Synthetic eicosanoid analogues for the treatment and prevention of diseases associated with elevated plasma levels of GDF15 - Patent application

Abstract

The present invention relates to compounds of general formula (I) that are metabolically robust analogues of bioactive lipid mediators derived from omega-3 polyunsaturated fatty acids (n-3 PUFAs) for use in the treatment or reducing the risk of developing or preventing diseases associated with elevated plasma concentrations of GDF-15.

Description

[Technical field]

[0001] The present invention relates to compounds of general formula (I) that are metabolically robust analogues of bioactive lipid mediators derived from omega-3 polyunsaturated fatty acids (n-3 PUFAs), for use in the treatment or reducing the risk of developing or preventing diseases associated with elevated plasma concentrations of GDF-15. [Background technology]

[0002] Omega-6 and omega-3 polyunsaturated fatty acids (n-6 and n-3 PUFAs) are essential components of the mammalian diet. The biologically most important n-3 PUFAs are eicosapentaenoic acid (EPA, 20:5 n-3) and docosahexaenoic acid (DHA, 22:6 n-3). Dietary n-3 PUFAs influence a variety of physiological processes that affect normal health and chronic disease, including regulation of plasma lipid levels, cardiovascular and immune function, inflammation, insulin action, neurodevelopment and visual function.

[0003] Upon ingestion, n-3 PUFAs are distributed to virtually every cell in the body, affecting membrane composition and function, eicosanoid synthesis, signal transduction, and the regulation of gene expression.

[0004] Simopoulos et al. summarized animal experiments and clinical intervention studies showing that n-3 PUFAs have anti-inflammatory properties and therefore may be useful in managing inflammatory and autoimmune diseases (Non-Patent Document 1).

[0005] One of the most important biological roles of PUFAs is to provide precursors for the generation of bioactive fatty acid metabolites that can regulate many functions. For example, arachidonic acid (AA; 20:4, n-6) is metabolized by cytochrome P450 (CYP) enzymes to several classes of oxygenated metabolites with potent biological activities. The main metabolites include 20-hydroxyeicosatetraenoic acid (20-HETE) and a series of positional and stereoisomeric epoxyeicosatrienoic acids (EETs). CYP4A and CYP4F isoforms generate 20-HETE, while CYP2C and CYP2J isoforms generate EETs.

[0006] It is known that EPA (20:5, n-3) and DHA (22:6, n-3) may function as alternative substrates for CYP isoforms that metabolize AA (Non-Patent Document 2). Members of the CYP2C and CYP2J subfamilies epoxidize AA to EETs, metabolize EPA to epoxyeicosatetraenoic acid (EEQ), and metabolize DHA to epoxydocosapentaenoic acid (EDP). The ω-3 double bond, which distinguishes EPA and DHA from AA, is the preferential site of attack by most epoxygenases, resulting in the formation of 17,18-EEQ and 19,20-EDP as the major metabolites. CYP4A and CYP4F isoforms hydroxylate AA to 20-HETE, metabolize EPA to 20-hydroxyeicosapentaenoic acid (20-HEPE), and metabolize DHA to 22-hydroxydocosahexaenoic acid (22-HDHA). CYP1A1, CYP2E1, and other isoforms that convert AA primarily to 19-HETE exhibit prominent ω-3 epoxygenase activity toward EPA and DHA. Human CYP1A1 variants result in distinct eicosapentaenoic acid metabolic patterns. Cytochrome P450-dependent eicosapentaenoic acid metabolites are novel BK channel activators. A notable feature of CYP-dependent n-3 PUFA metabolism is the preferential epoxidation of the n-3 double bond, which distinguishes EPA and DHA from AA. The resulting metabolites (EPA-derived 17,18-EEQ and DHA-derived 19,20-EDP) are unique in that they have no homologs within the set of AA products. Consistent with the substrate specificity of CYP isoforms, dietary EPA / DHA supplementation induces a significant shift from AA to EPA- and DHA-derived epoxy and ω-hydroxy metabolites in all major organs and tissues in rats, and possibly in humans as well.

[0007] EETs and 20-HETEs play an important role in regulating various cardiovascular functions (Non-Patent Document 3). AngII-induced hypertension has been shown to be associated with downregulation of CYP-dependent AA metabolism (Non-Patent Document 4), and has been shown in a double transgenic rat (dTGR) model of AngII-induced hypertension and end-organ damage (Non-Patent Document 5). Recently, it has been shown that eicosapentaenoic acid (EPA) supplementation significantly reduces the mortality rate of dTGR (Non-Patent Document 6). Furthermore, it has been shown that dTGR develops ventricular arrhythmias based on AngII-induced electrical remodeling (Non-Patent Document 7). Treatment of dTGR rats with PPAR-α activators potently induced CYP2C23-dependent EET production and protected them from hypertension and end-organ damage (Non-Patent Document 8).

[0008] Prolonged feeding (from the 4th to 7th week of life) of dTGR containing a mixture of pure EPA-ethyl esters and DHA-ethyl esters (Omacor, Solvay Arzneimittel, Hannover, Germany) improved cardiac electrical remodeling in this model of angiotensin II-induced hypertension. In particular, EPA and DHA reduced mortality, inhibited induction of arrhythmias, and prevented remodeling of connexin 43 gap junctions (Non-Patent Document 9). In general, CYP-dependent eicosanoids should be considered as second messengers: EETs and 20-HETEs are produced by CYP enzymes after the release of AA from membrane phospholipids (by phospholipase A2) by extracellular signals and exert their functions in association with signaling pathways that regulate ion transport, cell proliferation, and inflammation. Depending on the diet, n-3 PUFAs may partially replace AA at the sn2 position of phospholipids and participate as alternative molecules in subsequent signaling pathways.

[0009] Several studies on the biological activity of CYP-dependent eicosanoids in the heart have focused on L-type Ca 2+ and sarcolemmal and mitochondrial ATP-sensitive potassium (K ATP) channel. In cardiac myocytes, inhibition of EET production inhibits L-type Ca channels. 2+ Currents and cell shunting were reduced, and these effects could be reversed by the addition of 11,12-EET (10). ATP It has also been shown that it activates the K channel. This effect was highly stereoselective, affecting only the S,R enantiomer of 11,12-EET, but not the R,S enantiomer (Non-Patent Document 11). Overexpression of human CYP2J2, which produces EET, increases the K ATP 20-HETE improved the postischemic functional recovery of the transgenic mouse heart through activation of the channel (Non-Patent Document 12). ATP It appears to play the opposite role by acting as a channel blocker (Non-Patent Document 13, Non-Patent Document 14).

[0010] Although CYP metabolites derived from n-3 PUFAs, such as 17,18-EEQ and 19,20-EDP, play an important role in mediating the beneficial effects of n-3 PUFAs in mammals, they have not been used as therapeutic agents due to their limited bioavailability as well as chemical and metabolic instability. These epoxy metabolites of n-3 PUFAs are susceptible to autoxidation, rapid inactivation by soluble epoxide hydrolases, and degradation by β-oxidation. Improved analogs of n-3 PUFA metabolites have been disclosed in US Pat. No. 5,999,363, which have significantly improved pharmacological properties compared to the epoxy metabolites of n-3 PUFAs.

[0011] Growth differentiation factor 15 (GDF-15), also known as macrophage inhibitory cytokine 1 (MIC-1), placental transforming growth factor (PTGF-b), prostate-derived factor (PDF), placental bone morphogenetic protein (PLAB), prostate-derived factor, or nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1), is a marker of inflammation and oxidative stress and is associated with poor prognosis in cardiovascular disease. GDF-15 has been shown to be associated with major adverse cardiovascular events (MACE) and all-cause mortality in patients with coronary artery disease (CAD). It is therefore useful as a prognostic marker for long-term MACE and all-cause mortality (see Non-Patent Document 15, Non-Patent Document 16). Furthermore, studies have confirmed that GDF-15 is associated with other diseases, such as hypertension, diabetes, heart failure, renal function, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations (see Non-Patent Document 17). Furthermore, GDF-15 was identified as a strong predictor of all-cause mortality and was found to be strongly associated with many functional parameters and important biomarkers, regardless of age and sex (Non-Patent Document 18). Further studies investigating biomarkers associated with cardiovascular death in patients with atrial fibrillation (AF) identified GDF-15 as being strongly associated with the mechanisms underlying oxidative stress and inflammation (see Non-Patent Document 19). In summary, GDF-15 is a factor closely associated with heart disease, cardiovascular disease, hypertension, diabetes, and renal function, and therefore is of great importance as a prognostic marker for these diseases, but may also be implicated as a factor involved in the mechanisms underlying these diseases. Recent publications have also suggested that GDF-15 may be relevant as a therapeutic target for cardiovascular disease (Non-Patent Document 20, Patent Document 2), cancer, and metabolic diseases (Non-Patent Document 21). Therefore, any therapeutic approach that can reduce circulating GDF-15 levels may be relevant for the treatment of diseases associated with circulating GDF-15. [Prior art documents] [Patent documents]

[0012] [Patent Document 1] WO2017 / 013264 A1

Patent document 2

Non-licensed literature

[0013] [Non-licensed document 1] Simopoulos AP. Omega-3fatty acids ininflammation and autoimmune diseases. J Am. Coll. NutL 2L495-505 (2002)

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Summary of the Invention

Problems to be Solved by the Invention

[0014] The present invention provides the first experimental data that GDF-15 and other important biomarkers are reduced by the improved analog of n-3 PUFA metabolites.Furthermore, the reduction of GDF-15 levels leads to improved treatment of these patients, demonstrating that the improved analog of n-3 PUFA metabolites of the present invention can treat diseases associated with elevated GDF-15 levels. [Means for solving the problem]

[0015] In a first aspect, the above problem is solved by providing a compound of general formula (I) or a pharma- ceutically acceptable salt thereof: [ka] During the ceremony, P is a group of general formula (II): [ka] Where: n is 0 or an integer from 3 to 8, i.e., 3, 4, 5, 6, 7, or 8, preferably 3; and k is 0, 1, or 2, preferably with the exception that when n is 0 then k is 1, and most preferably k is 1; X is CH 2 OH, CH 2 OAc, CH(O) or a group selected from the group consisting of: [ka] JPEG2024542612000004.jpg53108JPEG2024542612000005.jpg55124Preferably, X is [ka] is; Where: R and R' each independently represent a hydrogen atom; or C optionally substituted with one or more fluorine or chlorine atoms or hydroxyl groups. 1 -C 6 Represents an alkyl group; R 1 is a hydroxyl group, C 1 -C 6 Alkoxy, -NHCN, -NH(C 1 -C 6 alkyl), -NH(C 3 -C 6 -cycloalkyl), -NH(aryl), or -O(C 1 -C 6 Alkyldiyl)O(C=O)R 11 Represents;R 11 is C optionally substituted with one or more fluorine or chlorine atoms 1 -C 6 or C optionally substituted with one or more fluorine atoms, chlorine atoms, or hydroxyl groups. 3 -C 6 is a cycloalkyl group; R 2 -NHR 3 ;-NR 20 R 21 ;-OR 22; -(OCH 2 -CH 2 ) i -R 23; Hydroxyl group, C 1 -C 6 Alkoxy, C 1 -C 6 -C optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, aryl, and oxo; 3 -C 10 -Heterocyclyl;-(Xaa) o ;represents a monosaccharide or disaccharide or derivative thereof linked to C(O) by an ester bond through the 1-O-, 3-O-, or 6-O-position of the sugar; or selected from the group consisting of the following formulas: [ka] Where: R 3 (SO 2 R 30 );(OR 31 );-C 1 -C 6 Alkanediyl (SO 2 R 32 );-C 1 -C 6 Alkanediyl(CO 2 H), an aryl group, a heteroaryl group, a cycloalkyl group or a heterocycloalkyl group, wherein the aryl group is 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylthio, fluorine or chlorine atom, hydroxyl group, amino group, -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 Dialkyl) and -C(=O)OR 51 wherein the heteroaryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylthio, fluorine or chlorine atom, hydroxyl group, amino group, -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 Dialkyl) and -C(=O)OR 51 wherein the cycloalkyl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6Alkylthio, fluorine or chlorine atom, hydroxyl group, amino group, -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 Dialkyl) and -C(=O)OR 51 and wherein the heterocycloalkyl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylthio, fluorine or chlorine atom, hydroxyl group, amino group, -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 Dialkyl) and -C(=O)OR 51 is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: R 30 is C 1 -C 6 an alkyl group, or an aryl group, where C 1 -C 6 The alkyl group is -NH 2 , -NH(C 1 -C 6 ) alkyl, -N(C 1 -C 6 ) Dialkyl, C 1 -C 6 Alkylcarbonyloxy-, C 1 -C 6 Alkoxycarbonyloxy-, C 1 -C 6 Alkylcarbonylthio-, C 1 -C 6 Alkylaminocarbonyl-, di(C 1 -C 6 ) alkylaminocarbonyl-, optionally substituted with 1, 2 or 3 fluorine or chlorine atoms, or a hydroxyl group; and wherein the aryl group is C 1 -C6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylthio, fluorine or chlorine atom, hydroxyl group, amino group, -NH(C 1 -C 6 alkyl), and -N(C 1 -C 6 dialkyl); R 31 is C optionally substituted with one or more fluorine atoms, chlorine atoms, or hydroxyl groups; 1 -C 6 or C optionally substituted with one or more fluorine atoms, chlorine atoms, or hydroxyl groups. 3 -C 6 is a cycloalkyl group; R 32 is C optionally substituted with one or more fluorine atoms, chlorine atoms, or hydroxyl groups; 1 -C 6 or C optionally substituted with one or more fluorine atoms, chlorine atoms, or hydroxyl groups. 3 -C 6 is a cycloalkyl group; R 20 and R 21 each independently represents a hydrogen atom; C which may be substituted with one or more fluorine atoms, chlorine atoms, or hydroxyl groups; 1 -C 6 an alkyl group; optionally substituted with one or more fluorine atoms, chlorine atoms, or hydroxyl groups; 3 -C 6 Cycloalkyl group; or -C 1 -C 6 Alkyldiyl(CO 2 H) or together with one or more C 1 -C 6 Alkyl group, C 1 -C 6C which may be substituted with an alkoxy group, a fluorine atom, a chlorine atom or a hydroxyl group 3 -C 10 -Forming heterocycloalkyl; R 22 is a hydrogen atom, C 1 -C 6 Alkyl group; or C 3 -C 6 Cycloalkyl groups, where C 1 -C 6 Alkyl group or C 3 -C 6 The cycloalkyl group is -NH 2 , -NH(C 1 -C 6 ) alkyl, -N(C 1 -C 6 )dialkyl, -NH(C 1 -C 6 ) Alkyldiyl-C 1 -C 6 Alkoxy, 1, 2 or 3 fluorine or chlorine atoms, hydroxyl, or C 1 -C 6 is optionally substituted with an alkoxy, aralkyl, heteroalkyl, or heteroalkylcycloalkyl group; R 23 -OH, -O(C 1 -C 3 ) alkyl, or -N(C 1 -C 6 ) dialkyl; i is an integer between 1 and 10; R 24 , R 25 and R 26 are each independently a hydrogen atom; -C(=O)C 11 -C 21 Alkyl; or -C(=O)C 11 -C 21 Represents alkenyl; R 27 -OH; -O(CH 2 ) 2 NH 2 , -OCH 2-[CH(NH 2 )(CO 2 H)], -O(CH 2 ) 2 N(CH 3 ) 3 ;or [ka] Represents; Xaa represents Gly, a conventional D,L, D or L amino acid, a non-conventional D,L, D or L amino acid, or a 2-10 mer peptide; and Xaa is attached to C(=O) by an amide bond; o is an integer between 1 and 10; R 4 is selected from the group consisting of the following formulas: [ka] h is 0, 1, or 2; R 5 is a hydrogen atom; a fluorine or chlorine atom; -CF 3 ;-C(=O)OR 51 ;-NHC(=O)OR 52 ;-C(=O)NR 53 R 54 ; or -S(O 2 ) represents OH; R 51 is a hydrogen atom; C 1 -C 6 Alkyl group; or C 3 -C 6 represents a cycloalkyl group, 1 -C 6 Alkyl group or C 3 -C 6 The cycloalkyl group is -NH 2 , -NH(C 1 -C 6 ) alkyl, -N(C 1 -C 6 )dialkyl, -NH(C 1 -C 6 ) Alkyldiyl-C 1 -C6 Alkoxy, 1, 2 or 3 fluorine or chlorine atoms, hydroxyl, or C 1 -C 6 optionally substituted with alkoxy; R 52 , R 53 and R 54 each independently represents C optionally substituted with one or more fluorine or chlorine atoms; 1 -C 6 Alkyl groups; C optionally substituted with one or more fluorine or chlorine atoms 3 -C 6 Cycloalkyl group; or C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylthio, fluorine or chlorine atom, hydroxyl group, amino group, -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 ) an aryl group that is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of dialkyl, and oxo substituents; R 6 , R 7 are each independently a hydroxyl group; -O(C 1 -C 6 ) alkyl group, -O(C 2 -C 6 ) alkenyl group, -O(C 1 -C 6 ) AlkyldiylO(C=O)(C 1 -C 6 ) alkyl group, or -O(C 1 -C 6 ) AlkyldiylO(C=O)(C 2 -C 6 ) an alkenyl group, 1 -C 6 Alkyl groups and C 2 -C 6The alkenyl group is NH 2 , -NH(C 1 -C 6 ) alkyl, -N(C 1 -C 6 ) Dialkyl, C 1 -C 6 Alkylcarbonyloxy-, C 1 -C 6 Alkoxycarbonyloxy-, C 1 -C 6 Alkylcarbonylthio-, C 1 -C 6 Alkylaminocarbonyl-, di(C 1 -C 6 ) alkylaminocarbonyl- or optionally substituted with 1, 2 or 3 fluorine or chlorine atoms; or R 6 represents a hydroxyl group, and R 7 represents the following group: [ka] R 9 is C 1 -C 6 Representing alkyl or aryl, C 1 -C 6 Alkyl is -NH 2 , -NH(C 1 -C 6 )Alkyl-N(C 1 -C 6 )dialkyl, -NH(C 1 -C 6 ) Alkyldiyl-C 1 -C 6 Alkoxy, 1, 2 or 3 fluorine or chlorine atoms, hydroxy, C 1 -C 6 Alkoxy, aryl, aryloxy, -C(=O)-aryl, -C(=O)C 1 -C 6 and the aryl group is C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C6 Alkylthio, fluorine or chlorine atom, hydroxyl group, amino group, -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 ) optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of dialkyl and oxo substituents; g is 1 or 2, preferably 2; X 1 represents an oxygen atom; a sulfur atom; or NH; X 2 is an oxygen atom; a sulfur atom; NH; or N(CH 3 ) ; X 3 represents an oxygen atom; a sulfur atom; a nitrogen atom; a carbon atom; or C-OH; and a dashed line represents a carbon-carbon bond or a carbon-carbon double bond; E is a group represented by general formula (III) or (IV): [ka] Here, R 12 and R 13 is preferably in a cis configuration, and wherein ring A in formula (III) represents a 5- or 6-membered carbocyclic or heterocyclic ring containing at least one double bond, including an aromatic carbocyclic or heterocyclic ring, and C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylthio, fluorine or chlorine atom, hydroxyl group, amino group, -NH(C 1 -C 6 alkyl) and -N(C 1 -C 6 ) dialkyl; and L and T each independently represent a ring atom, and L and T are adjacent to one another; R 12 and R 13each independently represents a hydrogen atom, a fluorine atom, a hydroxyl group, -NH 2 , C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, -C(=O)-aryl, -C(=O)C 1 -C 6 Alkyl, or -SO 2 (C 1 -C 6 alkyl); or -SO 2 aryl, 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or aryl is -NH 2 , -NH(C 1 -C 6 ) alkyl, -N(C 1 -C 6 ) Dialkyl, C 1 -C 6 Alkylcarbonyloxy-, C 1 -C 6 Alkoxycarbonyloxy-, C 1 -C 6 Alkylcarbonylthio-, C 1 -C 6 Alkylaminocarbonyl-, di(C 1 -C 6 ) optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkylaminocarbonyl-, fluorine or chlorine atoms, and hydroxyl; or R 12 and R 13 are joined together to form a five- or six-membered ring, which is -NH 2 , -NH(C 1 -C 6 ) alkyl, -N(C 1 -C 6 ) Dialkyl, C 1 -C 6 Alkylcarbonyloxy-, C 1 -C 6 Alkoxycarbonyloxy-, C 1 -C 6Alkylcarbonylthio-, C 1 -C 6 Alkylaminocarbonyl-, di(C 1 -C 6 ) alkylaminocarbonyl-, optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of fluorine or chlorine atoms, and hydroxyl; I is -(CH 2 ) m -Y, Where: m is an integer from 3 to 6, i.e. 3, 4, 5 or 6, with the proviso that when E is a group according to general formula (III), m is an integer from 3 to 5; Y is -UVW-(CH 2 ) p -(CH 3 ) q where p is an integer of 0 to 6; q is 0 or 1; and U is absent or CH, CH 2 and N.R. 40 with the proviso that, when taken together with V and W to form an epoxy group, U is only CH; V is selected from the group consisting of -C(O)-, -C(O)-C(O)-, -O-, and -S-; W is selected from the group consisting of CH, CH 2 and N.R. 40 with the proviso that W is only CH when it forms an epoxy group together with U and V; or Y represents a group selected from the group consisting of: [ka] Where: R 40 , R 41 , R 43 , R 44 , R 46 , R 48 and R 49 are each independently a hydrogen atom, -C 1 -C 6 Alkyl, -C 3 -C 6 Cycloalkyl, -C1 -C 6 Alkoxy, -C(=O)aryl, or -C(=O)C 1 -C 6 represents alkyl, 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 6 Alkoxy or aryl is -NH 2 , -NH(C 1 -C 6 ) alkyl, -N(C 1 -C 6 ) Dialkyl, C 1 -C 6 Alkylcarbonyloxy-, C 1 -C 6 Alkoxycarbonyloxy-, C 1 -C 6 Alkylcarbonylthio-, C 1 -C 6 Alkylaminocarbonyl-, di(C 1 -C 6 ) optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkylaminocarbonyl-, fluorine or chlorine atoms, and hydroxyl; or R 40 and R 41 , or R 43 and R 44 together form a five- or six-membered ring, which is -NH 2 , -NH(C 1 -C 6 ) alkyl, -N(C 1 -C 6 ) Dialkyl, C 1 -C 6 Alkylcarbonyloxy-, C 1 -C 6 Alkoxycarbonyloxy-, C 1 -C 6 Alkylcarbonylthio-, C 1 -C 6 Alkylaminocarbonyl-, di(C 1 -C 6) optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkylaminocarbonyl-, fluorine or chlorine atoms, and hydroxyl; R 42 , R 45 , R 47 and R 50 are each independently -C 1 -C 3 Representing alkyl, C 1 -C 3 Alkyl is -NH 2 , -NH(C 1 -C 3 ) alkyl, -N(C 1 -C 3 ) Dialkyl, C 1 -C 3 Alkylcarbonyloxy-, C 1 -C 3 Alkoxycarbonyloxy-, C 1 -C 3 Alkylcarbonylthio-, C 1 -C 3 Alkylaminocarbonyl-, di(C 1 -C 3 ) optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkylaminocarbonyl-, fluorine or chlorine atoms, and hydroxyl; or R 40 and R 41 ;R 43 and R 44 ;R 49 and R 50 together form a five- or six-membered ring, which is -NH 2 , -NH(C 1 -C 6 ) alkyl, -N(C 1 -C 6 ) Dialkyl, C 1 -C 6 Alkylcarbonyloxy-, C 1 -C 6 Alkoxycarbonyloxy-, C 1 -C 6 Alkylcarbonylthio-, C 1 -C 6Alkylaminocarbonyl-, di(C 1 -C 6 ) optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkylaminocarbonyl-, fluorine or chlorine atoms, and hydroxyl; f is an integer between 0 and 2; however, When X does not contain a -C(=O)O- motif with a carbonyl carbon alpha or beta to the oxygen atom of general formula (II), Y is an oxamide, carbamate or carbamide, preferably Y is an oxamide as defined above.

[0016] The compounds are for use in the treatment, reduction of the risk of developing, or prevention of diseases associated with elevated plasma concentrations of GDF-15, preferably wherein the plasma concentration of GDF-15 is at least 1000 ng / L, preferably wherein the diseases associated with elevated plasma concentrations of GDF-15 are selected from cardiovascular diseases and metabolic diseases.

[0017] In a preferred embodiment, the disease associated with elevated GDF-15 plasma concentrations is a metabolic disease, preferably diabetes, more preferably type 2 diabetes, most preferably pre-Diabetes, and the GDF-15 plasma concentration is at least 500 ng / L.

[0018] In one preferred embodiment, the compound of the present invention is a compound of formula (I) as defined above, With the proviso that when X does not contain a -C(=O)O- motif with a carbonyl carbon alpha or beta to the oxygen atom of general formula (II), then Y is an oxamide, carbamate or carbamide, preferably Y is an oxamide as defined above.

[0019] In a preferred embodiment, the compound of formula (I) is a compound as described above, but however, When n is 3, 5, 6, 7 or 8, preferably 3, k is 1 and E is a group represented by general formula (III) or (IV), Here, R 12 and R 13 each of is a hydrogen atom; P represents the following group: [ka] During the ceremony, X 81 represents a group selected from the group consisting of: [ka] R 1’ is the above R 1 is defined as; R 2’ -NHR 3’ ;-OR 22’ ; -(OCH 2 -CH 2 ) i -R 23 ;represents a monosaccharide or disaccharide or derivative thereof linked to the -C(=O) by an ester bond via the 1-O-, 3-O-, or 6-O-position of the sugar; Or, R 2 is selected from the group consisting of: [ka] Where: R 3’ (SO 2 R 30 );(OR 31 ); -C 1 -C 6 Alkanediyl (SO 2 R 32 ); or -C 2 -C 6 Alkanediyl(CO 2 H); R 22’ is hydrogen or C 3 -C 6 A cycloalkyl group, which is -NH 2, -NH(C 1 -C 6 ) alkyl, -N(C 1 -C 6 )dialkyl, -NH(C 1 -C 6 ) Alkyldiyl-C 1 -C 6 Alkoxy, 1, 2 or 3 fluorine or chlorine atoms, hydroxy or C 1 -C 6 optionally substituted with alkoxy; R 23 and i is as defined above; R 24 , R 25 , R 26 , and R 27 is as defined above; R 4’ is the above R 4 and h is as defined above; R 6’ and R 7’ is the above R 6 and R 7 is defined as; R 9’ is the above R 9 R 9’’ is C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylthio, fluorine or chlorine atom, hydroxyl group, amino group, -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 ) dialkyl, and aryl, which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of oxo substituents.

[0020] In a more preferred embodiment, the compound of the present invention is X is: [ka] In the formula, R 2 -OR 22 ; -(OCH 2 -CH 2 ) i -R 23 a monosaccharide or disaccharide or derivative thereof linked to the -C(=O) by an ester bond via the 1-O-, 3-O-, or 6-O-position of the sugar; Or, R 2 is selected from the group consisting of: [ka] R 23 and i is as defined above, preferably i is 3; and Here, R 22 and R 23 ~R 27 is as defined in claim 1, preferably R 22 is a hydrogen atom or C 1 -C 6 It is preferably an alkyl group, and more preferably a hydrogen atom.

[0021] In a further preferred embodiment, the compounds of the invention are those wherein X is -C(=O)OH or a suitable salt of a carboxylic acid, preferably the free carboxylic acid.

[0022] In another preferred embodiment, the compounds of the invention are those in which Y is one of the oxamides defined above.

[0023] Even more preferably, the compounds of the invention are those in which X is [ka] In the formula, R 2 -OR 22 ;-(OCH 2 -CH 2 ) i -R 23a monosaccharide or disaccharide or derivative thereof linked to the -C(=O) by an ester bond via the 1-O-, 3-O-, or 6-O-position of the sugar; or 2 is selected from the group consisting of: [ka] Here, R 22 , R 23 ~R 27 and i is as defined above, preferably R 22 is a hydrogen atom or C 1 -C 6 Preferably, i is an alkyl group, more preferably a hydrogen atom; preferably, i is 2 to 4, more preferably 3; and Y is preferably one of the oxamides defined above.

[0024] In a further preferred embodiment, the compounds of the invention are of the formula wherein X is C(=O)OH, preferably a free carboxylic acid, and Y is preferably one of the oxamides defined above. In another more preferred embodiment, the compound of the present invention has the formula (V): [ka] During the ceremony, R 55 -OH, -OR 22 ; -(OCH 2 -CH 2 ) i -R 23 ;represents a monosaccharide or disaccharide or derivative thereof linked to the -C(=O) by an ester bond via the 1-O-, 3-O-, or 6-O-position of the sugar; R 22 , R 23 and i is as defined above, preferably R 22 is a hydrogen atom or C 1 -C 6 i is preferably an alkyl group, or more preferably a hydrogen atom, and i is preferably 2 to 4, more preferably 3; Y represents a group selected from the group consisting of: [ka] During the ceremony, [ka] is preferred, and [ka] is particularly preferred; and In the formula, R 40 ~R 50 is as defined above, preferably R 40 is a hydrogen atom or C 1 -C 6 It is an alkyl group, and more preferably a hydrogen atom. R 57 and R 58 is hydrogen; or C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylthio, fluorine or chlorine atom, hydroxyl group, amino group, -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 ) dialkyl, oxo, and aryl groups together form a 5- or 6-membered ring, preferably an aromatic ring, optionally substituted with 1-3 or 1-4 substituents independently selected from the group consisting of dialkyl, oxo, and aryl groups. s is 0, 1, or 2, but R 57 and R 58 are taken together to form a 5- or 6-membered ring, then s is 0; The double bond in formula (V) is R 57 and R 58 is hydrogen, or this double bond is R 57 and R 58 When the carbon-carbon double bond is part of a five- or six-membered ring formed together with

[0025] In a further most preferred embodiment, the compound of formula (V) is: During the ceremony, R 55 is -OH or -(OCH 2 -CH 2 ) i -R 23 i is 2 to 4, preferably i is 3; R 23 is preferably OH; Y is oxamide, carbamide or carbamate, preferably C 1 -C 6 an alkyl substituted oxamide, carbamide or carbamate; R 57 and R 58 are both H or taken together form a substituted or unsubstituted 5- or 6-membered aromatic ring, preferably a substituted or unsubstituted benzyl ring; and R 57 and R 58 When taken together form a substituted or unsubstituted 5- or 6-membered aromatic ring, s is 1, or s is 0.

[0026] Most preferred specific compounds of the present invention are those selected from the group consisting of: [ka] JPEG2024542612000025.jpg103107JPEG2024542612000026.jpg93121JPEG2024542612000027.jpg95123

[0027] Of the above, the compound represented by the following formula (VI) or a pharma- ceutically acceptable salt thereof is most preferred. [ka] [Brief description of the drawings]

[0028] [Figure 1] FIG. 1 shows the layout of the clinical study described in Example 2. [Diagram 2] FIG. 2 shows GDF-15 plasma concentrations at baseline (V3) versus age for (A) all patients in the clinical study of Example 2, as well as for subgroups of patients with GDF-15 plasma concentrations at baseline (V3) of (B) less than 1000 ng / L or (C) greater than or equal to 1000 ng / L. [Diagram 3] FIG. 3 shows that GDF-15 plasma concentrations (right panel) in the subgroup of patients with baseline concentrations above 1000 ng / L were significantly reduced by treatment with Compound-02. [Figure 4] Figure 4 shows the change in GDF-15 plasma concentrations from baseline to the end of treatment (3 months). Compound-02 significantly reduced GDF-15 plasma concentrations by 30% in a dose-dependent manner compared to placebo. [Diagram 5] FIG. 5 shows significant reductions in the clinically relevant biomarkers hs-CRP, PTX-3, IL-6, MMP-1, MMP-9, and NT-proBNP in all treatment groups. [Figure 6] FIG. 6 shows that Compound-02 dose-dependently reduced AF recurrence in the patient group with GDF-15 ≧1000 ng / L. [Figure 7] Figure 7 shows that Compound-02 prevented the increase in circulating levels of PTX-3, a marker of plaque instability, in LDLr- / - mice fed a high-fat diet (HFD) for 12 weeks. Furthermore, treatment with Compound-02 significantly reduced whole aortic lesion size by 55%. [Figure 8] Figure 8 shows the change in IL-6 plasma concentration from baseline to the end of treatment (3 months). Compound-02 significantly reduced IL-6 plasma concentration by 30% in a dose-dependent manner compared to placebo. [Figure 9]Figure 9 shows the change in PTX-3 plasma concentration from baseline to the end of treatment (3 months). Compound-02 significantly reduced PTX-3 plasma concentrations by 55% in a dose-dependent manner compared to placebo. [Figure 10] Figure 10 shows the change in hsCRP plasma concentration from baseline to the end of treatment (3 months). Compound-02 significantly reduced hsCRP plasma concentrations. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029] In one embodiment, the compound has the general formula (I) or a pharma- ceutically acceptable salt thereof: [ka] In the formula, P is a group represented by general formula (II): [ka] During the ceremony, n is 0 or an integer from 3 to 8; and k is 0 or 1, preferably with the caveat that when n is 0 then k is 1, and most preferably k is 1; X is CH 2 OH, CH 2 OAc, CH(O) or a group selected from the group consisting of: [ka] and, Preferably, X is [ka] and; In the formula, R 2 -NHR 3 ;-NR 20 R 21 ;-OR 22; -(OCH 2 -CH 2 ) i -R 23 ; Hydroxyl group, C1 -C 6 Alkoxy, C 1 -C 6 -C optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, aryl, and oxo; 3 -C 10 -heterocyclyl; In the formula, R 3 represents a phenyl group; a 5-membered heteroaryl group having 1 to 4 ring heteroatoms selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heterocycloalkyl group having 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the phenyl group is 1 -C 6 Alkyl, C 1 -C 6 Alkoxy and -C(=O)OR 51 is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: R 20 and R 21 each independently represents a C which may be substituted with one or more hydroxyl groups; 1 -C 6 Alkyl group; C 3 -C 6 represents a cycloalkyl group; or together, C 3 -C 10 -Forming heterocycloalkyl; R 22 is a hydrogen atom, C 1 -C 6 is an alkyl group; R 23 is -OH; i is an integer between 1 and 10; R 5 is a hydrogen atom; a fluorine or chlorine atom; -CF 3 ;-C(=O)OR 51 ;-NHC(=O)OR 52 ;-C(=O)NR 53 R 54 ; or -S(O 2 ) represents OH; R 51 is a hydrogen atom; C1 -C 6 Represents an alkyl group; R 52 , R 53 and R 54 are each independently 1 -C 6 Represents an alkyl group; X 1 represents an oxygen atom; a sulfur atom; or NH; E is a group represented by general formula (III) or (IV): [ka] In the formula, R 12 and R 13 is preferably in the cis configuration, and Ring A in formula (III) represents a 5- or 6-membered carbocyclic ring containing at least one double bond, including an aromatic carbocyclic ring; and L and T each independently represent a ring atom, where L and T are adjacent to one another; R 12 and R 13 each independently represents a hydrogen atom, a fluorine atom, or a hydroxyl group; I is -(CH 2 ) m -Y, wherein m is an integer from 3 to 6, with the proviso that when E is a group according to general formula (III), m is an integer from 3 to 5; Y is -UVW-(CH 2 ) p -(CH 3 ) q where p is an integer of 0 to 6; q is 0 or 1; and U is absent or CH, CH 2 and N.R. 40 with the proviso that U is only CH when it forms an epoxy group together with V and W; V is selected from the group consisting of -C(O)-, -C(O)-C(O)-, -O-, and -S-; W is CH, CH 2 and N.R. 40with the proviso that W is only CH when it forms an epoxy group together with U and V; or Y represents a group selected from the group consisting of: [ka] During the ceremony, R 40 , R 41 , R 43 , R 44 are each independently a hydrogen atom, -C 1 -C 6 Represents alkyl; R 42 , R 45 are each independently -C 1 -C 3 Represents alkyl, provided that: When X does not contain a -C(=O)O- motif with the carbonyl carbon alpha or beta to the oxygen atom of general formula (II), Y is an oxamide, carbamate or carbamide, preferably Y is an oxamide as defined above.

[0030] In one preferred embodiment, the compound of formula (I) is as described above, except that when n is 3 or 5, k is 1, and E is a group represented by general formula (III) or general formula (IV), in which R 12 and R 13 are each a hydrogen atom; P represents the following group: [ka] During the ceremony, X 81 represents a group selected from the group consisting of: [ka] R 2’ -NHR 3’ ;-OR 22’ ; -(OCH 2 -CH 2 ) i -R23 Represents; During the ceremony, R 3’ is C 6 Represents aryl; R 22’ is hydrogen; R 23 and i is as defined above;

[0031] More preferably, the compound of the present invention is In the formula, X is [ka] and In the formula, R 2 -OR 22 ; -(OCH 2 -CH 2 ) i -R 23 is; In the formula, R 23 and i is as defined above; and In the formula, R 22 and R 33 is as defined in claim 1.

[0032] More preferably, the compound of the present invention is wherein X is -C(=O)OH or a suitable salt of a carboxylic acid, preferably the free carboxylic acid.

[0033] More preferably, the compound of the present invention is In the formula, X is [ka] and In the formula, R 2 -OR 22 ; -(OCH 2 -CH 2 ) i -R 23 and R 22 , R 23and i is as defined in claim 1 and Y is one of the oxamides defined in claim 1.

[0034] More preferably, the compounds of the invention are those in which X is -C(=O)OH, preferably a free carboxylic acid, and Y is one of the oxamides defined above.

[0035] In another more preferred embodiment, the compounds of the present invention have the following formula (V): [ka] During the ceremony, R 55 -OH, -OR 22 ; -(OCH 2 -CH 2 ) i -R 23 represents; R 22 , R 23 and i are as defined in claim 1, preferably R 22 is a hydrogen atom or C 1 -C 6 i is preferably an alkyl group, or more preferably a hydrogen atom, and i is preferably 2 to 4, more preferably 3; Y represents a group selected from the group consisting of: [ka] In the formula, R 40 ~R 50 is as defined in claim 1, preferably R 40 is a hydrogen atom or C 1 -C 6 It is an alkyl group, and more preferably a hydrogen atom. R 57 and R 58 is hydrogen; s is 0, 1 or 2; The double bond in formula (V) is R 57 and R 58 When is hydrogen, it represents a carbon-carbon double bond in the cis configuration.

[0036] In a further most preferred embodiment, the compound of formula (V) is: During the ceremony, R 55 is -OH or -(OCH 2 -CH 2 ) i -R 23 i is 2 to 4, preferably i is 3; R 23 is preferably OH; Y is oxamide, carbamide or carbamate, preferably C 1 -C 6 an alkyl substituted oxamide, carbamide or carbamate; R 57 and R 58 are both H.

[0037] The compounds of the present invention have the advantage that they are effective in treating, reducing the risk of developing, or preventing diseases associated with elevated GDF-15 plasma levels, preferably cardiovascular or metabolic diseases, as demonstrated in the following experimental section.The elevated GDF-15 plasma levels in these diseases are preferably at least 500ng / L, 750ng / L, 900ng / L, 1000ng / L, 1200ng / L or 1500ng / L, preferably at least 900ng / L, 1000ng / L, 1200ng / L, more preferably at least 1000ng / L.The compounds of the present invention are at the same time metabolically robust for pharmaceutical formulation and administration to subjects in need thereof.

[0038] The compounds described herein are generally described using standard nomenclature. For compounds having asymmetric centers, it is understood that all optical isomers and mixtures thereof are included unless otherwise specified. Compounds containing two or more asymmetric elements may exist as mixtures of diastereomers. Furthermore, compounds having carbon-carbon double bonds may exist in Z- and E-forms, and all isomeric forms of the compounds are included in the present invention unless otherwise specified. Where compounds exist in various tautomeric forms, the compounds listed are not limited to any one particular tautomer, but rather are intended to include all tautomeric forms. The compounds listed are further intended to include compounds in which one or more atoms are replaced with isotopes, i.e., atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon ... 11 C. 13 C, and 14 Contains C.

[0039] Compounds according to the formula provided herein that have one or more stereocenters have an enantiomeric excess of at least 50%. For example, such compounds may have an enantiomeric excess of at least 60%, 70%, 80%, 85%, 90%, 95%, or 98%. Some embodiments of the compounds have an enantiomeric excess of at least 99%. It is clear that single enantiomers (optically active forms) can be obtained by asymmetric synthesis, synthesis from optically pure precursors, for example, biosynthesis using modified CYP102 (CYPBM-3), or separation of racemates, for example, by conventional methods such as enzymatic separation or crystallization in the presence of a resolving agent, or by using chromatography, for example, using a chiral HPLC column.

[0040] Certain compounds are referred to herein as, for example, P, E, I, R 1 ~R 50 , X~X 81The compounds are described using general formulas that include variables such as R, R, and Y. Unless otherwise specified, each variable within such formula is defined independently of every other variable, and any variable that occurs more than once within a formula is defined independently at each occurrence. Thus, for example, a compound having 0-2 groups, R * When a group is shown to be substituted with R, the group may be unsubstituted or may have up to two R * R at each occurrence may be substituted with a group. * is R * Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds, i.e., compounds that can be isolated, characterized, and tested for biological activity.

[0041] A "pharmaceutically acceptable salt" of a compound disclosed herein is a salt of an acid or base that is generally considered in the art to be suitable for use in contact with human or animal tissues without undue toxicity or carcinogenicity, and preferably without irritation, allergic response, or other problems or complications. Such salts include inorganic and organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids.

[0042] Suitable pharmaceutical salts include, for example, hydrochloric acid, phosphoric acid, hydrobromic acid, malic acid, glycolic acid, fumaric acid, sulfuric acid, sulfamic acid, sulfanilic acid, formic acid, toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, ethanedisulfonic acid, 2-hydroxyethylsulfonic acid, nitric acid, benzoic acid, 2-acetoxybenzoic acid, citric acid, tartaric acid, lactic acid, stearic acid, salicylic acid, glutamic acid, ascorbic acid, pamoic acid, succinic acid, fumaric acid, maleic acid, propionic acid, hydroxymaleic acid, hydroiodic acid, phenylacetic acid, alkanoic acid, such as acetic acid, HOOC-(CH 2 ) nPharmaceutically acceptable salts include, but are not limited to, salts of acids such as -COOH (where n is any integer from 0 to 6, i.e., 0, 1, 2, 3, 4, 5, or 6). Similarly, pharma- ceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium. One of ordinary skill in the art will recognize additional pharma- ceutically acceptable salts of the compounds provided herein. In general, pharma- ceutically acceptable acid or base salts can be synthesized from parent compounds that contain a basic or acidic moiety by any conventional chemical method. Briefly, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or in a mixture of both. Generally, the use of non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is preferred.

[0043] It will be apparent that each compound of formula (I) may, but need not, exist as a hydrate, solvate, or non-covalent complex, and various crystal forms and polymorphs are within the scope of the present invention, as are prodrugs of the compounds of formula (I) provided herein.

[0044] A "prodrug" is a compound that may not fully meet the structural requirements of the compounds provided herein, but is modified in vivo after administration to a subject or patient to generate a compound of formula (I) provided herein. For example, a prodrug may be an acylated derivative of a compound provided herein. Prodrugs include compounds in which a hydroxy, carboxy, amine, or sulfhydryl group is bonded to any group that, upon administration to a mammalian subject, cleaves to form a free hydroxy, carboxy, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, phosphate, and benzoate derivatives of alcohol and amine functional groups within the compounds provided herein. Prodrugs of the compounds provided herein can be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved in vivo to generate the parent compound.

[0045] As used herein, a "substituent" refers to a molecular moiety that is covalently bonded to an atom in a molecule of interest. For example, a "ring substituent" can be a moiety such as a halogen, an alkyl group, a haloalkyl group, or other substituents described herein that are covalently bonded to an atom that is a ring member, preferably a carbon atom or a nitrogen atom. As used herein, the term "substituted" means that any one or more hydrogens on the specified atom are replaced with one selected from the specified substituents, provided that the normal valence of the specified atom is not exceeded, and that the replacement results in a stable compound, i.e., a compound that can be isolated, characterized, and tested for biological activity. When the substituent is oxo, i.e., =O, two hydrogens on the atom are replaced. An oxo group that is a substituent of an aromatic carbon atom converts -CH- to -C(=O)-, losing aromaticity. For example, a pyridyl group substituted with oxo is a pyridone.

[0046] The term "optionally substituted" refers to a group in which one, two, three or more hydrogen atoms may be replaced independently of one another by respective substituents.

[0047] As used herein, the term "amino acid" refers to any organic acid that contains one or more amino substituents, e.g., an α-, β-, or γ-amino, derivative of an aliphatic carboxylic acid. 5 , i.e., Xaa 1 Xaa 2 Xaa 3 Xaa 4 Xaa 5 About Xaa 1 ~Xaa 5 are each independently selected from the defined amino acids, with the left-hand direction being the amino terminal direction and the right-hand direction being the carboxy-terminal direction, in accordance with standard usage and convention.

[0048] The term "conventional amino acid" refers to the 20 naturally occurring amino acids, including all stereoisomeric isoforms thereof, i.e., D,L-, D- and L-amino acids. These conventional amino acids may also be referred to herein by their conventional three-letter or one-letter abbreviations, which abbreviations follow conventional usage (see, e.g., Immunology-;A Synthesis, 2nd Edition, ES Golub and DR Gren, Eds., Sinauer Associates, Sunderland Mass. (1991)).

[0049] The term "non-conventional amino acid" refers to unnatural amino acids or chemical amino acid analogs, such as α,α-disubstituted amino acids, N-alkyl amino acids, homoamino acids, dehydroamino acids, aromatic amino acids (excluding phenylalanine, tyrosine and tryptophan), and ortho-, meta- or para-aminobenzoic acid. Non-conventional amino acids also include compounds with amine and carboxyl functional groups separated by one, three or more substitution patterns, such as β-alanine, γ-aminobutyric acid, Freidinger lactam, bicyclic dipeptides (BTD), aminomethylbenzoic acid and others well known in the art. Statins-like isosteres, hydroxyethylene isosteres, reduced amide-linked isosteres, thioamide isosteres, urea isosteres, carbamate isosteres, thioether isosteres, vinyl isosteres and other amide-linked isosteres known in the art can also be used. The use of analogs or non-conventional amino acids may improve the stability and biological half-life of the added peptides due to their greater resistance to degradation under physiological conditions. One of ordinary skill in the art would recognize that similar types of substitutions could be made. A non-limiting list of non-conventional amino acids that can be used as suitable building blocks for peptides and their standard abbreviations (in parentheses) are as follows: α-aminobutyric acid (Abu), LN-methylalanine (Nmala), α-amino-α-methylbutyric acid (Mgabu), LN-methylarginine (Nmarg), aminocyclopropane (Cpro), LN-methylasparagine (Nmasn), LN-methylaspartic acid carboxylate (Nmasp), aniinoisobutyric acid (Aib), LN-methylcysteine ​​(Nmcys), aminonorbornyl (Norb), LN-methylglutamine (Nmgln), LN-methylglutamic acid carboxylate (Nmglu), cyclohexylalanine (Chexa), LN-methylhistidine (Nmhis), cyclopentylalanine (Cpen), LN-methylisoleucine (Nmile), LN-methylleucine (Nmleu), LN-methyllysine (Lys). (Nmlys), LN-methylmethionine (Nmmet), LN-methylnorleucine(Nmnle), LN-methylnorvaline (Nmnva), LN-methylornithine (Nmorn), LN-methylphenylalanine (Nmphe), LN-methylproline (Nmpro), LN-methylserine (Nmser), LN-methylthreonine (Nmthr), LN-methyltryptophan (Nmtrp), D-ornithine (Dorn), LN-methyltyrosine (Nmtyr), LN-methylvaline (Nmval), LN-methylethylglycine (Nmetg), LN-methyl-t-butylglycine (Nmtbug), L-norleucine (NIe), L-norvaline (Nva), α-methyl-aminoisobutyric acid (Maib), α-methyl-γ-aminobutyric acid (Mgabu), D-α-methylalanine (Dmala), α-methylcyclohexylalanine (Mchexa), D-α-methylarginine (Dmarg), α-methylcyclopentylalanine (Mcpen), D-α-methylasparagine (Dmasn), α-methyl-α-naphthylalanine (Manap), D-α-methylaspartic acid (Dmasp), α-methylpenicillamine (Mpen), D-α-methylcysteine ​​(Dmcys), N-(4-aminobutyl)glycine (NgIu), D-α-methylglutamine (Dmgln), N-(2-aminoethyl)glycine (Naeg), D-α-methylhistidine (Dmhis), N-(3-aminopropyl)glycine (Norn), D-α-methylisoleucine (Dmile), N-amino-α-methylbutyric acid (Nmaabu), D-α-methylleucine (Dmleu), α-naphthylalanine (Anap), D-α-methyllysine (Dmlys), N-benzylglycine (Nphe), D-α-methylmethionine (Dmmet), N-(2-carbamylethyl)glycine (NgIn), D-α-methylornithine (Dmorn), N-(carbamylmethyl)glycine (Nasn), D-α-methylphenylalanine (Dmphe), N-(2-carboxyethyl)glycine (NgIu), D-α-methylproline (Dmpro), N-(carboxymethyl)glycine (Nasp), D-α-methylserine (Dmser), N-cyclobutylglycine (Ncbut), D-α-methylthreonine(Dmthr), N-cycloheptylglycine (Nchep), D-α-methyltryptophan (Dmtrp), N-cyclohexylglycine (Nchex), D-α-methyltyrosine (Dmty), N-cyclodecylglycine (Ncdec), D-α-methylvaline (Dmval), N-cyclododecylglycine (Ncdod), DN-methylalanine (Dnmala), N-cyclooctylglycine (Ncoct), DN-methylarginine (Dnmarg), N-cyclopropylglycine (Ncpro), DN-methylasparagine (Dnmasn), N-cycloundecylglycine (Ncund), DN-methylaspartic acid (Dnmasp), N-(2,2-diphenylethyl)glycine (Nbhm), DN-methylcysteine ​​(Dnmcys), N-(3,3-diphenylpropyl)glycine (Nbhe), DN-methylglutamine (Dnmgln), N-(3-guanidinopropyl)glycine (Narg), DN-methylglutamate (Dnmglu), N-(1-hydroxyethyl)glycine (Ntbx), DN-methylhistidine (Dnmhis), N-(hydroxyethyl)glycine (Nser), DN-methylisoleucine (Dnmile), N-(imidazolylethyl)glycine (Nhis), DN-methylleucine (Dnmleu), N-(3-indolylethyl)glycine (Nhtrp), DN-methyllysine (Dnnilys), N-methyl-γ-aminobutyric acid (Nmgabu), N-methylcyclohexylalanine (Nmchexa), DN-methylmethionine (Dnmmet), DN-methylornithine (Dnmorn), N-methylcyclopentylalanine (Nmcpen), N-methylglycine (NaIa), DN-methylphenylalanine (Dnmphe), N-methylaminoisobutyric acid (Nmaib), DN-methylproline (Dnmpro), N-(1-methylpropyl)glycine (Nile), DN-methylserine (Dnmser), N-(2-methylpropyl)glycine (Nleu), DN-methylthreonine (Dnmthr), DN-methyltryptophan (Dnmtrp), N-(1-methylethyl)glycine (Nval), DN-methyltyrosine (Dnmtyr), N-methyl-α-naphthylalanine (Nmanap), DN-methylvaline (Dnmval), N-methylpenicillamine (Nmpen), γ-aminobutyric acid (Gabu), N-(p-hydroxyphenyl)glycine (Nhtyr), L- / -butylglycine (Tbug), N-(thiomethyl)glycine (Ncys), L-ethylglycine (Etg), penicillamine (Pen), L-homophenylalanine (Hphe), L-α-methylalanine (Mala), L-α-methylarginine (Marg), L-α-methylasparagine (Masn), L-α-methylaspartic acid (Masp), L-α-methyl-t-butylglycine (Mtbug), L-α-methylcysteine (Mcys), L-methylethylglycine (Metg), L-α-methylglutamine (MgIn), L-α-methylglutamic acid (MgIu), L-α-methylhistidine (Mhis), L-α-methylhomophenylalanine (Mhphe), L-α-methylisoleucine (Mile), N-(2-methylthioethyl)glycine (Nmet), L-α-methylleucine (Mleu), L-α-methyllysine (Mlys), L-α-methylmethionine (Mmet), L-α-methylnorleucine (MnIe), L-α-methylnorvaline (Mnva), L-α-methylornithine (Morn), L-α-methylphenylalanine (Mphe), L-α-methylproline (Mpro), L-α-methylserine (Mser), L-α-methylthreonine (Mthr), L-α-methyltryptophan (Mtrp), L-α-methyltyrosine (Mtyr), L-α-methylvaline (Mval), L-N-methylhomophenylalanine (Nmhphe), N-(N-(2,2-diphenylethyl)carbamylmethyl)glycine (Nnbhm), N-(N-(3,3-diphenylpropyl)carbamylmethyl)glycine (Nnbhe), 1-carboxy-1-(2,2-diphenylethylamino)cyclopropane (Nmbc), LO-methylserine (Omser), and LO-methylhomoserine (Omhser).

[0050] The expression alkyl refers to saturated linear or branched hydrocarbon groups containing 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, for example n-octyl groups, in particular 1 to 6, i.e. 1, 2, 3, 4, 5 or 6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl or 2,2 dimethylbutyl.

[0051] The expression alkenyl denotes at least partially unsaturated, linear or branched hydrocarbon radicals containing 2 to 21 carbon atoms, preferably 2 to 6 carbon atoms, i.e. 2, 3, 4, 5 or 6 carbon atoms, such as, for example, the ethenyl (vinyl), propenyl (allyl), isopropenyl, butenyl, isoprenyl or hex-2-enyl radicals, or hydrocarbon radicals containing 11 to 21 carbon atoms, i.e. 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21 carbon atoms, which contain a methylene chain interrupted by one double bond, as found, for example, in monounsaturated fatty acids, or methylene-interrupted polyenes, such as, for example, in polyunsaturated fatty acids, which have the following structural unit -[CH=CH-CH 2 An alkenyl group has one or more, preferably 1, 2, 3, 4, 5, or 6, double bonds.

[0052] The term alkynyl refers to an at least partially unsaturated, linear or branched hydrocarbon group containing 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms, in particular 2 to 6, i.e. 2, 3, 4, 5 or 6 carbon atoms, such as the ethynyl, propynyl, butynyl, acetylenyl or propargyl group. Preferably, the alkynyl group has one or two, particularly preferably one, triple bonds.

[0053] Furthermore, the terms alkyl, alkenyl and alkynyl refer to groups in which one or more hydrogen atoms have been replaced, for example by halogen atoms, preferably F or Cl, such as the 2,2,2-trichloroethyl or trifluoromethyl groups.

[0054] The term heteroalkyl refers to an alkyl, alkenyl or alkynyl group in which one or more, preferably one, two or three, carbon atoms are substituted, independently of one another, by oxygen, nitrogen, phosphorus, boron, selenium, silicon or sulfur atoms, preferably by oxygen, sulfur or nitrogen atoms. The term heteroalkyl can also refer to a carboxylic acid or a group derived from a carboxylic acid, such as, for example, acyl, acylalkyl, alkoxycarbonyl, acyloxy, acyloxyalkyl, carboxyalkylamide or alkoxycarbonyloxy.

[0055] Preferably, the heteroalkyl group contains 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur (especially oxygen and nitrogen). Particularly preferably, the heteroalkyl group contains 1 to 6, i.e. 1, 2, 3, 4, 5 or 6 carbon atoms and 1, 2 or 3, especially 1 or 2, heteroatoms selected from oxygen, nitrogen and sulfur, especially oxygen and nitrogen.

[0056] Examples of heteroalkyl groups are groups of the formula: R a -OY a -, R a -SY a -, R a -N(R b )-Y a -, R a -CO-Y a -, R a -O-CO-Y a -, R a -CO-OY a -, R a -CO-N(R b )-Y a -, R a -N(R b )-CO-Y a -, Ra -O-CO-N(R b )- Y a -、R a -N(R b )-WHAT-OY a -、R a -N(R b )-CO-N(R c )-Y a -、R a -O-WHAT-OY a -、R a -N(R b )-C(=NR d )-N(R c )-Y a -、R a -CS-Y a -、R a -O-CS-Y a -、R a -CS-OY a -、R a -CS-N(R b )-Y a -、R a -N(R b )-CS-Y a -、R a -O-CS-N(R b )-Y a -、R a -N(R b )-CS-OY a -、R a -N(R b )-CS-N(R c )-Y a -、R a -O-CS-OY a -、R a -S-WHAT-Y a -、R a -WHAT-S-Y a -、R a -S-CO-N(R b )-Y a -、R a -N(R b )-WHAT-S-Y a -、R a -S-CO-OY a -、R a -O-WHAT-S-Y a -、R a-S-CO-SY a -, R a -S-CS-Y a -, R a -CS-SY a -, R a -S-CS-N(R b )-Y a -, R a -N(R b )-CS-SY a -, R a -S-CS-OY a -, R a -O-CS-SY a - in which R a is a hydrogen atom, C 1 ~C 6 Alkyl group, C 2 ~C 6 Alkenyl group or C 2 ~C 6 R is an alkynyl group; b is a hydrogen atom, C 1 ~C 6 Alkyl group, C 2 ~C 6 Alkenyl group or C 2 ~C 6 R is an alkynyl group; c is a hydrogen atom, C 1 ~C 6 Alkyl group, C 2 ~C 6 Alkenyl group or C 2 ~C 6 R is an alkynyl group; d is a hydrogen atom, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl or C 2 ~C 6 alkynyl group; and Y a is a direct bond, C 1 ~C 6 Alkylene, C 2 ~C 6 Alkenylene, or C 2 ~C 6Alkynylene groups, where each heteroalkyl group contains at least one carbon atom and one or more hydrogen atoms may be replaced by fluorine or chlorine atoms.

[0057] Illustrative examples of heteroalkyl groups include: methoxy, trifluoromethoxy, ethoxy, n-propyloxy, isopropyloxy, butoxy, tert-butyloxy, methoxymethyl, ethoxymethyl, -CH 2 CH 2 OH, -CH 2 OH, methoxyethyl, 1-methoxyethyl, 1-ethoxyethyl, 2-methoxyethyl or 2-ethoxyethyl, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, isopropylethylamino, methylaminomethyl, ethylaminomethyl, diisopropylaminoethyl, methylthio, ethylthio, isopropylthio, enol ether, dimethylaminomethyl, dimethylaminoethyl, acetyl, propionyl, butyryloxy, acetyloxy, methoxycarbonyl, ethoxycarbonyl, propionyloxy, acetylamino or propionylamino, carboxymethyl, carboxyethyl or carboxypropyl, N-ethyl-N-methylcarbamoyl or N-methylcarbamoyl. Further examples of heteroalkyl groups are nitrile, isonitrile, cyanate, thiocyanate, isocyanate, isothiocyanate and alkylnitrile groups.

[0058] The term alkoxy refers to an alkyl group single-bonded to oxygen.

[0059] The term alkylthio refers to an alkyl group singly bonded to a sulfur.

[0060] The expressions cycloalkyl and carbocycle refer to saturated cyclic hydrocarbon radicals containing one or more rings, preferably one or two rings, and containing 3 to 14 ring carbon atoms, preferably 3 to 10, in particular 3, 4, 5, 6 or 7 ring carbon atoms, such as the cyclopropyl, cyclobutyl, cyclopentyl, spiro[4,5]decanyl, norbornyl, cyclohexyl, decalinyl, bicyclo-[4.3.0]nonyl, tetralin or cyclopentylcyclohexyl radicals. Furthermore, the expression cycloalkyl refers to a hydrocarbon radical which is substituted by one or more hydrogen atoms, such as fluorine, chlorine, bromine or iodine atoms, or by OH, =O, SH, NH 2 , =NH,N 3 Or NO 2 It refers to a group substituted by a group, thus, for example, a cycloketone such as cyclohexanone, 2-cyclohexenone or cyclopentanone. Further specific examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, spiro[4,5]decanyl, norbornyl, cyclohexyl, cyclopentenyl, cyclohexadienyl, decalinyl, bicyclo-[4.3.0]nonyl, tetralin, cyclopentylcyclohexyl, fluorocyclohexyl or cyclohex-2-enyl groups.

[0061] The term aryl refers to an aromatic group containing one or more rings containing from 6 to 14 ring carbon atoms, preferably from 6 to 10 and especially 6 ring carbon atoms.

[0062] The term heteroaryl refers to an aromatic group containing one or more rings containing 5 to 14 ring atoms, preferably 5 to 10, especially 5 or 6 ring atoms, and containing one or more, preferably 1, 2, 3 or 4, oxygen, nitrogen, phosphorus or sulfur ring atoms, preferably O, S or N. Examples are pyridyl (e.g. 4-pyridyl), imidazolyl (e.g. 2-imidazolyl), phenylpyrrolyl (e.g. 3-phenylpyrrolyl), thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, isoxazolyl, indazolyl, indolyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzthiazolyl, pyridazinyl, quinolinyl, isoquinolinyl, pyrrolyl, purinyl, carbazolyl, acridinyl, pyrimidyl, 2,3'-bifuryl, pyrazolyl (e.g. 3-pyrazolyl) and isoquinolinyl groups. The expression heterocycloalkyl refers to a cycloalkyl group as defined above in which one or more (preferably 1, 2 or 3) ring carbon atoms are each independently replaced by an oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atom (preferably by an oxygen, sulfur or nitrogen atom). Heterocycloalkyl groups preferably have one or two rings containing 3 to 10 (in particular 3, 4, 5, 6 or 7) ring atoms (preferably selected from C, O, N and S). The expression heterocycloalkyl further refers to a cycloalkyl group in which one or more hydrogen atoms are replaced by a fluorine, chlorine, bromine or iodine atom or by an OH, =O, SH, =S, NH 2 , =NH,N 3 Or NO 2 It refers to a group substituted by a group. Examples include piperidyl, prolinyl, imidazolidinyl, piperazinyl, morpholinyl, urotropinyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrofuryl or 2 pyrazolinyl groups, as well as lactams, lactones, cyclic imides and cyclic anhydrides.

[0063] The expression alkylcycloalkyl refers to groups which contain both cycloalkyl and alkyl, alkenyl or alkynyl groups as defined above, such as alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkenyl, alkenylcycloalkyl and alkynylcycloalkyl groups. Alkylcycloalkyl groups preferably include cycloalkyl groups which contain one or two ring systems with 3 to 10 (especially 3, 4, 5, 6 or 7) ring carbon atoms and one or two alkyl, alkenyl or alkynyl groups with 1 or 2 to 6 carbon atoms. The expression aralkyl refers to groups which contain both aryl groups and alkyl, alkenyl, alkynyl and / or cycloalkyl groups as defined above, such as arylalkyl, arylalkenyl, arylalkynyl, arylcycloalkyl, arylcycloalkenyl, alkylaryl-cycloalkyl and alkylarylcycloalkenyl groups. Specific examples of aralkyls are toluene, xylene, mesitylene, styrene, benzyl chloride, o-fluorotoluene, 1H-indene, tetralin, dihydronaphthalene, indanone, phenylcyclopentyl, cumene, cyclohexylphenyl, fluorene and indane. The aralkyl group preferably contains one or two aromatic ring systems (one or two rings) containing from 6 to 10 carbon atoms and one or two alkyl, alkenyl and / or alkynyl groups containing from 1 or 2 to 6 carbon atoms and / or cycloalkyl groups containing 5 or 6 ring carbon atoms.

[0064] The expression heteroalkylcycloalkyl refers to an alkylcycloalkyl group as defined above, in which one or more, preferably one, two or three, carbon atoms are replaced independently of one another by oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atoms (preferably by oxygen, sulfur or nitrogen atoms). Heteroalkylcycloalkyl groups preferably contain one or two ring systems having 3 to 10 (in particular 3, 4, 5, 6 or 7) ring atoms and one or two alkyl, alkenyl, alkynyl or heteroalkyl groups having 1 or 2 to 6 carbon atoms. Examples of such groups are alkylheterocycloalkyl, alkylheterocycloalkenyl, alkenylheterocycloalkyl, alkynylheterocycloalkyl, heteroalkylcycloalkyl, heteroalkylheterocycloalkyl and heteroalkylheterocycloalkenyl, in which the cyclic groups are saturated or mono-, di- or tri-unsaturated.

[0065] The term heterocycle refers to heteroaryl groups as defined above, as well as to cycloalkyl groups or carbocycles as defined above in which one or more (preferably 1, 2 or 3) ring carbon atoms are each independently replaced by an oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atom, preferably by an oxygen, sulfur or nitrogen atom. Heterocycles preferably have 1 or 2 rings containing 3 to 10, in particular 3, 4, 5, 6 or 7 ring atoms, preferably selected from C, O, N and S. Examples include aziridinyl, oxiranyl, thiiranyl, oxaziridinyl, dioxiranyl, azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, phosphoranyl, silolanyl, azolyl, thiazolyl, isothiazolyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperazinyl, morpholinyl, thiomorpholinyl, trioxanyl, azepanyl, oxepanyl, thiepanyl, homopiperazinyl, or urotropinyl groups.

[0066] The term heteroaralkyl refers to an aralkyl group as defined above in which one or more (preferably 1, 2, 3 or 4) carbon atoms are each independently replaced by an oxygen, nitrogen, silicon, selenium, phosphorus, boron or sulfur atom (preferably oxygen, sulfur or nitrogen), i.e. a group which contains both aryl or heteroaryl, respectively, and alkyl, alkenyl, alkynyl and / or heteroalkyl and / or cycloalkyl and / or heterocycloalkyl groups as defined above. Heteroaralkyl groups preferably contain one or two aromatic ring systems (one or two rings) containing 5 or 6 to 10 ring carbon atoms and one or two alkyl, alkenyl and / or alkynyl groups containing 1 or 2 to 6 carbon atoms and / or cycloalkyl groups containing 5 or 6 ring carbon atoms, of which 1, 2, 3 or 4 are replaced by oxygen, sulfur or nitrogen atoms.

[0067] Examples include arylheteroalkyl, arylheterocycloalkyl, arylheterocycloalkenyl, arylalkylheterocycloalkyl, arylalkenylheterocycloalkyl, arylalkynylheterocycloalkyl, arylalkylheterocycloalkenyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylcycloalkyl, heteroarylcycloalkenyl, heteroarylheterocycloalkyl, heteroarylheterocycloalkenyl, heteroarylalkylcycloalkyl, heteroarylalkylheterocycloalkenyl, heteroarylheterocycloalkyl, heteroarylheteroalkylcycloalkyl, heteroarylheteroalkylcycloalkenyl groups and heteroarylheteroalkylheterocycloalkyl groups, the cyclic groups being saturated or mono-, di-, or tri-unsaturated. Specific examples are tetrahydroisoquinolinyl, benzoyl, 2- or 3-ethylindolyl, 4-methylpyridino, 2-, 3-, or 4-methoxyphenyl, 4-ethoxyphenyl, 2-, 3-, or 4-carboxyphenyl alkyl groups.

[0068] As mentioned above, the expressions cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl mean that one or more hydrogen atoms of such groups may be replaced, independently of one another, by a fluorine, chlorine, bromine or iodine atom, or by OH, ═O, SH, ═S, NH 2 , =NH,N 3 , or NO 2 It also refers to a group that is substituted by a group.

[0069] The general term "ring" as used herein, unless otherwise defined, includes cycloalkyl groups or carbocycles, heterocycles, aryl groups, and heteroaryl groups.

[0070] The terms "halo", "halogen" or "halogen atom" as used herein mean fluorine, chlorine, bromine or iodine, preferably fluorine and / or chlorine.

[0071] As used herein, the expressions monosaccharide or disaccharide and derivatives thereof refer to carbohydrates or sugars belonging to or derived from the group of monosaccharides or disaccharides.

[0072] Examples of monosaccharides, disaccharides, and their derivatives include glucose, 3-O-methylglucose, 1-deoxy-glucose, 6-deoxyglucose, galactose, mannose, fructose, xylose, ribose, cellobiose, maltose, lactose, gentiobiose, saccharose, trehalose, and mannitol, sorbitol, and ribitol. Preferably, the sugars are D-sugars, such as D-glucose, 3-O-methyl-D-glucose, 1-deoxy-D-glucose, or 6-deoxy-D-glucose, D-galactose, D-mannose.

[0073] As used herein, phrases defining length range limits, such as "from 1 to 5," mean any integer from 1 to 5, i.e., 1, 2, 3, 4, and 5. In other words, any range defined by two integers explicitly recited is meant to include and disclose any integers defining said limits and any integers contained within said range.

[0074] The term "-C(=O)O- motif" refers to (i) a sp 2 Hybridized carbonyl carbon, and (ii) sp bonded to oxygen which may be bonded to hydrogen or any other chemical atom 2 It is used herein to clearly define groups that contain a hybridized carbonyl carbon. The term "carboxyl group" is avoided in the description of the "-C(=O)O- motif" because it may be misconstrued as describing only carboxylic acids.

[0075] The term "alpha" is used to denote a directly adjacent position, and the term "beta" denotes the adjacent position of an atom or group A and an atom or group B, characterized by the presence of one further atom or group located between A and B.

[0076] As used herein, the term oxaminde refers to an optionally substituted organic compound containing two carbonyl carbons and two nitrogens, which is an optionally substituted diamide derived from oxalic acid.

[0077] Those skilled in the art will readily appreciate that some of the n-3 PUFA analogs of the present invention of general formula (I) represent "bioisosteres" of naturally occurring epoxy metabolites produced by cytochrome P450 (CYP) enzymes from omega-3 (n-3) polyunsaturated fatty acids (PUFAs). A bioisostere is a compound produced by exchanging an atom or group of atoms with another, substantially similar atom or group of atoms, thereby producing a new compound with similar biological properties as the parent compound. For example, bioisosterism has been used by medicinal chemists to improve desirable biological or physical properties of a compound, for example, by reducing the toxicity of the compound, altering its activity, or altering its pharmacokinetics and / or metabolism. For example, replacing a hydrogen atom at a metabolic oxidation site in a compound with a fluorine atom may prevent such metabolism from occurring. Because fluorine is similar in size to a hydrogen atom, the overall topology of the molecule is not significantly affected and the desired biological activity is not affected. However, if a metabolic pathway is blocked, the half-life of the compound may be increased. Another example is the bioisosteric replacement of the carboxylic acid group, which results in analogues that exhibit improved bioavailability, enhanced blood-brain barrier penetration, increased activity, improved chemical stability, and / or improved selectivity towards the target (see, for example, the textbook "The practice of medicinal chemistry", edited by Camille Georges Wermuth, 3 rdedition, Academic Press, 2008, e.g. p. 303-310; see Ballatore C. et al., "Carboxylic Acid (Bio)Isosteres in Drug Design", ChemMedChem 8, 385-395 (2013)). Furthermore, bioisosterism can also be used to provide "prodrugs" of compounds, i.e. compounds that are initially administered to a subject or patient in an inactive (or less active) form and then converted to an active form through normal metabolic processes in the body. For example, conjugation of a compound with lipid and / or sugar units results in analogues (prodrugs) with improved drug delivery compared to the parent compound (see, e.g., Wong A. and Toth I. "Lipid, Sugar and Liposaccharide Based Delivery Systems", Current Medicinal Chemistry 8, 1123-1136 (2001)).

[0078] The n-3 PUFA analogues of the general formula (I) of the present invention can be prepared by several methods well known to those skilled in the art of organic synthesis.For example, the compounds of the present invention can be synthesized according to the general reaction scheme shown below using synthetic methods known in the art of organic synthetic chemistry, or variations thereof that will be understood by those skilled in the art.Unless otherwise stated, all variables, such as n, k, R 2 (R 2 Also called), R 6 , R 7 , R 8 , R 41 , R 42 , R 44 , and R 45 has the meaning defined above. As starting materials, standard commercially available grade reagents can be used without further purification or can be easily prepared from such materials by conventional methods. Those skilled in the art of organic synthesis will recognize that the starting materials and reaction conditions can vary, including additional steps used to prepare the compounds used in the present invention.

[0079] The compounds of the present invention are effective in treating, reducing the risk of developing, or preventing diseases associated with elevated plasma concentrations of GDF-15, wherein preferably the plasma concentration of GDF-15 is at least 1000 ng / L, and wherein preferably the diseases associated with elevated plasma concentrations of GDF-15 are selected from cardiovascular diseases and metabolic diseases.

[0080] In one embodiment, the cardiovascular disease is selected from atrial fibrillation, bleeding risk associated with atrial fibrillation, coronary artery disease (CAD), angina pectoris, myocardial infarction, stroke, heart failure, hypertensive heart disease, rheumatic heart disease, cardiomyopathy, congenital heart disease, valvular heart disease, carditis, aortic aneurysm, peripheral artery disease, thromboembolism, and venous thrombosis.In one preferred embodiment, the cardiovascular disease is selected from atrial fibrillation, bleeding risk associated with atrial fibrillation, heart failure, coronary artery disease (CAD) and peripheral artery disease.In a more preferred embodiment, the cardiovascular disease is atrial fibrillation or a disease associated therewith (such as bleeding risk).In the most preferred embodiment, the cardiovascular disease is atrial fibrillation.

[0081] In one preferred embodiment, the cardiovascular disease (or any of the cardiovascular diseases explicitly disclosed above) is associated with elevated GDF-15 plasma concentrations, preferably at least 500 ng / L, 750 ng / L, 900 ng / L, 1000 ng / L, 1200 ng / L or 1500 ng / L, preferably at least 900 ng / L, 1000 ng / L, 1200 ng / L, more preferably at least 1000 ng / L.

[0082] In one embodiment, the metabolic disease is selected from diabetes, dyslipidemia, and metabolic syndrome.

[0083] In one preferred embodiment, the metabolic disease (or any of the diseases identified above) is associated with elevated GDF-15 plasma concentrations, preferably at least 500ng / L, 750ng / L, 900ng / L, 1000ng / L, 1200ng / L or 1500ng / L, preferably at least 900ng / L, 1000ng / L, 1200ng / L, more preferably at least 1000ng / L.

[0084] In one embodiment, the disease associated with elevated plasma concentrations of GDF-15 is not a cardiovascular disease.

[0085] In one embodiment, the disease associated with elevated plasma concentrations of GDF-15 is not a metabolic disease.

[0086] In one embodiment, compositions, preferably pharmaceutical compositions, comprising the compounds of the invention are provided for the same uses as exemplified herein for the compounds of the invention.

[0087] In one preferred embodiment, the compound or composition used by the present invention is administered orally, topically, subcutaneously, intravitreally, intramuscularly, intraperitoneally, intravenously or intranasally, preferably orally or intravenously, more preferably orally or intraperitoneally.The preferred administration routes of ophthalmic drugs in the treatment of ophthalmic diseases are topically, locally ocular (e.g. subconjunctivally, intravitreal, retrobulbar, intracameral) and systemically.The latter is preferably achieved by oral, intramuscular or intravenous administration.

[0088] It is further preferred that the compound or composition used according to the invention is in a dosage form selected from the group consisting of sprays, aerosols, foams, inhalants, powders, tablets, capsules, soft gelatin capsules, teas, syrups, granules, chewable tablets, ointments, creams, gels, suppositories, lozenges, liposomal compositions, and solutions suitable for injection.

[0089] The compositions used according to the invention may further comprise at least one compound of formula (I) and, optionally, one or more carrier substances, for example, cyclodextrins such as hydroxypropyl β-cyclodextrin, micelles or liposomes, excipients and / or adjuvants. In addition, the compositions may further comprise, for example, one or more of water, buffers (for example, neutral buffered saline or phosphate buffered saline), ethanol, mineral oil, vegetable oil, dimethyl sulfoxide, carbohydrates (for example, glucose, mannose, sucrose or dextran), mannitol, proteins, adjuvants, amino acids such as polypeptides or glycine, antioxidants, chelating agents such as EDTA or glutathione, and / or preservatives. In addition, the compositions provided herein may, but need not, include one or more other active ingredients. For example, the compounds of the invention may be advantageously used in combination with direct thrombin inhibitors, statins, RAS drugs, beta blockers, diuretics, direct acting factor Xa inhibitors, vitamin K antagonists, calcium channel blockers and metformin.

[0090] The composition for use may be formulated for any suitable route of administration, including, for example, topical, oral, buccal, nasal, vaginal, rectal or parenteral administration, such as, for example, transdermal or ocular. The term "parenteral" as used herein includes subcutaneous, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intracranial, intrathecal, intraocular, periocular, intraorbital, intrasynovial, intraperitoneal and local intraocular (e.g., subconjunctival, intravitreal, retrobulbar, anterior chamber) injections and similar injection or infusion techniques. In certain embodiments, compositions in a form suitable for oral use are preferred. Such forms include, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs. In yet other embodiments, the compositions provided herein may be formulated as lyophilizates.

[0091] Compositions intended for oral use may further comprise one or more ingredients, such as sweeteners, flavorings, colorings, and / or preservatives, to provide an attractive and palatable preparation. Tablets contain the active ingredient mixed with physiologically acceptable excipients suitable for the manufacture of tablets. Such excipients include inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, sodium phosphate, granulating and disintegrating agents, such as corn starch, alginic acid, binding agents, such as starch, gelatin, acacia, and lubricating agents, such as magnesium stearate, stearic acid, talc. Tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, a delaying material, such as glyceryl monostearate or glyceryl distearate, may be used. Methods for preparing such compositions are known (see, e.g., HC Ansel and NG Popovish, Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th ed., Lea and Febiger (1990)).

[0092] Formulations for oral administration may be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (such as calcium carbonate, calcium phosphate, or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium (such as peanut oil, liquid paraffin, or olive oil).

[0093] Aqueous suspensions contain the active ingredient mixed with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia; and dispersing or wetting agents (e.g., natural phospholipids such as lecithin), condensation products of alkylene oxides and fatty acids such as polyoxyethylene stearates, condensation products of ethylene oxide and long-chain aliphatic alcohols such as heptadecaethyleneoxycetanol, condensation products of ethylene oxide and partial esters derived from fatty acids and hexitols such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide and partial esters derived from fatty acids and hexyl anhydrides (e.g., polyethylene sorbitan monooleate). The aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0094] Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil, such as peanut oil, olive oil, sesame oil, or coconut oil, or in a mineral oil, such as liquid paraffin. Oily suspensions can contain a thickening agent, such as beeswax, hard paraffin, or cetyl alcohol. Sweetening and / or flavoring agents, as mentioned above, may be added to provide a palatable oral preparation. Such suspensions can be preserved by the addition of an antioxidant, such as ascorbic acid.

[0095] Dispersible powders and granules suitable for preparing an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents include those already mentioned above. Additional excipients such as sweeteners, flavorings, colorants, etc. may also be present.

[0096] The composition for use may be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, for example olive oil or peanut oil, a mineral oil, for example liquid paraffin, or a mixture thereof. Suitable emulsifiers include natural gums, for example gum acacia or gum tragacanth, natural phospholipids, for example soybean lecithin, esters or partial esters derived from fatty acids and hexitols, anhydrides, for example sorbitan monooleate, and condensation products of partial esters derived from fatty acids and hexitols with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsion may also contain one or more sweeteners and / or flavoring agents.

[0097] Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose, and may also contain one or more demulcents, preservatives, flavorings and / or coloring agents.

[0098] The compounds used according to the present invention can be formulated for topical administration, for example for topical application to the skin or mucous membranes (such as the eye). Formulations for topical administration usually include a topical vehicle in combination with an active agent, with or without additional optional ingredients. Suitable topical vehicles and additional ingredients are well known in the art, and the choice of vehicle obviously depends on the particular physical form and mode of delivery. Topical vehicles include water; organic solvents, such as alcohols, such as ethanol and isopropyl alcohol, or glycerin; glycols, such as butylene, isoprene, and propylene glycol; aliphatic alcohols, such as lanolin, mixtures of water and organic solvents, and mixtures of organic solvents, such as alcohol and glycerin; lipid-based materials, such as acylglycerols, including fatty acids, oils (such as oils, such as mineral oil, fats of natural or synthetic origin, phosphoglycerides, sphingolipids, and waxes); protein-based materials, such as collagen and gelatin; silicone-based materials, both non-volatile and volatile; and hydrocarbon-based materials, such as microsponges and polymer matrices. The composition may further comprise one or more ingredients adapted to improve the stability or effectiveness of the applied formulation, such as, for example, stabilizers, suspending agents, emulsifiers, viscosity modifiers, gelling agents, preservatives, antioxidants, skin penetration enhancers, moisturizers, sustained release materials, etc. Examples of such ingredients are described in Martindale-The Extra Pharmacopoeia (Pharmaceutical Press, London 1993), Martin (ed.), Remington's Pharmaceutical Sciences. The formulation may include microcapsules, such as hydroxymethylcellulose or gelatin microcapsules, liposomes, albumin microspheres, microemulsions, nanoparticles, or nanocapsules.

[0099] Formulations for topical use can be prepared in a variety of physical forms, such as, for example, solids, pastes, creams, foams, lotions, gels, powders, aqueous liquids, emulsions, sprays, eye drops, and skin patches. The physical appearance and viscosity of such forms can be controlled by the presence and amount of emulsifiers and viscosity modifiers present in the formulation. Solids are generally stiff and non-pourable, and are usually formulated in the form of bars or sticks, or particles; solids can be opaque or transparent, and can optionally contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes / colorants, preservatives, and other active ingredients that increase or enhance the efficacy of the final product. Creams and lotions are often similar, with the main difference being viscosity; both lotions and creams can be opaque, translucent, or transparent, and can contain emulsifiers, solvents, viscosity modifiers, and moisturizers, emollients, fragrances, dyes / colorants, preservatives, and other active ingredients that increase the efficacy of the final product. Gels can be prepared in a variety of viscosities, from thick or highly viscous to thin or thin. Similar to lotions and creams, these formulations can also contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes / colorants, preservatives, and other active ingredients that enhance the efficacy of the final product. Liquids are thinner than creams, lotions, or gels and often do not contain emulsifiers. Liquid topical products often contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes / colorants, preservatives, and other active ingredients that enhance the efficacy of the final product.

[0100] Suitable emulsifiers for use in topical formulations include, but are not limited to, ionic emulsifiers, non-ionic emulsifiers such as cetearyl alcohol, polyoxyethylene oleyl ether, PEG-40 stearate, ceteareth-12, ceteareth-20, ceteareth-30, ceteareth alcohol, PEG-100 stearate, and glyceryl stearate. Suitable viscosity modifiers include, but are not limited to, protective colloids or non-ionic gums such as hydroxyethylcellulose, xanthan gum, magnesium aluminum silicate, silica, microcrystalline wax, beeswax, paraffin, and cetyl palmitate. Gel compositions can be formulated by adding gelling agents such as chitosan, methylcellulose, ethylcellulose, polyvinyl alcohol, polyquaternium, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carbomer, or ammoniated glycyrrhizic acid. Suitable surfactants include, but are not limited to, non-ionic, amphoteric, ionic, and anionic surfactants. For example, one or more of dimethicone copolyol, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, lauramide DEA, cocamide DEA, and cocamide MEA, oleyl betaine, cocamidopropyl phosphatidyl PG dimonium chloride, and ammonium laureth sulfate may be used in the topical formulation.

[0101] Suitable preservatives include, but are not limited to, antimicrobial agents such as methylparaben, propylparaben, sorbic acid, benzoic acid, and formaldehyde, as well as physical stabilizers and antioxidants such as vitamin E, sodium ascorbate / ascorbic acid, and propyl gallate. Suitable moisturizers include, but are not limited to, lactic acid and other hydroxy acids and their salts, glycerin, propylene glycol, and butylene glycol. Suitable emollients include lanolin alcohol, lanolin, lanolin derivatives, cholesterol, petrolatum, isostearyl neopentanoate, and mineral oil. Suitable fragrances and colorants include, but are not limited to, FD&C Red No. 40, and FD&C Yellow No. 5. Other suitable additional ingredients that may be included in the topical formulation include, but are not limited to, abrasives, absorbents, anti-caking agents, anti-foaming agents, anti-static agents, astringents such as witch hazel, alcohols, and herbal extracts such as chamomile extract, binders / excipients, buffers, chelating agents, film formers, conditioning agents, propellants, opacifying agents, pH adjusters, and protectants.

[0102] An example of a topical vehicle suitable for formulation as a gel is hydroxypropyl cellulose (2.1%), 70 / 30 isopropyl alcohol / water (90.9%), propylene glycol (5.1%), and polysorbate 80 (1.9%). An example of a topical vehicle suitable for formulation as a foam is cetyl alcohol (1.1%), stearyl alcohol (0.5%), quaternium 52 (1.0%), propylene glycol (2.0%), ethanol 95 PGF3 (61.05%), deionized water (30.05%), P75 hydrocarbon propellant (4.30%). All percentages are by weight.

[0103] Common methods of delivery of topical compositions include application with the fingers; application with a physical applicator such as a cloth, tissue, cotton swab, stick or brush; spraying, including mist, aerosol or foam spray; application with a dropper; dusting; dipping; and rinsing. Controlled release vehicles can also be used, and the compositions can be formulated for transdermal administration as a transdermal patch.

[0104] The composition for use may be formulated as an inhalation formulation, including a spray, mist, or aerosol. Such formulations are particularly useful for the treatment of asthma and other respiratory diseases. In the case of an inhalation formulation, the compounds provided herein may be delivered by any inhalation method known to those skilled in the art. Such inhalation methods and devices include, but are not limited to, metered dose inhalers using propellants such as CFCs and HFAs, or physiologically and environmentally acceptable propellants. Other suitable devices include breath-actuated inhalers, multi-dose dry powder inhalers, and aerosol nebulizers. The aerosol formulations used in the subject in the method of the present invention typically include a propellant, a surfactant, and a co-solvent, and can be filled into a conventional aerosol container that is closed by a suitable metering valve.

[0105] Inhalant compositions may include liquid or powder compositions containing the active ingredient suitable for nebulization and intrabronchial use, or aerosol compositions administered via an aerosol unit that dispenses a metered dose.Suitable liquid compositions comprise the active ingredient in an aqueous, pharma- ceutically acceptable inhalation solvent, such as isotonic saline or sterile water.The solution is administered by a pump or squeeze-activated aerosol spray dispenser, or by other conventional means that allows or allows the required dose of the liquid composition to be inhaled into the patient's lungs.Suitable formulations in which the carrier is liquid, for example for administration as a nasal spray or nasal drops, include aqueous or oily solutions of the active ingredient.

[0106] Formulations or compositions suitable for nasal administration (wherein the carrier is a solid) include, for example, coarse powders having a particle size in the range 20-500 microns, which are administered in the manner in which snuff is administered, i.e., by rapid inhalation through the nasal passages from a container of the powder held close to the nose. Suitable powder compositions include, for example, powder formulations of the active ingredient thoroughly mixed with lactose or other inert powder suitable for intrabronchial administration. Powder compositions may also be administered via an aerosol dispenser or may be enclosed in a crushable capsule which is punctured by the patient and inserted into a device which dispenses a steady stream of powder suitable for inhalation.

[0107] The composition for use may be prepared in the form of, for example, suppositories for rectal administration. Such compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at normal temperature but liquid at rectal temperature, and therefore melts in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycol.

[0108] The composition for use may be formulated as sustained release formulation, such as formulation such as capsule that slowly releases regulator after administration.Such formulations can generally be prepared using well-known technology and administered, for example, by oral, rectal or subcutaneous implantation, or implantation at desired target site.The carrier used in such formulations can be biocompatible and biodegradable; preferably, the formulation provides a relatively constant level of regulator release.The amount of regulator contained in sustained release formulation varies, for example, depending on the implantation site, release rate and expected release period, and the nature of the disease state to be treated or prevented.

[0109] However, it will be understood that the specific dosage level for a particular patient will depend on a variety of factors, including the activity of the particular compound used, age, body weight, general health, sex, diet, time of administration, route of administration and rate of excretion, drug combinations (i.e., other drugs being used to treat the patient), and the severity of the particular disease being treated.

[0110] Preferred compounds of the present invention have certain pharmacological properties, including but not limited to oral bioavailability, such that the preferred oral dosage forms described above are capable of providing therapeutically effective levels of the compounds in vivo.

[0111] The n-3 PUFA derivatives provided herein are preferably administered orally or parenterally to a patient, such as a human, and are present in at least one bodily fluid or tissue of the patient.

[0112] The term "treatment" as used herein includes any type of disease-modifying treatment, including symptomatic treatment, i.e., treatment after the onset of symptoms, but may be preventative. However, disease-modifying treatment may include administration before the onset of symptoms to prevent, or at least delay, the onset of symptoms, or to reduce the severity of symptoms after onset. Disease-modifying treatment may be therapeutic after the onset of symptoms to reduce the severity and / or duration of symptoms. Treatment after the onset of symptoms may simply result in stopping the progression of the disease (disease stabilization). In certain embodiments, the n-3 PUFA derivatives provided herein are ideally, but not necessarily, administered prophylactically to actually prevent the disease and / or symptoms, i.e., before the onset of the disease and / or symptoms. It is understood that the terms prevention and prophylactic in the context of the present invention simply refer to the administration of the compounds of the present invention before the onset of symptoms. Prophylactic administration may be administered prior to the onset of symptoms clearly related to the disease discussed herein: the n-3 PUFA derivatives provided herein may be administered prophylactically to a subject, for example, when the subject exhibits a particular condition that may indicate a tendency to develop one of the conditions or diseases treatable with one of the n-3 PUFA derivatives of the present invention. Such indicative symptoms include hypertension and diabetes. Such prophylactic treatment is referred to as primary prevention. In another embodiment, the n-3 PUFA derivatives provided herein may be administered prophylactically to a subject when the subject previously suffered from a condition or disease treatable with the n-3 PUFA derivatives of the present invention, but is not currently symptomatic. Such prophylactic treatment is referred to as secondary prevention. A patient who is administered an n-3 PUFA derivative for the purpose of primary or secondary prevention is considered to be in need of such treatment. Patients who are administered the doses described herein include, but are not limited to, mammals, particularly humans, domesticated pet animals such as dogs, cats, and horses, and livestock such as cows, pigs, and sheep.

[0113] The activity of the n-3 PUFA analogues according to the present invention can be measured, for example, by suitable in vitro and / or in vivo assays.For example, the biological activity of the n-3 PUFA analogues according to the present invention can be determined using the established cell model of Kang and Leaf (Proc Natl Acad Sci USA, 1994.91(21): p. 9886-90), which is known to those skilled in the art.

[0114] The figures and examples herein are intended to illustrate the invention and are not intended to limit the scope of the invention, which is set forth in the appended claims. EXAMPLES

[0115] Example 1 Synthesis of Compounds

[0116] The synthesis of the compounds of the present invention is described in patent applications WO2010 / 081683 A1, WO2015 / 110262 A1, WO2017 / 013264 A1 and WO2017 / 168007 A1.

[0117] Exemplary syntheses of the compounds of the present invention are disclosed below. Those skilled in the art will know how to synthesize other compounds of the present invention by following the synthetic routes below and the further synthetic instructions disclosed in the above patent applications, namely WO2010 / 081683A1, WO2015 / 110262A1, WO2017 / 013264A1 and WO2017 / 168007 A1.

[0118] Compound-01 (Comp-01) The synthesis of compound-01 (Comp-01) was similar to that of compound-03 (Comp-03), but the urea group was introduced according to the synthetic route described in patent application WO2010 / 081683 (Example 13).

[0119] Compound-02 (Comp-02) Synthesis Summary [ka]

[0120] Common methods The NMR spectrum is 1 For HNMR, we used a Bruker Avance 400 MHz spectrometer. 13 CNMR was recorded at 100 MHz. LCMS was obtained on a Shimadzu LCMS 2010 (column: sepax ODS 50x2.0 mm, 5um) or Agilent 1200 HPLC, 1956 MSD (column: Shim-pack XR-ODS 30x3.0 mm, 2.2um) quadrupole mass spectrometer operated in ES(+) ionization mode. Chromatographic purification was performed by flash chromatography using 100-200 mesh silica gel. Anhydrous solvents were pretreated on a 3AMS column before use. All commercially available reagents were used as received unless otherwise stated.

[0121] General procedure for the preparation of compound-02 [ka] [Table A] Methanamine (64.29 g, 952.17 mmol, 1.30 Eq) in 500 mL THF was added with Et3N (75 g, 732.44 mmol), and the solution was added to compound-01 (100.00 g, 732.44 mmol, 1.00 eq), Et3N (111 g, 1.1 mol) in THF (1.5 L) at -10 °C. The mixture was then stirred at 25 °C for 16 h. The mixture was then filtered, and the filtrate was washed with 2N HCl (500 mL), extracted with EA (300 mL × 4), concentrated, and purified on silica gel (PE:EA = 3:1 to 1:1) to give compound-02 (70.00 g, 533.82 mmol, 72.88% yield) as a yellow oil. TLC information (PE: ethyl acetate = 2:1); Rf (Comp-02) = 0.39; LCMS: ET2662-1-P1A (M+H +):131.7; 1 HNMR(CDCl 3 , 400 MHz) 4.36~4.24(q,J=8 Hz, 2H), 2.93~2.85(d,J=4 Hz, 3H), 1.38~1.30(t,J=8 Hz, 3H).

[0122] Example 2: Efficacy of Compound-02 in a Phase II Clinical Trial in Patients with Persistent Atrial Fibrillation (AF)

[0123] In a Phase II clinical trial, the therapeutic effect of Compound-02 (structure of general formula (VI)) was investigated in 119 patients with persistent atrial fibrillation. The patients were divided into a placebo group and three treatment groups with different doses of Compound-02. The low-dose, medium-dose, and high-dose groups were orally administered 4 mg, 12 mg, or 24 mg of Compound-02 once a day, respectively.

[0124] Study participants received an implantable cardiac monitor (ICM) at least 1 week prior to the start of treatment with Compound-02. Treatment with Compound-02 continued for a total of 3 months (i.e., from day 1 to day 99) and was initiated at least 1 week prior to direct current cardioversion (DCC) (see Figure 1 for details of the study protocol).

[0125] The study revealed a favorable safety profile of Compound-02, with no ECG changes or other types of arrhythmias observed in study participants. Treatment compliance was high in all study groups.

[0126] Plasma samples were collected from patients at different study visits. Biomarkers were analyzed at baseline (V3) and end of treatment (V8). A complete set of biomarkers was available for 119 study participants. Analysis revealed consistent decreases in biomarkers between baseline (V3) and end of treatment (V8), with particularly significant decreases in GDF-15, IL-6, and PTX-3.

[0127] GDF-15 concentrations were measured in EDTA-treated plasma samples by solid-phase sandwich ELISA (Human GDF-15 Quantikine ELISA kit, R&D Systems) using immobilized mouse monoclonal anti-GDF-15 antibody and horseradish peroxidase-conjugated monoclonal anti-GDF-15 antibody. The substrates for the enzymatic reaction are hydrogen peroxide and tetramethylbenzidine. The reaction is stopped by the addition of sulfuric acid. The reaction products are measured spectrophotometrically at 450 nm (Sunrise Absorbance Reader, TECAN).

[0128] Subgroups of patients with pathophysiological GDF-15 plasma concentrations

[0129] GDF-15 levels in the entire study population showed an age-dependent increase across the entire group of study participants (correlation r=0.4121, p<0.0001, see Figure 2A). However, a subgroup of patients showed pathophysiologically high GDF-15 plasma concentrations (above 1000 ng / L). Within this subgroup of patients, no significant correlation existed between GDF-15 plasma concentrations and age (see Figure 2C), whereas the subgroup of patients with GDF-15 plasma concentrations below 1000 ng / L showed a significant correlation with age (see Figure 2B). This indicates that pathophysiologically high GDF-15 plasma concentrations are caused by the disease and are not simply a result of age, as in the patient group with low GDF-15 plasma concentrations.

[0130] In the patient subgroup with high GDF-15 levels (i.e., GDF-15 plasma concentrations ≥ 1000 ng / L) at the baseline visit (V3), a significant decrease in GDF-15 levels was observed at the end of treatment with Compound-02 (V8) compared to the placebo-treated group (p = 0.02; see Figure 3, right panel). In contrast, in the patient subgroup with GDF-15 plasma concentrations < 1000 ng / L at the baseline visit, no significant change in GDF-15 plasma concentrations was observed at the end of treatment (see Figure 3, left panel). As can be seen in Figure 4, the observed decrease in GDF-15 plasma concentrations was also dose-dependent.

[0131] This suggests that there is an effect of Compound-02 in this particular patient subgroup, namely those with pathophysiological GDF-15 plasma concentrations above 1000 ng / L.

[0132] The subgroup with pathophysiologically elevated GDF-15 plasma concentrations also showed significant differences in the same clinical characteristics compared to the patient group with low GDF-15 plasma concentrations, as shown in Table 1 below. The subgroup with GDF-15 plasma concentrations ≥1000 ng / L also showed higher age and heart rate. Furthermore, a higher CHA2DS2-VASc score indicates a higher risk of stroke. The lower glomerular filtration rate (GFR) may be due to the aging of this patient group.

[0133] Table 1: Clinical baseline outcomes of the study population. Data are presented as mean ± SD, median (quartiles), or frequency (%). [Table 1]

[0134] Therapeutic effect of Compound-02 on atrial fibrillation

[0135] In the subgroup of patients with pathophysiological GDF-15 plasma concentrations ≥1000 ng / L, we further investigated other effects caused by treatment with Compound-02. Therefore, a panel of biomarkers known to be associated with the disease were measured and compared throughout the treatment period.

[0136] In addition to the reduction in GDF-15 plasma concentrations, significant reductions in plasma concentrations of hs-CRP, PTX-3, IL-6, MMP-1, MMP-9, and NT-proBNP were observed at the end of treatment in all treatment groups (see Figure 5). Furthermore, the reduction in clinically relevant markers, especially PTX-3 and IL-6, indicates a therapeutic effect of Compound-02, at least in the subgroup of patients with pathophysiological GDF-15 plasma concentrations of 1000 ng / L or higher.

[0137] Indeed, a significant reduction in atrial fibrillation (AF) recurrence was observed in the subgroup of patients with GDF-15 plasma concentrations ≥1000ng / L (see Figure 6). Moreover, the reduction in AF recurrence after cardioversion was dose-dependent. This demonstrates the therapeutic efficacy of Compound-02 in patients with persistent AF, especially those with GDF-15 plasma concentrations ≥1000ng / L before the start of treatment.

[0138] Example 3: Anti-atherosclerotic effect of Compound-02

[0139] Therapeutic effect of Compound-02 on coronary artery disease

[0140] The inventors further investigated the possible therapeutic effect of Compound-02 in the treatment of coronary artery disease (CAD) by reducing GDF-15 levels. Pentraxin-3 (PTX-3) is a known biomarker of cardiac inflammation, produced by macrophages and vascular smooth muscle cells, especially in the area of ​​atherosclerotic plaques. PTX-3 is also considered as a marker of plaque instability (Soeki et al., J Cardiol. 58:151-157. 2011), and is therefore clinically important in relation to coronary artery disease.

[0141] Furthermore, the study in Example 2 showed that the reduction of GDF-15 by Compound-02 correlated with the reduction of important biomarkers of systemic chronic inflammation (hs-CRP) and atherosclerotic plaque vulnerability (PTX-3), as well as the improvement of lipid metabolism (HDL / LDL ratio) (see Table 2 below). Furthermore, the reduction of GDF-15 correlated with the reduction of NT-proBNP (0.368), a risk stratification marker in patients with acute coronary syndrome.

[0142] Table 2: Time point comparisons Baseline (V3) and End of Treatment (V8); GDF-15 ≥ 1000 ng / L: Compound-02, All treatment groups combined; Spearman rank correlation delta V8-V3 (n=15) [Table 2]

[0143] Therapeutic Effects of Compound-02 in Animal Models of Atherosclerosis

[0144] The effects of Compound-02 were investigated in mice with disrupted low-density lipoprotein receptors (LDLr- / - mice) on a high-fat diet (HFD), a well-known animal model of atherosclerosis. These mice were either kept on a standard chow diet as a control group or fed a high-fat diet for 12 weeks to increase the formation of atherosclerotic plaques. The group of mice fed the high-fat diet was divided into three different groups: (1) HFD only, (2) HFD plus omega-3 acid ethyl esters (OMACOR), and (3) HFD plus Compound-02. OMACOR is the ethyl ester of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are omega-3 fatty acids naturally found in fish oil. Mice were fed 4 g / kg / day of OMACOR, based on an average dietary intake of 4 g for a 25 g mouse. Compound-02 was given at a dose of 120 mg / kg / day, based on an average dietary intake of 4 g for a 25 g mouse. Every group contained 10 mice (N=10).

[0145] Compared to control animals fed a standard chow diet, PTX-3 levels were significantly increased in mice fed a HFD (see Figure 7A), confirming the increased risk associated with feeding a HFD. A similar increase was observed in mice fed a HFD plus OMACOR. In contrast, mice fed a HFD supplemented with Compound-02 did not show an increase in PTX-3 levels, which remained at the level of control animals (see Figure 7A).

[0146] We also observed a significant reduction in whole aortic lesions in mice treated with Compound-02, consistent with the prevention of increased circulating PTX-3 levels observed in these mice (see FIG. 7B). Mice fed Compound-02 showed a 55% reduction in whole aortic lesion size compared to mice fed only a HFD.

[0147] The reduction in PTX-3, a biomarker of cardiac inflammation, upon treatment with Compound-02, already observed in the clinical trial of Example 2, was also observed in an animal model of atherosclerosis. Moreover, treatment with Compound-02 not only reduced the levels of the biomarker, but more importantly, reduced the size of the lesions, demonstrating therapeutic activity against atherosclerosis.

[0148] Atherosclerosis is the most common underlying mechanism of coronary and peripheral artery disease.

[0149] Example 4: Reducing Cardiovascular Risk in Patients with Coronary Artery Disease

[0150] In addition to the observed reduction in GDF-15 and PTX-3 levels, Compound-02 further reduced levels of interleukin-6 (IL-6) in the clinical trial reported in Example 2. Recently, it has been shown that reducing IL-6 levels by pharmacological intervention in patients with coronary artery disease (CAD) results in a reduction in cardiovascular event rates, independent of lipid lowering (Ridker PM et al., EurHeart J 2018, 39:3499-3507). In the CANTOS study, 4833 patients with CAD were treated with the anti-IL-1β antibody canakinumab, which modulates the IL-6 pathway to reduce circulating IL-6 levels.

[0151] Patients in the CANTOS study had reduced circulating IL-6 levels and demonstrated a 32% reduction in major adverse cardiac events (MACE) compared to the placebo group. Thus, the CANTOS study provides clinical proof of concept that lowering IL-6 levels in patients with CAD can have a significant therapeutic effect. Notably, this effect of lowering IL-6 was found to be independent of lipid-lowering effects.

[0152] Thus, the significant reduction in IL-6 levels by 25-40% in response to treatment with Compound-02 in the example clinical trial indicates that Compound-02 provides a therapeutic benefit to CAD patients, at least by reducing the incidence of MACE.

[0153] Example 5: Treatment with Compound-02 reduces the risk of heart failure

[0154] Further analysis of the patient subgroup from the clinical trial of Example 2 with GDF-15 plasma concentrations of 1000 ng / L or greater revealed that markers of heart failure were reduced in response to reduced GDF-15 levels following treatment with Compound-02.

[0155] Specifically, reductions in GDF-15 plasma concentrations with Compound-02 correlated with reductions in N-terminal pro-B-type natriuretic peptide (NT-proBNP), the current gold standard biomarker in heart failure (see McKie et al., J Am Coll Cardiol, 2016 Dec6;68(22):2437-2439). Comparisons between baseline (V3) and end-of-treatment (V8) time points showed a correlation between GDF-15 levels and NT-proBNP (see Table 3 below).

[0156] Table 3: Time point comparisons Baseline (V3) and End of Treatment (V8); GDF-15 ≥ 1000 ng / L: Compound-02, All treatment groups combined; Spearman rank correlation delta V8-V3 (n=26) [Table 3]

[0157] Example 6: Treatment with Compound-02 ameliorates diabetes

[0158] Further analysis of the subgroup of patients with GDF-15 plasma concentrations ≥1000 ng / L revealed that the reduction of GDF-15 levels by Compound-02 had a therapeutic effect in the treatment of diabetes.

[0159] Time point comparison of parameters at baseline (V3) and end of treatment (V8) revealed a correlation between the reduction in GDF-15 levels and the reduction in HbA1c (see Table 4 below). Glycated hemoglobin is the product of sugars attached to hemoglobin by glycation. An increase in the amount of glycated hemoglobin (HbA1c) indicates excessive blood glucose levels. As the average life span of a red blood cell is about 3 months, the amount of HbA1c reflects the average blood glucose level over the past 8-12 weeks. It is the most widely used marker in diabetes management, and a reduction in levels indicates improved glycemic control and is necessary to reduce the long-term effects of diabetes. The observed reduction in HbA1c therefore indicates a therapeutic benefit from lowering GDF-15 levels by treatment with Compound-02.

[0160] The therapeutic efficacy of Compound-02 in treating diabetes is further supported by the finding that reduced GDF-15 levels in response to Compound-02 treatment reduced key biomarkers of systemic chronic inflammation and vascular disease (hs-CRP, IL-6, PTX-3).

[0161] Table 4: Time point comparisons Baseline (V3) and End of Treatment (V8); GDF-15 ≥ 1000 ng / L: Compound-02, All treatment groups combined; Spearman rank correlation delta V8-V3 (n=15) [Table 4]

[0162] Example 7: Treatment with Compound-02 improves dyslipidemia

[0163] Further analysis of the patient subgroup with GDF-15 plasma concentrations ≥1000 ng / L revealed that compound-02-mediated reduction in GDF-15 levels was therapeutically effective in treating dyslipidemia.

[0164] Dyslipidemia is characterized by elevated lipids (eg, triglycerides and cholesterol, especially LDL) and is a risk factor for the development of cardiovascular disease, including coronary artery disease and peripheral artery disease, and metabolic syndrome.

[0165] In the subgroup of patients with GDF-15 plasma concentrations of 1000 ng / L or higher, an improvement in the HDL / LDL ratio was observed in response to the reduction in GDF-15 levels due to treatment with Compound-02 (see Table 2 above). Furthermore, a correlation was observed between triglyceride levels and the reduction in GDF-15 values ​​in response to treatment with Compound-02 (see Table 4 above), supporting the therapeutic effect in treating dyslipidemia.

[0166] Drawing Terminology Cardioversion Screening Day after last dose Insertion of ICM Treatment phase Continuous Monitoring GDF-15 levels in study population Age(year) GDF-15 at V3 GDF1-15 at V3 Delta GDF-15 level Placebo Compound-02 Compound-02 Change in GDF-15 from Baseline to End-of-Treatment (3 months) Selected population Persistent AF patients with GDF-15 baseline values ​​≧1000ng / L Group group N number Median CI of Median Confidence interval for median Median (Quartiles) of Differences p-value P value Comparison vs. Placebo Comparison V3 vs. V8 Comparison between V3 and V8 Median effect size Wilcoxon test without adjustment Wilcoxon paired test Treatment treatment ALL All Median effect sizes and timepoint comparison statistics Subgroup of GDF-15 ≧1000 ng / L Biomarkers For analyzing timepoint comparisons (delta V8-V3), paired Wilcozon test wasused see below colour code for p-value Significant increase Significant decrease No change Trend in increase Trend in decrease Recurrence of AF (Yes / No) Lesions in whole aorta Control Kruskal-Wallis with Dunn's multiple comparisons test One-way ANOVA with Dunnett's multiple comparisons test Change in IL-6 from Baseline to End-of-Treatment (3 months) Change in PTX-3 from Baseline to End-of-Treatment (3 months) Change in hsCRP from Baseline to End-of-Treatment (3 months)

Claims

1. A pharmaceutical comprising a compound of general formula (I) or a pharmaceutically acceptable salt thereof, 【Chemical 1】 During the ceremony, P is a group represented by general formula (II): 【Chemistry 2】 where: n is 0 or an integer from 3 to 8; and k is 0, 1, or 2, preferably with the proviso that when n is 0, k is 1, and most preferably k is 1; X is CH ２ OH, CH ２ OAc, CH(O), or a group selected from the group consisting of: 【Chemistry 3】 【change】 【change】 Preferably, X is 【Chemistry 4】 is; where: R and R′ each independently represent a hydrogen atom; or C optionally substituted with one or more fluorine or chlorine atoms or hydroxyl groups. １ -C ６ represents an alkyl group; R １ is a hydroxyl group, C １ -C ６ Alkoxy, -NHCN, -NH(C １ -C ６ alkyl), -NH(C ３ -C ６ -cycloalkyl), -NH(aryl), or -O(C １ -C ６ alkyldiyl)O(C=O)R １１ represents; R １１ is C optionally substituted with one or more fluorine or chlorine atoms; １ -C ６ alkyl group; or C optionally substituted with one or more fluorine atoms, chlorine atoms, or hydroxyl groups ３ -C ６ is a cycloalkyl group; R ２ is -NHR ３ ;-NR ２０ R ２１ ;-OR ２２ ; -(OCH ２ -CH ２ ) ｉ -R ２３； Hydroxyl group, C １ -C ６ Alkoxy, C １ -C ６ -C optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, and oxo ３ -C １０ -heterocyclyl; -(Xaa) ｏ ; represents a monosaccharide or disaccharide, or a derivative thereof, linked to C(O) by an ester bond via the 1-O-, 3-O-, or 6-O-position of the sugar; or one selected from the group consisting of the following formulas: 【Chemistry 5】 where: R ３ is (SO ２ R ３０ ); (OR ３１ );-C １ -C ６ Alkanediyl (SO ２ R ３２ );-C １ -C ６ Alkanediyl (CO ２ H), an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, wherein the aryl group is C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Alkylthio, fluorine atom or chlorine atom, hydroxyl group, amino group, -NH(C １ -C ６ alkyl), -N(C １ -C ６ dialkyl) and —C(═O)OR ５１ wherein the heteroaryl group is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Alkylthio, fluorine atom or chlorine atom, hydroxyl group, amino group, -NH(C １ -C ６ alkyl), -N(C １ -C ６ dialkyl) and —C(═O)OR ５１ wherein the cycloalkyl group is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Alkylthio, fluorine atom or chlorine atom, hydroxyl group, amino group, -NH(C １ -C ６ alkyl), -N(C １ -C ６ dialkyl) and —C(═O)OR ５１ and wherein the heterocycloalkyl group is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Alkylthio, fluorine atom or chlorine atom, hydroxyl group, amino group, —NH(C １ -C ６ alkyl), -N(C １ -C ６ dialkyl) and —C(═O)OR ５１ optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: R ３０ is C １ -C ６ an alkyl group, or an aryl group, wherein C １ -C ６ The alkyl group is —NH ２ , —NH(C １ -C ６ ) alkyl, —N(C １ -C ６ ) Dialkyl, C １ -C ６ Alkylcarbonyloxy-, C １ -C ６ Alkoxycarbonyloxy-, C １ -C ６ Alkylcarbonylthio-, C １ -C ６ Alkylaminocarbonyl-, di(C １ -C ６ ) alkylaminocarbonyl-, optionally substituted with 1, 2 or 3 fluorine or chlorine atoms or hydroxyl groups; and wherein the aryl group is C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Alkylthio, fluorine atom or chlorine atom, hydroxyl group, amino group, —NH(C １ -C ６ alkyl), and —N(C １ -C ６ optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, dialkyl; R ３１ is C optionally substituted with one or more fluorine atoms, chlorine atoms, or hydroxyl groups; １ -C ６ alkyl group; or C optionally substituted with one or more fluorine atoms, chlorine atoms, or hydroxyl groups ３ -C ６ is a cycloalkyl group; R ３２ is C optionally substituted with one or more fluorine atoms, chlorine atoms, or hydroxyl groups; １ -C ６ alkyl group; or C optionally substituted with one or more fluorine atoms, chlorine atoms, or hydroxyl groups. ３ -C ６ is a cycloalkyl group; R ２０ and R ２１ each independently represents a hydrogen atom; C optionally substituted with one or more fluorine atoms, chlorine atoms, or hydroxyl groups; １ -C ６ an alkyl group; a C group optionally substituted with one or more fluorine atoms, chlorine atoms, or hydroxyl groups; ３ -C ６ a cycloalkyl group; or —C １ -C ６ Alkyldiyl (CO ２ H), or together represent one or more C １ -C ６ Alkyl group, C １ -C ６ C optionally substituted with an alkoxy group, a fluorine atom, a chlorine atom, or a hydroxyl group ３ -C １０ -forms a heterocycloalkyl; R ２２ is a hydrogen atom, C １ -C ６ an alkyl group; or C ３ -C ６ Cycloalkyl groups, where C １ -C ６ Alkyl group or C ３ -C ６ The cycloalkyl group is —NH ２ , —NH(C １ -C ６ ) alkyl, —N(C １ -C ６ ) dialkyl, —NH(C １ -C ６ ) Alkyldiyl-C １ -C ６ Alkoxy, 1, 2 or 3 fluorine or chlorine atoms, hydroxyl, or C １ -C ６ optionally substituted with an alkoxy, aralkyl, heteroalkyl, or heteroalkylcycloalkyl group; R ２３ is -OH, -O(C １ -C ３ ) alkyl, or —N(C １ -C ６ ) dialkyl; i is an integer from 1 to 10; R ２４ , R ２５ and R ２６ are each independently a hydrogen atom; １１ -C ２１ alkyl; or —C(═O)C １１ -C ２１ represents alkenyl; R ２７ は、-OH;-O(CH ２ ) ２ NH ２ ,-OCH ２ -[H(NH) ２ )(CO ２ H)]、-O(CH ２ ) ２ N(CH) ３ ) ３ ; or 【Chemistry 6】 Represents; Xaa represents GIy, a conventional D, L, D, or L amino acid, a non-conventional D, L, D, or L amino acid, or a 2-10 mer peptide; and Xaa is attached to C(=O) by an amide bond; o is an integer from 1 to 10; R ４ is selected from the group consisting of the following formulas: 【Chemistry 7】 h is 0, 1, or 2; R ５ represents a hydrogen atom; a fluorine atom or a chlorine atom; ３ -C(=O)OR ５１ ;-NHC(=O)OR ５２ -C(=O)NR ５３ R ５４ or -S(O ２ ) represents OH; R ５１ is a hydrogen atom; C １ -C ６ an alkyl group; or C ３ -C ６ represents a cycloalkyl group, １ -C ６ Alkyl group or C ３ -C ６ The cycloalkyl group is —NH ２ , —NH(C １ -C ６ ) alkyl, —N(C １ -C ６ ) dialkyl, —NH(C １ -C ６ ) Alkyldiyl-C １ -C ６ Alkoxy, 1, 2 or 3 fluorine or chlorine atoms, hydroxyl, or C １ -C ６ optionally substituted with alkoxy; R ５２ , R ５３ and R ５４ are each independently a C optionally substituted with one or more fluorine or chlorine atoms. １ -C ６ alkyl group; C optionally substituted with one or more fluorine or chlorine atoms ３ -C ６ a cycloalkyl group; or C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ Alkylthio, fluorine atom or chlorine atom, hydroxyl group, amino group, —NH(C １ -C ６ alkyl), -N(C １ -C ６ ) an aryl group optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of dialkyl, and oxo substituents; R ６ , R ７ each independently represents a hydroxyl group; １ -C ６ ) alkyl group, —O(C ２ -C ６ ) alkenyl group, —O(C １ -C ６ ) alkyldiylO(C=O)(C １ -C ６ ) alkyl group, or —O(C １ -C ６ ) alkyldiylO(C=O)(C ２ -C ６ ) represents an alkenyl group, １ -C ６ Alkyl group and C ２ -C ６ The alkenyl group is NH ２ , —NH(C １ -C ６ ) alkyl, —N(C １ -C ６ ) Dialkyl, C １ -C ６ Alkylcarbonyloxy-, C １ -C ６ Alkoxycarbonyloxy-, C １ -C ６ Alkylcarbonylthio-, C １ -C ６ Alkylaminocarbonyl-, di(C １ -C ６ ) alkylaminocarbonyl-, or optionally substituted by 1, 2 or 3 fluorine or chlorine atoms; or R ６ represents a hydroxyl group, R ７ represents the following group: 【Chemistry 8】 R ９ is C １ -C ６ represents alkyl or aryl, and １ -C ６ Alkyl is —NH ２ , —NH(C １ -C ６ ) alkyl-N(C １ -C ６ ) dialkyl, —NH(C １ -C ６ ) Alkyldiyl-C １ -C ６ Alkoxy, 1, 2 or 3 fluorine or chlorine atoms, hydroxy, C １ -C ６ Alkoxy, aryl, aryloxy, —C(═O)-aryl, —C(═O)C １ -C ６ and the aryl group is C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Alkylthio, fluorine atom or chlorine atom, hydroxyl group, amino group, —NH(C １ -C ６ alkyl), -N(C １ -C ６ ) optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of dialkyl and oxo substituents; g is 1 or 2; X １ represents an oxygen atom; a sulfur atom; or NH; X ２ is an oxygen atom; a sulfur atom; NH; or N(CH ３ ) represents; X ３ is an oxygen atom; is a sulfur atom; nitrogen atom; represents a carbon atom; or C—OH; and the dashed line represents a carbon-carbon bond or a carbon-carbon double bond; E is a group represented by general formula (III) or (IV): 【Chemistry 9】 Here, R １２ and R １３ is preferably in a cis configuration, and wherein ring A in formula (III) represents a 5- or 6-membered carbocyclic or heterocyclic ring containing at least one double bond, including an aromatic carbocyclic or heterocyclic ring, and C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Alkylthio, fluorine atom or chlorine atom, hydroxyl group, amino group, —NH(C １ -C ６ alkyl) and —N(C １ -C ６ ) dialkyl; and L and T each independently represent a ring atom, and L and T are adjacent to each other; R １２ and R １３ are each independently a hydrogen atom, a fluorine atom, a hydroxyl group, or —NH ２ , C １ -C ６ Alkyl, C １ -C ６ Alkoxy, —C(═O)-aryl, —C(═O)C １ -C ６ Alkyl, or —SO ２ (C １ -C ６ alkyl); or —SO ２ represents aryl, and １ -C ６ Alkyl, C １ -C ６ Alkoxy or aryl is —NH ２ , —NH(C １ -C ６ ) alkyl, —N(C １ -C ６ ) Dialkyl, C １ -C ６ Alkylcarbonyloxy-, C １ -C ６ Alkoxycarbonyloxy-, C １ -C ６ Alkylcarbonylthio-, C １ -C ６ Alkylaminocarbonyl-, di(C １ -C ６ ) optionally substituted with one, two, or three substituents independently selected from the group consisting of alkylaminocarbonyl-, fluorine or chlorine atoms, and hydroxyl; or R １２ and R １３ are taken together to form a five- or six-membered ring, and the ring is -NH ２ , —NH(C １ -C ６ ) alkyl, —N(C １ -C ６ ) Dialkyl, C １ -C ６ Alkylcarbonyloxy-, C １ -C ６ Alkoxycarbonyloxy-, C １ -C ６ Alkylcarbonylthio-, C １ -C ６ Alkylaminocarbonyl-, di(C １ -C ６ ) optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkylaminocarbonyl, fluorine or chlorine atoms, and hydroxyl; I is -(CH ２ ) ｍ -Y, where: m is an integer from 3 to 6, provided that when E is a group according to general formula (III), m is an integer from 3 to 5; Y is -UV-W-(CH ２ ) ｐ - (CH ３ ) ｑ wherein p is an integer of 0 to 6; q is 0 or 1; and U is absent or is CH, CH ２ and N.R. ４０ with the proviso that when U is taken together with V and W to form an epoxy group, U is only CH; V is selected from the group consisting of —C(O)—, —C(O)—C(O)—, —O—, and —S—; and W is selected from the group consisting of CH, CH ２ and N.R. ４０ with the proviso that W is only CH when taken together with U and V to form an epoxy group; or Y represents a group selected from the group consisting of: 【Chemistry 10】 where: R ４０ , R ４１ , R ４３ , R ４４ , R ４６ , R ４８ and R ４９ are each independently a hydrogen atom, —C １ -C ６ Alkyl, -C ３ -C ６ cycloalkyl, —C １ -C ６ Alkoxy, —C(═O)aryl, or —C(═O)C １ -C ６ represents alkyl, and １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, C １ -C ６ Alkoxy or aryl is —NH ２ , —NH(C １ -C ６ ) alkyl, —N(C １ -C ６ ) Dialkyl, C １ -C ６ Alkylcarbonyloxy-, C １ -C ６ Alkoxycarbonyloxy-, C １ -C ６ Alkylcarbonylthio-, C １ -C ６ Alkylaminocarbonyl-, di(C １ -C ６ ) optionally substituted with one, two, or three substituents independently selected from the group consisting of alkylaminocarbonyl-, fluorine or chlorine atoms, and hydroxyl; or R ４０ and R ４１ , or R ４３ and R ４４ are taken together to form a five- or six-membered ring, and this ring is -NH ２ , —NH(C １ -C ６ ) alkyl, —N(C １ -C ６ ) Dialkyl, C １ -C ６ Alkylcarbonyloxy-, C １ -C ６ Alkoxycarbonyloxy-, C １ -C ６ Alkylcarbonylthio-, C １ -C ６ Alkylaminocarbonyl-, di(C １ -C ６ ) optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkylaminocarbonyl, fluorine or chlorine atoms, and hydroxyl; R ４２ , R ４５ , R ４７ and R ５０ are each independently -C １ -C ３ represents alkyl, and １ -C ３ Alkyl is —NH ２ , —NH(C １ -C ３ ) alkyl, —N(C １ -C ３ ) Dialkyl, C １ -C ３ Alkylcarbonyloxy-, C １ -C ３ Alkoxycarbonyloxy-, C １ -C ３ Alkylcarbonylthio-, C １ -C ３ Alkylaminocarbonyl-, di(C １ -C ３ ) optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkylaminocarbonyl-, fluorine or chlorine atoms, and hydroxyl; or R ４０ and R ４１ ;R ４３ and R ４４ ;R ４９ and R ５０ are taken together to form a five- or six-membered ring, and this ring is -NH ２ , —NH(C １ -C ６ ) alkyl, —N(C １ -C ６ ) Dialkyl, C １ -C ６ Alkylcarbonyloxy-, C １ -C ６ Alkoxycarbonyloxy-, C １ -C ６ Alkylcarbonylthio-, C １ -C ６ Alkylaminocarbonyl-, di(C １ -C ６ ) optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkylaminocarbonyl, fluorine or chlorine atoms, and hydroxyl; f is an integer from 0 to 2; however, When X does not contain a -C(=O)O- motif with the carbonyl carbon in the alpha or beta position relative to the oxygen atom of general formula (II), Y is an oxamide, carbamate or carbamide, preferably Y is an oxamide as defined above. A pharmaceutical composition comprising a compound of general formula (I) or a pharmaceutically acceptable salt thereof for use in treating, reducing the risk of developing, or preventing a disease (preferably selected from cardiovascular diseases and metabolic diseases) associated with elevated GDF-15 plasma levels (preferably, the GDF-15 plasma level is at least 1000 ng / L).

2. The pharmaceutical composition according to claim 1, however, When n is 3, 5, 6, 7, or 8, k is 1, and E is a group represented by general formula (III) or (IV), wherein R １２ and R １３ each of is a hydrogen atom; P represents the following group: 【Chemistry 11】 During the ceremony, X ８１ represents a group selected from the group consisting of: 【Chemistry 12】 R １’ is the above R １ It is defined as: R ２’ is -NHR ３’ ;-OR ２２’ ; -(OCH ２ -CH ２ ) ｉ -R ２３ ; a monosaccharide or disaccharide, or derivative thereof, linked to the —C(═O) by an ester bond through the 1-O—, 3-O—, or 6-O— position of the sugar; or R ２ is selected from the group consisting of: 【Chemistry 13】 where: R ３’ (SO ２ R ３０ ); (OR ３１ ); -C １ -C ６ Alkanediyl (SO ２ R ３２ ); or -C ２ -C ６ Alkanediyl (CO ２ H); R ２２’ is hydrogen or C ３ -C ６ is a cycloalkyl group, which is -NH ２ , —NH(C １ -C ６ ) alkyl, —N(C １ -C ６ ) dialkyl, —NH(C １ -C ６ ) Alkyldiyl-C １ -C ６ Alkoxy, 1, 2 or 3 fluorine or chlorine atoms, hydroxy or C １ -C ６ optionally substituted with alkoxy; R ２３ and i is as defined above; R ２４ , R ２５ , R ２６ , and R ２７ is as defined above; R ４’ is the above R ４ and h is as defined above; R ６’ and R ７’ is the above R ６ and R ７ It is defined as: R ９’ is the above R ９ is defined as: R ９’’ is C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Alkylthio, fluorine atom or chlorine atom, hydroxyl group, amino group, —NH(C １ -C ６ alkyl), -N(C １ -C ６ 2. The pharmaceutical composition of claim 1, wherein R represents aryl, which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of dialkyl, and oxo substituents.

3. The pharmaceutical composition according to claim 1 or 2, where X is: 【Chemistry 14】 In the formula, R ２ is -OR ２２ ; -(OCH ２ -CH ２ ) ｉ -R ２３ ; a monosaccharide or disaccharide, or derivative thereof, linked to the —C(═O) by an ester bond through the 1-O—, 3-O—, or 6-O— position of the sugar; or R ２ is selected from the group consisting of: 【Chemistry 15】 R ２３ and i is as defined above; and, Here, R ２２ and R ２３ ~R ２７ is as defined in claim 1; The pharmaceutical composition according to claim 1 or 2.

4. 3. A medicament according to claim 1 or 2, wherein X is -C(=O)OH or a suitable salt of a carboxylic acid, preferably a free carboxylic acid.

5. 3. The medicament according to claim 1 or 2, wherein Y is one of the oxamides defined in claim 1.

6. The pharmaceutical composition according to claim 1 or 2, X is: 【Chemistry 16】 In the formula, R ２ is -OR ２２ ; -(OCH ２ -CH ２ ) ｉ -R ２３ ; a monosaccharide or disaccharide, or derivative thereof, linked to the —C(═O) by an ester bond through the 1-O—, 3-O—, or 6-O— position of the saccharide; or ２ is selected from the group consisting of: 【Chemistry 17】 Here, R ２２ , R ２３ ~R ２７ 3. The method of claim 1, wherein i and i are as defined in claim 1, and Y is one of the oxamides defined in claim 1.

7. 3. A medicament according to claim 1 or 2, wherein X is C(=O)OH, preferably a free carboxylic acid, and Y is one of the oxamides defined in claim 1.

8. 10. The pharmaceutical of claim 1, having the following formula (V): 【Chemistry 18】 During the ceremony, R ５５ is -OH, -OR ２２ ; -(OCH ２ -CH ２ ) ｉ -R ２３ ; represents a monosaccharide or disaccharide, or derivative thereof, linked to the —C(═O) by an ester bond through the 1-O—, 3-O—, or 6-O— position of the sugar; R ２２ , R ２３ and i are as defined in claim 1, preferably R ２２ is a hydrogen atom or C １ -C ６ an alkyl group, more preferably a hydrogen atom, and i is preferably 2 to 4, more preferably 3; Y represents a group selected from the group consisting of: 【Chemistry 19】 In the formula, R ４０ ~R ５０ is as defined in claim 1, preferably R ４０ is a hydrogen atom or C １ -C ６ an alkyl group, more preferably a hydrogen atom; R ５７ and R ５８ is hydrogen; or C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Alkylthio, fluorine atom or chlorine atom, hydroxyl group, amino group, -NH(C １ -C ６ alkyl), -N(C １ -C ６ ) which together form a 5- or 6-membered ring, preferably an aromatic ring, optionally substituted with 1 to 3 or 1 to 4 substituents independently selected from the group consisting of dialkyl, and oxo substituents; s is 0, 1 or 2, but R ５７ and R ５８ are taken together to form a 5- or 6-membered ring, then s is 0; The double bond in formula (V) is R ５７ and R ５８ is hydrogen, or when this double bond is R ５７ and R ５８ represents a carbon-carbon double bond in a cis configuration when it is part of a five- or six-membered ring formed together by The pharmaceutical composition according to claim 1.

9. The pharmaceutical composition according to claim 8, During the ceremony, R ５５ is -OH or -(OCH ２ -CH ２ ) ｉ -R ２３ i is 2 to 4, preferably 3; R ２３ is preferably OH; Y is oxamide, carbamide or carbamate, preferably C １ -C ６ alkyl-substituted oxamides, carbamides, or carbamates; R ５７ and R ５８ are both H or taken together form a substituted or unsubstituted 5- or 6-membered aromatic ring, preferably a substituted or unsubstituted benzyl ring; and R ５７ and R ５８ when taken together to form a substituted or unsubstituted 5- or 6-membered aromatic ring, s is 1 or s is 0; The pharmaceutical composition according to claim 8.

10. The pharmaceutical composition according to claim 1 or 2, The compound is a compound selected from the group consisting of: 【Chemistry 20】 【change】 【change】 The pharmaceutical composition according to claim 1 or 2.

11. 10. The pharmaceutical composition of claim 1, 2, 8 or 9, which is a compound having the following formula (VI) or a pharmaceutically acceptable salt thereof: 【Chemical 21】 The pharmaceutical composition according to claim 1, 2, 8 or 9.

12. The medicament according to claim 1, 2, 8 or 9, wherein the disease associated with elevated GDF-15 plasma levels (preferably a GDF-15 plasma level of at least 1000 ng / L) is a cardiovascular disease, and preferably the cardiovascular disease is selected from atrial fibrillation, bleeding risk associated with atrial fibrillation, coronary artery disease (CAD), angina pectoris, myocardial infarction, stroke, heart failure, hypertensive heart disease, rheumatic heart disease, cardiomyopathy, congenital heart disease, valvular heart disease, carditis, aortic aneurysm, peripheral arterial disease, thromboembolism, and venous thrombosis.

13. The medicament according to claim 1, 2, 8 or 9, wherein the disease associated with an elevated GDF-15 plasma concentration (preferably a GDF-15 plasma concentration of at least 500 ng / L) is a metabolic disease, and preferably the metabolic disease is selected from diabetes, dyslipidemia, and metabolic syndrome.

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