NZ767476A - Novel pyridine and pyrazine compounds as inhibitors of cannabinoid receptor 2 - Google Patents

Abstract

The invention relates to a compound of formula (I) wherein A, A2, X and R1-R3are as defined in the description and in the claims. The compound of formula (I) can be used as a medicament, due to its inhibition of cannabinoid receptor 2.

Description

NOVEL NE AND PYRAZINE COMPOUNDS AS TORS OF CANNABINOID RECEPTOR 2 The present invention relates to c compounds useful for therapy and/or prophylaxis in a mammal, and in particular to compounds that are preferential agonists of the Cannabinoid Receptor 2.

The invention relates in particular to a compound of formula (I) wherein R1 is alkoxyazetidinyl, dihaloazetidinyl or pyrrolidinyl; R2 and R3 are ndently selected from hydrogen and alkyl; A1 is -CH- or nitrogen; A2 is -CH2- or carbonyl; X is halogen; n is 0 to 3; and m is 0 or 1; provided that m and n are not both 0 at the same time; or a pharmaceutically acceptable salt thereof.

Novel pyridine and pyrazine derivatives that have high affinity and great selectivity towards the inoid CB2 or have been found. These compounds have a tory effect on the ty of the CB2 receptor. The term ‘modulatory effect’ especially means agonist, antagonist and/or inverse agonist effects.

Agonists of the Cannabinoid Receptor 2 are useful for therapy and/or prophylaxis in a mammal. The compound of formula (I) is ularly useful in the treatment or prophylaxis of e. g. pain, atherosclerosis, age-related macular degeneration, diabetic pathy, glaucoma, diabetes mellitus, inflammation, inflammatory bowel disease, ischemia-reperfiision injury, acute liver failure, liver fibrosis, lung fibrosis, kidney fibrosis, systemic fibrosis, acute allograft rejection, chronic allograft nephropathy, diabetic nephropathy, glomerulonephropathy, cardiomyopathy, heart 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.

Inverse ts of the inoid Receptor 2 are useful for y and/or prophylaxis in a mammal.

The compound of formula (I) is particularly useful in the treatment or prophylaxis of pain, athic pain, asthma, osteoporosis, inflammation, psychiatric diseases, psychosis, oncology, encephalitis, malaria, allergy, immunological disorders, arthritis, gastrointestinal disorders, psychiatric disorders toid arthritis, psychosis and allergy.

The inoid receptors are a class of cell membrane receptors belonging to the G protein-coupled receptor superfamily. There are currently two known subtypes, termed Cannabinoid Receptor 1 (CB1) and Cannabinoid or 2 (CB2). The CB1 receptor is mainly expressed in the central nervous (i.e. amygdala cerebellum, hippocampus) system and to a lesser amount in the periphery. CB2, which is encoded by the CNR2 gene, is mostly expressed peripherally, on cells of the immune system, such as macrophages and s (Ashton, J. C. et al. Curr Neuropharmacol 2007, 5(2), 73-80; Miller, A. M. et al. Br J col 2008, 153(2), 299-308; Centonze, D., et al. Curr Pharm Des 2008, , 2370-42), and in the gastrointestinal system (Wright, K. L. et al. Br J Pharmacol 2008, 153(2), 263-70). The CB2 receptor is also widely distributed in the brain where it is found primarily on microglia and not neurons (Cabral, G. A. et al. Br J Pharmacol 2008, 153(2): 240-51).

Modulators of the Cannabinoid Receptor 2 are useful for therapy and/or prophylaxis in a mammal.

The interest in CB2 receptor agonists has been steadily on the rise during the last decade (currently 30-40 patent applications/year) due to the fact that several of the early compounds have been shown to have beneficial effects in pre-clinical models for a number of human diseases including chronic pain (Beltramo, M. Mini Rev Med Chem 2009, 9(1), 11-25), atherosclerosis (Mach, F. et al. J Neuroendocrinol 2008, 20 Suppl 1, 53-7), regulation of bone mass (Bab, I. et al. Br J Pharmacol 2008, 153(2), 182-8), neuroinflammation (Cabral, G. A. et al. J Leukoc Biol 2005, 78(6), ), ischemia/reperfusion injury (Pacher, P. et al. Br J Pharmacol 2008, 153(2), 252-62), systemic s (Akhmetshina, A. et a1. Arthritis Rheum 2009, 60(4), 1129-36; Garcia- Gonzalez, E. et a1. Rheumatology (Oxford) 2009, 48(9), 1050-6), liver fibrosis (Julien, B. et a1. enterology 2005, 128(3), 742-55; Munoz—Luque, J. et al. J Pharmacol Exp Ther 2008, 324(2), 475-83).

Ischemia/reperfusion (I/R) injury is the principal cause of tissue damage occurring in conditions such as stroke, myocardial tion, cardiopulmonary bypass and other vascular surgeries, and organ transplantation, as well as a major ism of end—organ damage cating the course of circulatory shock of s etiologies. All these conditions are characterized by a disruption of normal blood supply resulting in an insufficient tissue oxygenation. Re-oxygenation e.g., reperfusion is the ultimate treatment to restore normal tissue oxygenation. However the absence of oxygen and nutrients from blood creates a condition in which the restoration of circulation results in further tissue damage. The damage of reperfusion injury is due in part to the inflammatory response of damaged tissues. White blood cells, carried to the area by the newly returning blood, release a host of inflammatory factors such as interleukins as well as free radicals in response to tissue damage. The restored blood flow reintroduces oxygen within cells that damages cellular proteins, DNA, and the plasma membrane.

Remote ischemic preconditioning (RIPC) represents a gy for harnessing the body’s endogenous protective capabilities against the injury incurred by ischemia and usion. It describes the intriguing phenomenon in which transient non-lethal ischemia and reperfusion of one organ or tissue confers resistance to a subsequent episode of “lethal” ischemia reperfusion injury in a remote organ or tissue. The actual mechanism through which transient ischemia and reperfusion of an organ or tissue s protection is currently unknown although several eses have been ed.

The humoral hypothesis es that the endogenous substance (such as adenosine, bradykinin, opioids, CGRP, endocannabinoids, Angiotensin I or some other as yet unidentified humoral factor) generated in the remote organ or tissue enters the blood stream and activates its respective receptor in the target tissue and thereby ting the various intracellular pathways of cardioprotection ated in ischemicpreconditioning.

Recent data indicates that nnabinnoids and their receptors, in particular CB2 might be involved in pre-conditioning and contribute to prevent reperfiision injury by downregulation of the inflammatory response (Pacher, P. et al. Br J Pharmacol 2008, 153(2), 252-62). Specifically, recent studies using CB2 tool ts demonstrated the efficacy of this concept for reducing the I/R injury in the heart (Defer, N. et al. Faseb J 2009, 23(7), 2120-30), the brain (Zhang, M. et al. J Cereb Blood Flow Metab 2007, 27(7), 6), the liver (Batkai, S. et al. Faseb J 2007, 21(8), 1788-800) and the kidney (Feizi, A. et al. Exp Toxicol Pathol 2008, 60(4-5), 405-10).

Moreover, over the last few years, a growing body of literature indicates that CB2 can also be of interest in sub-chronic and chronic setting. Specific upregulation of CB1 and CB2 has been shown to be associated in animal models of chronic diseases associated with fibrosis (Garcia-Gonzalez, E. et al. Rheumatology d) 2009, 48(9), ; Yang, Y. Y. et al. Liver Int 2009, 29(5), 678-85) with a relevant expression of CB2 in myofibroblasts, the cells responsible for fibrosis progression.

Activation of CB2 receptor by ive CB2 t has in fact been shown to exert anti-fibrotic effect in diffuse systemic sclerosis (Garcia-Gonzalez, E. et al. Rheumatology (Oxford) 2009, 48(9), 1050-6) and CB2 receptor has emerged as a critical target in experimental dermal fibrosis (Akhrnetshina, A. et al. tis Rheum 2009, 60(4), 1129- 36) and in in liver pathophysiology, including fibrogenesis associated with c liver diseases (Lotersztajn, S. et al. Gastroenterol Clin Biol 2007, 31(3), 255-8; Mallat, A. et al.

Expert Opin Ther Targets 2007, 11(3), 403-9; Lotersztajn, S. et al. Br J Pharmacol 2008, 153(2), 286-9).

Inverse ts of the Cannabinoid Receptor 2 are useful for therapy and/or prophylaxis in a mammal.

The compound of a (I) is particularly useful in the treatment or prophylaxis of pain, neuropathic pain, asthma, osteoporosis, inflammation, psychiatric diseases, psychosis, oncology, encephalitis, malaria, allergy, immunological disorders, arthritis, gastrointestinal disorders, psychiatric disorders rheumatoid arthritis, psychosis and allergy.

The interest in CB2 or ligands has been steadily on the rise during the last decade (currently 30-40 patent applications/year). Evidence from different s support the view that lipid endocannabinoid signaling through CB2 receptors represents an aspect of the ian protective armamentarium (Pacher, P. Prog Lipid Res 2011, 50, 193).

Its modulation by either selective CB2 receptor agonists or inverse agonists/antagonists (depending on the disease and its stage) holds unique therapeutic potential in a huge number of diseases. For CB2 inverse agonists/antagonists eutic opportunities have been demonstrated for many pathological conditions ing pain (Pasquini, S. J Med Chem 2012, 55(11): 5391), athic pain (Garcia-Gutierrez, M.S. Br J col 2012, 165(4): 951), psychiatric disorders (Garcia-Gutierrez, M.S. Br J col 2012, 165(4): 951), psychosis (Garcia-Gutierrez, M.S. Br J Pharmacol 2012, 165(4): 951), osteoporosis and ation (Sophocleous, A. Calcif Tissue Int 2008, 82(Suppl. 1):Abst OC18), psychiatric diseases and psychosis a-Gutierrez, M.S. Br J Pharmacol 2012, 165(4): 951), oncology (Preet, A. Cancer Prev Res 2011, 4: 65), alitis and malaria (Zimmer, A. WO 2011045068), allergy and inflammation (Ueda, Y. Life Sci 2007, 80(5): 414), encephalitis and malaria (Zimmer, WO 2011045068), asthma (Lunn, CA. J col Exp Ther 2006, 316(2): 780), immunological disorders (Fakhfouri, G.

Neuropharmacology 2012, 63(4): 653), rheumatoid arthritis (Chackalamannil, S. US 7776889), arthritis (Lunn, CA. J Pharmacol Exp Ther 2006, 316(2): 780), and gastrointestinal disorders (Barth, F. FR 2887550 ).

The compounds of the invention bind to and modulate the CB2 receptor and have lower CB1 or activity.

In the present ption the term ”, alone or in combination, signifies a straight-chain or branched-chain alkyl group with 1 to 8 carbon atoms, particularly a straight or branched-chain alkyl group with 1 to 6 carbon atoms and more particularly a straight or branched-chain alkyl group with 1 to 4 carbon atoms. es of straight- chain and branched-chain C1-C8 alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, the isomeric pentyls, the isomeric hexyls, the isomeric heptyls and the isomeric octyls, particularly methyl, ethyl, propyl, butyl and pentyl. Particular examples of alkyl are methyl, ethyl, isopropyl, butyl, isobutyl, tert.-buty1 and pentyl. Methyl, ethyl and propyl are particular examples of “alkyl” in the compound of formula (I).

The term “alkoxy” or “alkyloxy”, alone or in combination, signifies a group of the formula O- in which the term "alkyl" has the previously given significance, such as methoxy, ethoxy, n-propoxy, isopropoxy, xy, isobutoxy, sec-butoxy and tert— . A particular examples of “alkoxy” is methoxy.

The term “oxy”, alone or in combination, signifies the group.

The terms “halogen” or “halo”, alone or in combination, signifies e, chlorine, bromine or iodine and particularly fluorine, chlorine or bromine, more particularly fluorine. The term “halo”, in combination with another group, denotes the substitution of said group with at least one halogen, particularly substituted with one to five halogens, particularly one to four halogens, i.e. one, two, three or four halogens. Fluoro is a particular halogen.

The term “carbonyl”, alone or in combination, es the -C(O)- group.

The term “pharmaceutically acceptable salts” refers to those salts which retain the biological iveness and ties of the free bases or free acids, which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, particularly hydrochloric acid, and organic acids such as acetic acid, nic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, ic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, enesulfonic acid, salicylic acid, ylcystein. In addition these salts may be prepared form addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not d to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts. Salts derived from organic bases include, but are not limited to salts of primary, secondary, and ry amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N—ethylpiperidine, piperidine, polyamine resins. The compound of formula (I) can also be present in the form of zwitterions. Particularly preferred pharmaceutically acceptable salts of nds of formula (I) are the salts of hydrochloric acid, hydrobromic acid, ic acid, phosphoric acid and methanesulfonic acid.

If one of the starting materials or compounds of formula (1) contain one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups (as described e.g. in ctive Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wuts, 3rd Ed., 1999, Wiley, New York) can be introduced before the critical step applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature. Examples of protecting groups are tert-butoxycarbonyl (Boc), 9-fluorenylmethyl carbamate (Fmoc), 2-trimethylsilylethyl carbamate (Teoc), carbobenzyloxy (Cbz) and p-methoxybenzyloxycarbonyl (Moz).

The compound of formula (I) can contain several asymmetric centers and can be present in the form of optically pure enantiomers, es of enantiomers such as, for example, racemates, mixtures of diastereOfiisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.

The term “asymmetric carbon atom” means a carbon atom with four different substituents. According to the Cahn-Ingold—Prelog tion an asymmetric carbon atom can be of the “R” or “S” configuration. _ 7 _ The invention relates in particular to: A compound according to the ion wherein R1 is methoxyazetidinyl, difluoroazetidinyl or pyrrolidinyl.

A compound according to the invention wherein R2 and R3 are ndently selected from hydrogen, ethyl and butyl.

A compound according to the invention wherein R2 and R3 are both ethyl at the same time, or one of R2 and R3 is hydrogen and the other one is butyl.

A compound according to the invention n A1 is —CH-.

A compound according to the invention wherein X is fluorine; and A compound according to the invention wherein n is 1, 2 or 3.

The invention further relates to a compound or formula (I) ed from: fluoromethyl 2- {[6-(cyclopropylrnethoxy)-5—(3-rnethoxyazetidin- 1 —y1)pyridine carbonyl]amino } ethylbutanoate; Z-fluoroethyl 2— { [6-(cyclopropylmethoxy)—5 -(3-methoxyazetidin- l -y1)pyridine carbony1]amino}—2-ethylbutanoate; 3-fluoropropy1 2- {[6-(cyclopropylmethoxy)-5 -(3-methoxyazetidinyl)pyridine carbonyl]amino } ethylbutanoate; fluoromethyl 2- {[6-(cyclopropylrnethoxy)-5 -(3 ,3 -difluoroazetidinyl)pyridine carbonyl]amino } ylbutanoate; 2-fluoroethyl 2- { clopropylmethoxy)-5 -(3 ,3 roazetidin- l -yl)pyridine-2— carbonyl]amino } —2-ethylbutanoate; 3-fluoropropyl 2- {[6-(cyclopropylmethoxy)-5 -(3 ,3 -difluoroazetidinyl)pyridine carbonyl]amino } ethylbutanoate; 3—fluoropropy1 2— yclopropylmethoxy)-5 -(pyrrolidinyl)pyridine—2- carbony1]amino}ethylbutanoate; fluoromethyl 2— {[6-(cyclopropylmethoxy)-5 -(pyrrolidin- l -yl)pyridine carbonyl]amino } ethylbutanoate; W0 2020/002320 _ 8 _ 2-fluoroethy1 2- { [6-(cyclopropylmethoxy)-5 -(pyrr01idin-1 -yl)pyridine carbonyl]amino } ethy1butanoate; fluoromethyl N-[6-(cyclopropylmethoxy)-5 -(3—methoxyazetidiny1)pyridine y1]-L-leucinate; 2-fluoroethyl N—[6-(cyclopropy1methoxy)-5 -(3—rneth0xyazetidiny1)pyridine-2— carbonyl]—L-leucinate; 0propyl N—[6-(cyclopropylmethoxy)-5 -(3—methoxyazetidin— 1 -yl)pyridine carbonyl]—L-leucinate; fluoromethyl N-[6-(cyclopropylmethoxy)(pyrr01idin-1 -y1)pyridine—2-carbony1]-L- 1 0 ate; 2-fluoroethyl cyclopr0py1methoxy)—5 -(pyrr01idiny1)pyridinecarbonyl]—L- leucinate; 0propyl N—[6-(Cyclopropylmethoxy)-5 -(pyrrolidinyl)pyridine—2-carbony1] - L-leucinate; 1 5 6-(cyc10propy1methoxy)-N—[(ZS)(fluoromethoxy)—4-methylpentany1]-5 - (pyrrolidiny1)pyridinecarboxarnide; 6-(cyc10propy1methoxy)-N—[(2R)(2-fluoroethoxy)—4-rnethylpentan-Z-yl] -5 - lidinyl)pyridinecarboxarnide; 6—(cyc10propy1methoxy)—N-[(ZS)(2-fluoroethoxy)methylpentan-2—y1]-5 - (pyrrolidiny1)pyridinecarboxarnide; 6-(cyclopropylmethoxy)-N-[(ZS)(3-fluoropropoxy)—4-methylpentany1] -5 - (pyrrolidiny1)pyridinecarboxarnide; 6-(cyc10propy1methoxy)-N—[(2S)(fluorornethoxy)—3-methy1butanyl]-5 - (pyrrolidin—1-yl)pyridine—2-carboxamide; 6—(cyc10propy1methoxy)-N—[(ZS)(2-fluoroethoxy)-3—rnethylbutan-2—y1] -5 - (pyrrolidiny1)pyridinecarboxarnide; 6-(cyc10propy1methoxy)—N—[(ZS)(3-fluoropropoxy)—3 -rnethylbutany1] (pyrrolidiny1)pyridinecarboxarnide; W0 2020/002320 _ 9 _ 6-(cyclopropylmethoxy)-N—[(2S)(fluorornethoxy)propany1]-5 -(pyrrolidin yl)pyridinecarboxamide; 6-(cyc10propy1methoxy)-N—[(ZS)(2-fluoroethoxy)propany1]-5 -(pyrrolidin y1)pyridinecarboxamide; 6-(cyclopropylmethoxy)-N-[(ZS)(3-fluoropropoxy)propanyl] -5 -(pyrrolidin-1 - idinecarboxamide; 6—(cyclopropylmethoxy)—N—[(ZS)—1-(fluorornethoxy)-4—methylpentan-2—yl]-5 -(3 — yazetidiny1)pyridine—2-carb0xamide; 6-(cyclopropy1methoxy)(3,3-difluoroazetidiny1)-N-[(ZS)(2-fluoroethoxy)—4- 1 0 methy1pcntan-2—y1]pyridinecarb0xamide; 10pr0py1methoxy)-N—[(2R)(2-fluor0ethoxy)—4-methylpentany1] (3 - methoxyazetidiny1)pyridinecarboxamide; 6—(cyclopropylmethoxy)—N—[(ZS)—1-(2-fluoroethoxy)-4—methylpentan-2—y1]-5 -(3 - methoxyazetidiny1)pyridine—2-carboxamide; 1 5 6-(cyc10propy1methoxy)-N—[(ZS)(3-fluoropropoxy)—4-methylpentany1] (3 - methoxyazetidiny1)pyridinecarb0xarnide; 6-(cyc10propy1methoxy)-N—[(2S)(fluorornethoxy)—3-methylbutanyl] -5 -(3- methoxyazetidin- 1 ridinecarb0xamide; 6—(cyc10propy1meth0xy)-N—[(ZS)(2-fluoroethoxy)-3—methylbutan-2—y1]-5 -(3 — methoxyazetidiny1)pyridine—2-carboxamide; 6-(cyc10pr0py1methoxy)-N—[(ZS)(3-fluoropr0poxy)—3-methylbutany1] (3 - methoxyazetidiny1)pyridinecarboxarnide; 6-(cyc10propy1methoxy)-N—[(ZS)(2-fluoroethoxy)propany1]-5 -(3- methoxyazetidin—1-y1)pyridine—2—carboxamide; 6—(cyc10propylmethoxy)—N-[(ZS)(3-fluoropropoxy)propan-2—yl] -5 -(3 - methoxyazetidiny1)pyridine—2-carboxamide; 6-(cyc10propy1methoxy)—N— {3-[(fluoromethoxy)rnethyl]pentan-3 -y1} -5 -(pyrrolidin- 1-y1)pyridinecarboxamide; 6-(cyclopropylmethoxy)-N— {3-[(2-fluoroethoxy)methyl]pentan-3 -yl} -5 -(pyrrolidin- 1 ridinecarboxan1ide; 6-(cyclopropylrnethoxy)-N— {3 -[(3-fluoropropoxy)n1ethyl]pentan-3 -yl} -5 - (pyrrolidin- l -yl)pyridine—2-carboxan1ide; lopropylmethoxy)-N— uoromethoxy)n1ethyl]pentan-3 -yl} -5 -(3 - methoxyazetidin- l -yl)pyridinecarboxamide; 6—(cyclopropylmethoxy)—N— {3-[(2—fluoroethoxy)methyl]pentan-3 -yl} -5 -(3 - methoxyazetidin- l -yl)pyridine—2-carboxan1ide; lopropylrnethoxy)-N— {3 -[(3-fluoropropoxy)n1ethyl]pentan-3 -yl} -5 -(3 - 1 0 methoxyazetidin— l -yl)pyridinecarboxan1ide; fluoromethyl 2- {[6-(cyclopropyln1ethoxy)-5 -(3-n1ethoxyazetidin- l -yl)pyrazine carbonyl] arnino } ethylbutanoate; 2—fluoroethyl 2- { [6-(cyclopropylmethoxy)—5 -(3—methoxyazetidinyl)pyrazine—2- carbonyl]amino } ethylbutanoate; 1 5 3-fluoropropyl 2- {[6-(cyclopropylmethoxy)-5 —(3 -n1ethoxyazetidin- l -yl)pyrazine carbonyl]amino } ethylbutanoate; fluoro(dideuterio)n1ethyl 2- { [6-(cyclopropyln1ethoxy)-5 -(3 -n1ethoxyazetidin yl)pyridinecarbonyl]amino} ethylbutanoate; 2—fluoro(2,2-dideuterio)ethyl 2— {[6-(cyclopropylrnethoxy)—5 -(3—rnethoxyazetidin- l - yl)pyridinecarbonyl]amino } ethylbutanoate; 3-fluoro(3 ,3 -dideuterio)propyl 2- {[6-(cyclopropylrnethoxy)(3 oxyazetidin- l - yl)pyridinecarbonyl]amino } —2-ethylbutanoate; fluoro(dideuterio)n1ethyl 2- {[6—(cyclopropyln1ethoxy)—5 -(3 ,3 -difluoroazetidin- l - yl)pyridinecarbonyl]amino} —2—ethylbutanoate; 2—fluoro(2,2-dideuterio)ethyl 2— { [6-(cyclopropyln1ethoxy)-5 -(3 ,3 -difluoroazetidin- l - idinecarbonyl]amino } ethylbutanoate; 3-fluoro(3 ,3 -dideuterio)propyl 2- yclopropylmethoxy)(3 ,3 -difluoroazetidinyl)pyridinecarbonyl]amino} ethylbutanoate; _ 11 _ 3-fluor0(3 ,3 -dideuterio)propyl 2- {[6-(cyclopropylrnethoxy)(pyrrolidin yl)pyridinecarbonyl]amino } ethy1butanoate; fluoro(dideuterio)methyl 2- yclopropy1methoxy)-5 -(pyrrolidin- 1-y1)pyridine carbonyl]amino } —2-ethy1butan0ate; 2-fluor0(2,2-dideuteri0)ethy1 2- { [6-(cyclopr0py1methoxy)-5 -(pyrr01idin-1 - yl)pyridinecarbony1]amino} ethy1butanoate; 6—(cyclopropylmethoxy)—N-[(ZS) {[fluoro(dideuterio)methyl]oxy} methylpentan-Z-yl]-5 -(pyrr01idin-1 -y1)pyridinecarboxarnide; 6-(cyc10propy1methoxy)-N—[(ZS) {[2-fluoro(2,2-dideuterio)ethy1]oxy} 1 0 methylpentan-Z—yl]—5 -(pyrr01idin-1 -y1)pyridine—2-carboxarnide; 6-(cyclopropylmethoxy)-N-[(ZS) {[3-fluor0(3 ,3-dideuterio)propyl]oxy} methylpentan—Z—yl]—5 -(pyrrolidin-1 -y1)pyridinecarboxamide; 6—(cyc10propylmethoxy)—N—[(ZS) {[fluoro(dideuterio)methyl]oxy} methy1butan- 2-y1] -5 -(pyrr01idin-1 -y1)pyridinecarboxarnide; 1 5 6-(cyc10propy1methoxy)-N—[(ZS) {[2-fluoro(2,2-dideuterio)ethy1]oxy} -3 - methylbutan-Z-yl] -5 -(pyrr01idin-1 -y1)pyridinecarb0xarnide; 6-(cyclopropylmethoxy)-N-[(2S)— 1 - {[3-fluoro(3 ,3 - dideuterio)propy1]oxy} -3 - butan-Z-y1]-5 -(pyrrolidiny1)pyridinecarboxamide; 6—(cyc10propylmethoxy)—N—[(ZS) {[fluoro(dideuterio)methyl]oxy}propan-Z-y1]-5 - (pyrrolidiny1)pyridinecarboxarnide; 6-(cyclopropylmethoxy)-N-[(ZS) {[2-fluoro(2,2-dideuterio)ethy1]oxy}propan-Z- yl]—5 -(pyrr01idiny1)pyridinecarboxarnide; 6-(cyc10propy1methoxy)-N—[(2S)— 1 - {[3-fluoro(3 ,3 -dideuterio)propyl]oxy}propan-Z- y1]—5 -(pyrrolidin—1-y1)pyridine-2—carboxamide; 10propylmethoxy)—N-[(ZS) {[fluoro(dideuterio)methy1]oxy} methylpentan-Z—yl]—5-(3-methoxyazetidin-1 ridinecarboxarnide; 6-(cyc10propy1methoxy)—N—[(ZS) {[2-fluoro(2,2-dideuterio)ethy1]oxy} pentan-Z—yl]—5-(3-rnethoxyazetidin-1 -y1)pyridinecarboxarnide; WO 02320 _ 12 _ 6-(cyclopropylmethoxy)-N—[(2S)- l - {[3-fluoro(3 ,3 -dideuterio)propyl]oxy} methylpentan-Z-yl]—5 -(3-rneth0xyazetidin- l -yl)pyridinecarboxarnide; lopropylmethoxy)-N—[(ZS)- l - {[fluoro(dideuterio)methyl]oxy} methylbutan- 2—yl] -5 -(3 -methoxyazetidin- l -yl)pyridinecarboxarnide; 6-(cyclopropylmethoxy)-N—[(ZS)- l - {[2—fluoro(2,2-dideuterio)ethyl]oxy} -3 - methylbutan-Z-yl] (3-methoxyazetidin- l -yl)pyridinecarboxamide; 6—(cyclopropylmethoxy)—N—[(ZS)— l - {[3—fluoro(3 ,3 -dideuterio)propyl]oxy} -3 - butan-Z-yl] (3—methoxyazetidin- l -yl)pyridinecarboxarnide; 6-(cyclopropylmethoxy)-N—[(ZS) {[2-fluoro(2,2-dideuterio)ethyl]oxy}propan-Z- 1 0 yl]-5 -(3—meth0xyazetidin- l -yl)pyridine—2-carboxarnide; 6-(cyclopropylmethoxy)-N—[(ZS)- l - or0(3 ,3 - dideuterio)propyl]oxy}propan-Z- yl]-5 -(3-rnethoxyazetidin- l -yl)pyridinecarboxamide; 6—(cyclopropylmethoxy)—N—[3 -( { [fluoro(dideuterio)methyl]oxy}methyl)pentan—3 - yl]-5 -(pyrrolidin- l -yl)pyridine—2-carb0xarnide; 1 5 6-(cyclopropylmethoxy)-N—[3 -( { [2-flu0ro(2,2-dideuterio)ethyl]oxy}methyl)pentan- 3-yl] -5 -(pyrrolidin-l -yl)pyridinecarboxarnide; 6-(cyclopropylmethoxy)-N—[3-({[3-fluoro(3,3-dideuterio)propyl]oxy}methyl)pentan- 3-yl](pyrrolidinyl)pyridinecarboxarnide; 6—(cyclopropylmethoxy)—N—[3 -( { (dideuterio)methyl]oxy}methyl)pentan—3 - yl]-5 -(3-methoxyazetidin- l -yl)pyridinecarboxarnide; 6-(cyclopropylmethoxy)-N—[3 -( { [2-flu0ro(2,2-dideuterio)ethyl]oxy}methyl)pentanyl] -5 -(3 -rneth0xyazetidin- l -yl)pyridinecarboxamide; 6-(cyclopropylmethoxy)-N—[3-({[3-flu0ro(3,3-dideuterio)propyl]oxy}methyl)pentan- 3—yl](3 —methoxyazetidin—1-yl)pyridine—2-carboxamide; ethyl 2- { [6-(cyclopropylmethoxy)—5 -(3—meth0xyazetidin- l -yl)pyridine—2- carbonyl]amino} ethylflu0ro(4,4-dideuterio)butan0ate; ethyl 2— { [6-(cyclopropylrnethoxy)—5 —(3-rnethoxyazetidin- l -yl)pyridine carbonyl]amino} ethylflu0r0(4,4-dideuteri0)butanoate; 6-(cyclopropylmethoxy)-5 -(3 -fluoro-3 -rnethylazetidiny1)-N-(3 -(3 - fluoropropylcarbanioyl)pentan-3 -yl)picolinan1ide; ethyl 2- { [6-(cyclopropyln1ethoxy)—5 -(3-rnethoxyazetidin- l -yl)pyridine-2 - yl] arnino } —2-ethyl—4-fluorobutanoate; ethyl 2- { [6-(cyclopropyln1ethoxy)—5 -(3—n1ethoxyazetidin- l -yl)pyridine-2 - carbonyl]amino } ylfluorobutanoate; ethyl 2- { [6-(cyclopropylmethoxy)—5 -(3—methoxyazetidin— 1 -yl)pyridine—2— carbonyl]amino} ethylfluorobutanoate; and ethyl 2— { [6-(cyclopropylrnethoxy)—5 -(3-rnethoxyazetidin- l -yl)pyridine carbonyl]an1ino} ethylfluorobutanoate.

The invention further relates to a compound according to the invention selected from: oethyl 2- { [6-(cyclopropylmethoxy)—5 -(3—methoxyazetidinyl)pyridine—2- carbonyl]amino } ethylbutanoate; 1 5 opropyl 2- {[6-(cyclopropylmethoxy)-5 —(3 -n1ethoxyazetidin- l —yl)pyridine carbonyl]amino } ethylbutanoate; 2-fluoroethyl N—[6-(cyclopropylmethoxy)—5 -(3-n1ethoxyazetidin- l -yl)pyridine carbonyl]-L-leucinate; 2—fluoroethyl N—[6-(cyclopropylmethoxy)—5 olidin— l -yl)pyridine—2-carbonyl]-L- leucinate; 6-(cyclopropylmethoxy)-N—[(ZS)(fluorornethoxy)—4-rnethylpentanyl]-5 - (pyrrolidin- l -yl)pyridinecarboxan1ide; 6-(cyclopropylrnethoxy)-N—[(2S)(2-fluoroethoxy)n1ethylpentanyl]-5 - (pyrrolidin—1-yl)pyridine—2-carboxamide; 6—(cyclopropylmethoxy)-N—[(ZS)(fluoromethoxy)—4—rnethylpentanyl] -5 -(3 - methoxyazetidin- l -yl)pyridine—2-carboxamide; 6-(cyclopropylmethoxy)—5-(3,3-difluoroazetidinyl)-N-[(ZS)(2-fluoroethoxy)—4- methylpentan-2—yl]pyridinecarboxan1ide; and _ 14 _ 6-(cyclopropylmethoxy)-N—[(2S)- l -(2-fluoroethoxy)methylpentanyl]-5 -(3 - methoxyazetidin- l ridinecarboxamide.

The invention also relates in particular to 6-(cyclopropylmethoxy)—N—[(28)-l-(2- fluoroethoxy)—4-methylpentan—2-yl] -5 —(pyrrolidin- l -yl)pyridinecarboxamide.

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

Following the procedure according to scheme 1, compound AA (R’ = H, methyl, ethyl, isopropyl, tert. butyl or another suitable protecting group described for example in T.W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc.

New York 1999, 3rd edition) can be used as starting material. AA is either commercially available, bed in the literature or can be synthesized by a person skilled in the art.

Schemel ,R' + _. ’1 —. X ’Rv AA AB AC R"—H C R2R3 AD R" if "' AZ'M002m " ‘ R OH <— Compound AB can be prepared from AA by oxidation with a suitable oxidizing reagent under conditions known to a person d in the art (step a), e.g. by treatment with 3-chloro perbenzoic acid in dichloromethane at ambient temperature. sion of compound AB to 6-chloro or 6-bromo-picoline AC (X = Cl, Br) can be ed e.g. by treatment with phosphoryl trichloride or mide either without an additional solvent or in a suitable t such as chloroform at temperatures between 20 oC and the boiling point of the solvent, or by using other conditions known in the literature (step b). ro- or bromo-picoline AC (X = Cl, Br) can be ormed to compound AE by reaction with a suitably substituted primary or ary alcohol AD such as ropylmethanol in the presence of a base, for example sodium hydride, with or without an inert solvent, for example dimethylformamide, at temperatures g from room temperature to the reflux temperature of the solvent, particularly at room temperature (step c).

The saponification of the ester of general formula AE (R’ 75 H) by methods well known to the ones skilled in the art - using e.g. aqueous LiOH, NaOH or KOH in ydrofuran / ethanol or another suitable solvent at temperatures between 0 oC and the reflux temperature of the solvent employed - leads to an acid of l formula 11 (step nd I (R’ ’ = cyclopropylmethyloxy) can be prepared from 11 and the corresponding amine of formula III by suitable amide bond forming reactions (step e).

These reactions are known in the art. For example coupling reagents like N,N’-carbonyl- diimidazole (CDI), N,N’-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl) ethylcarbodiimide hloride (EDCI), l-[bis(dimethylamino)-methylene]-1H—l,2,3- triazolo[4,5-b]pyridinium—3-oxide hexafluorophosphate (HATU), l-hydroxy-l,2,3- benzotriazole (HOBT), O-benzotriazoly1—N,N,N’,N’ -tetramethyluronium tetrafluoroborate (TBTU), and O-benzotriazole-N,N,N’,N’-tetramethyl-uronium- hexafluoro-phosphate (HBTU) can be employed to affect such transformation. A convenient method is to use for example HBTU and a base, for example N- methylmorpholine in an inert solvent such as for example dimethylformamide at room temperature.

Alternatively, compound AC (R’ = methyl, ethyl, isopropyl, tert. butyl or another suitable protecting group described for example in T.W. Greene et al., Protective Groups in Organic try, John Wiley and Sons Inc. New York 1999, 3rd edition) can be: i) converted into its acid congener AC (R’ = H) as described in step (1; ii) transformed into 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 arrive at compound I.

Amines III and alcohols AD are either commercially available, described in the literature, can be sized by a person skilled in the art or as described in the experimental part.

If one of the starting materials, compounds of ae AA, AD or III, contains one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups (P) (as described WO 02320 e.g. in T.W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3rd edition) can be introduced before the al step applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods known in the art.

If one or more compounds of formulae AA to AE, AD, 11 or III contain chiral centers, nes of formula I can be obtained as mixtures of diastereomers or enantiomers, which can be separated by s well known in the art, e.g. (chiral) HPLC or crystallization. Racemic compounds can e.g. be separated into their antipodes Via diastereomeric salts by llization or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbent or a chiral eluent.

Following the procedure according to scheme 2, nd BA (R’ = H, methyl, ethyl, isopropyl, tert. butyl or another suitable protecting group described for example in T.W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc.

New York 1999, 3rd edition) can be used as starting material. BA is either commercially available (e.g. for R’ = methyl: 5-bromochloro-pyridinecarboxylic acid methyl ester CAN 12143533), described in the literature or can be synthesized by a person skilled in the art.

Scheme 2 R1—M { M0R' BB , ("r Br RMMOR BA AC' R"—H AD R2 H2 AZ'OVCJgf RLM R2 R2 "' BB R" O’R' R" N>Z::2.o\/cpz R" a fizwoozm l X n X c l H l H / / / Br Br BC BD I Compound AC’ can be prepared from BA by coupling with an amine BB (M is H) by methods well known to a person d in the art, e.g. using a palladium catalyst such as tris(dibenzylideneacetone)dipalladium/ dimethylbisdiphenyl-phosphinoxanthene and a base such as cesium carbonate in a solvent such as l,4-dioxane, preferentially at the boiling point of the solvent (step a).

Compound AC’ can be further elaborated to compound I (R” = ropylmethyloxy) 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 ion as described in step e of scheme 1.

Furthermore, compound BA can be converted into compound BC by treatment with compound AD as bed in step c of scheme 1 (step b). uent transformation of compound BC into compound AE can be achieved as discussed for the conversion of BA into AC’ (step a). nd AE can be further ated to compound I (R” = cyclopropylmethyloxy) by: i) saponiflcation as described in step d of scheme 1; ii) amide bond formation as described in step e of scheme 1.

Alternatively, compound BC (R’ = methyl, ethyl, isopropyl, tert. butyl or another le protecting group described for example in T.W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3rd edition) can be: i) converted into its acid congener BC (R’ = H) as described in step d of scheme 1; ii) transformed into 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 arrive at compound I (R’ ’ = cyclopropylmethyloxy).

Furthermore, compound I can also be synthesized applying the ing reaction sequence: i) saponification of compound BA (R’ = methyl, ethyl, isopropyl, tert. butyl or another suitable protecting group described for example in T.W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3rd edition) to its acid congener 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) on with compound 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.

If one of the starting materials, compounds of ae CA, CB or BC contains one or more functional groups which are not stable or are ve under the reaction conditions of one or more reaction steps, appropriate protecting groups (P) (as described e.g. in T.W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3rd edition) can be uced before the critical step applying methods well known in the art. Such protecting groups can be d at a later stage of the synthesis using standard methods known in the art.

If one or more compounds of formulae BA, BB or AD contain chiral centers, picolines of formula AC’ and AE can be ed as mixtures of diastereomers or enantiomers, which can be ted by methods well known in the art, e.g. (chiral) HPLC or crystallization. Racemic compounds can e.g. be separated into their antipodes via diastereomeric salts by crystallization or by separation of the antipodes by specific chromatographic s using either a chiral adsorbent or a chiral eluent.

The invention also relates to a process for the preparation of a compound of a (1) comprising one of the following steps: (a) the reaction of a compound of formula (A) koleLN Abowcozymx H Y A1 in the presence of Rl-H, a palladium catalyst and a base; (b) the reaction of a compound of formula (B) ”II 1’ R A (B) in the presence ofNH2-C(R2R3)—A2-O-(CH2)n-(CD2)m-X, a coupling agent and a base; wherein A1, A2, X, Rl-R3, m and n are as defined above and Y is halogen.

The coupling agent of step (b) is conveniently an amide bond forming agent, like e.g. N,N’-carbonyl-diimidazole (CD1), N,N’-dicyclohexylcarbodiimide (DCC), 1-(3- dimethylaminopropyl)—3-ethylcarbodiimide hydrochloride (EDCI), 1—[bis(dimethylamino)- methylene]—IH-l,2,3-triazolo[4,5-b]pyridinium—3-oxide hexafluorophosphate (HATU), 1- y- l ,2,3—benzotriazole , O-benzotriazol— l -yl-N,N,N’,N’-tetramethyluronium tetrafluoroborate (TBTU) or and otriazole-N,N,N’,N ’-tetramethyl-uronium— hexafluoro-phosphate (HBTU).

N-methylmorpholine is a convenient base for step (b).

HBTU can ageously be used in combination with N—methylmorpholine in step (b).

The solvent of step (b) can advantageously be ylformamide.

In step (a), the palladium catalyst can be for example tris(dibenzylideneacetone)dipalladium / dimethylbisdiphenyl-phosphinoxanthene.

In step (a) the base can be e.g. cesium carbonate.

In step (a), the solvent is advantageously 1,4-dioxane.

In step (a), Y can conveniently be e.

The ion also relates to a compound according to the invention when manufactured according to a process of the invention.

Another embodiment of the invention provides a pharmaceutical composition or medicament containing a nd of the invention and a therapeutically inert carrier, diluent or excipient, as well as a method of using the compounds of the invention to prepare such composition and medicament. In one example, the compound of formula (I) may be ated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form. The pH of the formulation depends mainly on the particular use and the concentration of nd, but preferably ranges anywhere from about 3 to about 8.

In one example, a compound of formula (I) is formulated in an acetate buffer, at pH 5. In another embodiment, the nd of formula (I) is sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lized formulation or as an aqueous solution.

Compositions are formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context e the particular disorder being treated, the ular mammal being treated, the clinical ion of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical tioners.

The compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration.

Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

The compounds of the present invention may be administered in any convenient administrative form, e. g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, itories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical ations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.

A typical formulation is prepared by mixing a compound of the t ion and a r or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e. g., Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et a1. Remington: The Science and ce of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, d C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, ating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the t invention or pharmaceutical ition thereof) or aid in the cturing of the pharmaceutical product (i.e., ment).

The invention also relates in particular to: The use of a compound of formula (I) for the treatment or prophylaxis of 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 pathy, ic nephropathy, ulonephropathy, cardiomyopathy, heart e, myocardial ischemia, myocardial infarction, systemic sclerosis, l injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors, regulation of bone mass, neurodegeneration, stroke, transient ischemic attack or uveitis; The use of a nd ing of formula (I) for the preparation of a medicament for the treatment or prophylaxis of pain, atherosclerosis, age-related macular degeneration, diabetic retinopathy, glaucoma, diabetes mellitus, inflammation, inflammatory bowel disease, ischemia-reperfusion , acute liver failure, liver fibrosis, lung fibrosis, kidney fibrosis, systemic fibrosis, acute allograft rejection, chronic allograft nephropathy, ic nephropathy, glomerulonephropathy, cardiomyopathy, heart failure, myocardial ischemia, myocardial infarction, systemic sclerosis, thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors, tion of bone mass, neurodegeneration, stroke, transient ischemic attack or uveitis, A compound of a (I) for use in the treatment or laxis of pain, atherosclerosis, age-related macular degeneration, diabetic pathy, glaucoma, diabetes mellitus, inflammation, inflammatory bowel disease, ia-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, myocardial ischemia, myocardial infarction, systemic sis, thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors, tion of bone mass, neurodegeneration, stroke, transient ischemic attack or uveitis, and A method for the treatment or prophylaxis of pain, atherosclerosis, age-related macular degeneration, ic retinopathy, glaucoma, diabetes mellitus, inflammation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver failure, liver fibrosis, lung s, kidney s, systemic fibrosis, acute allograft ion, chronic allograft nephropathy, diabetic nephropathy, ulonephropathy, cardiomyopathy, heart failure, myocardial ischemia, myocardial infarction, systemic sclerosis, thermal injury, burning, hypertrophic scars, s, gingivitis pyrexia, liver cirrhosis or tumors, regulation of bone mass, neurodegeneration, stroke, transient ischemic attack or uveitis, which method comprises administering an ive amount of a compound of formula (I) to a patient in need thereof.

The invention particularly relates to a compound of formula (I) for the treatment or prophylaxis of ischemia, reperfusion , liver fibrosis or kidney fibrosis, in particular ischemia or reperfusion .

The invention will now be illustrated by the following examples which have no limiting character. 2019/066811 _ 22 _ Examples Abbreviations CAN = chemical cts service number; DIPEA = N-ethyl-N—isopropylpropanamine; DMF = dimethylformamide; EtOAc = ethyl acetate; hept. = heptane; HPLC = LC = high mance liquid chromatography; ISP = ion spray, corresponds to ESI (electrospray); MS = mass spectrometry; NMR data are reported in parts per million (8) relative to internal tetramethylsilane and are referenced to the deuterium lock signal from the sample solvent (ds-DMSO unless ise ); coupling constants (J) are in Hertz; RT = room temperature; TBTU = O-(benzotriazol-l -yl)-N,N,N’,N’-tetramethyl-uronium— tetrafluoroborate; THF = tetrahydrofuran; tlc = thin layer chromatography.

Example 1 Fluoromethyl 2-{[6-(cyclopr0pylmethoxy)—5-(3-meth0xyazetidinyl)pyridine carbonyl] amin0}ethylbutan0ate a) 2-(6-(Cyclopropylmethoxy)-5 -(3-methoxyazetidin- l -yl)picolinamido)—2-ethylbutanoic acid In a 25 mL round-bottomed flask, ethyl 2-(6—(cyclopropylmethoxy)(3-methoxyazetidin- 1-yl)picolinamido)—2-ethylbutanoate (CAN 1778678—14-0, 210 mg, 501 umol, 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 e was stirred at 100 0C for 19 h. KOH (75 mg) and 1 mL 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 (l N HCl). The resulting white suspension was extracted with EtOAc (3 x 25 mL). The combined c layers were washed with brine (l x 20 mL), dried over NazSO4 and concentrated in vacuo to give the crude title compound as light brown oil which was used in the next step without further purification, MS (ISP): 392.314 [MH+]. b) methyl 2- { [6—(cyclopropylmethoxy)—5 -(3-methoxyazetidin—l -yl)pyridine-2— carbonyl]amino} ethylbutanoate In a 10 mL round-bottomed flask, 2—(6-(cyclopropylmethoxy)—5-(3 —methoxyazetidin-l- yl)picolinamido)ethylbutanoic acid (37 mg, 94.5 umol, Eq: 1) was combined with DMF (500 uL) to give a light brown solution. K2C03 (65.3 mg, 473 umol, Eq: 5) and fluoro- iodo-methane (76.3 mg, 32.2 uL, 473 umol, Eq: 5) were added. The reaction mixture was stirred at RT for 30 min, diluted with EtOAc and washed with sat. NaCl (3 x 10 mL). The organic layer was dried over Na2S04 and concentrated in vacuo. The crude t was purified by column chromatography (SiOz, 5 g, hept./ EtOAc) to give the title compound (27 mg, 68%) as ess oil, MS (ISP): 424.341 [MH+].

Example 2 2-Flu0r0ethy] 2-{[6-(cyclopr0pylmeth0xy)(3-meth0xyazetidinyl)pyridine yl] amin0}ethylbutan0ate In analogy to the procedure described in example 1 b, 2-(6-(cyclopropylmethoxy)—5—(3- methoxyazetidin-l-yl)picolinamido)ethylbutanoic acid (example 1 a) was d with fluoro-iodo-methane to give the title compound as colorless oil, MS (ISP): 438.346 [MH+].

Example 3 3-Flu0r0pr0pyl 2-{[6-(cyclopropylmeth0xy)—5-(3-meth0xyazetidinyl)pyridine—2- carbonyl] amin0}ethylbutanoate W0 2020l002320 2019/066811 l/ Hog—L In analogy to the procedure described in example 1 b, cyclopropylmethoxy)-5—(3- methoxyazetidin-l-yl)picolinamido)ethylbutanoic acid (example 1 a) was reacted with l-iodo—3-fluoropropane to give the title compound as colorless oil, MS (ISP): 452.4 [MH+].

Example 4 Fluoromethyl 2-{[6-(cyclopropylmethoxy)—5-(3,3-diflu0r0azetidinyl)pyridine—2- carbonyl] amino}ethylbutanoate Whig In analogy to the procedure described in example 1 b, cyclopropylmethoxy)(3,3- difluoroazetidin-l-yl)picolinamido)-2—ethylbutanoic acid (CAN 1415896-50—2) was reacted with fluoro-iodo-methane to give the title compound as colorless oil, LC-MS (UV peak area/ESI) 100%, 430.1952 [MH+].

Example 5 2-Flu0r0ethyl 2-{[6-(cyclopropylmethoxy)—5-(3,3-diflu0roazetidinyl)pyridine—2- carbonyl] amino}ethylbutanoate | NiiH / 0 ({fi W0 2020l002320 In analogy to the procedure described in example 1 b, 2-(6-(cyclopropylmethoxy)(3,3- difluoroazetidin-l-yl)picolinamido)—2-ethylbutanoic acid (CAN 62) was reacted with fluoro-iodo-ethane to give the title compound as colorless oil, LC-MS (UV peak area/ESI) 100%, 444.2109 [MH+].

Example 6 3-Flu0r0pr0pyl 2-{[6-(cyclopropylmethoxy)(3,3-difluor0azetidinyl)pyridine carbonyl] amin0}ethylbutan0ate “315%l/ HoR In analogy to the procedure bed in example 1 b, 2-(6-(cyclopropylmethoxy)-5—(3,3- difluoroazetidin-l-yl)picolinamido)—2-ethylbutanoic acid (CAN 14158962) was reacted with 1—iodo-3—fluoropropane to give the title compound as colorless oil, LC—MS (UV peak area/ESI) 100%, 458.2263 [MH+].

Example 7 3-Flu0r0pr0py1 2-{ clopropy]meth0xy)—5-(pyrrolidinyl)pyridine—2- carbonyl] amin0}ethylbutan0ate fiififiéia In analogy to the procedure described in example 1 b, 2-(6-(cyclopropylmethoxy) (pyrrolidin-l-yl)picolinamido)—2-ethylbutanoic acid (CAN 1415897—34-5) was reacted with l-iodofluoropropane to give the title compound as colorless oil, LC-MS (UV peak area/ESI) 98%, 4362615 [MH+].

Example 8 methyl 2-{[6-(cyclopropylmethoxy)—5-(pyrrolidin-l-yl)pyridine carbonyl] amino}ethylbutan0ate 2:19th In analogy to the procedure described in example 1 b, 2-(6-(cyclopropylmethoxy) (pyrrolidin-l-yl)picolinamido)—2-ethylbutanoic acid (CAN 1415897—34-5) was reacted with iodo-methane to give the title compound as colorless oil, LC-MS (UV peak SI) 96%, 408.2301 [MH+].

Example 9 2-Flu0r0ethyl 2-{[6-(cyclopr0pylmeth0xy)(pyrrolidin-l-yl)pyridine—2- carbonyl] amino}ethylbutan0ate “OVER In analogy to the procedure described in example 1 b, 2-(6-(cyclopropylmethoxy) (pyrrolidinyl)picolinamido)ethylbutanoic acid (CAN 14158975) was reacted with fluoro-iodo-ethane to give the title compound as colorless oil, LC-MS (UV peak area/ESI) 97%, 422.2463 [MH+].

Example 10 Fluoromethyl N- [6-(cyclopr0pylmeth0xy)—5-(3-meth0xyazetidinyl)pyridine—2- yl]-L-leucinate a) (S)—Methyl 2-(5-bromo(cyclopropylmethoxy)picolinamido)—4-methylpentanoate k 0\ I H / O In a 100 mL round-bottomed flask, 5-bromo(cyclopropylmethoxy)picolinic acid (CAN 14158981, 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 mrnol, Eq: 1.1), DIPEA (1.61 g, 2.18 mL, 12.5 mmol, Eq: 4) and L-leucine methyl ester hydrochloride (CAN 75173, 794 mg, 4.37 mmol, Eq: 1.4) were added and the mixture was stirred at RT for 30 min. The t was removed under reduced pressure and the residue dissolved in EtOAc. The organic layers were combined, washed with sat. NaHC03 (3 x 20 mL), 1 M HCl (3 x 20 mL), and sat.

NaCl (3 x 20 mL). The c layers were dried over Na2S04 and concentrated in vacuo to obtain crude title product (1.1 g, 88%) as light brown oil which was used in the next reaction step without further purificaition, MS (ISP): 399.162 [MH+]. b) (S)-Methyl 2-(6-(cyclopropylmethoxy)-5 thoxyazetidinyl)picolinamido)—4- methylpentanoate In a 20 mL sealed tube, (S)-methyl 2—(5-bromo(cyclopropylmethoxy)picolinamido) methylpentanoate (385 mg, 964 umol, Eq: 1) was combined with toluene (10 mL) to give a colorless solution. 3-Methoxyazetidine hydrochloride (CAN 1486441, 179 mg, 1.45 mrnol, Eq: 1.5) and CszCOs (943 mg, 2.89 mmol, Eq: 3) were added. rac-2,2'— Bis(diphenylphosphino)—1,1'—binaphthyl (120 mg, 193 umol, Eq: 0.2) and palladium(II) e (43.3 mg, 193 umol, Eq: 0.2) were added. The white suspension was heated to 110 0C for 1 h, d with EtOAc and filtered through celite. The organic layers were combined, washed with 1 M HCl (3 x 50 mL) and sat. NaCl (1 x 100 mL). The organic layers were dried over Na2S04 and concentrated in vacuo. The crude product was purified by column tography (SiOz, 50 g, hept./EtOAc) to give the title compound (287 mg, 73%) as light yellow oil, MS (ISP): 406.319 [MH+]. c) (S)—2-(6-(Cyclopropylmethoxy)-5 -(3-methoxyazetidinyl)picolinamido) methylpentanoic acid In a 25 mL round-bottomed flask, (S)-methyl 2-(6-(cyclopropylmethoxy)(3- yazetidin-l-yl)picolinamido)methylpentanoate (270 mg, 666 umol, Eq: 1) was combined with THF (2 mL), water (2 mL) and MeOH (2 mL) to give a light yellow solution. KOH (l 12 mg, 2 mmol, Eq: 3) was added and the mixture was stirred for l h at RT. The organic solvent was removed under reduced pressure. The aqueous phase was ed to pH 2 with l M HCl and extracted with EtOAc (3 x 20 mL) and brine (l x 25 mL). The organic layers were dried over NazSO4 and concentrated in vacuo to give crude title compound (quant) as light brown oil which was used in the next reaction step without further purification, MS (ISP): 392.316 [MH+]. d) Fluoromethyl N—[6—(cyclopropylmethoxy)—5-(3-methoxyazetidin-l —yl)pyridine-2— yl]-L-leucinate In analogy to the procedure described in example 1 b, (S)-2—(6-(cyclopropylmethoxy) (3 -methoxyazetidin- l colinamido)—4-methylpentanoic acid was reacted with fluoro- iodo-methane to give the title compound as ess oil, MS (ISP): 424.289 [MH+].

Example 11 2-Flu0r0ethyl N-[6-(cyclopr0pylmethoxy)(3-methoxyazetidinyl)pyridine—2- carbonyl]-L-leucinate wwfifikfli W0 2020l002320 In analogy to the procedure described in example 1 b, (S)(6-(cyclopropylmethoxy) (3-methoxyazetidinyl)picolinamido)methylpentanoic acid (example 10 c) was reacted with fluoro-iodo-ethane to give the title compound as colorless oil, MS (ISP): 438.294 [MH+].

Example 12 3-Flu0r0pr0pyl N-[6-(cyclopropylmethoxy)(3-methoxyazetidinyl)pyridine—2- carbonyl]-L-leucinate In analogy to the procedure described in example 1 b, (6-(cyclopropy1methoxy) (3 -methoxyazetidin-1—yl)picolinamido)methylpentanoic acid (example 10 c) was reacted with 1-fluoroiodopropane to give the title compound as colorless oil, MS (ISP): 452.351 [MH+].

Example 13 Fluoromethyl N-[6-(cyclopropylmethoxy)—5-(pyrrolidinyl)pyridine-2—carb0nyl]-L- leucinate a) thyl 2-(6-(cyclopropylmethoxy)—5-(pyrrolidinyl)picolinamido) methylpentanoate In analogy to the ure described in example 10 b, (S)-methyl 2-(5-bromo (cyclopropylmethoxy)picolinamido)-4—methylpentanoate (example 10 a) was reacted with pyrrolidine to give the title compound as light yellow oil, LC-MS (UV peak area/ESI) 95%, 390.2403 [MH+]. b) (S)(6-(Cyclopropylmethoxy)-5 -(pyrrolidin- l -y1)picolinamido)—4-methy1pentanoic acid ACMQOH In analogy to the procedure described in example 10 c, thyl 2-(6- (cyclopropylmethoxy)—5-(pyrrolidin- l —y1)picolinamido)methylpentanoate was hydrolyzed with KOH to give the title compound as brown oil which was used in the next reaction step without r purification, MS (ISP): 376.307 [MH+]. c) Fluoromethyl N—[6—(cyclopropylmethoxy)—5 -(pyrrolidin- l —yl)pyridinecarbony1]-L- leucinate In y to the procedure described in example 1 b, (S)(6-(cyclopropylmethoxy) (pyrrolidin-l-yl)picolinamido)methylpentanoic acid was reacted with fluoro-iodo- methane to give the title compound as light yellow oil, MS (ISP): 408.276 [MH+]. e 14 2-Flu0r0ethyl N-[6-(cyclopr0pylmethoxy)(pyrrolidinyl)pyridine-2—carb0nyl]-L- leucinate W0 2020l002320 2> 0%“ In y to the procedure described in example 1 b, (S)(6-(cyclopropylmethoxy) (pyrrolidin-l -yl)picolinamido)—4-methylpentanoic acid (example 13 b) was reacted with iodo-ethane to give the title compound as light brown oil, MS (ISP): 422.332 [MH+].

Example 15 3-Flu0r0pr0pyl N-[6-(cyclopr0pylmethoxy)(pyrrolidinyl)pyridine—2-carbonyl]- L-leucinate l/ H In analogy to the procedure described in e 1 b, (S)-2—(6-(cyclopropylmethoxy) (pyrrolidin-l -y1)picolinamido)methylpentanoic acid (example 13 b) was reacted With l- fluoroiodopropane to give the title compound as light brown oil, MS (ISP): 436.338 [MH+].

Example 16 6-(Cyclopr0pylmethoxy)—N-[(ZS)(fluoromethoxy)methylpentan-Z-yl] (pyrrolidinyl)pyridine—2-carboxamide W0 2020l002320 In a 5 mL round-bottomed flask, (S)(cyclopropylmethoxy)-N-(1-hydroxy methylpentanyl)(pyrrolidiny1)picolinamide (CAN 14158941, 40 mg, 11 1 umol, Eq: 1) was combined with DMF (1 mL) to give a ess solution which was cooled to 0 oC. Sodium hydride on mineral oil (22.1 mg, 553 umol, Eq: 5) was added and stirring was continued for 30 min. Fluoro-iodo-methane (88.5 mg, 37.3 uL, 553 umol, Eq: ) was added, the e was allowed to warm to ambient temperature and ng was continued for l h. The reaction mixture was diluted with EtOAc. The organic layers were combined and washed with sat. NaCl (3 x 25 mL). The c layers were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column tography (SiOz, 5 g, hept./EtOAc) to give the title compound (24 mg, 55%) as white solid, MS (ISP): 394.271 [MH+].

Example 17 6-(Cyclopr0pylmethoxy)-N-[(ZS)(2-fluoroethoxy)methylpentan-Z-yl] (pyrrolidinyl)pyridinecarb0xamide In analogy to the procedure described in example 16, (S)(cyclopropylmethoxy)—N-(1- hydroxymethy1pentanyl)(pyrrolidiny1)picolinamide (CAN 14158941) was reacted with 1-fluoroiodoethane to give the title compound as colorless oil, MS (ISP): 408.327 [MH+].

Example 18 6-(Cyclopropylmethoxy)—N-[(ZS)(3-fluoropropoxy)—4-methylpentan-Z-yl] (pyrrolidinyl)pyridine—2-carboxamide 2019/066811 In analogy to the procedure described in example 16, (S)(cyclopropylmethoxy)-N-(1- hydroxymethylpentanyl)(pyrrolidinyl)picolinamide (CAN 41) was reacted with 1-fluorofluoropropane to give the title compound as colorless oil, MS (ISP): 422.332 [MH+].

Example 19 6-(Cylopr0pylmethoxy)—N- [(28)(fluor0methoxy)—3-methylbutanyl] (pyrrolidinyl)pyridine—2-carb0xamide a) (S)(Cyclopropylmethoxy)—N-(1-hydroxymethylbutanyl)—5 -(pyrrolidin olinamide In a 50 mL round-bottomed flask, 6-(cyclopropylmethoxy)(pyrrolidinyl)picolinic acid (CAN 14158981, 295 mg, 1.12 mmol, Eq: 1) was combined with DMF (15 mL) to give a yellow solution. DIPEA (727 mg, 982 uL, 5.62 mmol, Eq: 5) and TBTU (397 mg, 1.24 mmol, Eq: 1.1) were added. L-Valinol (CAN 20264, 174 mg, 1.69 mmol, Eq: 1.5) was added and the e was stirred at ambient temperature for 1 h. EtOAc was added and the solution was washed with sat. NaHCO3 (3 X 20 mL), 1 M HCl (3 x 20 mL), and sat. NaCl (3 x 20 mL). The organic layer was dried over NazSO4 and concentrated in vacuo to give the title compound (240 mg, 61%) as light yellow oil which was used in the next step t further purification, MS (ISP): 348.239 [MH+]. b) 6-(Cylopropylmethoxy)—N-[(2S)— 1-(fluoromethoxy)methylbutanyl]—5 -(pyrrolidin- 1-yl)pyridinecarboxamide In analogy to the procedure described in example 16, (S)(cyclopropylmethoxy)—N-(1- hydroxymethylbutanyl)—5-(pyrrolidinyl)picolinamide was reacted with fluoro- iodo-methane to give the title compound as colorless oil, MS (ISP): 380.265 [MH+].

W0 2020l002320 Example 20 6-(Cyclopropylmethoxy)—N-[(ZS)(2-flu0roethoxy)—3-methylbutanyl] (pyrrolidinyl)pyridine—2-carb0xamide kmji In analogy to the procedure described in example 16, (S)(cyclopropylmethoxy)-N-(l- hydroxymethylbutanyl)—5-(pyrrolidinyl)picolinamide (example 19 a) was reacted with 1-fluoroiodoethane to give the title compound as colorless oil, MS (ISP): 394.326 [MH+].

Example 21 lopr0pylmethoxy)—N-[(ZS)(3-fluor0prop0xy)—3-methylbutanyl] (pyrrolidinyl)pyridine—2-carb0xamide In y to the procedure bed in example 16, (S)(cyclopropylmethoxy)-N-(1- hydroxymethylbutanyl)—5-(pyrrolidin-1—yl)picolinamide (example 19 a) was reacted with 1-iodofluoropropane to give the title compound as colorless oil, MS (ISP): 408.391 [MH+].

Example 22 6-(Cyclopr0pylmethoxy)—N-[(ZS)(fluoromethoxy)propanyl](pyrrolidin yl)pyridinecarb0xamide a) (S)(Cyclopropylmethoxy)-N-( l -hydroxypropany1)—5-(pyrrolidin yl)picolinamide 2%Km.

In analogy to the procedure described in example 19 a, 6-(cyclopropylmethoxy)—5- lidin-l-yl)picolinic acid (CAN 14158981) was reacted with L-alaninol (CAN 2749—11-3) to give the title compound as light yellow oil, MS (ISP): 320.209 [MH+]. b) 6-(Cyclopropylmethoxy)-N—[(2S)— l —(fluoromethoxy)propany1]—5 -(pyrrolidin- l — idine-2—carboxamide In analogy to the procedure described in example 16, (cyclopropylmethoxy)—N-(l- hydroxypropanyl)(pyrrolidin-l—yl)picolinamide was reacted With fluoro-iodo- methane to give the title compound as colorless oil, MS (ISP): 352.204 [MH+]. e 23 6-(Cyclopr0pylmethoxy)—N-[(ZS)-l-(2-flu0r0ethoxy)propany]](pyrrolidin yl)pyridine-2—carb0xamide In analogy to the procedure described in example 16, (S)(cyclopropylmethoxy)-N—(l- hydroxypropanyl)—5-(pyrrolidin-l-yl)picolinamide (example 22 a) was reacted with l- fluoroiodoethane to give the title compound as colorless oil, MS (ISP): 366.298 [MH+]. e 24 6-(Cyclopropylmethoxy)—N-[(2S)—1-(3-fluoropropoxy)propanyl] (pyrrolidin yl)pyridinecarb0xamide In analogy to the procedure bed in example 16, (S)(cyclopropylmethoxy)-N—(l- hydroxypropanyl)—5-(pyrrolidin-l-yl)picolinamide (example 22 a) was reacted with liodofluoropropane to give the title compound as colorless oil, MS (ISP): 380.265 [MH+].

Example 25 6-(Cyclopropylmethoxy)-N-[(ZS)(flu0rometh0xy)methylpentan-Z-yl](3- methoxyazetidinyl)pyridine—2-carb0xamide 1 0 a) (S)—6-(Cyclopropylmethoxy)—N—( l -hydroxymethylpentanyl)—5 -(3 - yazetidin- l -yl)picolinamide In analogy to the procedure described in example 19 a, 6-(cyclopropylmethoxy)(3- methoxyazetidin-l colinic acid (CAN 16132923) was condensed with L-leucinol (CAN 75336) to give the title compound as light yellow oil, MS (ISP): 378.309 [MH+]. b) 6-(Cyclopropylmethoxy)-N-[(ZS)- l -(fluoromethoxy)methylpentanyl] -5 -(3 - methoxyazetidin- l -yl)pyridinecarboxamide In analogy to the ure described in example 16, (S)(cyclopropylmethoxy)-N-(l- hydroxymethylpentanyl)—5-(3 -methoxyazetidin—l -yl)picolinamide was reacted with iodo-methane to give the title compound as colorless oil, LC-MS (UV peak area/ESI) 100%, 5 [MH+].

Example 26 6-(Cyclopropylmethoxy)—5-(3,3-difluoroazetidinyl)—N-[(ZS)(2-fluor0ethoxy)—4- methylpentan-Z-yl]pyridine-Z-carboxamide | " a) (S)(Cyclopropylmethoxy)—5 -(3 ,3 -difluoroazetidin- l -yl)-N-( l -hydroxy methylpentan—2—yl)picolinamide k MG In analogy to the procedure described in e 19 a, 6-(cyclopropylmethoxy)—5-(3,3- difluoroazetidin-l-yl)picolinic acid (CAN 82) was condensed with L-leucinol (CAN 75336) to give the title compound as light yellow oil, MS (ISP): 384.279 [MH+]. b) 6-(Cyclopropylmethoxy)-5—(3 ,3-difluoroazetidinyl)-N-[(ZS)-l-(2-fluoroethoxy)—4- methylpentanyl]pyridinecarboxamide In analogy to the procedure described in example 16, (S)(cyclopropylmethoxy)(3,3- difluoroazetidin- l -yl)—N-( l -hydroxymethylpentanyl)picolinamide was reacted with W0 2020l002320 l-fluoroiodoethane to give the title compound as colorless oil, MS (ISP): 430.338.

[MH+].

Example 27 6-(Cyclopr0pylmethoxy)—N-[(2S)—1-(2-fluor0ethoxy)methylpentan-Z-yl] (3- methoxyazetidinyl)pyridine—2-carb0xamide In analogy to the procedure described in example 16, (S)(cyclopropylmethoxy)—N-(l- ymethylpentanyl)—5-(3 -methoxyazetidin—l -yl)picolinamide (example 25 a) was reacted with l-fluoroiodoethane to give the title nd as colorless oil, MS (ISP): 424.362 [MH+]. e 28 6-(Cyclopropylmethoxy)—N-[(ZS)(3-fluoropropoxy)—4-methylpentan-Z-yl] (3- yazetidinyl)pyridine—2-carb0xamide In analogy to the procedure described in example 16, (S)(cyclopropylmethoxy)-N-(l- hydroxymethylpentanyl)(3 -methoxyazetidin-l -yl)picolinamide (example 25 a) was reacted with l-iodofluoropropane to give the title compound as colorless oil, MS (ISP): 438.375 [MH+].

Example 29 W0 2020l002320 6-(Cyclopropylmethoxy)-N-[(ZS)(flu0rometh0xy)methylbutanyl](3- methoxyazetidinyl)pyridine—2-carb0xamide a) (S)(Cyclopropylmethoxy)—N—( l —hydroxymethylbutanyl)-5 -(3-methoxyazetidin- l -yl)picolinamide k r\T/COH | M In analogy to the procedure described in example 19 a, 6-(cyclopropylmethoxy)(3- methoxyazetidin-l -y1)picolinic acid (CAN 16132923) was sed with nol (CAN 20264) to give the title compound as light yellow oil, MS (ISP): 364.252 [MH+]. b) lopropylmethoxy)-N-[(2S)— l -(fluoromethoxy)methylbutanyl] -5 -(3 - methoxyazetidin- l -yl)pyridinecarboxamide In analogy to the procedure described in example 16, (S)(cyclopropylmethoxy)-N—(l- hydroxymethylbutanyl)—5-(3-methoxyazetidin—l -yl)picolinamide was reacted with fluoro-iodo-methane to give the title compound as colorless oil, MS (ISP): 396.3 [MH+].

Example 30 6-(Cyclopropylmethoxy)—N-[(ZS)(2-fluor0ethoxy)methylbutanyl](3- methoxyazetidinyl)pyridine—2-carboxamide W0 2020l002320 In analogy to the procedure bed in example 16, (S)(cyclopropylmethoxy)-N-(l- hydroxy—3-methylbutan—2-yl)—5—(3-methoxyazetidin-l—yl)picolinamide (example 29 b) was reacted with l-fluoroiodoethane to give the title compound as colorless oil, MS (ISP): 410.335 [MH+]. e 31 6-(Cyclopropylmethoxy)—N-[(ZS)(3-fluoropropoxy)—3-methylbutanyl](3- methoxyazetidinyl)pyridine—2-carb0xamide 1O In analogy to the ure described in example 16, (S)(cyclopropylmethoxy)—N-(l- hydroxymethylbutanyl)—5-(3-methoxyazetidin-l-yl)picolinamide (example 29 b) was reacted with l-iodofluoropropane to give the title compound as colorless oil, MS (ISP): 424.362 [MH+].

Example 32 6-(Cyclopr0pylmethoxy)—N-[(ZS)(2-fluor0ethoxy)propanyl](3- methoxyazetidinyl)pyridine—2-carboxamide a) 6-(Cyclopropylmethoxy)-N- [(1 S)hydroxymethy1-ethy1] (3-methoxyazetidin yl)pyridinecarboxamide In analogy to the procedure described in example 19 a, 6-(cyclopropylmethoxy)(3- methoxyazetidin-l colinic acid (CAN 16132923) was condensed with L-alaninol (CAN 27493) to give the title compound as light yellow oil, MS (ISP): 336.242 [MH+]. b) 6-(Cyclopropylmethoxy)-N—[(2S)—1-(2-fluoroethoxy)propanyl]-5 -(3 - methoxyazetidin- l -yl)pyridinecarboxamide In analogy to the procedure described in example 16, 6-(cyclopropylmethoxy)-N—[(1S) hydroxy- l -methyl-ethyl]—5 -(3-methoxyazetidin- l -yl)pyridinecarboxamide was reacted with l-fluoroiodoethane to give the title compound as ess oil, MS (ISP): 0 [MH+].

Example 33 6-(Cyclopr0pylmeth0xy)—N-[(ZS)(3-fluor0propoxy)propan-Z-yl] (3- methoxyazetidinyl)pyridine—2-carb0xamide In analogy to the procedure described in example 16, 6-(cyclopropy1methoxy)-N—[(1S) hydroxy- l -methyl-ethyl]—5 -(3-methoxyazetidin- l -yl)pyridinecarboxamide (example 32 a) was d with l—iodofluoropropane to give the title compound as colorless oil, MS (ISP): 396.279 [MH+].

Example 34 2019/066811 6-(Cyclopr0pylmethoxy)-N-{3-[(fluoromethoxy)methyl] pentanyl}(3- methoxyazetidinyl)pyridine—2-carb0xamide a) 6-(Cyclopropylmethoxy)—N—(3-(hydroxymethyl)pentan-3 -yl)-5 thoxyazetidin- l - yl)picolinamide In analogy to the procedure described in example 19 a, 6-(cyclopropylmethoxy)(3- methoxyazetidin-l colinic acid (CAN 16132923) was condensed with 2-amino ethylbutan-l-ol (CAN 197920) to give the title compound as light yellow oil, MS (ISP): 378.303 [MH+]. b) 6-(Cyclopropylmethoxy)-N— {3 -[(fluoromethoxy)methyl]pentan-3—yl} -5 -(3 — methoxyazetidin- l -yl)pyridinecarboxamide In analogy to the procedure described in example 16, 6-(cyclopropylmethoxy)-N-(3- (hydroxymethyl)pentanyl)—5-(3-methoxyazetidin-l-y1)picolinamide was reacted with fluoro-iodo-methane to give the title compound as colorless oil, MS (ISP): 410.348 [MH+].

Example 35 6-(Cyclopropylmethoxy)—N-{3-[(2-fluoroethoxy)methyl] yl}(3- methoxyazetidinyl)pyridine—2-carb0xamide W0 2020l002320 In analogy to the procedure described in example 16, 6-(cyclopropylmethoxy)-N-(3— (hydroxymethyl)pentanyl)—5-(3-methoxyazetidin-l-yl)picolinamide (example 34 a) was reacted with l—fluoroiodoethane to give the title compound as light brown oil, MS (ISP): 424.362 [MH+].

Example 36 6-(Cyclopropylmethoxy)—N-{3-[(3-fluoropropoxy)methyl]pentanyl}-5—(3- methoxyazetidinyl)pyridine—2-carb0xamide l/Hq—L ‘3 m In analogy to the procedure bed in example 16, 6-(cyclopropylmethoxy)-N-(3- (hydroxymethyl)pentan—3-yl)—5—(3-methoxyazetidin-l—yl)picolinamide (example 34 a) was reacted with l-iodofluoropropane to give the title nd as light brown oil, MS (ISP): 6 [MH+].

Example 37 6-(Cyclopr0pylmethoxy)—N-[(2R)—1-(2-fluor0ethoxy)—4-methylpentan-Z-yl] (pyrrolidinyl)pyridinecarb0xamide 42W“ _ 44 _ a) (R)(Cyclopropylmethoxy)-N—( 1 -hydroxymethylpentanyl)-5 -(pyrrolidin yl)picolinamide In analogy to the procedure described in example 19 a, 6-(cyclopropylmethoxy)—5- (pyrrolidin-l-yl)picolinic acid (CAN 81) was condensed with D—leucinol (CAN 534482) to give the title compound as colorless oil, MS (ISP): 362.725. [MH+]. b) 6-(Cyclopropylmethoxy)-N-[(2R)(2-fluoroethoxy)methylpentanyl]-5 - (pyrrolidin-l ridinecarboxamide In analogy to the procedure described in e 16, (R)(cyclopropylmethoxy)—N-(l- hydroxymethylpentanyl)—5-(pyrrolidin—l colinamide was reacted with l—fluoro- 2-iodoethane to give the title compound as colorless oil, MS (ISP): 408.359 [MH+].

Example 38 6-(Cyclopr0pylmethoxy)—N-[(2R)—1-(2-fluor0ethoxy)—4-methylpentan-Z-yl] (3- methoxyazetidinyl)pyridine—2-carboxamide a) (R)(Cyclopropylmethoxy)-N-( l -hydroxymethylpentany1)-5 -(3 - methoxyazetidin- l -yl)picolinamide In analogy to the procedure described in example 19 a, 6-(cyclopropylmethoxy)—5-(3— methoxyazetidin-l -y1)picolinic acid (CAN 16132923) was condensed with D-leucinol (CAN 09—2) to give the title compound as light yellow oil, MS (ISP): 378.3 [MHI]. b) 6-(Cyclopropylmethoxy)-N—[(2R)-1 -(2-fluoroethoxy)methy1pentany1]-5 -(3— methoxyazetidiny1)pyridinecarboxamide In analogy to the procedure described in example 16, (R)(cyclopropylrnethoxy)—N-(1— hydroxymethy1pentanyl)—5-(3-methoxyazetidiny1)picolinamide was reacted with 1-fluoroiodoethane to give the title compound as colorless oil, MS (ISP): 424.327 [MH+]. e 39 6-(Cyclopropylmethoxy)—5-(3-fluoromethylazetidinyl)-N-(3-(3- fluoropropylcarbamoyl)pentanyl)picolinamide In a 5 mL pear-shaped flask, lopropylmethoxy)(3-fluoromethy1azetidin-1 - yl)picolinic acid (CAN 18128888, 5 mg, 17.8 umol, Eq: 1.0), oethyl-N-(3- fluoropropyl)butanamide hloride (CAN 1613239-88—5, 4.45 mg, 19.6 umol, Eq: 1.10), 2-bromoethy1pyridinium tetrafluoroborate (5.37 mg, 19.6 umol, Eq: 1.10) and DIPEA (8.07 mg, 10.7 uL, 62.4 umol, Eq: 3.50) were combined with 1,4-dioxane (100 uL) to give a light yellow solution. The reaction mixture was stirred for 16 h at ambient temperature and brought to dryness. The crude was purified by preparative TLC (silica gel, EtOAc, elution with CHzClz/EtOAc 1:1) to give the title compound (5 mg, 62%) as white solid, MS (ESI): 453.3 [MHl].

Example 40 Pharmacological tests The following tests were carried out in order to determine the activity of the compounds of formula I: Radioligand binding assay The y of the compounds of the invention for cannabinoid CB1 receptors was determined using recommended amounts ofmembrane preparations (PerkinElmer) of human embryonic kidney (HEK) cells sing the human CNRl or CNR2 receptors in conjunction with 1.5 or 2.6 nM [3H]—CP-55,940 (Perkin Elmer) as radioligand, respectively. Binding was performed in binding buffer (50 mM Tris, 5 mM MgC12, 2.5 mM EDTA, and 0.5% l) fatty acid free BSA, pH 7.4 for CB1 receptor and 50 mM Tris, 5 mM MgCl2, 2.5 mM EGTA, and 0.1% (wt/vol) fatty acid free BSA, pH 7.4 for CB2 receptor) in a total volume of 0.2 ml for 1h at 30°C shaking. The reaction was terminated by rapid filtration through ltration plates coated with 0.5% polyethylenimine (UniFilter GF/B filter plate; Packard). Bound radioactivity was analyzed for Ki using nonlinear regression analysis (Activity Base, ID ss Solution, Limited), with the Kd values for [3H]CP55,940 determined from tion ments. The compounds of a (I) show an excellent affinity for the CB2 receptor.

The compounds according to formula (I) have an activity in the above assay (Ki) between 0.5 nM and 10 uM. Particular compounds of formula (I) have an activity in the above assay (Ki) between 0.5 nM and 3 uM. Other particular compounds of formula (I) have an activity in the above assay (Ki) between 0.5 nM and 100 nM. cAMP Assay CHO cells expressing human CB1 or CB2 receptors are seeded 17-24 hours prior to the experiment 50.000 cells per well in a black 96 well plate with flat clear bottom (Corning Costar #3904) in DMEM (Invitrogen No. 31331), 1x HT supplement, with 10 % fetal calf serum and incubated at 5% C02 and 37°C in a humidified incubator. The growth medium was exchanged with Krebs Ringer Bicarbonate buffer with 1 mM IBMX and incubated at °C for 30 min. Compounds were added to a final assay volume of 100 ul and incubated for 30 min at 30°C. Using the cAMP—Nano-TRF ion kit the assay (Roche Diagnostics) was stopped by the addition of 50 ul lysis reagent (Tris, NaCl, 1.5% Triton X100, 2.5% NP40, 10% NaN3) and 50 ul detection solutions (20 uM mAb Alexa700- CAMP 1:1, and 48 uM RutheniumAHA-cAMP) and shaken for 2h at room temperature.

The time-resolved energy er is measured by a TRF reader (Evotec Technologies GmbH), equipped with a ND2YAG laser as excitation source. The plate is measured twice with the excitation at 355 nm and at the emission with a delay of 100 ns and a gate of 100 ns, total re time 10s at 730 (bandwidth 30 nm) or 645 nm (bandwidth 75 nm), respectively. The FRET signal is calculated as follows: FRET = T730-Alexa730-P(T645- B645) with P = B730/Ru645-B645, where T730 is the test well measured at 730 nM, T645 is the test well measured at 645 nm, B730 and B645 are the buffer controls at 730 nm and 645 nm, respectively. cAMP content is ined from the function of a standard curve spanning from 10 uM to 0.13 nM CAMP.

ECso values were determined using Activity Base analysis (ID Business Solution, Limited). The ECso values for a wide range of cannabinoid agonists generated from this assay for reference compounds were in agreement with the values published in the scientific literature.

In the foregoing assay, the compounds according to the invention have a human CB2 ECso which is between 0.5 nM and 10 nM. ular compounds ing to the invention have a human CB2 ECso between 0.5 nM and 1 uM. Further particular compounds according to the invention have a human CB2 ECso between 0.5 nM and 100 nM. They exhibit at least 10 fold selectivity against the human CB1 receptor in, either both of the radioligand and cAMP assay, or in one of these two assays.

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

Binding assay human CB2 Ki [HM] 2019/066811 Binding assay human CBZ Ki [HM] )—l O )—A p-A >—A)—A>—A #UJN j—A £11 >—A>—A)—t OO\]O\ NNN NHO NNN GUI-b DJNN COCO UJUJ DJN WO 02320 Binding assay human CBZ Ki _ 50 _

Claims (8)

Claims
1. l. A compound of formula (I) O R2 R3 ROI \j/lL”N >4 0 co AZ/ W 2)\mx R1 A1/ 5 R1 is alkoxyazetidinyl, dihaloazetidinyl or pyrrolidinyl; R2 and R3 are independently selected from hydrogen and alkyl; A1 is -CH- or nitrogen; A2 is -CH2- or carbonyl; X is halogen; 10 nis Oto 3;and m is 0 or 1; provided that m and n are not both 0 at the same time; or a pharmaceutically able salt thereof.
2. 2. A compound according to claim 1, wherein R1 is methoxyazetidinyl, 15 difluoroazetidinyl or pyrrolidinyl.
3. 3. A compound according to claim 1 or 2, wherein R2 and R3 are independently selected from en, ethyl and butyl.
4. 4. A compound according to any one of claims 1 to 3, wherein R2 and R3 are both ethyl at the same time, or one of R2 and R3 is hydrogen and the other one is butyl. 20
5. 5. A compound according to any one of claims 1 to 4, wherein A1 is -CH-.
6. 6. A compound according to any one of claims 1 to 5, wherein X is fluorine.
7. 7. A nd according to any one of claims 1 to 6, wherein n is l, 2 or 3.
8. 8. A compound according to any one of claims 1 to 7 selected from W0