R)-1-[5-cyclopropyl-6-(cyclopropylmethoxy)pyridine-2-carbonyl]-4-fluoropyrrolidine-2-carboxamide; 3-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazacyclobutane-1-yl)pyridin-2-carbonyl]-1-oxo-1,3-thiazolidin-4-carboxamide; 3-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazacyclobutane-1-yl)pyridin-2-carbonyl]-1,1-dioxo-1,3-thiazolidin-4-carboxamide; (2S,4R)-1-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazacyclobutan-1-yl)pyridine-2-carbonyl]-4-fluoropyrrolidine-2-carboxamide; (-)-3-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazacyclobutane-1-yl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidin-4-carboxamide; 3-[6-(cyclopropylmethoxy)-5-(3-methoxyazacyclobutane-1-yl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidin-4-carboxamide; (2S)-1-[6-(cyclopropylmethoxy)-5-(1-hydroxycyclobutyl)pyridine-2-carbonyl]-4,4-difluoropyrrolidine-2-carboxamide; (2S)-1-[6-(cyclopropylmethoxy)-5-(1-fluorocyclobutyl)pyridine-2-carbonyl]-4,4-difluoropyrrolidine-2-carboxamide; 3-[6-(cyclopropylmethoxy)-5-(1-hydroxycyclobutyl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidin-4-carboxamide; (2S)-1-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazacyclobutan-1-yl)pyridin-2-carbonyl]-4-hydroxy-4-methylpyrrolidine-2-carboxamide; 3-[6-(cyclopropylmethoxy)-5-(1-fluorocyclobutyl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidin-4-carboxamide; (2S)-1-[6-(cyclopropylmethoxy)-5-(3-fluorooxetane-3-yl)pyridine-2-carbonyl]-4,4-difluoropyrrolidine-2-carboxamide; 5-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazacyclobutane-1-yl)pyridin-2-carbonyl]-5-azaspiro[2,4]heptane-6-carboxamide; [6-(cyclopropylmethoxy)-5-(3,3-difluoroazacyclobutan-1-yl)pyridin-2-yl]-[3-(2,2,2-trifluoro-1-hydroxyethyl)pyrrolidine-1-yl] methyl ketone; [6-(cyclopropylmethoxy)-5-(3,3-difluoroazacyclobutan-1-yl)pyridin-2-yl]-[3-(hydroxymethyl)-3-(trifluoromethyl)pyrrolidin-1-yl] methyl ketone; [6-(cyclopropylmethoxy)-5-(3,3-difluoroazacyclobutan-1-yl)pyridin-2-yl]-[3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl] ketone; [6-(cyclopropylmethoxy)-5-(3,3-difluoroazacyclobutan-1-yl)pyridin-2-yl]-[3-hydroxy-3-(trifluoromethyl)azacyclobutan-1-yl] methyl ketone; (+)-(2S)-1-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazacyclobutan-1-yl)pyridin-2-carbonyl]-4-hydroxy-4-methylpyrrolidine-2-carboxamide; [5-Cyclopropyl-6-(Cyclopropylmethoxy)pyridin-2-yl]-[3-(2,2,2-trifluoro-1-hydroxyethyl)pyrrolidine-1-yl] methyl ketone; [5-Cyclopropyl-6-(Cyclopropylmethoxy)pyridin-2-yl]-[3-(hydroxymethyl)-3-(trifluoromethyl)pyrrolidone-1-yl] ketone; [5-Cyclopropyl-6-(Cyclopropylmethoxy)pyridin-2-yl]-[3-hydroxy-3-(trifluoromethyl)pyrrolidone-1-yl] ketone; [5-Cyclopropyl-6-(Cyclopropylmethoxy)pyridin-2-yl]-[3-hydroxy-3-(trifluoromethyl)azacyclobutane-1-yl] methyl ketone; (6S)-5-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazacyclobutane-1-yl)pyridin-2-carbonyl]-5-azaspiro[2,4]heptane-6-carboxamide; [(3aR,6aS)-1,3,3a,4,6,6a-hexahydrofurano[3,4-c]pyrrolo-5-yl]-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazacyclobutan-1-yl)pyridin-2-yl] ketone; (2S)-1-[5-(3,3-difluoroazacyclobutane-1-yl)-6-(2-fluoroethoxy)pyridine-2-carbonyl]-4,4-difluoro-pyrrolidine-2-carboxamide; [6-(cyclopropylmethoxy)-5-(3,3-difluoroazacyclobutan-1-yl)-2-pyridyl]-[3-fluoro-3-(hydroxymethyl)azacyclobutan-1-yl] methyl ketone; [6-(cyclopropylmethoxy)-5-(3,3-difluoroazacyclobutan-1-yl)-2-pyridyl]-(3-fluoro-3-methyl-azacyclobutan-1-yl) methyl ketone; (3-Cyclopropyl-3-fluoroazacyclobutane-1-yl)-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazacyclobutane-1-yl)pyridin-2-yl] methyl ketone; (-)-5-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazacyclobutane-1-yl)pyridin-2-carbonyl]-5-azaspiro[2,4]heptane-4-carboxamide; and (+)-5-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazacyclobutane-1-yl)pyridine-2-carbonyl]-5-azaspiro[2,4]heptane-4-carboxamide. 12. The compound according to claim 1 or 2, wherein the compound is selected from: 6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridine-2-carboxylic acid tert-butyl-methyl-amide; 5-Cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)pyridine-2-carboxylic acid tert-butyl-methyl-amide; [6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)pyridin-2-yl]-(4,4-dimethyl-azolidin-3-yl)-methyl ketone; 6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)pyridine-2-carboxylic acid methyl-(1-trifluoromethyl-cyclopropyl)-amide; [6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)pyridin-2-yl]-(3,3-dimethylmorpholin-4-yl)-methyl ketone; [5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridin-2-yl]-(2,2-dimethyl-pyrrolidin-1-yl)-methyl ketone; [5-Cyclopropyl-6-(4-Fluoro-benzyl)-pyridin-2-yl]-(4,4-Dimethyl-azolidin-3-yl)-methyl ketone; [6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridin-2-yl]-((1S,5R)-1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methyl ketone; [6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridin-2-yl]-((S)-4,4-difluoro-2-hydroxymethyl-pyrrolidine-1-yl)-methyl ketone; (4-aza-spiro[2.4]hept-4-yl)-[6-cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)pyridin-2-yl]-methyl ketone; [6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridin-2-yl]-(1S,4S)-2-thia-5-aza-bicyclo[2.2.1]hept-5-yl methyl ketone; (S)-1-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-4,4-difluoro-pyrrolidine-2-carboxamide; (-)-1-[6-cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridine-2-carbonyl]-4,4-dimethyl-pyrrolidine-2-carboxamide; (5-aza-spiro[3.4]oct-5-yl)-[6-cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)pyridin-2-yl]-methyl ketone; [6-Cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)-pyridin-2-yl]-(1,1-difluoro-5-aza-spiro[2,4]hept-5-yl)-methyl ketone; (5-aza-spiro[2.4]hept-5-yl)-[6-cyclopropylmethoxy-5-(3,3-difluoro-azacyclobutane-1-yl)pyridin-2-yl]-methyl ketone; 1-[5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carbonyl]-1,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester; (-)-3-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-1,1-dioxo-1λ6-thiazolidin-4-carboxamide; 3-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazacyclobutane-1-yl)pyridin-2-carbonyl]-1,1-dioxo-1,3-thiazolidin-4-carboxamide; (-)-3-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazacyclobutane-1-yl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidin-4-carboxamide; (2S)-1-[6-(cyclopropylmethoxy)-5-(1-hydroxycyclobutyl)pyridine-2-carbonyl]-4,4-difluoropyrrolidine-2-carboxamide; (2S)-1-[6-(cyclopropylmethoxy)-5-(1-fluorocyclobutyl)pyridine-2-carbonyl]-4,4-difluoropyrrolidine-2-carboxamide; (2S)-1-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazacyclobutan-1-yl)pyridin-2-carbonyl]-4-hydroxy-4-methylpyrrolidine-2-carboxamide; 3-[6-(cyclopropylmethoxy)-5-(1-fluorocyclobutyl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidin-4-carboxamide; and 5-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazacyclobutane-1-yl)pyridine-2-carbonyl]-5-azaspiro[2,4]heptane-6-carboxamide. 13. A method for preparing a compound according to any one of claims 1 to 12, the method comprising one of the following steps: (a) Compound of formula (A) The reaction in the presence of NHR ³ R ⁴ , a coupling agent that forms an amide bond, and a base; or (b) Compound of formula (B) Reaction with compounds of formula ^R4 -X; Wherein ^R1 to ^R4 are as defined in any one of claims 1 to 10, and X is a leaving group. 14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 and a therapeutically inert carrier. 15. Use of the compound according to any one of claims 1 to 12 for the preparation of a medicament for the treatment or prevention of diseases related to the regulation of CB2 receptors, wherein the diseases are: pain, atherosclerosis, age-related macular degeneration, diabetic retinopathy, glaucoma, retinal vein occlusion, retinopathy of prematurity, ocular ischemia syndrome, geographic atrophy, diabetes, inflammation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver failure, liver fibrosis, pulmonary fibrosis, renal fibrosis, systemic fibrosis, acute allogeneic transplant rejection, chronic allogeneic transplant nephropathy, diabetic nephropathy, glomerular nephropathy, cardiomyopathy, heart failure, myocardial ischemia, myocardial infarction, systemic sclerosis, thermal injury, burns, hypertrophic scars, keloids, gingivitis with fever, cirrhosis or tumors, bone regulation, neurodegeneration, amyotrophic lateral sclerosis, stroke or transient ischemic attack. 16. Use of the compound according to any one of claims 1 to 12 for the preparation of a medicament for the treatment or prevention of a disease related to the regulation of the CB2 receptor, wherein the disease is uveitis.