HK40035571A - Novel azetidine-substituted pyridine and pyrazine compounds as inhibitors of cannabinoid receptor 2 - Google Patents

Description

Novel azetidine-substituted pyridine and pyrazine compounds as inhibitors of cannabinoid receptor 2

Novel compounds useful in medicine

The present invention relates to organic compounds useful for the treatment and/or prophylaxis of mammals, and in particular to compounds which are preferential agonists of cannabinoid receptor 2.

The invention relates in particular to compounds of the formula (I)

Wherein

A is-CH-or nitrogen;

R¹is haloalkoxyazacyclobutyl, 3-fluoroazacyclobutyl, fluoroethylazacyclobutyl, fluoromethylazacyclobutyl, halosulfonylazetidinyl, 3-fluoro-3, 3-dideuteropropyloxyazacyclobutyl, 2-fluoro-2, 2-dideutero-ethyloxyazacyclobutyl, fluorodideuteromethoxyazetidinyl, 2-fluoro-2, 2-dideuteroethylazacyclobutyl or fluorodideuteromethylazacyclobutyl;

R²and R³And are both alkyl; or

R²And R³Together with the carbon atom to which they are attached form an oxetanyl group; and

R⁴is alkoxycarbonyl or aminocarbonylalkyl;

or a pharmaceutically acceptable salt thereof.

The compounds of formula (I) are particularly useful for the treatment or prophylaxis of, for example, pain (pain), atherosclerosis (atherosclerosis), age-related macular degeneration (age-related macular degeneration), diabetic retinopathy (diabetic retinopathy), glaucoma (glaucoma), diabetes mellitus (diabetes mellitis), inflammation (inflammation), inflammatory bowel disease (inflammatory bowel disease), ischemia-reperfusion injury (ischemia-reperfusion injury), acute liver failure (acute liver failure), liver fibrosis (liver fibrosis), lung fibrosis (lung fibrosis), kidney fibrosis (kidney fibrosis), systemic fibrosis (systemic fibrosis), acute allograft rejection (acute allograft rejection), chronic allograft nephropathy (chronic allograft nephropathy), myocardial fibrosis (ischemic nephropathy), diabetic nephropathy (ischemic nephropathy), diabetic nephropathy (diabetic nephropathy), diabetic neuropathy, diabetic nephropathy (diabetic nephropathy, diabetic neuropathy, diabetic nephropathy, diabetic neuropathy, diabetic nephropathy, diabetic neuropathy, myocardial infarction (myocardial infarction), systemic sclerosis (systemic sclerosis), thermal injury (thermal intuury), burns (burning), hypertrophic scars (hypertrophic scars), keloids (keloids), gingivitis pyrexia (gingivitis), liver cirrhosis or tumors (liver cirrhosis or tumors), regulation of bone mass (bone mass), neurodegeneration (neurodegeneration), stroke (stroke), transient ischemic attack (transient ischemic attack) or uveitis (uveitis).

Cannabinoid receptors are a class of cell membrane receptors belonging to the G protein-coupled receptor superfamily. There are currently two known subtypes, known as cannabinoid receptor 1(CB1) and cannabinoid receptor 2(CB 2). The CB1 receptor is expressed predominantly in the central nervous (i.e. amygdala cerebellum, hippocampus) system and in lesser amounts in the periphery. CB2 encoded by the CNR2 gene is expressed predominantly on cells of the immune system, such as macrophages and T-cells (Ashton, J.C. et al, Curr Neuropharmacol 2007, 5(2), 73-80; Miller, A.M. et al, Br J Pharmacol2008, 153(2), 299-308; Centonze, D., et al, Curr Pharm Des 2008, 14(23), 2370-42), and peripherally in the gastrointestinal system (Wright, K.L. et al, Br J Pharmacol2008, 153(2), 263-70). The CB2 receptor is also widely distributed in the brain, where it is found primarily on microglia rather than neurons (Cabral, g.a. et al Br J Pharmacol2008, 153 (2): 240-51).

Interest in agonists of the CB2 receptor has steadily risen in the past decade (current 30-40 patent applications/year) due to the fact that many of the early compounds have been shown to have beneficial effects in preclinical models of a large number of human diseases including chronic pain (Beltramo, m.mini Rev Med Chem 2009, 9(1), 11-25), atherosclerosis (Mach, f. et al J neuroendinor 2008, 20Suppl 1, 53-7), regulation of bone mass (Bab, i. et al Br J Pharmacol2008, 153(2), 182-8), neurogenic inflammation (Cabral, g.a. et al J leuc Biol 2005, 78(6), 1192-7), ischemia/reperfusion injury (pocher, p. et al Br J Pharmacol2008, 153(2), 252-62), systemic fibrosis (akhminshi, a. hetis et al, r 2009, 60(4, 2009), 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).

Ischemia/reperfusion (I/R) injury is the leading cause of tissue damage that occurs in conditions such as stroke, myocardial infarction, cardiopulmonary bypass and other vascular surgeries and organ transplants, as well as the major mechanism of end organ injury that complicates the process of circulatory shock of multiple etiologies. All of these disorders are characterized by a breakdown in the normal blood pressure supply, which results in inadequate tissue oxygenation. Reoxygenation, e.g. reperfusion, is the ultimate treatment for restoring normal tissue oxygenation. However, the lack of oxygen and nutrients from the blood creates conditions in which the return of circulation leads to further tissue damage. The damage of reperfusion injury is due in part to the inflammatory response of the damaged tissue. The leukocytes carried to this area by the new returning blood release a number of inflammatory factors such as interleukins and free radicals in response to tissue damage. The restored blood flow reintroduces oxygen within the cell, which damages cellular proteins, DNA and plasma membranes.

Remote Ischemic Preconditioning (RIPC) represents a strategy to exploit the body's endogenous protective capacity against damage due to ischemia and reperfusion. It describes a very interesting phenomenon in which transient non-lethal ischemia and reperfusion of one organ or tissue provides resistance to the subsequent onset of a "lethal" ischemia-reperfusion injury in a distant organ or tissue (subsequent diabetes). Although various hypotheses have been proposed, the exact mechanism by which transient ischemia and reperfusion of an organ or tissue provides protection is currently unknown.

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

Recent data suggest that endocannabinoids and their receptors, in particular CB2, may be involved in pre-adaptation and help to prevent reperfusion injury by down-regulating the inflammatory response (Pacher, p. et al Br J Pharmacol2008, 153(2), 252-62). In particular, recent studies using CB2 tool agonists demonstrated the efficacy of this concept for reducing I/R damage in the heart (Defer, n. et al faeb J2009, 23(7), 2120-30), brain (Zhang, m. et al J Cereb Blood Flow Metab 2007, 27(7), 1387-96), liver (Batkai, s. et al faeb J2007, 21(8), 1788-.

Furthermore, in the last few years, increasing literature has shown that CB2 may also be of interest in sub-chronic and chronic situations. Specific up-regulation of CB1 and CB2 has been shown to be associated with the associated expression of CB2 in myofibroblasts (cells responsible for the progression of fibrosis) in animal models of chronic diseases associated with fibrosis (Garcia-Gonzalez, e. et al rheumatology (oxford)2009, 48(9), 1050-6; Yang, y. et al Liver Int 2009, 29(5), 678-85).

Activation of the CB2 receptor by selective CB2 agonists has in fact been shown to exert an anti-fibrotic effect in diffuse systemic sclerosis (Garcia-Gonzalez, e. et al rhematology (oxford)2009, 48(9), 1050-6) and CB2 receptor has emerged as a key target in experimental skin fibrosis (akhmithshina, a. et al Arthritis Rheum 2009, 60(4), 1129-36) and liver pathophysiology, including fibrogenesis associated with chronic liver disease (fibrosesis) (Lotersztajn, s. et al gastroentrerol Clin Biol 2007, 31(3), 255-8; Mallat, a. et al Expert Opin Targets 2007, 11(3), 403-9; Lotersztajn, s. et al Br J surgery 2008, phas (2), 286-9) 153.

The compounds of the present invention bind and modulate the CB2 receptor and have reduced CB1 receptor activity.

In the present specification, the term "alkyl", alone or in combination, denotes a linear or branched alkyl group having from 1 to 8 carbon atoms, in particular a linear or branched alkyl group having from 1 to 6 carbon atoms, more in particular a linear or branched alkyl group having from 1 to 4 carbon atoms. Straight and branched C₁-C₈Examples of alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, the isomeric pentyl groups, the isomeric hexyl groups, the isomeric heptyl groups and the isomeric octyl groups, in particular methyl, ethyl, propyl, butyl and pentyl groups. Specific examples of alkyl groups are methyl, ethyl, isopropyl, butyl, isobutyl, tert-butyl and pentyl. Methyl and ethyl are particular examples of "alkyl" groups in the compounds of formula (I).

The term "alkoxy" or "alkyloxy", alone or in combination, denotes a group of the formula alkyl-O-, wherein the term "alkyl" has the previously given meaning, e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. Particular examples of "alkoxy" are methoxy and ethoxy.

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

The term "halogen" or "halo", alone or in combination, denotes fluorine, chlorine, bromine or iodine and especially fluorine, chlorine or bromine and more especially fluorine. The term "halo", in combination with another group, means that the group is substituted with at least one halogen, in particular with one to five halogens, in particular with one to four halogens, i.e. one, two, three or four halogens. Fluorine is a particular halogen.

The term "haloalkyl", alone or in combination, denotes an alkyl substituted by at least one halogen, in particular by one to five halogens, in particular one to three halogens. Particular "haloalkyl" groups are fluoromethyl, fluoroethyl, fluoropropyl and fluorobutyl.

The term "haloalkoxy", alone or in combination, denotes an alkoxy group substituted by at least one halogen, in particular by one to five halogens, in particular by one to three halogens. Particular "haloalkoxy" groups are fluoromethoxy and fluoroethoxy.

The term "carbonyl", alone or in combination, denotes a-c (o) -group.

The term "amino", alone or in combination, denotes a primary amino group (-NH2), a secondary amino group (-NH-), or a tertiary amino group (-N-).

The term "aminocarbonyl", alone or in combination, denotes-C (O) -NH₂A group.

The term "sulfonyl", alone or in combination, means-SO₂-a group.

The term "pharmaceutically acceptable salts" refers to those salts that retain the biological effectiveness and properties of the free base or free acid, 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, in particular 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 an inorganic base or an organic base to the free acid. 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 compounds of formula (I) may also be present in zwitterionic form. Particularly preferred pharmaceutically acceptable salts of the compounds of formula (I) are salts of hydrochloric, hydrobromic, sulfuric, phosphoric and methanesulfonic acids.

By "pharmaceutically acceptable ester" is meant that the compound of formula (I) may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives such as methoxymethyl, methylthiomethyl and pivaloyloxymethyl esters. In addition, any physiologically acceptable equivalent of a compound of formula (I) that is capable of producing the parent compound of formula (I) in vivo, like metabolically labile esters, is within the scope of the invention.

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

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

The term "asymmetric carbon atom" means a carbon atom having four different substituents. According to the Cahn-Ingold-Prelog protocol, the asymmetric carbon atoms may be in either the "R" or "S" configuration.

Accordingly, the present invention relates to:

a compound according to the invention, wherein a is-CH-;

a compound according to the invention, wherein R¹Is haloalkoxyazacyclobutyl or 3-fluoroazacyclobutyl;

a compound according to the invention, wherein R¹Is fluoroethoxyazacyclobutyl or 3-fluoroazacyclobutyl;

a compound according to the invention, wherein R²And R³And are all ethyl radicals;

a compound according to the invention, wherein R⁴Is alkoxycarbonyl; and

a compound according to the invention, wherein R⁴Is an ethoxycarbonyl group;

the invention also relates in particular to compounds according to the invention selected from:

ethyl 2- ({6- (cyclopropylmethoxy) -5- [3- (3-fluoropropoxy) azetidin-1-yl ] pyridine-2-carbonyl } amino) -2-ethylbutanoate;

ethyl 2- ({6- (cyclopropylmethoxy) -5- [3- (2-fluoroethoxy) azetidin-1-yl ] pyridine-2-carbonyl } amino) -2-ethylbutanoate;

ethyl 2- ({6- (cyclopropylmethoxy) -5- [3- (fluoromethoxy) azetidin-1-yl ] pyridine-2-carbonyl } amino) -2-ethylbutanoate;

2- { [6- (cyclopropylmethoxy) -5- (3-fluoroazetidin-1-yl) pyridine-2-carbonyl ] amino } -2-ethylbutyric acid ethyl ester;

n- [3- (2-amino-2-oxoethyl) oxetan-3-yl ] -6- (cyclopropylmethoxy) -5- [3- (2-fluoroethoxy) azetidin-1-yl ] pyridine-2-carboxamide;

2- { [6- (cyclopropylmethoxy) -5- (3-fluoroazetidin-1-yl) pyrazine-2-carbonyl ] amino } -2-ethylbutyric acid ethyl ester;

ethyl 2- ({6- (cyclopropylmethoxy) -5- [3- (fluorosulfonyl) azetidin-1-yl ] pyridine-2-carbonyl } amino) -2-ethylbutanoate;

ethyl 2- ({6- (cyclopropylmethoxy) -5- [3- (fluorosulfonyl) azetidin-1-yl ] pyridine-2-carbonyl } amino) -2-ethylbutanoate;

ethyl 2- { [6- (cyclopropylmethoxy) -5- (3- { [ 3-fluoro (3, 3-dideuterio) propyl ] oxy } azetidin-1-yl) pyridine-2-carbonyl ] amino } -2-ethylbutanoate;

ethyl 2- { [6- (cyclopropylmethoxy) -5- (3- { [ 2-fluoro (2, 2-dideuterio) ethyl ] oxy } azetidin-1-yl) pyridine-2-carbonyl ] amino } -2-ethylbutanoate;

ethyl 2- { [6- (cyclopropylmethoxy) -5- (3- { [ fluoro (dideuterio) methyl ] oxy } azetidin-1-yl) pyridine-2-carbonyl ] amino } -2-ethylbutanoate;

n- [3- (2-amino-2-oxoethyl) oxetan-3-yl ] -6- (cyclopropylmethoxy) -5- (3- { [ 2-fluoro (2, 2-dideuterio) ethyl ] oxy } azetidin-1-yl) pyridine-2-carboxamide;

2- { [6- (cyclopropylmethoxy) -5- {3- [ 2-fluoro (2, 2-dideuterio) ethyl ] azetidin-1-yl } pyridine-2-carbonyl ] amino } -2-ethylbutyric acid ethyl ester;

ethyl 2- { [6- (cyclopropylmethoxy) -5- {3- [ fluoro (dideuterio) methyl ] azetidin-1-yl } pyridine-2-carbonyl ] amino } -2-ethylbutanoate;

ethyl 2- ({6- (cyclopropylmethoxy) -5- [3- (2-fluoroethyl) azetidin-1-yl ] pyridine-2-carbonyl } amino) -2-ethylbutanoate;

ethyl 2- ({6- (cyclopropylmethoxy) -5- [3- (fluoromethyl) azetidin-1-yl ] pyridine-2-carbonyl } amino) -2-ethylbutanoate;

ethyl 2- ({6- (cyclopropylmethoxy) -5- [3- (2-fluoroethyl) azetidin-1-yl ] pyridine-2-carbonyl } amino) -2-ethylbutanoate; and

ethyl 2- ({6- (cyclopropylmethoxy) -5- [3- (fluoromethyl) azetidin-1-yl ] pyridine-2-carbonyl } amino) -2-ethylbutanoate.

The invention also relates to a compound according to the invention selected from:

ethyl 2- ({6- (cyclopropylmethoxy) -5- [3- (2-fluoroethoxy) azetidin-1-yl ] pyridine-2-carbonyl } amino) -2-ethylbutanoate; and

2- { [6- (cyclopropylmethoxy) -5- (3-fluoroazetidin-1-yl) pyridine-2-carbonyl ] amino } -2-ethylbutyric acid ethyl ester.

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

Following the procedure according to scheme 1, compound AA (R' ═ H, methyl, ethyl, isopropyl, tert-butyl or another suitable protecting group, e.g. as described in t.w. greene et al, Protective Groups in Organic Chemistry, John Wiley and Sons inc.new York 1999, 3 rd edition) can be used as starting material. AA is commercially available, described in the literature, or can be synthesized by one skilled in the art.

Scheme 1

Compound AB may be prepared from AA by oxidation with a suitable oxidant under conditions known to those skilled in the art (step a), for example by treatment with 3-chloroperbenzoic acid in dichloromethane at ambient temperature.

The conversion of compound 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 of 20 ℃ to the boiling point of the solvent, or by using other conditions known in the literature (step b).

6-chloro-or bromo-methylpyridine AC (X ═ Cl, Br) can be converted to compound AE (R ═ cyclopropylmethyloxy) by reaction with a suitable substituted primary or secondary alcohol AD such as cyclopropylmethanol, in the presence of a base such as sodium hydride, in the presence or absence of an inert solvent such as dimethylformamide, at a temperature in the range from room temperature to the reflux temperature of the solvent, particularly at room temperature (step c).

The saponification of esters of the 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 temperatures from 0 ℃ to the reflux temperature of the solvent employed-gives acids II of the general formula II (step d).

Compound I can be prepared from II and the corresponding amine of formula III by a suitable amide bond formation reaction (step e). These reactions are known in the art. For example, coupling agents such as N, N '-carbonyl-diimidazole (CDI), N' -Dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 1- [ bis (dimethylamino) -methylene ] -may be used]-1H-1, 2, 3-triazolo [4, 5-b]Pyridine compound-3-oxide Hexafluorophosphate (HATU), 1-hydroxy-1, 2, 3-benzotriazole (HOBT), O-benzotriazol-1-yl-N, N' -tetramethylureaTetrafluoroborate (TBTU) and O-benzotriazole-N, N, N ', N' -tetramethyl-ureaHexafluoro-phosphate (HBTU) to achieve such conversion. 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.

Alternatively, compound AC (R' ═ methyl, ethyl, isopropyl, tert-butyl or another suitable protecting group, such as those described in t.w. greene et al, Protective Groups in Organic Chemistry, John Wiley and Sons inc.new York 1999, 3 rd edition) may: i) conversion to its acid congener AC (R' ═ H) as described in step d; ii) conversion to the corresponding amide by treatment with an amine III as described in step e; and iii) reaction with alcohol AD as described in step c to give compound I.

Amine III and alcohol AD are commercially available, described in the literature, can be synthesized by one skilled in the art or as described in the experimental section.

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

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

Following the procedure according to scheme 2, compound BA (R' ═ H, methyl, ethyl, isopropyl, tert-butyl or another suitable protecting group, such as described in t.w. greene et al, Protective Groups in Organic Chemistry, John Wiley and Sons inc.new York 1999, 3 rd edition) can be used as starting material. BA is commercially available (e.g. 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 the skilled person.

Scheme 2

By methods well known to those skilled in the art, for example, using a palladium catalyst such as tris (dibenzylideneacetone) dipalladium/dimethylbisdiphenyl-phosphinothioxanthene and a base such as cesium carbonate in a solvent such as 1, 4-bisCompound AC' can be prepared from BA in an alkane by coupling with an amine BB (M is H), preferably at the boiling point of the solvent (step a).

Compound AC' can be further converted to compound I by: i) reacting 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.

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

The subsequent conversion of compound BC (R ═ cyclopropylmethyloxy) to compound AE can be achieved as described for the conversion of BA to AC' (step a).

Compound AE can be further converted to compound I by: i) saponification 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 suitable protecting group, such as those described in t.w. greene et al, Protective Groups in Organic Chemistry, John Wiley and Sons inc.new York 1999, 3 rd edition) may: i) conversion to its acid congener BC (R' ═ H) as described in step d of scheme 1; ii) conversion to the corresponding amide BD by treatment with amine III as described in step e of scheme 1; and iii) reacting with BB as described in step a to give compound I.

Furthermore, compound I can also be synthesized using the following reaction sequence: i) as described in scheme 1, step d, compound BA (R '═ methyl, ethyl, isopropyl, tert-butyl or another suitable protecting group, such as those described in t.w. greene et al, Protective Groups in Organic Chemistry, John Wiley and Sons inc.new York 1999, 3 rd edition) is saponified to its acid analogue BA (R' ═ H); ii) conversion to the corresponding amide by treatment with amine III as described in step e of scheme 1; iii) reacting with BB as described in step a; and iv) reacting with compound AD as described in step b. Optionally, step iii) and step iv) may be interchanged.

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

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 diastereomers or mixtures of enantiomers, which may be separated by methods well known in the art, such as (chiral) HPLC or crystallization. Racemic compounds can be separated into their enantiomers, for example, by crystallization via diastereomeric salts, or by enantiomeric separation by specific chromatographic methods, using chiral adsorbents or chiral eluents.

Accordingly, the present invention also relates to a process for the preparation of a compound according to the invention, said process comprising one of the following steps:

(a) reacting a compound of formula (A)

At R¹-H, a palladium catalyst and a base;

(b) reacting a compound of formula (B)

At NH₂-C(R²R³R⁴) Reacting in the presence of a coupling agent and a base;

wherein A is¹And R¹-R⁴As defined above.

The coupling agent of step (b) is conveniently an amide bond forming agent, such as for example N, N '-carbonyl-diimidazole (CDI), N' -Dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 1- [ bis (dimethylamino) -methylene-bis (meth) imide]-1H-1, 2, 3-triazolo [4, 5-b]Pyridine compound-3-oxide Hexafluorophosphate (HATU), 1-hydroxy-1, 2, 3-benzotriazole (HOBT), O-benzotriazol-1-yl-N, N' -tetramethylureaTetrafluoroborate (TBTU) and O-benzotriazole-N, N, N ', N' -tetramethyl-urea-hexafluoro-phosphate (HBTU).

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

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

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

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

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

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

The invention also relates to compounds according to the invention prepared by the process according to the invention.

Another embodiment of the invention provides pharmaceutical compositions or medicaments comprising a compound of the invention and a therapeutically inert carrier, diluent or excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments. In one example, the compound of formula (I) may be administered in a galenical form by mixing at ambient temperature, at a suitable pH, and with the desired degree of purity, with a physiologically acceptable carrier, i.e. a carrier which is non-toxic to the recipient at the dosages and concentrations employed. The pH of the formulation depends primarily on the particular use and concentration of the compound, but is preferably any value in 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 compounds of formula (I) are sterile. The compounds may be stored, for example, as solid or amorphous compositions, as lyophilized formulations, or as aqueous solutions.

The compositions are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered in this regard include the particular condition being treated, the particular 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 the practitioner.

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 topical treatment is desired, intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.

The compounds of the invention may be administered in any convenient form of administration, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches and the like. Such compositions may contain conventional ingredients of pharmaceutical formulations such as diluents, carriers, pH adjusting agents, sweeteners, fillers and other active agents.

Typical formulations are prepared by mixing a compound of the invention with a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel, Howard c. et al, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, philiadelphia: 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 (handbook of Pharmaceutical adjuvants), Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, fragrances, flavoring agents, 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 aid in the preparation of the pharmaceutical product (i.e., a pharmaceutical product).

The invention also relates in particular to:

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 nephropathy, diabetic nephropathy, glomerulonephropathy, cardiomyopathy, heart failure, myocardial ischemia, myocardial infarction, systemic sclerosis, thermal injury, burns, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors, regulation of bone mass, neurodegeneration, stroke, transient ischemic attack or uveitis;

use of a compound according to formula (I) for the manufacture 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 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 sclerosis, thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors, regulation of bone mass, neurodegeneration, stroke, transient ischemic attack or uveitis;

a compound of formula (I) for use in the treatment or prevention of pain, atherosclerosis, age-related macular degeneration, diabetic retinopathy, glaucoma, 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, myocardial ischemia, myocardial 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; and

a method 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 nephropathy, diabetic nephropathy, glomerulonephropathy, cardiomyopathy, heart failure, myocardial ischemia, myocardial infarction, systemic sclerosis, thermal injury, burns, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors, regulation of bone mass, neurodegeneration, stroke, transient ischemic attack or uveitis, comprising administering to a patient in need thereof an effective amount of a compound of formula (I).

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

The invention will now be described by the following examples, which are not of a limiting nature.

Examples

Abbreviations

CAN is a chemical abstract service number; DCM ═ dichloromethane; DIPEA ═ N-ethyl-N-isopropylpropan-2-amine; DMF ═ dimethylformamide; EI is electron bombardment; EtOAc ═ ethyl acetate; HATU 2- (3H- [1, 2, 3)]Triazolo [4, 5-b]Pyridin-3-yl) -1, 1, 3, 3-tetramethylisoureaHexafluorophosphate (V); HBTU ═ O-benzotriazole-N, N' -tetramethylmethyl-urea-hexafluoro-phosphate; heptanes; HPLC ═ LC ═ high performance liquid chromatography; ISP — ion injection, corresponding to ESI (electrospray); MS ═ mass spectrum; NMR data are reported in parts per million () relative to tetramethylsilane as an internal standard, and the reference is from the sample solvent (d)₆-DMSO, unless otherwise specified); coupling constants (J) are reported in Hertz (Hertz); RT ═ room temperature; rt ═ retention time; TBAF ═ tetra-n-butylammonium fluoride; TBTU ═ O- (benzotriazol-1-yl) -N, N' -tetramethyl-urea-a tetrafluoroborate salt; THF ═ tetrahydrofuran.

Example 1

2- ({6- (cyclopropylmethoxy) -5- [3- (3-fluoropropoxy) azetidin-1-yl ] pyridine-2-carbonyl } amino) -2-ethylbutanoic acid ethyl ester

In a 10mL three-necked flask, ethyl 2- (6- (cyclopropylmethoxy) -5- (3-hydroxyazetidin-1-yl) picolinamido) -2-ethylbutanoate (CAN 1778678-40-2, 26mg, 64.1. mu. mol, Eq: 1) was combined with DMF (500. mu.L) to give a pale yellow solution. Hydrogen added in mineral oilSodium dispersion (12.8mg, 321. mu. mol, Eq: 5) and the reaction mixture was stirred at ambient temperature for 30 min. 1-iodo-3-fluoropropane (60.3mg, 32.8. mu.L, 321. mu. mol, Eq: 5) was added and the mixture was stirred for 1 h. Another portion of the sodium hydride dispersion in mineral oil (5mg, 125. mu. mol, Eq: 2) was added and stirring continued at ambient temperature for 30 min. The reaction mixture was diluted with EtOAc and washed with brine (3 × 10 mL). The organic layer was washed with Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (6mg, 19%) as a colourless oil, ms (esi): 466.4[ MH⁺]。

Example 2

2- ({6- (cyclopropylmethoxy) -5- [3- (2-fluoroethoxy) azetidin-1-yl ] pyridine-2-carbonyl } amino) -2-ethylbutanoic acid ethyl ester

In analogy to the procedure described in example 1, ethyl 2- (6- (cyclopropylmethoxy) -5- (3-hydroxyazetidin-1-yl) picolinamido) -2-ethylbutanoate (CAN 1778678-40-2) was reacted with 1-fluoro-2-iodoethane to give the title compound as colorless oil, ms (esi): 452.351[ MH⁺]。

Example 3

2- ({6- (cyclopropylmethoxy) -5- [3- (fluoromethoxy) azetidin-1-yl ] pyridine-2-carbonyl } amino) -2-ethylbutanoic acid ethyl ester

In analogy to the procedure described in example 1, 2- (6- (cyclopropylmethoxy) -5- (3-hydroxyazetidin-1-yl) picolinamido) -2-ethylbutanoic acid ethyl ester (CAN 1778678-40-2) was reacted with fluoro-iodomethane to give the title compound as light yellow solid, ms (esi): 436.389[ MH⁺]。

Example 4

2- { [6- (cyclopropylmethoxy) -5- (3-fluoroazetidin-1-yl) pyridine-2-carbonyl ] amino } -2-ethylbutyric acid ethyl ester

a)2- (6- (cyclopropylmethoxy) -5- (3- ((methylsulfonyl) oxy) azetidin-1-yl) pyridinecarboxamido) -2-ethylbutanoic acid ethyl ester

In a 5mL round bottom flask, ethyl 2- (6- (cyclopropylmethoxy) -5- (3-hydroxyazetidin-1-yl) picolinamido) -2-ethylbutanoate (CAN 1778678-40-2, 88mg, 217. mu. mol, Eq: 1) was combined with DCM (1.5mL) to give a colorless solution which was cooled to 0 ℃. Triethylamine (65.9mg, 90.7. mu.L, 651. mu. mol, Eq: 3) and methanesulfonyl chloride (49.7mg, 33.7. mu.L, 434. mu. mol, Eq: 2) were added and the mixture was warmed to ambient temperature. After 90min, the mixture was diluted with EtOAc and saturated NaHCO₃(3X 10mL), 1M HCl (3X 10mL), and saturated NaCl (1X 10 mL). The organic layer was washed with Na₂SO₄Dried and concentrated in vacuo to give the crude title compound, which was used in the next step without further purification, ms (esi): 484.3[ MH⁺]。

b)2- { [6- (cyclopropylmethoxy) -5- (3-fluoroazetidin-1-yl) pyridine-2-carbonyl ] amino } -2-ethylbutyric acid ethyl ester

Ethyl 2- (6- (cyclopropylmethoxy) -5- (3- ((methylsulfonyl) oxy) azetidin-1-yl) picolinamido) -2-ethylbutanoate (105mg, 217. mu. mol, Eq: 1) was combined with DMF (5mL) in a 5mL sealed tube to give a colorless solution. A THF solution of TBAF (1.08mL, 1.09mmol, Eq: 5) was added and the reaction mixture was stirred at 100 ℃ for 17 h. The mixture was diluted with EtOAc and washed with brine (3 × 20 mL). The organic layer was washed with Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (26mg, 29%) as a light yellow oil, ms (esi):408.276[MH⁺]。

example 5

N- [3- (2-amino-2-oxoethyl) oxetan-3-yl ] -6- (cyclopropylmethoxy) -5- [3- (2-fluoroethoxy) azetidin-1-yl ] pyridine-2-carboxamide

a) N- (3- (2-amino-2-oxoethyl) oxetan-3-yl) -5-bromo-6- (cyclopropylmethoxy) pyridinecarboxamide

In a 50mL round bottom flask, 5-bromo-6- (cyclopropylmethoxy) picolinic acid (CAN1415898-37-1, 941mg, 3.46mmol, Eq: 1.5) was combined with DMF (20mL) to give a pale yellow solution. TBTU (1.04g, 3.23mmol, Eq: 1.4), DIPEA (1.19g, 1.61mL, 9.22mmol, Eq: 4) and 2- (3-aminooxetan-3-yl) acetamide (CAN1417638-25-5, 300mg, 2.31mmol, Eq: 1) were added and the reaction mixture was stirred at ambient temperature for 12 h. The solvent was removed under reduced pressure and the residue was diluted with EtOAc. The organic layer was washed with saturated NaHCO₃(3X 25mL), 1M HCl (3X 25mL) and saturated NaCl (1X 50mL), washed with Na₂SO₄Dried and concentrated in vacuo. The crude product is purified by column chromatography (SiO)₂50g, DCM/MeOH) to afford the title compound (315mg, 65%) as a white solid, MS (ISP): 384.127/386.084 MH⁺]。

b) N- (3- (2-amino-2-oxoethyl) oxetan-3-yl) -5- (3- (benzyloxy) azetidin-1-yl) -6- (cyclopropylmethoxy) pyridinecarboxamide

In a 20mL sealed tube, N- (3- (2-amino-2-oxoethyl) oxetan-3-yl) -5-bromo-6- (cyclopropylmethoxy) pyri-dinePyridinecarboxamide (400mg, 1.04mmol, Eq: 1) was combined with toluene (10mL) to give a colorless solution. Adding Cs₂CO₃(1.02g, 3.12mmol, Eq: 3), 3- (benzyloxy) azetidinobenzenesulfonate (CAN 1993178-75-8, 335mg, 1.04mmol, Eq: 1), rac-2, 2 '-bis (diphenylphosphino) -1, 1' -binaphthyl (130mg, 208. mu. mol, Eq: 0.2), and palladium II acetate) (46.7mg, 208. mu. mol, Eq: 0.2). The reaction mixture was stirred at 110 ℃ for 3h, diluted with EtOAc and filtered through celite. The organic solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with 1M HCl (3X 25mL) and saturated NaCl (1X 25 mL). The organic layer was washed with Na₂SO₄Dried and concentrated in vacuo. The crude product is purified by column chromatography (SiO)₂50g, DCM/MeOH) to afford the title compound (315mg, 65%) as a white solid, MS (ISP): 467.335[ MH⁺]。

c) N- (3- (2-amino-2-oxoethyl) oxetan-3-yl) -6- (cyclopropylmethoxy) -5- (3-hydroxyazetidin-1-yl) pyridinecarboxamide

A50 mL pressure reactor was charged with N- (3- (2-amino-2-oxoethyl) oxetan-3-yl) -5- (3- (benzyloxy) azetidin-1-yl) -6- (cyclopropylmethoxy) pyridinecarboxamide (240mg, 516. mu. mol, Eq: 1) and MeOH (25mg) and placed under an argon atmosphere. Pd-C on charcoal (120mg, 113. mu. mol, Eq: 0.5) was added. The suspension was placed under a hydrogen atmosphere (5bar) and stirred at 50 ℃ for 18 h. The mixture was filtered and concentrated in vacuo to give the crude title compound, which was used in the next step without further purification, ms (esi): 377.279[ MH⁺]。

d) N- [3- (2-amino-2-oxoethyl) oxetan-3-yl ] -6- (cyclopropylmethoxy) -5- [3- (2-fluoroethoxy) azetidin-1-yl ] pyridine-2-carboxamide

In analogy to the procedure described in example 1, N- (3- (2-amino-2-oxoethyl) oxetan-3-yl) -6- (cyclopropylmethoxy) -5- (3-hydroxyazetidin-1-yl) pyridinecarboxamide was reacted with 1-fluoro-2-iodoethane to give the title compound as white solid, ms (esi): 423.311[ MH + ].

Example 6

Pharmacological testing

The following assays were performed to determine the activity of the compounds of formula I:

radioligand binding assays

Membrane preparations (Perkinelmers) of Human Embryonic Kidney (HEK) cells expressing human CNR1 or CNR2 receptors were used in recommended amounts to bind 1.5 or 2.6nM [3H ] respectively]-CP-55, 940(Perkin Elmer) as radioligand to determine the affinity of the compounds of the invention for the cannabinoid CB1 receptor. Binding buffer (for CB1 receptor: 50mM Tris, 5mM MgCl) in a total volume of 0.2ml₂2.5mM EDTA, and 0.5% (wt/vol) fatty acid free BSA, pH 7.4; and for the CB2 receptor: 50mM Tris, 5mM MgCl2, 2.5mM EGTA, and 0.1% (wt/vol) fatty acid free BSA, pH 7.4), with shaking at 30 ℃ for 1 h. The reaction was terminated by rapid filtration through a 0.5% polyethyleneimine coated micro filter plate (UniFilter GF/B filter plate; Packard). Bound radioactivity was analyzed for Ki using non-linear regression analysis (Activity Base, ID Business Solution, Limited) and determined from saturation assays for [3H]Kd value of CP55,940. The compounds of formula (I) show excellent affinity for the CB2 receptor.

In the above assay (Ki), the compounds according to formula (I) have an activity of 0.5nM to 10. mu.M. In the above assay (Ki), the particular compound of formula (I) has an activity of 0.5nM to 3. mu.M. In the above assay (Ki), other particular compounds of formula (I) have an activity of 0.5nM to 100 nM.

cAMP assay

CHO cells expressing human CB1 or CB2 receptors were seeded 17-24 hours prior to the experiment at 50.000 cells/well in black 96-well plates with clear flat bottom (Corning Costar #3904), in DMEM (Invitrogen No.31331) (supplemented with 1 HT, with 10% fetal calf serum) and in a humidified incubator at 5% CO₂And incubated at 37 ℃. The growth medium was exchanged with Krebs Ringer Bicarbonate buffer with 1mM IBMX,and incubated at 30 ℃ for 30 minutes. The compound was added to a final assay volume of 100. mu.l and incubated at 30 ℃ for 30 minutes. Using the cAMP-Nano-TRF detection kit (Roche Diagnostics), by adding 50. mu.l lysis reagent (Tris, NaCl, 1.5% Triton X100, 2.5% NP40, 10% NaN)₃) And 50. mu.l of detection solution (20. mu.M mAb Alexa700-cAMP 1: 1, and 48. mu.M ruthenium-2-AHA-cAMP) stop the assay and oscillate at room temperature for 2 h. The time-resolved energy transfer was measured by a TRF reader (Evotec Technologies GmbH) equipped with an ND: YAG laser as excitation source. The plate was measured twice, excited at 355nm and emitted at 730 (bandwidth 30nm) or 645nm (bandwidth 75nm) with a 100ns delay and a 100ns gate (gate) respectively, for a total exposure time of 10 s. The FRET signal is calculated as follows: FRET-T730-Alexa 730-P (T645-B645), P-Ru 730-B730/Ru645-B645, where T730 is the test well measured at 730nM, T645 is the test well measured at 645nM, and B730 and B645 are buffer controls at 730nM and 645nM, respectively. cAMP content is determined as a function of a standard curve spanning 10. mu.M to 0.13nM cAMP.

EC is determined using Activity Base analysis (ID Business Solution, Limited)₅₀The value is obtained. EC for a wide range of cannabinoid agonists generated from this assay for the reference compound₅₀The values are in agreement with those disclosed in the scientific literature.

In the aforementioned assay, the compounds according to the invention have a concentration of 0.5nM to 10. mu.M of human CB2EC₅₀. Particular compounds according to the invention have a human CB2EC of 0.5nM to 1. mu.M₅₀. Further particular compounds according to the invention have a human CB2EC of 0.5nM to 100nM₅₀. They exhibit at least 10-fold selectivity over the human CB1 receptor in both radioligand and cAMP assays or in either assay.

The results obtained for representative compounds of the invention are given in the table below.

Example A

Film-coated tablets containing the following ingredients can be prepared in a conventional manner:

the active ingredient is sieved and mixed with microcrystalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidone in water. The granules were then mixed with sodium starch glycolate and magnesium stearate and extruded to give 120 or 350mg of inner core, respectively. These cores are coated with the aqueous solution/suspension of the film coating described above.

Example B

Capsules containing the following ingredients can be prepared in a conventional manner:

composition (I)	Capsule
		A compound of formula (I)	25.0mg
Lactose	150.0mg
		Corn starch	20.0mg
Talc	5.0mg

The components were sieved and mixed and filled into size 2 capsules.

Example C

The injection solution may have the following composition:

a compound of formula (I)	3.0mg
		Polyethylene glycol 400	150.0mg
Acetic acid	Adding proper amount of the mixture to pH 5.0
		Water for injection	Adding to 1.0ml

The active ingredient is dissolved in a mixture of polyethylene glycol 400 and water for injection (part). The pH was adjusted to 5.0 by addition of acetic acid. The volume was adjusted to 1.0ml by adding the remaining amount of water. The solution was filtered, filled into vials with the appropriate excess and sterilized.

Claims (18)

1. A compound of formula (I)

Wherein

A is-CH-or nitrogen;

R¹is haloalkoxyazacyclobutyl, 3-fluoroazacyclobutyl, fluoroethylazacyclobutyl, fluoromethylazacyclobutyl, halosulfonylazetidinyl, 3-fluoro-3, 3-dideuteropropyloxyazacyclobutyl, 2-fluoro-2, 2-dideutero-ethyloxyazacyclobutyl, fluorodideuteromethoxyazetidinyl, 2-fluoro-2, 2-dideuteroethylazacyclobutyl or fluorodideuteromethylazacyclobutyl;

R²and R³And are both alkyl; or

R²And R³Together with the carbon atom to which they are attached form an oxetanyl group; and

R⁴is alkoxycarbonyl or aminocarbonylalkyl;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein a is-CH-.

3. The compound of claim 1 or 2, wherein R¹Is haloalkoxyazacyclobutyl or 3-fluoroazacyclobutyl.

4. A compound according to any one of claims 1 to 3, wherein R¹Is fluoroethyloxyazetidinyl or 3-fluoroazacyclobutyl.

5. A compound according to any one of claims 1 to 4, wherein R²And R³And are both ethyl groups.

6. A compound according to any one of claims 1 to 5, wherein R⁴Is an alkoxycarbonyl group.

7. A compound according to any one of claims 1 to 6, wherein R⁴Is an ethoxycarbonyl group.

8. A compound according to any one of claims 1 to 7, selected from

Ethyl 2- ({6- (cyclopropylmethoxy) -5- [3- (3-fluoropropoxy) azetidin-1-yl ] pyridine-2-carbonyl } amino) -2-ethylbutanoate;

ethyl 2- ({6- (cyclopropylmethoxy) -5- [3- (2-fluoroethoxy) azetidin-1-yl ] pyridine-2-carbonyl } amino) -2-ethylbutanoate;

ethyl 2- ({6- (cyclopropylmethoxy) -5- [3- (fluoromethoxy) azetidin-1-yl ] pyridine-2-carbonyl } amino) -2-ethylbutanoate;

2- { [6- (cyclopropylmethoxy) -5- (3-fluoroazetidin-1-yl) pyridine-2-carbonyl ] amino } -2-ethylbutyric acid ethyl ester;

n- [3- (2-amino-2-oxoethyl) oxetan-3-yl ] -6- (cyclopropylmethoxy) -5- [3- (2-fluoroethoxy) azetidin-1-yl ] pyridine-2-carboxamide;

2- { [6- (cyclopropylmethoxy) -5- (3-fluoroazetidin-1-yl) pyrazine-2-carbonyl ] amino } -2-ethylbutyric acid ethyl ester;

ethyl 2- ({6- (cyclopropylmethoxy) -5- [3- (fluorosulfonyl) azetidin-1-yl ] pyridine-2-carbonyl } amino) -2-ethylbutanoate;

ethyl 2- ({6- (cyclopropylmethoxy) -5- [3- (fluorosulfonyl) azetidin-1-yl ] pyridine-2-carbonyl } amino) -2-ethylbutanoate;

ethyl 2- { [6- (cyclopropylmethoxy) -5- (3- { [ 3-fluoro (3, 3-dideuterio) propyl ] oxy } azetidin-1-yl) pyridine-2-carbonyl ] amino } -2-ethylbutanoate;

ethyl 2- { [6- (cyclopropylmethoxy) -5- (3- { [ 2-fluoro (2, 2-dideuterio) ethyl ] oxy } azetidin-1-yl) pyridine-2-carbonyl ] amino } -2-ethylbutanoate;

ethyl 2- { [6- (cyclopropylmethoxy) -5- (3- { [ fluoro (dideuterio) methyl ] oxy } azetidin-1-yl) pyridine-2-carbonyl ] amino } -2-ethylbutanoate;

n- [3- (2-amino-2-oxoethyl) oxetan-3-yl ] -6- (cyclopropylmethoxy) -5- (3- { [ 2-fluoro (2, 2-dideuterio) ethyl ] oxy } azetidin-1-yl) pyridine-2-carboxamide;

2- { [6- (cyclopropylmethoxy) -5- {3- [ 2-fluoro (2, 2-dideuterio) ethyl ] azetidin-1-yl } pyridine-2-carbonyl ] amino } -2-ethylbutyric acid ethyl ester;

ethyl 2- { [6- (cyclopropylmethoxy) -5- {3- [ fluoro (dideuterio) methyl ] azetidin-1-yl } pyridine-2-carbonyl ] amino } -2-ethylbutanoate;

ethyl 2- ({6- (cyclopropylmethoxy) -5- [3- (2-fluoroethyl) azetidin-1-yl ] pyridine-2-carbonyl } amino) -2-ethylbutanoate;

ethyl 2- ({6- (cyclopropylmethoxy) -5- [3- (fluoromethyl) azetidin-1-yl ] pyridine-2-carbonyl } amino) -2-ethylbutanoate;

ethyl 2- ({6- (cyclopropylmethoxy) -5- [3- (2-fluoroethyl) azetidin-1-yl ] pyridine-2-carbonyl } amino) -2-ethylbutanoate; and

ethyl 2- ({6- (cyclopropylmethoxy) -5- [3- (fluoromethyl) azetidin-1-yl ] pyridine-2-carbonyl } amino) -2-ethylbutanoate.

9. A compound according to any one of claims 1 to 8, selected from

Ethyl 2- ({6- (cyclopropylmethoxy) -5- [3- (2-fluoroethoxy) azetidin-1-yl ] pyridine-2-carbonyl } amino) -2-ethylbutanoate; and

2- { [6- (cyclopropylmethoxy) -5- (3-fluoroazetidin-1-yl) pyridine-2-carbonyl ] amino } -2-ethylbutyric acid ethyl ester.

10. A process for the preparation of a compound according to any one of claims 1 to 9, comprising one of the following steps:

(a) reacting a compound of formula (A)

At R¹-H, a palladium catalyst and a base;

(b) reacting a compound of formula (B)

At NH₂-C(R²R³R⁴) Reacting in the presence of a coupling agent and a base;

wherein A is¹And R¹-R⁴As defined in any one of claims 1 to 7.

11. A compound according to any one of claims 1 to 9, when manufactured according to a process of claim 10.

12. A compound according to any one of claims 1 to 9 for use as therapeutically active substance.

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 and a therapeutically inert carrier.

14. The use of a compound according to any one of claims 1 to 9 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 nephropathy, diabetic nephropathy, glomerulonephropathy, cardiomyopathy, heart failure, myocardial ischemia, myocardial 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.

15. Use of a compound according to any one of claims 1 to 9 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 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 sclerosis, thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors, regulation of bone mass, neurodegeneration, stroke, transient ischemic attack or uveitis.

16. A compound according to any one of claims 1 to 9 for use in 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 nephropathy, diabetic nephropathy, glomerulonephropathy, cardiomyopathy, heart failure, myocardial ischemia, myocardial infarction, systemic sclerosis, heat injury, burns, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors, regulation of bone mass, neurodegeneration, stroke, transient ischemic attack or uveitis.

17. A method for treating or preventing 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, myocardial ischemia, myocardial 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, the method comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 9.

18. The invention as hereinbefore described.