Novel pyridine and pyrazine compounds as inhibitors of cannabinoid receptor 2

Abstract

The present invention relates to novel pyridine and pyrazine compounds as inhibitors of cannabinoid receptor 2. Specifically, the invention relates to compounds of formula (I) wherein A, A2, X and R1-R3 are as defined in the description and in the claims. The compounds of formula (I) can be used as medicaments due to their inhibition of cannabinoid receptor 2. # imgabs0 #

Description

[0001] This application is a divisional application of an application with a PCT international application date of June 25, 2019, a PCT international application number of PCT / EP2019 / 066811, a Chinese national application number of 201980025482.7, and an invention name of "Novel pyridine and pyrazine compounds as inhibitors of cannabinoid receptor 2".

[0002] The present invention relates to organic compounds useful for the treatment and / or prevention of mammals and in particular to compounds that are preferential agonists of cannabinoid receptor 2.

[0003] The present invention particularly relates to compounds of formula (I)

[0004]

[0005] in

[0006] R 1 is alkoxyazetidinyl, dihaloazetidinyl or pyrrolidinyl;

[0007] R 2 and R 3 are independently selected from hydrogen and alkyl;

[0008] A 1 is -CH- or nitrogen;

[0009] A 2 is -CH2- or carbonyl;

[0010] X is a halogen;

[0011] n is 0 to 3; and

[0012] m is 0 or 1;

[0013] The condition is that m and n are not both 0;

[0014] or a pharmaceutically acceptable salt thereof.

[0015] New pyridine and pyrazine derivatives have been found which have high affinity and great selectivity for the cannabinoid CB2 receptor. These compounds have a modulatory effect on the activity of the CB2 receptor. The term 'modulatory effect' means in particular an agonist, antagonist and / or inverse agonist effect.

[0016] Agonists of cannabinoid receptor 2 may be used for therapeutic and / or prophylactic use in mammals. The compounds of formula (I) are particularly useful for the treatment or prevention of, for example, pain, atherosclerosis, age-related macular degeneration, diabetic retinopathy, glaucoma, diabetes mellitus, inflammation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver failure, liver fibrosis, lung fibrosis, kidney fibrosis, systemic fibrosis, acute allograft rejection, chronic allograft nephropathy, diabetic nephropathy, glomerulonephropathy, cardiomyopathy, heart failure, and the like. failure, myocardial ischemia / infarction, systemic sclerosis, thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors, regulation of bone mass, neurodegeneration, stroke, transient ischemic attack, or uveitis.

[0017] Inverse agonists of cannabinoid receptor 2 may be used for therapeutic and / or prophylactic use in mammals.

[0018] The compounds of formula (I) are particularly useful for treating or preventing pain, neuropathic pain, asthma, osteoporosis, inflammation, mental illness, psychosis, tumors, encephalitis, malaria, allergies, immune disorders, arthritis, gastrointestinal disorders, psychiatric disorders, rheumatoid arthritis, psychosis and allergies.

[0019] 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 mainly expressed in the central nervous system (i.e., amygdala cerebellum, hippocampus) system and in the periphery in a smaller amount. CB2 encoded by the CNR2 gene is mainly expressed in cells of the immune system, such as macrophages and T-cells (Ashton, JC, etc. Curr Neuropharmacol 2007, 5 (2), 73-80; Miller, AM, etc. Br J Pharmacol 2008, 153 (2), 299-308; Centonze, D., etc. Curr PharmDes 2008, 14 (23), 2370-42), and in the gastrointestinal system (Wright, KL, etc. Br J Pharmacol 2008, 153 (2), 263-70) peripheral expression. The CB2 receptor is also widely distributed in the brain, where it is primarily found on microglia rather than neurons (Cabral, GA et al. Br J Pharmacol 2008, 153(2):240-51).

[0020] Modulators of cannabinoid receptor 2 may be used in mammals for therapeutic and / or prophylactic treatment.

[0021] Interest in CB2 receptor agonists has been rising steadily over the past decade (currently 30-40 patent applications / year), driven by the fact that many of the early compounds have been shown to have beneficial effects in a number of preclinical models 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 mass 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, 153(2), 252-62), systemic fibrosis (Akhmetshina, A. et al. Artritis Rheum 2009, 60(4), 1129-36; Garcia-Gonzalez, E. et al. Rheumatology (Oxford) 2009, 48(9), 1050-6), liver fibrosis (Julien, B. et al. Gastroenterology 2005, 128(3), 742-55; Munoz-Luque, J. et al. J Pharmacol Exp Ther 2008, 324(2), 475-83).

[0022] Ischemia / reperfusion (I / R) injury is the main cause of tissue damage occurring in illnesses such as stroke, myocardial infarction, cardiopulmonary bypass and other vascular surgeries and organ transplantation, and the main mechanism of end-organ damage that complicates the process of circulatory shock of multiple etiologies. All of these illnesses are characterized by destruction of the normal blood pressure supply, which results in insufficient tissue oxygenation. Reoxygenation such as reperfusion is the ultimate treatment for restoring normal tissue oxygenation. However, the lack of oxygen and nutrition from the blood produces a condition in which circulation recovery leads to further tissue damage. The damage of reperfusion injury is partly due to the inflammatory response of damaged tissue. The leukocytes carried to the region by the new return blood release many inflammatory factors such as interleukins and free radicals in response to tissue damage. The restored blood flow reintroduces oxygen in the cell, which damages cell proteins, DNA and plasma membrane.

[0023] Remote ischemic preconditioning (RIPC) represents a strategy to exploit the body's endogenous protective capacity against damage caused by ischemia and reperfusion. It describes a very interesting phenomenon in which a brief non-lethal ischemia and reperfusion of one organ or tissue provides resistance to subsequent episodes of "lethal" ischemia-reperfusion injury in a distant organ or tissue. Although multiple hypotheses have been proposed, the exact mechanism by which brief ischemia and reperfusion of an organ or tissue provides protection is currently unknown.

[0024] The humoral hypothesis proposes that endogenous substances produced in distant organs or tissues (such as adenosine, bradykinin, opioids, CGRP, endocannabinoids, angiotensin I, or some other humoral factor that has not yet been identified) enter the bloodstream and activate their corresponding receptors in target tissues, thereby recruiting various intracellular pathways of cardioprotection involved in ischemic preconditioning.

[0025] 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 inflammatory responses (Pacher, P. et al. Br J Pharmacol 2008, 153(2), 252-62). Specifically, recent studies using CB2 tool agonists have demonstrated the efficacy of this concept in 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).

[0026] 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 situations. 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, YY et al. Liver Int 2009, 29(5), 678-85) with the associated expression of CB2 in myofibroblasts (cells responsible for the progression of fibrosis).

[0027] Activation of CB2 receptors by selective CB2 agonists has in fact been shown to exert an antifibrotic effect 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 skin 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).

[0028] Inverse agonists of cannabinoid receptor 2 may be used for therapeutic and / or prophylactic use in mammals.

[0029] The compounds of formula (I) are particularly useful for treating or preventing pain, neuropathic pain, asthma, osteoporosis, inflammation, mental illness, psychosis, tumors, encephalitis, malaria, allergies, immune disorders, arthritis, gastrointestinal disorders, psychiatric disorders, rheumatoid arthritis, psychosis and allergies.

[0030] Interest in CB2 receptor ligands has been rising steadily over the past decade (currently 30-40 patent applications / year). Evidence from different sources supports the view that lipid endocannabinoid signaling through CB2 receptors represents one aspect of the protective medical armamentarium of mammals (Pacher, P. Prog Lipid Res 2011, 50, 193). Its modulation by selective CB2 receptor agonists or inverse agonists / antagonists (depending on the disease and its stage) holds unique therapeutic potential in a large number of diseases. For CB2 inverse agonists / antagonists, therapeutic possibilities are shown for many pathological conditions: the pathological conditions include pain (Pasquini, SJ Med Chem 2012, 55(11):5391), neuropathic pain (Garcia-Gutierrez, MSBr J Pharmacol 2012, 165(4):951), psychiatric disorders (Garcia-Gutierrez, MSBr J Pharmacol 2012, 165(4):951), psychosis (Garcia-Gutierrez, MSBr J Pharmacol 2012, 165(4):951), osteoporosis and inflammation (Sophocleous, A. Calcif Tissue Int 2008, 82(Suppl. 1):Abst OC18), mental illness and psychosis (Garcia-Gutierrez, MSBr J Pharmacol 2012, 165(4):951). 2012, 165(4):951), tumors (Preet, A. Cancer Prev Res 2011, 4:65), encephalitis and malaria (Zimmer, A. WO2011045068), allergy and inflammation (Ueda, Y. Life Sci 2007, 80(5):414), encephalitis and malaria (Zimmer, WO 2011045068), asthma (Lunn, CAJ Pharmacol Exp Ther 2006, 316(2):780), immune disorders (Fakhfouri, G. Neuropharmacology 2012, 63(4):653), rheumatoid arthritis (Chackalamannil, S. US 7776889), arthritis (Lunn, CAJ Pharmacol Exp Ther 2006, 316(2):780), and gastrointestinal disorders (Barth, F. FR 2887550).

[0031] The compounds of the present invention bind to and modulate CB2 receptors and have reduced CB1 receptor activity.

[0032] In this specification, the term "alkyl", alone or in combination, means a straight or branched chain alkyl group having 1 to 8 carbon atoms, in particular a straight or branched chain alkyl group having 1 to 6 carbon atoms, more particularly a straight or branched chain alkyl group having 1 to 4 carbon atoms. Examples of straight and branched C1-C8 alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, isomeric pentyls, isomeric hexyls, isomeric heptyls and isomeric octyl groups, in particular methyl, ethyl, propyl, butyl and pentyl. Particular examples of alkyl groups are methyl, ethyl, isopropyl, butyl, isobutyl, tert-butyl and pentyl. Methyl, ethyl and propyl are particular examples of "alkyl" in compounds of formula (I).

[0033] The term "alkoxy" or "alkyloxy", 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. A particular example of an "alkoxy" is methoxy.

[0034] The term "oxy", alone or in combination, signifies a -O- group.

[0035] 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. 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, in particular one to four halogens, i.e. one, two, three or four halogens. Fluorine is a particular halogen.

[0036] The term "carbonyl", alone or in combination, signifies a -C(O)- group.

[0037] The term "pharmaceutical salt" refers to those salts that maintain the biological effectiveness and properties of free alkali or free acid, which are not biologically or otherwise unsuitable. The 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 acids. The salts derived 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.

[0038] 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 known in the art (such as, for example, TW Greene and PGM 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).

[0039] 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.

[0040] 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.

[0041] The present invention particularly relates to:

[0042] According to a compound of the present invention, wherein R1 is methoxyazetidinyl, difluoroazetidinyl or pyrrolidinyl.

[0043] According to a compound of the present invention, wherein R 2 and R 3 are independently selected from hydrogen, ethyl and butyl.

[0044] According to a compound of the present invention, wherein R 2 and R 3 Both are ethyl, or R 2 and R 3 One of them is hydrogen and the other is butyl.

[0045] According to a compound of the present invention, wherein A 1 It is -CH-.

[0046] A compound according to the invention, wherein X is fluorine; and

[0047] A compound according to the invention, wherein n is 1, 2 or 3.

[0048] The present invention also relates to compounds of formula (I) selected from:

[0049] Fluoromethyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate;

[0050] 2-Fluoroethyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate;

[0051] 3-Fluoropropyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate;

[0052] Fluoromethyl 2-{[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate;

[0053] 2-Fluoroethyl 2-{[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate;

[0054] 3-Fluoropropyl 2-{[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate;

[0055] 3-Fluoropropyl 2-{[6-(cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate;

[0056] Fluoromethyl 2-{[6-(cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate;

[0057] 2-Fluoroethyl 2-{[6-(cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate;

[0058] N-[6-(Cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]-L-leucine fluoromethyl ester;

[0059] N-[6-(Cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]-L-leucine 2-fluoroethyl ester;

[0060] N-[6-(Cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]-L-leucine 3-fluoropropyl ester;

[0061] N-[6-(Cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridine-2-carbonyl]-L-leucine fluoromethyl ester;

[0062] N-[6-(Cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridine-2-carbonyl]-L-leucine 2-fluoroethyl ester;

[0063] N-[6-(Cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridine-2-carbonyl]-L-leucine 3-fluoropropyl ester;

[0064] 6-(Cyclopropylmethoxy)-N-[(2S)-1-(fluoromethoxy)-4-methylpentan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

[0065] 6-(Cyclopropylmethoxy)-N-[(2R)-1-(2-fluoroethoxy)-4-methylpentan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

[0066] 6-(Cyclopropylmethoxy)-N-[(2S)-1-(2-fluoroethoxy)-4-methylpentan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

[0067] 6-(Cyclopropylmethoxy)-N-[(2S)-1-(3-fluoropropoxy)-4-methylpentan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

[0068] 6-(Cyclopropylmethoxy)-N-[(2S)-1-(fluoromethoxy)-3-methylbutan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

[0069] 6-(Cyclopropylmethoxy)-N-[(2S)-1-(2-fluoroethoxy)-3-methylbutan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

[0070] 6-(Cyclopropylmethoxy)-N-[(2S)-1-(3-fluoropropoxy)-3-methylbutan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

[0071] 6-(Cyclopropylmethoxy)-N-[(2S)-1-(fluoromethoxy)propan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

[0072] 6-(Cyclopropylmethoxy)-N-[(2S)-1-(2-fluoroethoxy)propan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

[0073] 6-(Cyclopropylmethoxy)-N-[(2S)-1-(3-fluoropropoxy)propan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

[0074] 6-(Cyclopropylmethoxy)-N-[(2S)-1-(fluoromethoxy)-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

[0075] 6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-N-[(2S)-1-(2-fluoroethoxy)-4-methylpentan-2-yl]pyridine-2-carboxamide;

[0076] 6-(Cyclopropylmethoxy)-N-[(2R)-1-(2-fluoroethoxy)-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

[0077] 6-(Cyclopropylmethoxy)-N-[(2S)-1-(2-fluoroethoxy)-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

[0078] 6-(Cyclopropylmethoxy)-N-[(2S)-1-(3-fluoropropoxy)-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

[0079] 6-(Cyclopropylmethoxy)-N-[(2S)-1-(fluoromethoxy)-3-methylbutan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

[0080] 6-(Cyclopropylmethoxy)-N-[(2S)-1-(2-fluoroethoxy)-3-methylbutan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

[0081] 6-(Cyclopropylmethoxy)-N-[(2S)-1-(3-fluoropropoxy)-3-methylbutan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

[0082] 6-(Cyclopropylmethoxy)-N-[(2S)-1-(2-fluoroethoxy)propan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

[0083] 6-(Cyclopropylmethoxy)-N-[(2S)-1-(3-fluoropropoxy)propan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

[0084] 6-(Cyclopropylmethoxy)-N-{3-[(fluoromethoxy)methyl]pentan-3-yl}-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

[0085] 6-(Cyclopropylmethoxy)-N-{3-[(2-fluoroethoxy)methyl]pentan-3-yl}-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

[0086] 6-(Cyclopropylmethoxy)-N-{3-[(3-fluoropropoxy)methyl]pentan-3-yl}-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

[0087] 6-(Cyclopropylmethoxy)-N-{3-[(fluoromethoxy)methyl]pentan-3-yl}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

[0088] 6-(Cyclopropylmethoxy)-N-{3-[(2-fluoroethoxy)methyl]pentan-3-yl}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

[0089] 6-(Cyclopropylmethoxy)-N-{3-[(3-fluoropropoxy)methyl]pentan-3-yl}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

[0090] Fluoromethyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyrazine-2-carbonyl]amino}-2-ethylbutanoate;

[0091] 2-Fluoroethyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyrazine-2-carbonyl]amino}-2-ethylbutanoate;

[0092] 3-Fluoropropyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyrazine-2-carbonyl]amino}-2-ethylbutanoate;

[0093] Fluoro(dideuterated)methyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate;

[0094] 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoic acid 2-fluoro(2,2-dideutero)ethyl ester;

[0095] 3-Fluoro(3,3-dideutero)propyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate;

[0096] Fluoro(dideuterated)methyl 2-{[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate;

[0097] 2-{[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoic acid 2-fluoro(2,2-dideutero)ethyl ester;

[0098] 3-Fluoro(3,3-dideutero)propyl 2-{[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate;

[0099] 3-Fluoro(3,3-dideutero)propyl 2-{[6-(cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate;

[0100] Fluoro(dideuterated)methyl 2-{[6-(cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate;

[0101] 2-{[6-(cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoic acid 2-fluoro(2,2-dideutero)ethyl ester;

[0102] 6-(Cyclopropylmethoxy)-N-[(2S)-1-{[fluoro(dideutero)methyl]oxy}-4-methylpentan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

[0103] 6-(Cyclopropylmethoxy)-N-[(2S)-1-{[2-fluoro(2,2-dideutero)ethyl]oxy}-4-methylpentan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

[0104] 6-(Cyclopropylmethoxy)-N-[(2S)-1-{[3-fluoro(3,3-dideuterated)propyl]oxy}-4-methylpentan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

[0105] 6-(Cyclopropylmethoxy)-N-[(2S)-1-{[fluoro(dideutero)methyl]oxy}-3-methylbutan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

[0106] 6-(Cyclopropylmethoxy)-N-[(2S)-1-{[2-fluoro(2,2-dideutero)ethyl]oxy}-3-methylbutan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

[0107] 6-(Cyclopropylmethoxy)-N-[(2S)-1-{[3-fluoro(3,3-dideuterated)propyl]oxy}-3-methylbutan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

[0108] 6-(Cyclopropylmethoxy)-N-[(2S)-1-{[fluoro(dideutero)methyl]oxy}propan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

[0109] 6-(Cyclopropylmethoxy)-N-[(2S)-1-{[2-fluoro(2,2-dideutero)ethyl]oxy}propan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

[0110] 6-(Cyclopropylmethoxy)-N-[(2S)-1-{[3-fluoro(3,3-dideuterated)propyl]oxy}propan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

[0111] 6-(Cyclopropylmethoxy)-N-[(2S)-1-{[fluoro(dideutero)methyl]oxy}-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

[0112] 6-(Cyclopropylmethoxy)-N-[(2S)-1-{[2-fluoro(2,2-dideutero)ethyl]oxy}-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

[0113] 6-(Cyclopropylmethoxy)-N-[(2S)-1-{[3-fluoro(3,3-dideutero)propyl]oxy}-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

[0114] 6-(Cyclopropylmethoxy)-N-[(2S)-1-{[fluoro(dideutero)methyl]oxy}-3-methylbutan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

[0115] 6-(Cyclopropylmethoxy)-N-[(2S)-1-{[2-fluoro(2,2-dideutero)ethyl]oxy}-3-methylbutan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

[0116] 6-(Cyclopropylmethoxy)-N-[(2S)-1-{[3-fluoro(3,3-dideutero)propyl]oxy}-3-methylbutan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

[0117] 6-(Cyclopropylmethoxy)-N-[(2S)-1-{[2-fluoro(2,2-dideutero)ethyl]oxy}propan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

[0118] 6-(Cyclopropylmethoxy)-N-[(2S)-1-{[3-fluoro(3,3-dideutero)propyl]oxy}propan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

[0119] 6-(Cyclopropylmethoxy)-N-[3-({[fluoro(dideutero)methyl]oxy}methyl)pentan-3-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

[0120] 6-(cyclopropylmethoxy)-N-[3-({[2-fluoro(2,2-dideutero)ethyl]oxy}methyl)pentan-3-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

[0121] 6-(cyclopropylmethoxy)-N-[3-({[3-fluoro(3,3-dideuterated)propyl]oxy}methyl)pentan-3-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

[0122] 6-(Cyclopropylmethoxy)-N-[3-({[fluoro(dideutero)methyl]oxy}methyl)pentan-3-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

[0123] 6-(Cyclopropylmethoxy)-N-[3-({[2-fluoro(2,2-dideutero)ethyl]oxy}methyl)pentan-3-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

[0124] 6-(cyclopropylmethoxy)-N-[3-({[3-fluoro(3,3-dideutero)propyl]oxy}methyl)pentan-3-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

[0125] 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethyl-4-fluoro(4,4-dideutero)butanoic acid ethyl ester;

[0126] 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethyl-4-fluoro(4,4-dideutero)butanoic acid ethyl ester;

[0127] 6-(Cyclopropylmethoxy)-5-(3-fluoro-3-methylazetidin-1-yl)-N-(3-(3-fluoropropylcarbamoyl)pentan-3-yl)picolinamide;

[0128] Ethyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethyl-4-fluorobutyrate;

[0129] Ethyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethyl-3-fluorobutyrate;

[0130] 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethyl-4-fluorobutyric acid ethyl ester; and

[0131] Ethyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethyl-3-fluorobutyrate.

[0132] The present invention also relates to compounds according to the invention selected from:

[0133] 2-Fluoroethyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate;

[0134] 3-Fluoropropyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate;

[0135] N-[6-(Cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]-L-leucine 2-fluoroethyl ester;

[0136] N-[6-(Cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridine-2-carbonyl]-L-leucine 2-fluoroethyl ester;

[0137] 6-(Cyclopropylmethoxy)-N-[(2S)-1-(fluoromethoxy)-4-methylpentan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

[0138] 6-(Cyclopropylmethoxy)-N-[(2S)-1-(2-fluoroethoxy)-4-methylpentan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

[0139] 6-(Cyclopropylmethoxy)-N-[(2S)-1-(fluoromethoxy)-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

[0140] 6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-N-[(2S)-1-(2-fluoroethoxy)-4-methylpentan-2-yl]pyridine-2-carboxamide; and

[0141] 6-(Cyclopropylmethoxy)-N-[(2S)-1-(2-fluoroethoxy)-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide.

[0142] The present invention also particularly relates to 6-(cyclopropylmethoxy)-N-[(2S)-1-(2-fluoroethoxy)-4-methylpentan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide.

[0143] The synthesis of compounds having the general structure I can be achieved, for example, according to the following scheme.

[0144] According to the procedure according to Scheme 1, compound AA (R' = H, methyl, ethyl, isopropyl, tert-butyl or another suitable protecting group, for example described in TW Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3rd edition) can be used as starting material. AA is commercially available, described in the literature or can be synthesized by a person skilled in the art.

[0145] Solution 1

[0146]

[0147] Compounds AB can be prepared from AA 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.

[0148] Conversion of compound AB to 6-chloro or 6-bromo-methylpyridine AC (X = Cl, Br) can be achieved, for example, by treatment with phosphoryl trichloride or phosphoryl tribromide in the absence of 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 (step b).

[0149] 6-Chloro- or bromo-methylpyridine AC (X = Cl, Br) can be converted into compound AE by reaction with a suitable substituted primary or secondary alcohol AD, such as cyclopropylmethanol, in the presence of a base such as sodium hydride with or without an inert solvent such as dimethylformamide at a temperature in the range of room temperature to the reflux temperature of the solvent, in particular at room temperature (step c).

[0150] Saponification of esters of general formula AE (R'≠H) by methods well known to those skilled in the art - 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 employed - affords acids II of general formula II (step d).

[0151] Compound I (R" = cyclopropylmethyloxy) can be prepared from II and the corresponding amine of formula III by a suitable amide bond forming reaction (step e). 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 can be used. -3-oxide hexafluorophosphate (HATU), 1-hydroxy-1,2,3-benzotriazole (HOBT), O-benzotriazol-1-yl-N,N,N',N'-tetramethylurea Tetrafluoroborate (TBTU) and O-benzotriazole-N,N,N',N'-tetramethyl-urea -hexafluoro-phosphate (HBTU) to effect such a transformation. A convenient method is to use HBTU and a base, such as N-methylmorpholine, for example in an inert solvent such as, for example, dimethylformamide, at room temperature.

[0152] Alternatively, compound AC (R' = methyl, ethyl, isopropyl, tert-butyl or another suitable protecting group, such as those described in TW 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 AC (R' = H) as described in step d; ii) converted to the corresponding amide by treatment with amine III as described in step e; and iii) reacted with alcohol AD ​​as described in step c to give compound I.

[0153] Amines III and alcohols AD are commercially available, described in the literature, can be synthesized by one skilled in the art or as described in the experimental part.

[0154] If one of the compounds of the starting materials formula AA, AD or III contains one or more functional groups that are unstable or reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups (P) can be introduced prior to key steps 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.

[0155] If one or more compounds of formula AA to AE, AD, II or III contain a chiral center, the picoline of formula I can 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 via diastereomeric salts by crystallization or by specific chromatographic methods, using chiral adsorbents or chiral eluents to separate the enantiomers.

[0156] According to the procedure according to Scheme 2, compound BA (R' = H, methyl, ethyl, isopropyl, tert-butyl or another suitable protecting group, such as described in TW 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 (for example, for R' = methyl: 5-bromo-6-chloro-pyridine-2-carboxylic acid methyl ester CAN1214353-79-3), described in the literature or can be synthesized by a person skilled in the art.

[0157] Solution 2

[0158]

[0159] The reaction is carried out by methods well known to those skilled in the art, for example, using a palladium catalyst such as tris(dibenzylideneacetone)dipalladium / dimethylbis(diphenyl)-phosphinoxanthene and a base such as cesium carbonate in a solvent such as 1,4-dihydroquinone. Compounds AC' can be prepared from BA by coupling with an amine BB (M is H) in an alkane, preferentially at the boiling point of the solvent (step a).

[0160] Compound AC' can be further converted to compound I (R" = cyclopropylmethyloxy) by: i) reaction with compound AD to form compound AE as described in step c of Scheme 1; ii) saponification as described in step d of Scheme 1; and iii) amide bond formation as described in step e of Scheme 1.

[0161] Furthermore, as described in step c of Scheme 1, compound BA can be converted to compound BC by treatment with compound AD (step b).

[0162] Subsequent conversion of compound BC to compound AE can be achieved as described for the conversion of BA to AC' (step a).

[0163] Compound AE can be further converted to compound I (R" = cyclopropylmethyloxy) by: i) saponification as described in step d of Scheme 1; ii) amide bond formation as described in step e of Scheme 1.

[0164] Alternatively, compound BC (R' = methyl, ethyl, isopropyl, tert-butyl or another suitable protecting group, such as those described in TW 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 BC (R' = H) as described in step d of Scheme 1; ii) converted to the corresponding amide BD by treatment with amine III as described in step e of Scheme 1; and iii) reacted with BB as described in step a to give compound I (R" = cyclopropylmethyloxy).

[0165] In addition, compound I can also be synthesized using the following reaction sequence: i) saponification of compound BA (R' = methyl, ethyl, isopropyl, tert-butyl or another suitable protecting group, such as those described in TW Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3rd edition) to its acid analog BA (R' = H) as described in step d of Scheme 1; ii) conversion to the corresponding amide by treatment with amine III as described in step e of Scheme 1; iii) reaction with BB as described in step a; and iv) reaction with compound AD as described in step b. Optionally, step iii) and step iv) can be interchanged.

[0166] If one of the compounds of the starting material formula CA, CB or BC contains one or more functional groups that are unstable or reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups (P) can be introduced prior to the key steps 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.

[0167] If one or more compounds of formula BA, BB or AD contain a chiral center, the picolines of formula AC' and AE may be obtained as mixtures of diastereomers or enantiomers, which may be separated by methods known in the art, such as (chiral) HPLC or crystallization. Racemic compounds may be separated into their enantiomers, for example, via diastereomeric salts by crystallization or by specific chromatographic methods, using chiral adsorbents or chiral eluents to separate the enantiomers.

[0168] The present invention also relates to a process for preparing a compound of formula (I), comprising one of the following steps:

[0169] (a) making a compound of formula (A)

[0170]

[0171] In R 1 -H, a palladium catalyst and a base;

[0172] (b) making a compound of formula (B)

[0173]

[0174] In NH2-C(R 2 R 3 )-A 2 -O-(CH2) n -(CD2) m -X, a coupling agent and a base;

[0175] Among them A 1 , A 2 ,X,R 1 -R 3 , m and n are as defined above, and Y is halogen.

[0176] The coupling agent of step (b) is conveniently an amide bond forming agent such as, for example, N,N'-carbonyl-diimidazole (CDI), N,N'-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridine -3-oxide hexafluorophosphate (HATU), 1-hydroxy-1,2,3-benzotriazole (HOBT), O-benzotriazol-1-yl-N,N,N',N'-tetramethylurea Tetrafluoroborate (TBTU) and O-benzotriazole-N,N,N',N'-tetramethyl-urea - Hexafluoro-phosphate (HBTU).

[0177] N-Methylmorpholine is a convenient base for use in step (b).

[0178] In step (b), HBTU may advantageously be used in combination with N-methylmorpholine.

[0179] The solvent of step (b) may advantageously be dimethylformamide.

[0180] In step (a), the palladium catalyst may be, for example, tris(dibenzylideneacetone)dipalladium / dimethylbis(diphenylphosphine)xanthene.

[0181] In step (a), the base may be, for example, cesium carbonate.

[0182] In step (a), the solvent is advantageously 1,4-dihydro- alkyl.

[0183] In step (a), Y may conveniently be bromo.

[0184] The invention furthermore relates to compounds according to the invention prepared by a process according to the invention.

[0185] Another embodiment of the present invention provides a pharmaceutical composition or medicine, which comprises a compound of the present invention and a therapeutic inert carrier, diluent or excipient, and a method for preparing such a composition and medicine using the compound of the present invention. In one example, the compound of formula (I) can be mixed into a galenic administration form at ambient temperature at a suitable pH, and with 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 adopted. The pH of the preparation depends primarily on the specific use and the 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 an 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 freeze-dried preparation or as an aqueous solution.

[0186] The composition is formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered in this regard 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.

[0187] The compounds of the present invention can be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if local treatment is desired, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.

[0188] 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.

[0189] Typical formulations are prepared by mixing a compound of the invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, 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, aromas, flavor enhancers, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or a pharmaceutical composition thereof) or to assist in the preparation of a drug product (i.e., a pharmaceutical product).

[0190] The present invention also particularly relates to:

[0191] The compounds of formula (I) are used for the treatment or prevention of pain, atherosclerosis, age-related macular degeneration, diabetic retinopathy, glaucoma, 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, liver cirrhosis or tumors, bone mass regulation, neurodegeneration, stroke, transient ischemic attack or uveitis;

[0192] Use of a compound according to formula (I) for the preparation of a medicament for the treatment or prevention of pain, atherosclerosis, age-related macular degeneration, diabetic retinopathy, glaucoma, 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, liver cirrhosis or tumors, bone mass regulation, neurodegeneration, stroke, transient ischemic attack or uveitis;

[0193] A compound of formula (I) for use in the treatment or prevention of pain, atherosclerosis, age-related macular degeneration, diabetic retinopathy, glaucoma, 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 mass regulation, neurodegeneration, stroke, transient ischemic attack or uveitis; and

[0194] A method for treating or preventing pain, atherosclerosis, age-related macular degeneration, diabetic retinopathy, glaucoma, 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 mass regulation, neurodegeneration, stroke, transient ischemic attack or uveitis, the method comprising administering an effective amount of a compound of formula (I) to a patient in need thereof.

[0195] The present invention particularly relates to a compound of formula (I) for use in treating or preventing ischemia, reperfusion injury, liver fibrosis or kidney fibrosis, in particular ischemia or reperfusion injury.

[0196] The invention will now be described by the following examples, which have no limiting nature. Example

[0197] abbreviation

[0198] CAN = Chemical Abstracts Service Number; DIPEA = N-ethyl-N-isopropylpropan-2-amine; DMF = dimethylformamide; EtOAc = ethyl acetate; hept. = heptane; HPLC = LC = high performance liquid chromatography; ISP = ion spray, corresponding to ESI (electrospray); MS = mass spectrometry; NMR data are reported in parts per million (δ) relative to the internal standard tetramethylsilane and referenced to the deuterium lock signal from the sample solvent (d6-DMSO unless otherwise stated); coupling constants (J) are reported in Hertz; RT = room temperature; TBTU = O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyl-urea -tetrafluoroborate; THF = tetrahydrofuran; tlc = thin layer chromatography.

[0199] Example 1

[0200] Fluoromethyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate

[0201]

[0202] a) 2-(6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridinylamido)-2-ethylbutanoic acid

[0203]

[0204] In a 25 mL round bottom flask, ethyl 2-(6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridinecarboxamide)-2-ethylbutanoate (CAN 1778678-14-0, 210 mg, 501 μmol, Eq: 1) was combined with THF (3 mL) and MeOH (3.3 mL) to give a colorless solution. KOH (140 mg, 2.5 mmol, Eq: 5) dissolved in water (3 mL) was added and the reaction mixture was stirred at 100 °C for 19 h. KOH (75 mg) and 1 mL of THF, MeOH and water were added and stirring was continued at 100 °C for 3 h. The organic solvent was removed under reduced pressure and the aqueous phase was acidified (1 N HCl). The resulting white suspension was extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with brine (1 x 20 mL), dried over Na2SO4 and concentrated in vacuo to give the crude title compound as a light brown oil, which was used in the next step without further purification, MS (ISP): 392.314 [MH + ].

[0205] b) 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoic acid fluoromethyl ester

[0206] In a 10 mL round bottom flask, 2-(6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine amide)-2-ethylbutanoic acid (37 mg, 94.5 μmol, Eq: 1) was combined with DMF (500 μL) to give a light brown solution. K2CO3 (65.3 mg, 473 μmol, Eq: 5) and fluoro-iodo-methane (76.3 mg, 32.2 μL, 473 μmol, Eq: 5) were added. The reaction mixture was stirred at room temperature for 30 min, diluted with EtOAc and washed with saturated NaCl (3 x 10 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 5 g, hept. / EtOAc) to give the title compound (27 mg, 68%) as a colorless oil, MS (ISP): 424.341 [MH + ].

[0207] Example 2

[0208] 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoic acid 2-fluoroethyl ester

[0209]

[0210] Analogously to the procedure described in Example 1b, 2-(6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridinamido)-2-ethylbutanoic acid (Example 1a) was reacted with fluoro-iodo-methane to give the title compound as a colorless oil, MS (ISP): 438.346 [MH + ].

[0211] Example 3

[0212] 3-Fluoropropyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate

[0213]

[0214] Analogously to the procedure described in Example 1b, 2-(6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridinamido)-2-ethylbutanoic acid (Example 1a) was reacted with 1-iodo-3-fluoropropane to give the title compound as a colorless oil, MS (ISP): 452.4 [MH +].

[0215] Example 4

[0216] Fluoromethyl 2-{[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate

[0217]

[0218] Analogously to the procedure described in Example 1b, 2-(6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridinamido)-2-ethylbutanoic acid (CAN 1415896-50-2) was reacted with fluoro-iodo-methane to give the title compound as a colorless oil, LC-MS (UV peak area / ESI) 100%, 430.1952 [MH + ].

[0219] Example 5

[0220] 2-{[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoic acid 2-fluoroethyl ester

[0221]

[0222] Analogously to the procedure described in Example 1b, 2-(6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridinamido)-2-ethylbutanoic acid (CAN 1415896-50-2) was reacted with fluoro-iodo-ethane to give the title compound as a colorless oil, LC-MS (UV peak area / ESI) 100%, 444.2109 [MH + ].

[0223] Example 6

[0224] 3-Fluoropropyl 2-{[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate

[0225]

[0226] Analogously to the procedure described in Example 1b, 2-(6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridinamido)-2-ethylbutanoic acid (CAN 1415896-50-2) was reacted with 1-iodo-3-fluoropropane to give the title compound as a colorless oil, LC-MS (UV peak area / ESI) 100%, 458.2263 [MH + ].

[0227] Example 7

[0228] 3-Fluoropropyl 2-{[6-(cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate

[0229]

[0230] Analogously to the procedure described in Example 1b, 2-(6-(cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridinamido)-2-ethylbutanoic acid (CAN 1415897-34-5) was reacted with 1-iodo-3-fluoropropane to give the title compound as a colorless oil, LC-MS (UV peak area / ESI) 98%, 436.2615 [MH + ].

[0231] Example 8

[0232] Fluoromethyl 2-{[6-(cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate

[0233]

[0234] Analogously to the procedure described in Example 1b, 2-(6-(cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridinamido)-2-ethylbutanoic acid (CAN 1415897-34-5) was reacted with fluoro-iodo-methane to give the title compound as a colorless oil, LC-MS (UV peak area / ESI) 96%, 408.2301 [MH+].

[0235] Example 9

[0236] 2-{[6-(Cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoic acid 2-fluoroethyl ester

[0237]

[0238] Analogously to the procedure described in Example 1b, 2-(6-(cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridinamido)-2-ethylbutanoic acid (CAN 1415897-34-5) was reacted with fluoro-iodine-ethane to give the title compound as a colorless oil, LC-MS (UV peak area / ESI) 97%, 422.2463 [MH+].

[0239] Example 10

[0240] N-[6-(Cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]-L-leucine fluoromethyl ester

[0241]

[0242] a) (S)-2-(5-bromo-6-(cyclopropylmethoxy)pyridinylamido)-4-methylpentanoic acid methyl ester

[0243]

[0244] In a 100 mL round bottom flask, 5-bromo-6-(cyclopropylmethoxy)picolinic acid (CAN 1415898-37-1, 850 mg, 3.12 mmol, Eq: 1) was combined with DMF (15 mL) to give a light yellow solution. TBTU (1.1 g, 3.44 mmol, Eq: 1.1), DIPEA (1.61 g, 2.18 mL, 12.5 mmol, Eq: 4) and L-leucine methyl ester hydrochloride (CAN 7517-19-3, 794 mg, 4.37 mmol, Eq: 1.4) were added and the mixture was stirred at room temperature for 30 min. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc. The organic layers were combined and washed with saturated NaHCO3 (3 x 20 mL), 1 M HCl (3 x 20 mL) and saturated NaCl (3 x 20 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to give the crude title product (1.1 g, 88%) as a light brown oil, which was used in the next reaction step without further purification, MS (ISP): 399.162 [MH + ].

[0245] b) (S)-2-(6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridinamido)-4-methylpentanoic acid methyl ester

[0246]

[0247] In a 20 mL sealed test tube, (S)-2-(5-bromo-6-(cyclopropylmethoxy)pyridine amide)-4-methylpentanoic acid methyl ester (385 mg, 964 μmol, Eq: 1) was combined with toluene (10 mL) to give a colorless solution. 3-Methoxyazetidine hydrochloride (CAN 148644-09-1, 179 mg, 1.45 mmol, Eq: 1.5) and Cs2CO3 (943 mg, 2.89 mmol, Eq: 3) were added. Racemic-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (120 mg, 193 μmol, Eq: 0.2) and palladium(II) acetate (43.3 mg, 193 μmol, Eq: 0.2) were added. The white suspension was heated to 110 °C for 1 h, diluted with EtOAc and filtered through celite. The organic layers were combined and washed with 1M HCl (3 x 50 mL) and saturated NaCl (1 x 100 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 50 g, hept. / EtOAc) to give the title compound (287 mg, 73%) as a light yellow oil, MS (ISP): 406.319 [MH + ].

[0248] c) (S)-2-(6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridinylamido)-4-methylpentanoic acid

[0249]

[0250] In a 25 mL round-bottom flask, (S)-2-(6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine amide)-4-methylpentanoic acid methyl ester (270 mg, 666 μmol, Eq: 1) was combined with THF (2 mL), water (2 mL) and MeOH (2 mL) to give a light yellow solution. KOH (112 mg, 2 mmol, Eq: 3) was added and the mixture was stirred at room temperature for 1 h. The organic solvent was removed under reduced pressure. The aqueous phase was adjusted to pH 2 with 1 M HCl and extracted with EtOAc (3 x 20 mL) and brine (1 x 25 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to give the crude title compound (quantitative) as a light brown oil, which was used in the next reaction step without further purification, MS (ISP): 392.316 [MH + ].

[0251] d) N-[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]-L-leucine fluoromethyl ester

[0252] Analogously to the procedure described in Example 1b, (S)-2-(6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridinamido)-4-methylpentanoic acid was reacted with fluoro-iodo-methane to give the title compound as a colorless oil, MS (ISP): 424.289 [MH + ].

[0253] Embodiment 11

[0254] N-[6-(Cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]-L-leucine 2-fluoroethyl ester

[0255]

[0256] Analogously to the procedure described in Example 1b, (S)-2-(6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridinamido)-4-methylpentanoic acid (Example 10c) was reacted with fluoro-iodo-ethane to give the title compound as a colorless oil, MS (ISP): 438.294 [MH + ].

[0257] Example 12

[0258] N-[6-(Cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]-L-leucine 3-fluoropropyl ester

[0259]

[0260] Analogously to the procedure described in Example 1b, (S)-2-(6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridinamido)-4-methylpentanoic acid (Example 10c) was reacted with 1-fluoro-3-iodopropane to give the title compound as a colorless oil, MS (ISP): 452.351 [MH + ].

[0261] Example 13

[0262] N-[6-(Cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridine-2-carbonyl]-L-leucine fluoromethyl ester

[0263]

[0264] a) (S)-2-(6-(cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridinamido)-4-methylpentanoic acid methyl ester

[0265]

[0266] Analogously to the procedure described in Example 10b, (S)-methyl 2-(5-bromo-6-(cyclopropylmethoxy)picolinamido)-4-methylpentanoate (Example 10a) was reacted with pyrrolidine to give the title compound as a pale yellow oil, LC-MS (UV peak area / ESI) 95%, 390.2403 [MH + ].

[0267] b) (S)-2-(6-(cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridinylamido)-4-methylpentanoic acid

[0268]

[0269] Analogously to the procedure described in Example 10c, (S)-methyl 2-(6-(cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridinamido)-4-methylpentanoate was hydrolyzed with KOH to give the title compound as a brown oil which was used in the next reaction step without further purification, MS (ISP): 376.307 [MH + ].

[0270] c) N-[6-(Cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridine-2-carbonyl]-L-leucine fluoromethyl ester

[0271] Analogously to the procedure described in Example 1b, (S)-2-(6-(cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridinamido)-4-methylpentanoic acid was reacted with fluoro-iodo-methane to give the title compound as a light yellow oil, MS (ISP): 408.276 [MH + ].

[0272] Embodiment 14

[0273] N-[6-(Cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridine-2-carbonyl]-L-leucine 2-fluoroethyl ester

[0274]

[0275] Analogously to the procedure described in Example 1b, (S)-2-(6-(cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridinamido)-4-methylpentanoic acid (Example 13b) was reacted with fluoro-iodo-ethane to give the title compound as a light brown oil, MS (ISP): 422.332 [MH + ].

[0276] Embodiment 15

[0277] N-[6-(Cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridine-2-carbonyl]-L-leucine 3-fluoropropyl ester

[0278]

[0279] Analogously to the procedure described in Example 1b, (S)-2-(6-(cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridinamido)-4-methylpentanoic acid (Example 13b) was reacted with 1-fluoro-3-iodopropane to give the title compound as a light brown oil, MS (ISP): 436.338 [MH + ].

[0280] Example 16

[0281] 6-(Cyclopropylmethoxy)-N-[(2S)-1-(fluoromethoxy)-4-methylpentan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide

[0282]

[0283] In a 5 mL round bottom flask, (S)-6-(cyclopropylmethoxy)-N-(1-hydroxy-4-methylpentan-2-yl)-5-(pyrrolidin-1-yl)picolinamide (CAN 1415894-55-1, 40 mg, 111 μmol, Eq: 1) was combined with DMF (1 mL) to give a colorless solution which was cooled to 0°C. Sodium hydride in mineral oil (22.1 mg, 553 μmol, Eq: 5) was added and stirring was continued for 30 min. Fluoro-iodo-methane (88.5 mg, 37.3 μL, 553 μmol, Eq: 5) was added and the mixture was allowed to warm to ambient temperature and stirring was continued for 1 h. The reaction mixture was diluted with EtOAc. The organic layers were combined and washed with saturated NaCl (3 x 25 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 5 g, hept. / EtOAc) to give the title compound (24 mg, 55%) as a white solid, MS (ISP): 394.271 [MH + ].

[0284] Embodiment 17

[0285] 6-(Cyclopropylmethoxy)-N-[(2S)-1-(2-fluoroethoxy)-4-methylpentan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide

[0286]

[0287] Analogously to the procedure described in Example 16, (S)-6-(cyclopropylmethoxy)-N-(1-hydroxy-4-methylpentan-2-yl)-5-(pyrrolidin-1-yl)picolinamide (CAN 1415894-55-1) was reacted with 1-fluoro-2-iodoethane to give the title compound as a colorless oil, MS (ISP): 408.327 [MH + ].

[0288] Embodiment 18

[0289] 6-(Cyclopropylmethoxy)-N-[(2S)-1-(3-fluoropropoxy)-4-methylpentan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide

[0290]

[0291] Analogously to the procedure described in Example 16, (S)-6-(cyclopropylmethoxy)-N-(1-hydroxy-4-methylpentan-2-yl)-5-(pyrrolidin-1-yl)picolinamide (CAN 1415894-55-1) was reacted with 1-fluoro-3-fluoropropane to give the title compound as a colorless oil, MS (ISP): 422.332 [MH + ].

[0292] Embodiment 19

[0293] 6-(Cyclopropylmethoxy)-N-[(2S)-1-(fluoromethoxy)-3-methylbutan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide

[0294]

[0295] a) (S)-6-(Cyclopropylmethoxy)-N-(1-hydroxy-3-methylbutan-2-yl)-5-(pyrrolidin-1-yl)picolinamide

[0296]

[0297] In a 50 mL round bottom flask, 6-(cyclopropylmethoxy)-5-(pyrrolidin-1-yl)picolinic acid (CAN1415898-45-1, 295 mg, 1.12 mmol, Eq: 1) was combined with DMF (15 mL) to give a yellow solution. DIPEA (727 mg, 982 μL, 5.62 mmol, Eq: 5) and TBTU (397 mg, 1.24 mmol, Eq: 1.1) were added. L-Valinol (CAN2026-48-4, 174 mg, 1.69 mmol, Eq: 1.5) was added and the mixture was stirred at ambient temperature for 1 h. EtOAc was added and the solution was washed with saturated NaHCO3 (3 x 20 mL), 1 M HCl (3 x 20 mL) and saturated NaCl (3 x 20 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to give the title compound (240 mg, 61%) as a light yellow oil, which was used in the next step without further purification, MS (ISP): 348.239 [MH + ].

[0298] b) 6-(Cyclopropylmethoxy)-N-[(2S)-1-(fluoromethoxy)-3-methylbutan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide

[0299] Analogously to the procedure described in Example 16, (S)-6-(cyclopropylmethoxy)-N-(1-hydroxy-3-methylbutan-2-yl)-5-(pyrrolidin-1-yl)picolinamide was reacted with fluoro-iodo-methane to give the title compound as a colorless oil, MS (ISP): 380.265 [MH + ].

[0300] Embodiment 20

[0301] 6-(Cyclopropylmethoxy)-N-[(2S)-1-(2-fluoroethoxy)-3-methylbutan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide

[0302]

[0303] Analogously to the procedure described in Example 16, (S)-6-(cyclopropylmethoxy)-N-(1-hydroxy-3-methylbutan-2-yl)-5-(pyrrolidin-1-yl)picolinamide (Example 19a) was reacted with 1-fluoro-2-iodoethane to give the title compound as a colorless oil, MS (ISP): 394.326 [MH + ].

[0304] Embodiment 21

[0305] 6-(Cyclopropylmethoxy)-N-[(2S)-1-(3-fluoropropoxy)-3-methylbutan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide

[0306]

[0307] Analogously to the procedure described in Example 16, (S)-6-(cyclopropylmethoxy)-N-(1-hydroxy-3-methylbutan-2-yl)-5-(pyrrolidin-1-yl)picolinamide (Example 19a) was reacted with 1-iodo-3-fluoropropane to give the title compound as a colorless oil, MS (ISP): 408.391 [MH + ].

[0308] Embodiment 22

[0309] 6-(Cyclopropylmethoxy)-N-[(2S)-1-(fluoromethoxy)propan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide

[0310]

[0311] a) (S)-6-(Cyclopropylmethoxy)-N-(1-hydroxypropan-2-yl)-5-(pyrrolidin-1-yl)picolinamide

[0312]

[0313] Analogously to the procedure described in Example 19a, 6-(cyclopropylmethoxy)-5-(pyrrolidin-1-yl)picolinic acid (CAN 1415898-45-1) was reacted with L-alaninol (CAN 2749-11-3) to give the title compound as a pale yellow oil, MS (ISP): 320.209 [MH + ].

[0314] b) 6-(Cyclopropylmethoxy)-N-[(2S)-1-(fluoromethoxy)propan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide

[0315] Analogously to the procedure described in Example 16, (S)-6-(cyclopropylmethoxy)-N-(1-hydroxypropan-2-yl)-5-(pyrrolidin-1-yl)picolinamide was reacted with fluoro-iodo-methane to give the title compound as a colorless oil, MS (ISP): 352.204 [MH + ].

[0316] Embodiment 23

[0317] 6-(Cyclopropylmethoxy)-N-[(2S)-1-(2-fluoroethoxy)propan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide

[0318]

[0319] Analogously to the procedure described in Example 16, (S)-6-(cyclopropylmethoxy)-N-(1-hydroxypropan-2-yl)-5-(pyrrolidin-1-yl)picolinamide (Example 22a) was reacted with 1-fluoro-2-iodoethane to give the title compound as a colorless oil, MS (ISP): 366.298 [MH + ].

[0320] Embodiment 24

[0321] 6-(Cyclopropylmethoxy)-N-[(2S)-1-(3-fluoropropoxy)propan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide

[0322]

[0323] Analogously to the procedure described in Example 16, (S)-6-(cyclopropylmethoxy)-N-(1-hydroxypropan-2-yl)-5-(pyrrolidin-1-yl)picolinamide (Example 22a) was reacted with 1-iodo-3-fluoropropane to give the title compound as a colorless oil, MS (ISP): 380.265 [MH + ].

[0324] Embodiment 25

[0325] 6-(Cyclopropylmethoxy)-N-[(2S)-1-(fluoromethoxy)-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide

[0326]

[0327] a) (S)-6-(Cyclopropylmethoxy)-N-(1-hydroxy-4-methylpentan-2-yl)-5-(3-methoxyazetidin-1-yl)picolinamide

[0328]

[0329] Analogously to the procedure described in Example 19a, 6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)picolinic acid (CAN 1613292-59-3) was reacted with L-leucinol (CAN 7533-40-6) to give the title compound as a light yellow oil, MS (ISP): 378.309 [MH+ ].

[0330] b) 6-(Cyclopropylmethoxy)-N-[(2S)-1-(fluoromethoxy)-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide

[0331] Analogously to the procedure described in Example 16, (S)-6-(cyclopropylmethoxy)-N-(1-hydroxy-4-methylpentan-2-yl)-5-(3-methoxyazetidin-1-yl)picolinamide was reacted with fluoro-iodo-methane to give the title compound as a colorless oil, LC-MS (UV peak area / ESI) 100%, 380.265 [MH + ].

[0332] Embodiment 26

[0333] 6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-N-[(2S)-1-(2-fluoroethoxy)-4-methylpentan-2-yl]pyridine-2-carboxamide

[0334]

[0335] a)(S)-6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-N-(1-hydroxy-4-methylpentan-2-yl)picolinamide

[0336]

[0337] Analogously to the procedure described in Example 19a, 6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinic acid (CAN 1415898-88-2) was reacted with L-leucinol (CAN 7533-40-6) to give the title compound as a light yellow oil, MS (ISP): 384.279 [MH + ].

[0338] b) 6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-N-[(2S)-1-(2-fluoroethoxy)-4-methylpentan-2-yl]pyridine-2-carboxamide

[0339] Analogously to the procedure described in Example 16, (S)-6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-N-(1-hydroxy-4-methylpentan-2-yl)picolinamide was reacted with 1-fluoro-2-iodoethane to give the title compound as a colorless oil, MS (ISP): 430.338. [MH + ].

[0340] Embodiment 27

[0341] 6-(Cyclopropylmethoxy)-N-[(2S)-1-(2-fluoroethoxy)-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide

[0342]

[0343] Analogously to the procedure described in Example 16, (S)-6-(cyclopropylmethoxy)-N-(1-hydroxy-4-methylpentan-2-yl)-5-(3-methoxyazetidin-1-yl)picolinamide (Example 25a) was reacted with 1-fluoro-2-iodoethane to give the title compound as a colorless oil, MS (ISP): 424.362 [MH + ].

[0344] Embodiment 28

[0345] 6-(Cyclopropylmethoxy)-N-[(2S)-1-(3-fluoropropoxy)-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide

[0346]

[0347] Analogously to the procedure described in Example 16, (S)-6-(cyclopropylmethoxy)-N-(1-hydroxy-4-methylpentan-2-yl)-5-(3-methoxyazetidin-1-yl)picolinamide (Example 25a) was reacted with 1-iodo-3-fluoropropane to give the title compound as a colorless oil, MS (ISP): 438.375 [MH + ].

[0348] Embodiment 29

[0349] 6-(Cyclopropylmethoxy)-N-[(2S)-1-(fluoromethoxy)-3-methylbutan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide

[0350]

[0351] a) (S)-6-(Cyclopropylmethoxy)-N-(1-hydroxy-3-methylbutan-2-yl)-5-(3-methoxyazetidin-1-yl)picolinamide

[0352]

[0353] Analogously to the procedure described in Example 19a, 6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)picolinic acid (CAN 1613292-59-3) was condensed with L-valinol (CAN 2026-48-4) to give the title compound as a light yellow oil, MS (ISP): 364.252 [MH + ].

[0354] b) 6-(Cyclopropylmethoxy)-N-[(2S)-1-(fluoromethoxy)-3-methylbutan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide

[0355] Analogously to the procedure described in Example 16, (S)-6-(cyclopropylmethoxy)-N-(1-hydroxy-3-methylbutan-2-yl)-5-(3-methoxyazetidin-1-yl)picolinamide was reacted with fluoro-iodo-methane to give the title compound as a colorless oil, MS (ISP): 396.3 [MH + ].

[0356] Embodiment 30

[0357] 6-(Cyclopropylmethoxy)-N-[(2S)-1-(2-fluoroethoxy)-3-methylbutan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide

[0358]

[0359] Analogously to the procedure described in Example 16, (S)-6-(cyclopropylmethoxy)-N-(1-hydroxy-3-methylbutan-2-yl)-5-(3-methoxyazetidin-1-yl)picolinamide (Example 29b) was reacted with 1-fluoro-2-iodoethane to give the title compound as a colorless oil, MS (ISP): 410.335 [MH + ].

[0360] Embodiment 31

[0361] 6-(Cyclopropylmethoxy)-N-[(2S)-1-(3-fluoropropoxy)-3-methylbutan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide

[0362]

[0363] Analogously to the procedure described in Example 16, (S)-6-(cyclopropylmethoxy)-N-(1-hydroxy-3-methylbutan-2-yl)-5-(3-methoxyazetidin-1-yl)picolinamide (Example 29b) was reacted with 1-iodo-3-fluoropropane to give the title compound as a colorless oil, MS (ISP): 424.362 [MH + ].

[0364] Embodiment 32

[0365] 6-(Cyclopropylmethoxy)-N-[(2S)-1-(2-fluoroethoxy)propan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide

[0366]

[0367] a) 6-(Cyclopropylmethoxy)-N-[(1S)-2-hydroxy-1-methyl-ethyl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide

[0368]

[0369] Analogously to the procedure described in Example 19a, 6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)picolinic acid (CAN 1613292-59-3) was condensed with L-alaninol (CAN 2749-11-3) to give the title compound as a pale yellow oil, MS (ISP): 336.242 [MH + ].

[0370] b) 6-(Cyclopropylmethoxy)-N-[(2S)-1-(2-fluoroethoxy)propan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide

[0371] Analogously to the procedure described in Example 16, 6-(cyclopropylmethoxy)-N-[(1S)-2-hydroxy-1-methyl-ethyl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide was reacted with 1-fluoro-2-iodoethane to give the title compound as a colorless oil, MS (ISP): 382.270 [MH + ].

[0372] Embodiment 33

[0373] 6-(Cyclopropylmethoxy)-N-[(2S)-1-(3-fluoropropoxy)propan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide

[0374]

[0375] Analogously to the procedure described in Example 16, 6-(cyclopropylmethoxy)-N-[(1S)-2-hydroxy-1-methyl-ethyl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide (Example 32a) was reacted with 1-iodo-3-fluoropropane to give the title compound as a colorless oil, MS (ISP): 396.279 [MH + ].

[0376] Embodiment 34

[0377] 6-(Cyclopropylmethoxy)-N-{3-[(fluoromethoxy)methyl]pentan-3-yl}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide

[0378]

[0379] a) 6-(Cyclopropylmethoxy)-N-(3-(hydroxymethyl)pentan-3-yl)-5-(3-methoxyazetidin-1-yl)picolinamide

[0380]

[0381] Analogously to the procedure described in Example 19a, 6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)picolinic acid (CAN 1613292-59-3) was condensed with 2-amino-2-ethylbutan-1-ol (CAN 19792-52-0) to give the title compound as a light yellow oil, MS (ISP): 378.303 [MH + ].

[0382] b) 6-(Cyclopropylmethoxy)-N-{3-[(fluoromethoxy)methyl]pentan-3-yl}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide

[0383] Analogously to the procedure described in Example 16, 6-(cyclopropylmethoxy)-N-(3-(hydroxymethyl)pentan-3-yl)-5-(3-methoxyazetidin-1-yl)picolinamide was reacted with fluoro-iodo-methane to give the title compound as a colorless oil, MS (ISP): 410.348 [MH + ].

[0384] Embodiment 35

[0385] 6-(Cyclopropylmethoxy)-N-{3-[(2-fluoroethoxy)methyl]pentan-3-yl}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide

[0386]

[0387] Analogously to the procedure described in Example 16, 6-(cyclopropylmethoxy)-N-(3-(hydroxymethyl)pentan-3-yl)-5-(3-methoxyazetidin-1-yl)picolinamide (Example 34a) was reacted with 1-fluoro-2-iodoethane to give the title compound as a light brown oil, MS (ISP): 424.362 [MH + ].

[0388] Embodiment 36

[0389] 6-(Cyclopropylmethoxy)-N-{3-[(3-fluoropropoxy)methyl]pentan-3-yl}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide

[0390]

[0391] Analogously to the procedure described in Example 16, 6-(cyclopropylmethoxy)-N-(3-(hydroxymethyl)pentan-3-yl)-5-(3-methoxyazetidin-1-yl)picolinamide (Example 34a) was reacted with 1-iodo-3-fluoropropane to give the title compound as a light brown oil, MS (ISP): 438.346 [MH + ].

[0392] Embodiment 37

[0393] 6-(Cyclopropylmethoxy)-N-[(2R)-1-(2-fluoroethoxy)-4-methylpentan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide

[0394]

[0395] a) (R)-6-(Cyclopropylmethoxy)-N-(1-hydroxy-4-methylpentan-2-yl)-5-(pyrrolidin-1-yl)picolinamide

[0396]

[0397] Analogously to the procedure described in Example 19a, 6-(cyclopropylmethoxy)-5-(pyrrolidin-1-yl)picolinic acid (CAN 1415898-45-1) was condensed with D-leucinol (CAN 53448-09-2) to give the title compound as a colorless oil, MS (ISP): 362.725. [MH + ].

[0398] b) 6-(Cyclopropylmethoxy)-N-[(2R)-1-(2-fluoroethoxy)-4-methylpentan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide

[0399] Analogously to the procedure described in Example 16, (R)-6-(cyclopropylmethoxy)-N-(1-hydroxy-4-methylpentan-2-yl)-5-(pyrrolidin-1-yl)picolinamide was reacted with 1-fluoro-2-iodoethane to give the title compound as a colorless oil, MS (ISP): 408.359 [MH + ].

[0400] Embodiment 38

[0401] 6-(Cyclopropylmethoxy)-N-[(2R)-1-(2-fluoroethoxy)-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide

[0402]

[0403] a) (R)-6-(Cyclopropylmethoxy)-N-(1-hydroxy-4-methylpentan-2-yl)-5-(3-methoxyazetidin-1-yl)picolinamide

[0404]

[0405] Analogously to the procedure described in Example 19a, 6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)picolinic acid (CAN 1613292-59-3) was condensed with D-leucinol (CAN 53448-09-2) to give the title compound as a pale yellow oil, MS (ISP): 378.3 [MH + ].

[0406] b) 6-(Cyclopropylmethoxy)-N-[(2R)-1-(2-fluoroethoxy)-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide

[0407] Analogously to the procedure described in Example 16, (R)-6-(cyclopropylmethoxy)-N-(1-hydroxy-4-methylpentan-2-yl)-5-(3-methoxyazetidin-1-yl)picolinamide was reacted with 1-fluoro-2-iodoethane to give the title compound as a colorless oil, MS (ISP): 424.327 [MH + ].

[0408] Embodiment 39

[0409] 6-(Cyclopropylmethoxy)-5-(3-fluoro-3-methylazetidin-1-yl)-N-(3-(3-fluoropropylcarbamoyl)pentan-3-yl)picolinamide

[0410]

[0411] In a 5 mL pear-shaped flask, 6-(cyclopropylmethoxy)-5-(3-fluoro-3-methylazetidin-1-yl)picolinic acid (CAN 1812888-92-8, 5 mg, 17.8 μmol, Eq: 1.0), 2-amino-2-ethyl-N-(3-fluoropropyl)butanamide hydrochloride (CAN 1613239-88-5, 4.45 mg, 19.6 μmol, Eq: 1.10), 2-bromo-1-ethylpyridinium tetrafluoroborate (5.37 mg, 19.6 μmol, Eq: 1.10) and DIPEA (8.07 mg, 10.7 μL, 62.4 μmol, Eq: 3.50) were mixed with 1,4-dihydropyridine tetrafluoroborate. The mixture was stirred at room temperature for 16 h and dried. The crude product was purified by preparative TLC (silica gel, EtOAc, eluted with CH2Cl2 / EtOAc 1:1) to give the title compound (5 mg, 62%) as a white solid, MS (ESI): 453.3 [MH + ].

[0412] Embodiment 40

[0413] Pharmacological tests

[0414] The following test was performed to determine the activity of the compounds of formula I:

[0415] Radioligand binding assay

[0416] The affinity of the compounds of the invention for the cannabinoid CB1 receptor was determined using the suggested amount of membrane preparations (PerkinElmer) of human embryonic kidney (HEK) cells expressing the human CNR1 or CNR2 receptors, respectively, in combination 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 (for CB1 receptors: 50 mM Tris, 5 mM MgCl2, 2.5 mM EDTA, and 0.5% (wt / vol) fatty acid-free BSA, pH 7.4, and for CB2 receptors: 50 mM Tris, 5 mM MgCl2, 2.5 mM EGTA, and 0.1% (wt / vol) fatty acid-free BSA, pH 7.4) with shaking at 30° C. for 1 h. 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 for Ki using nonlinear regression analysis (Activity Base, ID Business Solution, Limited) and Kd values ​​for [3H]CP55,940 were determined from saturation experiments. The compounds of formula (I) showed excellent affinity for CB2 receptors.

[0417] In the above assay (Ki), compounds according to formula (I) have an activity of 0.5 nM to 10 μM. In the above assay (Ki), specific compounds of formula (I) have an activity of 0.5 nM to 3 μM. In the above assay (Ki), other specific compounds of formula (I) have an activity of 0.5 nM to 100 nM.

[0418] cAMP assay

[0419] 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#

[0420] 3904), 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. Using the cAMP-Nano-TRF detection kit (Roche Diagnostics), the assay was terminated 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 by a TRF reader (Evotec Technologies GmbH) equipped with a ND:YAG laser as excitation source. The plate was measured twice, excitation at 355 nm and emission at 730 (bandwidth 30 nm) or 645 nm (bandwidth 75 nm) with a delay of 100 ns and a gate of 100 ns, respectively, with a total exposure time of 10 s. The FRET signal was calculated as follows: FRET = T730-Alexa730-P (T645-B645), P =

[0421] Ru730-B730 / Ru645-B645, where T730 is the test well measured at 730 nM, T645 is the test well measured at 645 nm, B730 and B645 are buffer controls at 730 nm and 645 nm respectively. cAMP content was determined as a function of a standard curve spanning 10 μM to 0.13 nM cAMP.

[0422] EC was determined using Activity Base assay (ID Business Solution, Limited). 50 EC values ​​for a wide range of cannabinoid agonists generated from this assay for the reference compound 50 The values ​​are consistent with those published in the scientific literature.

[0423] In the aforementioned assay, the compounds according to the invention have a human CB2EC of 0.5 nM to 10 μM. 50 Particular compounds according to the invention have a human CB2 EC of 0.5 nM to 1 μM. 50 Further particular compounds according to the invention have a human CB2 EC of 0.5 nM to 100 nM. 50They exhibit at least 10-fold selectivity over the human CB1 receptor in both the radioligand and cAMP assays or in either of these two assays.

[0424] The results obtained for representative compounds of the invention are given in the following table.

[0425]

[0426]

Claims

1. A compound of formula (I) in R 1 is alkoxyazetidinyl, dihaloazetidinyl or pyrrolidinyl; R 2 and R 3 are independently selected from hydrogen and alkyl; A 1 is -CH- or nitrogen; A 2 Yes-CH 2 - or carbonyl; X is fluorine; n is 0 to 3; and m is 0 or 1; The condition is that m and n are not both 0; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein R 1 is methoxyazetidinyl, difluoroazetidinyl or pyrrolidinyl.

3. The compound according to claim 1 or 2, wherein R 2 and R 3 are independently selected from hydrogen, ethyl and butyl.

4. A compound according to any one of claims 1 to 3, wherein R 2 and R 3 Both are ethyl, or R 2 and R 3 One of them is hydrogen and the other is butyl.

5. A compound according to any one of claims 1 to 4, wherein A 1 It is -CH-.

6. The compound according to any one of claims 1 to 5, wherein n is 1, 2 or 3.

7. A compound according to any one of claims 1 to 6, selected from Fluoromethyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate; 2-Fluoroethyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate; 3-Fluoropropyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate; Fluoromethyl 2-{[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate; 2-Fluoroethyl 2-{[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate; 3-Fluoropropyl 2-{[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate; 3-Fluoropropyl 2-{[6-(cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate; Fluoromethyl 2-{[6-(cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate; 2-Fluoroethyl 2-{[6-(cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate; N-[6-(Cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]-L-leucine fluoromethyl ester; N-[6-(Cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]-L-leucine 2-fluoroethyl ester; N-[6-(Cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]-L-leucine 3-fluoropropyl ester; N-[6-(Cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridine-2-carbonyl]-L-leucine fluoromethyl ester; N-[6-(Cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridine-2-carbonyl]-L-leucine 2-fluoroethyl ester; N-[6-(Cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridine-2-carbonyl]-L-leucine 3-fluoropropyl ester; 6-(Cyclopropylmethoxy)-N-[(2S)-1-(fluoromethoxy)-4-methylpentan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-[(2R)-1-(2-fluoroethoxy)-4-methylpentan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-[(2S)-1-(2-fluoroethoxy)-4-methylpentan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-[(2S)-1-(3-fluoropropoxy)-4-methylpentan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-[(2S)-1-(fluoromethoxy)-3-methylbutan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-[(2S)-1-(2-fluoroethoxy)-3-methylbutan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-[(2S)-1-(3-fluoropropoxy)-3-methylbutan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-[(2S)-1-(fluoromethoxy)propan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-[(2S)-1-(2-fluoroethoxy)propan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-[(2S)-1-(3-fluoropropoxy)propan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-[(2S)-1-(fluoromethoxy)-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-N-[(2S)-1-(2-fluoroethoxy)-4-methylpentan-2-yl]pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-[(2R)-1-(2-fluoroethoxy)-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-[(2S)-1-(2-fluoroethoxy)-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-[(2S)-1-(3-fluoropropoxy)-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-[(2S)-1-(fluoromethoxy)-3-methylbutan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-[(2S)-1-(2-fluoroethoxy)-3-methylbutan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-[(2S)-1-(3-fluoropropoxy)-3-methylbutan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-[(2S)-1-(2-fluoroethoxy)propan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-[(2S)-1-(3-fluoropropoxy)propan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-{3-[(fluoromethoxy)methyl]pentan-3-yl}-5-(pyrrolidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-{3-[(2-fluoroethoxy)methyl]pentan-3-yl}-5-(pyrrolidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-{3-[(3-fluoropropoxy)methyl]pentan-3-yl}-5-(pyrrolidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-{3-[(fluoromethoxy)methyl]pentan-3-yl}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-{3-[(2-fluoroethoxy)methyl]pentan-3-yl}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-{3-[(3-fluoropropoxy)methyl]pentan-3-yl}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; Fluoromethyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyrazine-2-carbonyl]amino}-2-ethylbutanoate; 2-Fluoroethyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyrazine-2-carbonyl]amino}-2-ethylbutanoate; 3-Fluoropropyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyrazine-2-carbonyl]amino}-2-ethylbutanoate; Fluoro(dideuterated)methyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate; 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoic acid 2-fluoro(2,2-dideutero)ethyl ester; 3-Fluoro(3,3-dideutero)propyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate; Fluoro(dideuterated)methyl 2-{[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate; 2-{[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoic acid 2-fluoro(2,2-dideutero)ethyl ester; 3-Fluoro(3,3-dideutero)propyl 2-{[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate; 3-Fluoro(3,3-dideutero)propyl 2-{[6-(cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate; Fluoro(dideuterated)methyl 2-{[6-(cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate; 2-{[6-(cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoic acid 2-fluoro(2,2-dideutero)ethyl ester; 6-(Cyclopropylmethoxy)-N-[(2S)-1-{[fluoro(dideutero)methyl]oxy}-4-methylpentan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-[(2S)-1-{[2-fluoro(2,2-dideutero)ethyl]oxy}-4-methylpentan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-[(2S)-1-{[3-fluoro(3,3-dideuterated)propyl]oxy}-4-methylpentan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-[(2S)-1-{[fluoro(dideutero)methyl]oxy}-3-methylbutan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-[(2S)-1-{[2-fluoro(2,2-dideutero)ethyl]oxy}-3-methylbutan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-[(2S)-1-{[3-fluoro(3,3-dideuterated)propyl]oxy}-3-methylbutan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-[(2S)-1-{[fluoro(dideutero)methyl]oxy}propan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-[(2S)-1-{[2-fluoro(2,2-dideutero)ethyl]oxy}propan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-[(2S)-1-{[3-fluoro(3,3-dideuterated)propyl]oxy}propan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-[(2S)-1-{[fluoro(dideutero)methyl]oxy}-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-[(2S)-1-{[2-fluoro(2,2-dideutero)ethyl]oxy}-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-[(2S)-1-{[3-fluoro(3,3-dideutero)propyl]oxy}-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-[(2S)-1-{[fluoro(dideutero)methyl]oxy}-3-methylbutan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-[(2S)-1-{[2-fluoro(2,2-dideutero)ethyl]oxy}-3-methylbutan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-[(2S)-1-{[3-fluoro(3,3-dideutero)propyl]oxy}-3-methylbutan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-[(2S)-1-{[2-fluoro(2,2-dideutero)ethyl]oxy}propan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-[(2S)-1-{[3-fluoro(3,3-dideutero)propyl]oxy}propan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-[3-({[fluoro(dideutero)methyl]oxy}methyl)pentan-3-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide; 6-(cyclopropylmethoxy)-N-[3-({[2-fluoro(2,2-dideutero)ethyl]oxy}methyl)pentan-3-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide; 6-(cyclopropylmethoxy)-N-[3-({[3-fluoro(3,3-dideuterated)propyl]oxy}methyl)pentan-3-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-[3-({[fluoro(dideutero)methyl]oxy}methyl)pentan-3-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-[3-({[2-fluoro(2,2-dideutero)ethyl]oxy}methyl)pentan-3-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-(cyclopropylmethoxy)-N-[3-({[3-fluoro(3,3-dideutero)propyl]oxy}methyl)pentan-3-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethyl-4-fluoro(4,4-dideutero)butanoic acid ethyl ester; 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethyl-4-fluoro(4,4-dideutero)butanoic acid ethyl ester; 6-(Cyclopropylmethoxy)-5-(3-fluoro-3-methylazetidin-1-yl)-N-(3-(3-fluoropropylcarbamoyl)pentan-3-yl)picolinamide; Ethyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethyl-4-fluorobutyrate; Ethyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethyl-3-fluorobutyrate; 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethyl-4-fluorobutyric acid ethyl ester; and Ethyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethyl-3-fluorobutyrate.

8. A compound according to any one of claims 1 to 7, selected from 2-Fluoroethyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate; 3-Fluoropropyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate; N-[6-(Cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]-L-leucine 2-fluoroethyl ester; N-[6-(Cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridine-2-carbonyl]-L-leucine 2-fluoroethyl ester; 6-(Cyclopropylmethoxy)-N-[(2S)-1-(fluoromethoxy)-4-methylpentan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-[(2S)-1-(2-fluoroethoxy)-4-methylpentan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-N-[(2S)-1-(fluoromethoxy)-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-N-[(2S)-1-(2-fluoroethoxy)-4-methylpentan-2-yl]pyridine-2-carboxamide; and 6-(Cyclopropylmethoxy)-N-[(2S)-1-(2-fluoroethoxy)-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide.

9. A method for preparing a compound according to any one of claims 1 to 8, comprising one of the following steps: (a) making a compound of formula (A) In R 1 -H, a palladium catalyst and a base; (b) making a compound of formula (B) In NH 2 -C(R 2 R 3 )-A 2 -O-(CH 2 ) n -(CD 2 ) m -X, a coupling agent and a base; Among them A 1 , A 2 ,X,R 1 -R 3 , m and n are as defined in any one of claims 1 to 6, and Y is halogen.

10. Compounds according to any one of claims 1 to 8 for use as therapeutically active substances.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 and a therapeutically inert carrier.

12. Use of a compound according to any one of claims 1 to 8 for the preparation of a medicament for the treatment or prevention of pain, atherosclerosis, age-related macular degeneration, diabetic retinopathy, glaucoma, 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, liver cirrhosis or tumors, bone mass regulation, neurodegeneration, stroke, transient ischemic attack or uveitis.

13. A compound according to any one of claims 1 to 8 for use in the treatment or prevention of pain, atherosclerosis, age-related macular degeneration, diabetic retinopathy, glaucoma, 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, liver cirrhosis or tumors, bone mass regulation, neurodegeneration, stroke, transient ischemic attack or uveitis.

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