CYP-eicosanoid analogs for treatment or prevention of diseases associated with neovascularization and / or inflammation

Abstract

The present invention relates to compounds of formula (VI) which are metabolically stable analogs of bioactive lipid mediators derived from omega-3 polyunsaturated fatty acids (n-3 PUFAs), the compounds are useful for treating (i) a neovascularization disease and / or (ii) an inflammatory disease or for reducing the risk of developing (i) a neovascularization disease and / or (ii) an inflammatory disease or for preventing (i) a neovascularization disease and / or (ii) an inflammatory disease, in particular ophthalmic diseases associated with neovascularization and / or inflammation.

Description

[0001] This application is a divisional application of the Chinese invention application with application number 201780030614.6, application date April 3, 2017, and invention name “CYP-eicosanoid analogs for treating or preventing diseases associated with neovascularization and / or inflammation”. Technical Field

[0002] The present invention relates to compounds according to general formula (I), which are metabolically stable analogs of bioactive lipid mediators derived from ω-3 polyunsaturated fatty acids (n-3 PUFA), for use in treating or reducing the risk of developing or preventing: (i) neovascularization diseases and / or (ii) inflammatory diseases, in particular ophthalmic diseases associated with neovascularization and / or inflammation. Background Art

[0003] Omega-6 and omega-3 polyunsaturated fatty acids (n-6 and n-3 PUFAs) are important components of the mammalian diet. The biologically most important n-3 PUFAs are eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3). Dietary n-3 polyunsaturated fatty acids have an impact on a variety of physiological processes that affect normal health and chronic diseases, such as the regulation of blood lipid levels, cardiovascular and immune function, inflammation, the action of insulin, neuronal development, and visual function.

[0004] Ingestion of n-3 PUFAs results in their distribution to nearly every cell in the body, influencing membrane composition and function, eicosanoid synthesis, signal transduction, and regulation of gene expression.

[0005] Epidemiological and experimental studies have shown that consumption of n-3PUFAs is associated with a reduced risk of macular degeneration. A major common mechanism for protection against macular degeneration and cancer lies in the ability of n-3PUFAs to inhibit pathological angiogenesis. EPA and DHA inhibit abnormal retinal neovascularization, vascular permeability, and inflammation. Angiogenesis is an essential step in tumor growth and metastasis, which is promoted by n-6PUFAs and n-6PUFA-derived metabolites but inhibited by n-3PUFAs and n-3PUFA-derived metabolites.

[0006] Simopoulos and colleagues summarized animal experiments and clinical intervention studies, indicating that n-3-PUFA has anti-inflammatory properties and may be useful for the control of inflammation and autoimmune diseases (Simopoulos AP. Omega-3 fatty acids in inflammation and autoimmune diseases. J Am. Coll. NutL 2L 495-505 (2002)). Among n-3-PUFA, EPA and DHA play an important and powerful role in anti-inflammatory effects (Calder CP, Marine omega-3 fatty acids and inflammatory processes: Effects, mechanisms and clinical relevance, Biochimica et Biophsica Acta-Molecular and Cell Biology of Lipid, Vol. 1851 (4), April 2015, 469-484).

[0007] Koto and colleagues showed that EPA has anti-inflammatory activity in a mouse choroidal neovascularization (CNV) model (Koto et al., Eicosapentaenoic Acid Is Anti-Inflammatory in Preventing ChoroidalNeovascularization in Mice. Invest Ophthalmol Vis Sci. 2007; 48: 4328–4334). They demonstrated that a diet rich in EPA significantly inhibited CNV-associated inflammatory molecules, such as ICAM-1 and MCP-1 in endothelial cells and VEGF and IL-6 in macrophages in vivo and in vitro. Yanai and colleagues demonstrated that dietary n-3 PUFA enrichment inhibited choroidal neovascularization in a mouse model of age-related macular degeneration (AMD) (Yanai et al., Cytochrome P450-generated metabolites derived from ω-3 fatty acids attenuateneovascularization. Proc Natl Acad Sci USA. 2014 Jul 1; 111(26): 9603-8.). In addition, they have demonstrated that n-3PUFA has anti-inflammatory properties in this model. This is manifested in a significant reduction in systemic immune cell recruitment and downregulation of Icam-1 and E-selectin expression on endothelial cells and downregulation of ICAM-1 ligand CD11b-CD18 on the surface of circulating leukocytes. N-3PUFA can also inhibit macrophage invasion of CNV lesions. They further showed that this effect is mediated by bioactive lipid mediators generated by CYP derived from ω-3 LCPUFA, in particular by the main CYP epioxidase metabolites derived from EPA (17, 18-EEQ) and DHA (19, 20-EDP) (Yanai et al., Cytochrome P450-generated metabolites derived from ω-3 fatty acids attenuateneovascularization Proc Natl Acad Sci USA. 2014 July 1; 111 (26): 9603-8 and WO2014 / 110261 A1).

[0008] The laser-induced mouse CNV model is a widely accepted model for testing the effectiveness of potential drugs in treating ophthalmic diseases associated with neovascularization and / or inflammation, particularly AMD. In addition, ocular neovascularization diseases such as AMD are suspected to have an important inflammatory component (Lopez et al., Pathologic features of surgically excised subretinal neovascular membranes in age-related macular degeneration. Am J Ophthalmol. 1991; 112(6):647-656.; Grossniklaus et al., Macrophage and retinal pigment epithelium expression of angiogenic cytokines inchoroidal neovascularization. Mol Vis. 2002 Apr 21; 8:119-26; Lopez et al., Transdifferentiated retinal pigment epithelial cells are immunoreactive for vascular endothelial growth factor in surgically excised age-related macular degeneration-related choroidal neovascular membranes. Invest Ophthalmol Vis Sci. 1996, 37(5):855-868; Tezel et al., Pathogenesis of age-related macular degeneration. Trends Mol Med. 2004; 10(9): 417-420.; Schlingemann RO-Role of growth factors and the wound healing response in age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol. 2004; 242(1): 91-101). Grossniklaus and colleagues showed that in choroidal samples from patients with AMD, the progression of CNV exhibits a dynamic process with not only angiogenesis but also a strong inflammatory component, especially macrophages.Based on the fact that Ambati and his colleagues linked the pathogenesis of AMD to the complement system and macrophages (Ambati et al. An animal model of age-related macular degeneration in senescent Ccl-2-or Ccr-2-deficient mice. Nat. Med. 2003, 9, 1390–1397), the inflammatory component of AMD was further deciphered and greatly changed the understanding of the pathogenesis of AMD. After that, many research groups further explored the role of inflammatory processes in the pathogenesis of AMD and CNV, such as the recent work analyzing macrophage polarization in experimental and clinical choroidal neovascularization (Yang et al. Macrophage polarization in experimental and clinical choroidalneovascularization. Sci Rep., August 4, 2016, 6: 30933). A recent review by David Hinton's group, a pioneer in CNV research, and Campa et al. (Inflammatory mediators and angiogenic factors in choroidal neovascularization: pathogenic interactions and therapeutic implications. Mediators of Inflammation, 2010) has well summarized the role of inflammation in the pathogenesis of AMD and the resulting fibrosis (Ishikawa et al. Molecular mechanisms of subretinal fibrosis in age-related macular degeneration. Exp Eye Res. 2016 January, 142: 19-252016) and summarized that CNV causes a heterogeneous disease affecting the posterior segment of the eye, which is more appropriately defined as an abnormal tissue invasion of endothelial cells and inflammatory cells, involving angiogenesis and inflammation.

[0009] Obviously, the laser-induced CNV model, which is widely used to elucidate the pathology of choroidal angiogenesis and identify new therapeutic applications (Grossniklaus et al., 2010), has a strong inflammatory stimulus due to the damage after laser burn of Bruch's membrane. Therefore, in addition to anti-angiogenic compounds, many anti-inflammatory compounds show a wide range of activities, and this model can also be considered a model of ocular inflammation and treatment response, and technicians regard the model of ocular inflammation as evidence of the applicability of compounds in the treatment of these inflammations.

[0010] During inflammation, circulating monocytes increasingly leave the circulation and migrate into tissues where they differentiate into macrophages or dendritic cell populations after being regulated by local growth factors, proinflammatory cytokines, and microbial products. In the rat model shown in Example 5, this event can be seen by staining the ED1-positive monocytes / macrophages infiltrating heart and kidney sections with their respective antibodies. In general, the recruitment of monocytes is essential for the effective control and removal of viral, bacterial, fungal, and protozoan infections, but recruited monocytes also contribute to the pathogenesis of inflammatory and degenerative diseases (Shi C., et al., Monocyte recruitment during infection and inflammation. Nat Rev Immunol. 2011 Oct 10; 11(11)762-74). In addition to promoting atherosclerosis, recruited monocytes / macrophages are known to contribute to acute and chronic inflammatory diseases of the heart and kidney (Ingersoll et al., Monocyte trafficking in acute and chronic inflammation. Trends Immuno 2011 Oct. 32(10)470-7; Hansson G., Inflammation, Atherosclerosis, and Coronary Artery Disease. New Engl Jour Med 2005, (352)1685-95; Kinsey et al., Imflammation in Acute Kidney Injury. Experim Nephro 2008, (109)e102-e107; Bonventre, J. Cellular pathophysiology of ischemic acute kidney injury. J Clinic Invest 2011 Nov, (121)4210-4221; Guiteras R. et al., Macrophage in chronic kidney disease. Cli Kidney Injury 2011 Nov, (121)4210-4221). j2016,vol.9,no 6,765-771).

[0011] The production of TNF-α plays an important role in chronic inflammatory conditions, in vivo metabolism and cardiovascular risk (Popa C. et al., The role of TNF-alpha in chronic inflammatory conditions, intermediarymetabolism, and cardiovascular risk. J Lipid Res 2007, (48) 752-761). The pathogenesis of several chronic inflammatory diseases is related to abnormal TNF-α production and TNF receptor signaling (Parameswaran N. et al., Tumor Necrosis Factor-αSignaling in Macrophages. Crit Rev Eukaryot Gene Expr 2010 20 (2) 87-103). TNF-α has multiple and potentially conflicting roles in cardiac function and pathology (Sack M., Tumor necrosis factor-alpha in cardiovascular biology and the potential role for anti-tumor necrosis factor-alpha therapy in heartdisease. Pharmacol Ther 2002 April to May 2002, 94 (1-2) 123-135). As also shown in Example 4, TNF-α can be produced in response to proinflammatory stimuli in cardiomyocytes themselves. After release into peripheral tissues, TNF-α, together with a variety of other mediators, triggers the activation and recruitment of leukocytes (Ghigo A. et al., Myocyte signalling in leucocyte recruitment to the heart. Cardiovasc Res 2014 May. 102(2)270-280).

[0012] One of the most important biological roles of PUFAs is to provide precursors for the production of bioactive fatty acid metabolites that regulate a variety of functions. For example, arachidonic acid (AA; 20:4, n-6) is metabolized by cytochrome P450 (CYP) enzymes into several classes of oxygenated metabolites with strong biological activity. The major metabolites include 20-hydroxyeicosatetraenoic acid (20-HETE) and a series of regioisomeric and stereoisomeric epoxyeicosatrienoic acids (EETs). CYP4A and CYP4F isoforms produce 20-HETE and CYP2C and CYP2J isoforms produce EETs.

[0013] It is known that EPA (20: 5, n-3) and DHA (22: 6, n-3) can be used as alternative substrates for AA-metabolizing CYP isoforms (Arnold C. et al., J Biol Chem. 2010 Oct 22; 285(43): 32720-33.; Fischer R. et al., J Lipid Res. 2014 Mar 16; 55(6): 1150-1164.). CYP2C and CYP2J subfamily members that epoxidize AA to EET metabolize EPA to epoxyeicosatetraenoic acid (EEQ) and DHA to epoxydocosapentaenoic acid (EDP). The ω-3 double bond that distinguishes EPA and DHA from AA is the preferred attack site for most cyclooxygenases, resulting in the formation of 17,18-EEQ and 19,20-EDP as the major metabolites. CYP4A and CYP4F isoforms that hydroxylate AA to 20-HETE metabolize EPA to 20-hydroxyeicosapentaenoic acid (20-HEPE) and DHA to 22-hydroxydocosahexaenoic acid (22-HDHA). CYP1A1, CYP2E1, and other isoforms that primarily convert AA to 19-HETE show significant ω-3 epioxidase activity for EPA and DHA. Human CYP1A1 variants result in differential eicosapentaenoic acid metabolite patterns. Cytochrome P450-dependent eicosapentaenoic acid metabolites are a novel BK channel activator. A notable feature of CYP-dependent n-3PUFA metabolism is the preferred epoxidation of the n-3 double bond, which distinguishes EPA and DHA from AA. The resulting metabolites (17,18-EEQ from EPA and 19,20-EDP from DHA) are unique in that there are no homologues in the AA series of products. Consistent with the substrate specificity of the CYP isoforms, dietary EPA / DHA supplementation resulted in a profound shift from AA-derived epoxy and ω-hydroxy metabolites to EPA- and DHA-derived epoxy and ω-hydroxy metabolites in all major organs and tissues of rats and, presumably, humans.

[0014] EET and 20-HETE play an important role in the regulation of various cardiovascular functions (Roman RJ., Physiol Rev. 2002; 82: 131-85). It has been shown that in the double transgenic rat (dTGR) model of Ang II-induced hypertension and end-organ damage (Luft et al., Hypertension. 1999; 33: 212-8), Ang II-induced hypertension is associated with downregulation of CYP-dependent AA metabolism (Kaergel et al., Hypertension. 2002; 40: 273-9). Transgenic rats carry human renin and angiotensinogen genes, locally produce Ang II and develop significant hypertension, myocardial infarction and albuminuria. Animals die of myocardial and renal failure before the eighth week of age. This model shows severe features of Ang II-induced inflammation. Reactive oxygen species are produced, transcription factors NF-κB and AP-1 are activated, and genes with binding sites for these transcription factors are activated.

[0015] Recently, it has been shown that supplementation with eicosapentaenoic acid (EPA) significantly reduces mortality in dTGR (Theuer et al., Kidney Int. 2005; 67: 248-58). In addition, it has been shown that the development of ventricular arrhythmias in dTGR is based on Ang II-induced electrical remodeling (Fischer et al., Am J Physiol Heart Circ Physiol. 2007; 293: H1242-1253). Treatment of dTGR rats with PPAR-α activators strongly induced the generation of CYP2C23-dependent EETs and prevented hypertension and end-organ damage (Muller et al., Am J Pathol. 2004; 164: 521-32).

[0016] Long-term feeding of dTGR (from 4 to 7 weeks of age) with a mixture of pure EPA-ethyl ester and DHA-ethyl ester (Omacor from Solvay Arzneimittel, Hannover, Germany) improved electrical remodeling of the heart in this model of angiotensin II-induced hypertension. In particular, EPA and DHA reduced mortality, inhibited the inducibility of arrhythmias and prevented connexin 43 gap junction remodeling (Fischer et al., Hypertension. 2008 Feb; 51(2):540-6). In general, CYP-dependent eicosanoids must be considered as second messengers: EETs and 20-HETEs are produced by CYP enzymes after extracellular signals induce the release of AA from membrane phospholipids (via phospholipase A2) and play their role in signal transduction pathways that regulate ion transport, cell proliferation and inflammation. Depending on the diet, n-3 PUFA partially replaces AA at the sn2 position of phospholipids and can therefore participate in subsequent signal transduction pathways as alternative molecules.

[0017] The few studies on the bioactivity of CYP-dependent eicosanoids in the heart have shown that EETs and 20-HETE play a role in regulating L-type Ca 2+ ATP-sensitive potassium (K) channels and sarcolemmal and mitochondrial ATP ) channels. In cardiac myocytes, L-type Ca 2+ Current flow and cell shorting were reduced when EET production was inhibited, and these effects could be reversed by adding 11,12-EET (Xiao et al., J Physiol. 1998;508(Pt 3):777-92). EETs have also been shown to activate cardiac K ATP The effect is highly stereoselective: only the S, R enantiomers of 11,12-EET are effective, but not their R, S enantiomers (Lu et al., Mol Pharmacol. 2002; 62: 1076-83). Overexpression of human CYP2J2 produced by EET activates K ATP 20-HETE appears to improve post-ischemic functional recovery in transgenic mouse hearts (Seubert et al., Circ Res. 2004; 95: 506-14). ATP Channel blockers have the opposite effect (Gross et al., J Mol Cell Cardiol. 2004; 37: 1245-9; Nithipatikom et al., Circ Res. 2004; 95: e65-71).

[0018] Although n-3PUFA-derived CYP metabolites, such as 17,18-EEQ and 19,20-EDP, play an important role in mediating the beneficial effects of n-3PUFA in mammals, they cannot be used as therapeutic drugs due to their limited bioavailability and chemical and metabolic instability. These n-3PUFA epoxy metabolites are susceptible to auto-oxidation, are rapidly inactivated by soluble epoxide hydrolases, and are degraded by β-oxidation.

[0019] The problem underlying the present invention is therefore to provide improved n-3 PUFA metabolite analogs for use in treating, reducing the risk of developing or preventing diseases associated with neovascularization and / or inflammation, in particular ophthalmic diseases associated with neovascularization and / or inflammation. Summary of the invention

[0020] In a first aspect, the above problem is solved by providing the following solution: a compound of formula (I)

[0021] PEI(I)

[0022] or a pharmaceutically acceptable salt thereof, for use in treating a disease associated with neovascularization and / or inflammation, reducing the risk of developing a disease associated with neovascularization and / or inflammation, or preventing a disease associated with neovascularization and / or inflammation, wherein

[0023] P is a group represented by the general formula (II):

[0024] –(CH2) n -O-(CH2) k -X(II)

[0025] in

[0026] n is 0 or an integer from 3 to 8, i.e. 3, 4, 5, 6, 7 or 8, preferably 3; and

[0027] k is 0, 1 or 2; preferably, provided that when n is 0, k is 1, and most preferably k is 1;

[0028] X represents CH2OH, CH2OAc, CH(O) or a group selected from the following:

[0029]

[0030]

[0031] Preferably X is

[0032] in

[0033] R and R' each independently represent a hydrogen atom; or a C1 to C6 alkyl group which may be substituted with one or more fluorine atoms or chlorine atoms or a hydroxyl group;

[0034] R 1 represents a hydroxyl group, a C1 to C6 alkoxy group, -NHCN, -NH(C1 to C6 alkyl group), -NH(C3 to C6 cycloalkyl group), -NH(aryl group) or -O(C1 to C6 alkanediyl group)O(C=O)R 11 ; R 11 is a C1 to C6 alkyl group optionally substituted by one or more fluorine atoms or chlorine atoms; or a C3 to C6 cycloalkyl group optionally substituted by one or more fluorine atoms or chlorine atoms or hydroxyl groups;

[0035] R 2 Representative - NHR 3 ;-NR 20 R 21 ;-OR 22 ; -(OCH2-CH2) i -R 23 ;-C3 to C 10 heterocyclyl, which is optionally substituted by one, two or three substituents independently selected from hydroxy, C1 to C6 alkoxy, C1 to C6 alkyl and oxo; -(Xaa) o ; a monosaccharide, or a disaccharide, or a derivative thereof, which is linked to -C(O) at the 1-O-, 3-O- or 6-O-position of the sugar via an ester bond;

[0036] Or choose from:

[0037]

[0038] in

[0039] R 3 stands for (SO2R 30 );(OR 31 ); -C1 to C6 alkanediyl (SO2R 32 ); -C1 to C6 alkanediyl (CO2H); aryl; heteroaryl; cycloalkyl or heterocycloalkyl; wherein the aryl group is optionally independently selected from C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 alkylthio, fluorine or chlorine atoms, hydroxyl, amino, -NH (C1 to C6 alkyl), -N (C1 to C6) dialkyl and -C (= O) OR 51 wherein the heteroaryl group is optionally substituted by one, two or three substituents independently selected from C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 alkylthio, fluorine or chlorine atoms, hydroxyl, amino, -NH (C1 to C6 alkyl), -N (C1 to C6) dialkyl and -C (= O) OR 51wherein the cycloalkyl group is optionally independently selected from C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 alkylthio, fluorine atom or chlorine atom, hydroxyl, amino, -NH (C1 to C6 alkyl), -N (C1 to C6) dialkyl, -C (= O) OR 51 wherein the heterocycloalkyl group is optionally independently selected from C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 alkylthio, fluorine or chlorine atoms, hydroxyl, amino, -NH (C1 to C6 alkyl), -N (C1 to C6) dialkyl and -C (= O) OR 51 substituted with one, two or three substituents;

[0040] R 30 is a C1 to C6 alkyl group or an aryl group, wherein the C1 to C6 alkyl group is optionally substituted by -NH2, -NH(C1 to C6)alkyl, -N(C1 to C6)dialkyl, C1 to C6 alkylcarbonyloxy-, C1 to C6 alkoxycarbonyloxy-, C1 to C6 alkylcarbonylthio-, C1 to C6 alkylaminocarbonyl-, di(C1 to C6)alkylaminocarbonyl-, one, two or three fluorine atoms or chlorine atoms, or hydroxyl group; wherein the aryl group is optionally substituted by one, two or three substituents independently selected from C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 alkylthio, fluorine atoms or chlorine atoms, hydroxyl, amino, -NH(C1 to C6 alkyl), and -N(C1 to C6)dialkyl;

[0041] R 31 is a C1 to C6 alkyl group optionally substituted by one or more fluorine atoms, chlorine atoms or hydroxyl groups; or a C3 to C6 cycloalkyl group optionally substituted by one or more fluorine atoms, chlorine atoms or hydroxyl groups;

[0042] R 32 is a C1 to C6 alkyl group optionally substituted by one or more fluorine atoms, chlorine atoms or hydroxyl groups; or a C3 to C6 cycloalkyl group optionally substituted by one or more fluorine atoms, chlorine atoms or hydroxyl groups;

[0043] R 20 and R 21 each independently represents a hydrogen atom; a C1 to C6 alkyl group which may be substituted by one or more fluorine atoms, chlorine atoms or hydroxyl groups; a C3 to C6 cycloalkyl group which may be substituted by one or more fluorine atoms, chlorine atoms or hydroxyl groups; a -C1 to C6 alkanediyl group (CO2H) or a C3 to C6 cycloalkyl group which may be substituted by one or more fluorine atoms, chlorine atoms or hydroxyl groups; 10 -heterocycloalkyl, the C3 to C 10 - the heterocycloalkyl group may be substituted by one or more than one C1 to C6 alkyl group, C1 to C6 alkoxy group, fluorine atom or chlorine atom or hydroxyl group;

[0044] R22 is a hydrogen atom, a C1 to C6 alkyl group; or a C3 to C6 cycloalkyl group; wherein the C1 to C6 alkyl group or the C3 to C6 cycloalkyl group is optionally substituted by -NH2, -NH(C1 to C6)alkyl, -N(C1 to C6)dialkyl, -NH(C1 to C6)alkanediyl-C1 to C6 alkoxy, one, two or three fluorine atoms or chlorine atoms, a hydroxyl group, or a C1 to C6 alkoxy group, an aralkyl group, a heteroalkyl group or a heteroalkylcycloalkyl group;

[0045] R 23 is -OH, -O(C1 to C3)alkyl, or -N(C1 to C3)dialkyl;

[0046] i is an integer from 1 to 10;

[0047] R 24 , R 25 and R 26 Each independently represents a hydrogen atom; -C(=O)C 11 To C 21 Alkyl; or -C(=O)C 11 To C 21 alkenyl;

[0048] R 27 represents -OH; -O(CH2)2NH2, -OCH2-[CH(NH2)(CO2H)], -O(CH2)2N(CH3)3; or

[0049] Xaa represents Gly, conventional D, L-, D- or L-amino acid, unconventional D, L-, D- or L-amino acid, or 2 to 10 peptides; linked to -C(=O) via an amide bond;

[0050] o is an integer from 1 to 10;

[0051] R 4 Selected from:

[0052]

[0053] h is 0, 1, or 2;

[0054] R 5 represents a hydrogen atom; a fluorine atom or a chlorine atom; -CF3; -C(=O)OR 51 ;

[0055] -NHC(=O)R 52 ; -C(=O)NR 53 R 54 ; or -S(O2)OH;

[0056] R 51represents a hydrogen atom, a C1 to C6 alkyl group; or a C3 to C6 cycloalkyl group; wherein the C1 to C6 alkyl group or the C3 to C6 cycloalkyl group is optionally substituted by -NH2, -NH(C1 to C6)alkyl, -N(C1 to C6)dialkyl, -NH(C1 to C6)alkanediyl-C1 to C6alkoxy, one, two or three fluorine atoms or chlorine atoms, a hydroxyl group, or a C1 to C6alkoxy group;

[0057] R 52 , R 53 and R 54 each independently represents a C1 to C6 alkyl group optionally substituted by one or more than one fluorine atom or chlorine atom; a C3 to C6 cycloalkyl group optionally substituted by one or more than one fluorine atom or chlorine atom; or an aryl group optionally substituted by one, two or three substituents independently selected from the group consisting of a C1 to C6 alkyl group, a C1 to C6 haloalkyl group, a C1 to C6 alkoxy group, a C1 to C6 alkylthio group, a fluorine atom or a chlorine atom, a hydroxyl group, an amino group, -NH(C1 to C6 alkyl group), -N(C1 to C6)dialkyl group and an oxo substituent;

[0058] R 6 and R 7 each independently represents a hydroxyl group; -O(C1 to C6)alkyl, -O(C2 to C6)alkenyl, -O(C1 to C6)alkanediylO(C=O)(C1 to C6)alkyl, or -O(C1 to C6)alkanediylO(C=O)(C2 to C6)alkenyl; wherein the C1 to C6 alkyl and C2 to C6 alkenyl groups may be substituted by NH2, -NH(C1 to C6)alkyl, -N(C1 to C6)dialkyl, C1 to C6 alkylcarbonyloxy-, C1 to C6 alkoxycarbonyloxy-, C1 to C6 alkylcarbonylthio-, C1 to C6 alkylaminocarbonyl-, di(C1 to C6)alkylaminocarbonyl-, or one, two or three fluorine atoms or chlorine atoms; or

[0059] R 6 represents hydroxyl group and R 7 Represents the following groups:

[0060]

[0061] R 9represents a C1 to C6 alkyl or aryl group; wherein the C1 to C6 alkyl group is optionally substituted by -NH2, -NH(C1 to C6)alkyl, -N(C1 to C6)dialkyl, -NH(C1 to C6)alkanediyl-C1 to C6alkoxy, one, two or three fluorine atoms or chlorine atoms, hydroxyl, C1 to C6alkoxy, aryl, aryloxy, -C(=O)-aryl, -C(=O)C1 to C6alkoxy; wherein the aryl group is optionally substituted by one, two or three substituents independently selected from C1 to C6 alkyl, C1 to C6alkoxy, C1 to C6alkylthio, fluorine atoms or chlorine atoms, hydroxyl, amino, -NH(C1 to C6alkyl),

[0062] -N(C1 to C6)dialkyl, and oxo substituents;

[0063] g is 1 or 2, preferably 2;

[0064] X 1 represents an oxygen atom; a sulfur atom; or NH;

[0065] X 2 represents an oxygen atom; a sulfur atom; NH; or N(CH3);

[0066] X 3 represents an oxygen atom; a sulfur atom; a nitrogen atom; a carbon atom; or C-OH; and a dotted line represents a carbon-carbon bond or a carbon-carbon double bond;

[0067] E is a group represented by the general formula (III) or (IV):

[0068]

[0069] Where R 12 and R 13 The cis configuration is preferred, and wherein

[0070] Ring A in formula (III) represents a 5-membered or 6-membered carbocyclic or heterocyclic ring containing at least one double bond, including an aromatic carbocyclic or heterocyclic ring which may be substituted by one to three or one to four substituents, wherein the substituents are independently selected from C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 alkylthio, fluorine atom or chlorine atom, hydroxyl, amino, -NH(C1 to C6 alkyl), and -N(C1 to C6)dialkyl; L and T each independently represent a ring-forming atom, wherein L and T are adjacent to another ring-forming atom;

[0071] R 12 and R 13Each independently represents a hydrogen atom, a fluorine atom, a hydroxyl group, -NH2, a C1 to C6 alkyl group, a C1 to C6 alkoxy group, -C(=O)-aryl group, -C(=O)C1 to C6 alkyl group, or -SO2(C1 to C6 alkyl group); or -SO2 alkyl group; wherein any of the aforementioned C1 to C6 alkyl groups, C1 to C6 alkoxy groups or aryl groups are optionally substituted by one, two or three substituents independently selected from -NH2, -NH(C1 to C6)alkyl group, -N(C1 to C6)dialkyl group, C1 to C6 alkylcarbonyloxy-, C1 to C6 alkoxycarbonyloxy-, C1 to C6 alkylcarbonylthio-, C1 to C6 alkylaminocarbonyl-, di(C1 to C6)alkylaminocarbonyl-, a fluorine atom or a chlorine atom, and a hydroxyl group; or R 12 and R 13 together form a 5-membered or 6-membered ring, which is optionally substituted by one, two or three substituents independently selected from -NH2, -NH(C1 to C6)alkyl, -N(C1 to C6)dialkyl, C1 to C6 alkylcarbonyloxy-, C1 to C6 alkoxycarbonyloxy-, C1 to C6 alkylcarbonylthio-, C1 to C6 alkylaminocarbonyl-, di(C1 to C6)alkylaminocarbonyl-, fluorine atom or chlorine atom, and hydroxyl group;

[0072] I is -(CH2) m -Y, where

[0073] m is an integer from 3 to 6, i.e. 3, 4, 5 or 6, provided that when E is a group according to formula (III), m is an integer from 3 to 5;

[0074] Y represents -UVW-(CH2) p -(CH3) q , wherein p is an integer from 0 to 6; q is 0 or 1; U is absent or selected from CH, CH2 and NR 40 , provided that if U together with V and W form an epoxy group, then U is only CH; V is selected from -C(O)-, -C(O)-C(O)-, -O-, and -S-; W is selected from CH, CH2 and NR 40 , provided that if W together with U and V forms an epoxy group, then W is only CH;

[0075] Or Y represents a group selected from the following:

[0076]

[0077] in

[0078] R 40 , R 41 , R 43 , R 44 , R 46 , R48 and R 49 Each independently represents a hydrogen atom, a -C1 to C6 alkyl group, a -C3 to C6 cycloalkyl group, a -C1 to C6 alkoxy group, a -C(═O)aryl group, or a -C(═O)C1 to C6 alkyl group, wherein any of the aforementioned C1 to C6 alkyl groups, C3 to C6 cycloalkyl groups, C1 to C6 alkoxy groups or aryl groups are optionally substituted by one, two or three substituents independently selected from -NH2, -NH(C1 to C6)alkyl groups, -N(C1 to C6)dialkyl groups, C1 to C6 alkylcarbonyloxy-, C1 to C6 alkoxycarbonyloxy-, C1 to C6 alkylcarbonylthio, C1 to C6 alkylaminocarbonyl-, di(C1 to C6)alkylaminocarbonyl-, a fluorine atom or a chlorine atom, and a hydroxyl group; or R 40 and R 41 , or R 43 and R 44 , together forming a 5-membered or 6-membered ring, which may be substituted by one, two or three substituents independently selected from -NH2, -NH(C1 to C6)alkyl, -N(C1 to C6)dialkyl, C1 to C6 alkylcarbonyloxy-, C1 to C6 alkoxycarbonyloxy-, C1 to C6 alkylcarbonylthio-, C1 to C6 alkylaminocarbonyl-, di(C1 to C6)alkylaminocarbonyl-, fluorine atom or chlorine atom, and hydroxyl group;

[0079] R 42 , R 45 , R 47 and R 50 Each independently represents -C1-C3 alkyl, wherein the C1-C3 alkyl may be substituted by one, two or three substituents independently selected from -NH2, -NH(C1-C3)alkyl, -N(C1-C3)dialkyl, C1-C3 alkylcarbonyloxy-, C1-C3 alkoxycarbonyloxy-, C1-C3 alkylcarbonylthio-, C1-C3 alkylaminocarbonyl-, di(C1-C3)alkylaminocarbonyl-, fluorine atom or chlorine atom, and hydroxyl group; or R 40 and R 41 ; R 43 and R 44 ; R 49 and R 50 together form a 5-membered or 6-membered ring, which may be substituted by one, two or three substituents independently selected from -NH2, -NH(C1 to C6)alkyl, -N(C1 to C6)dialkyl, C1 to C6 alkylcarbonyloxy-, C1 to C6 alkoxycarbonyloxy-, C1 to C6 alkylcarbonylthio-, C1 to C6 alkylaminocarbonyl-, di(C1 to C6)alkylaminocarbonyl-, fluorine atom or chlorine atom, and hydroxyl;

[0080] f is an integer from 0 to 2;

[0081] Provided that when X does not contain a -C(=O)O- moiety wherein the carbonyl carbon is alpha or beta to the oxygen atom of formula (II), Y is an oxalamide, carbamate or carboxamide, preferably Y is an oxalamide as defined above.

[0082] In a preferred embodiment, the compound of the present invention is a compound of formula (I) as described above, provided that

[0083] When X does not contain a -C(=O)O- moiety, wherein the carbonyl carbon is alpha or beta to the oxygen atom of formula (II), Y is an oxalamide, carbamate or carboxamide, preferably Y is an oxalamide as defined above.

[0084] In a preferred embodiment, the compound of formula (I) is a compound as described above with the further condition that

[0085] When n is 3, 5, 6, 7 or 8, preferably 3, k is 1 and E is a group of the general formula (III) or (IV), wherein R 12 and R 13 Each is a hydrogen atom;

[0086] P represents the following group:

[0087] -(CH2)3-O-(CH2)-X 81 ; -(CH2)5-O-(CH2)-X 81 ;

[0088] in

[0089] or X 81 represents a group selected from the following:

[0090]

[0091] R 1 The definition of ' is the same as above R 1 ;

[0092] R 2 ' indicates -NHR 3 ';-OR 22 ';-(OCH2-CH2) i -R 23 ; a monosaccharide, or a disaccharide or a derivative thereof, which is linked to -C(=O) via an ester bond through the 1-O-, 3-O- or 6-O-position of the sugar;

[0093] or where R 2 Selected from:

[0094]

[0095] in

[0096] R 3 'Represents (SO2R 30 );(OR 31 ); -C1 to C6 alkanediyl (SO2R 32 ); or -C2 to C6 alkanediyl (CO2H);

[0097] R 22 ' is hydrogen or C3 to C6 cycloalkyl, which is optionally substituted by -NH2, -NH(C1 to C6)alkyl, -N(C1 to C6)dialkyl, -NH(C1 to C6)alkanediyl-C1 to C6alkoxy, one, two or three fluorine or chlorine atoms, hydroxyl, or C1 to C6alkoxy;

[0098] R 23 and i is as defined above;

[0099] R 24 , R 25 , R 26 , and R 27 As defined above;

[0100] R 4 ' is R as defined above 4 ; and h is as defined above;

[0101] R 6 ' and R 7 The definition of ' is the same as above R 6 and R 7 ;

[0102] R 8" and R 8" The definition of R is the same as above 8 and R 8 ';

[0103] R 9 The definition of ' is the same as above R 9 ; R 9" represents an aryl group optionally substituted by one, two or three substituents independently selected from C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 alkylthio, fluorine or chlorine atoms, hydroxyl, amino, -NH(C1 to C6 alkyl), -N(C1 to C6)dialkyl, and oxo substituents.

[0104] In a more preferred embodiment, the compound of the present invention is a compound wherein X is

[0105]

[0106] Where R 2 Yes-OR 22; -(OCH2-CH2) i -R 23 ; a monosaccharide, or a disaccharide or a derivative thereof, which is linked to -C(=O) via an ester bond through the 1-O-, 3-O- or 6-O-position of the sugar;

[0107] or where R 2 Selected from:

[0108]

[0109] Where R 23 and i is as defined above, preferably i is 3;

[0110] Where R 22 and R 23 To R 27 As defined in claim 1, preferably R 22 It is a hydrogen atom or a C1 to C6 alkyl group, and is more preferably a hydrogen atom.

[0111] In another more preferred embodiment, the compound of the present invention is a compound wherein X is -C(=O)OH or a suitable carboxylate, preferably a free carboxylic acid.

[0112] In another more preferred embodiment, the compound of the invention is the compound wherein Y is an oxamide as defined above.

[0113] It is further preferred that the compound of the present invention is a compound wherein X is

[0114]

[0115] Where R 2 Yes-OR 22 ; -(OCH2-CH2) i -R 23 ; a monosaccharide, or a disaccharide or a derivative thereof, which is linked to -C(=O) via an ester bond through the 1-O-, 3-O- or 6-O-position of the sugar; or wherein R 2 Selected from:

[0116]

[0117] Where R 22 , R 23 To R 27 and i are as defined above, preferably R 22 is a hydrogen atom or a C1 to C6 alkyl group, more preferably a hydrogen atom, preferably i is 2 to 4, more preferably 3, wherein Y is preferably one of the oxamides defined above.

[0118] In a more preferred embodiment, the compound of the invention is a compound wherein X is C(=O)OH, preferably a free carboxylic acid, and Y is preferably one of the oxamides as defined above.

[0119] In another more preferred embodiment, the compound of the present invention is a compound having the following formula (V):

[0120]

[0121] in

[0122] R 55 Indicates -OH; -OR 22 ; -(OCH2-CH2) i -R 23 ; a monosaccharide, or a disaccharide or a derivative thereof, which is linked to -C(=O) via an ester bond through the 1-O-, 3-O- or 6-O-position of the sugar;

[0123] R 22 , R 23 and i are as defined above, preferably R 22 is a hydrogen atom or a C1 to C6 alkyl group, more preferably a hydrogen atom, and i is preferably 2 to 4, more preferably 3;

[0124] Y represents a group selected from the following:

[0125]

[0126] Among them, the preferred And particularly preferably and

[0127] Where R 40 To R 50 As defined above, preferably R 40 is a hydrogen atom or a C1 to C6 alkyl group, more preferably a hydrogen atom;

[0128] R 57 and R 58 is hydrogen; or together form a five-membered or six-membered ring, preferably an aromatic ring, optionally substituted by one to three or one to four substituents independently selected from C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 alkylthio, fluorine or chlorine atoms, hydroxyl, amino, -NH(C1 to C6 alkyl), -N(C1 to C6)dialkyl, and oxo substituents;

[0129] s is 0, 1, or 2, provided that if R 57 and R 58 Together they form a five-membered or six-membered ring, then s is 0;

[0130] If R 57 and R 58is hydrogen, then the double bond in formula (V) represents a carbon-carbon double bond in the cis configuration, or the double bond is formed by R 57 and R 58 Together they form part of a five- or six-membered ring.

[0131] In another most preferred embodiment, compounds of formula (V) are those compounds wherein

[0132] R 55 Indicates -OH or -(OCH2-CH2) i -R 23 ; i is 2 to 4, preferably i is 3; R 23 Preferably OH;

[0133] Y is oxalamide, carbonamide or carbamate, preferably C1 to C6 alkyl substituted oxalamide, carbonamide or carbamate;

[0134] R 57 and R 58 are all H, or together form a substituted or unsubstituted five-membered or six-membered aromatic ring, preferably a substituted or unsubstituted benzyl ring; and

[0135] If R 57 and R 58 When the two radicals together form a substituted or unsubstituted five-membered or six-membered aromatic ring, s is 1 or s is 0.

[0136] The most preferred specific compounds of the present invention are selected from:

[0137]

[0138]

[0139] and or a pharmaceutically acceptable salt thereof.

[0140] Among the above compounds, the compound having the following formula (VI)

[0141]

[0142] Or a pharmaceutically acceptable salt thereof is most preferred.

[0143] The compounds of the present invention have the advantages demonstrated in the experimental part that they are effective for treating diseases associated with neovascularization and / or inflammation, reducing the risk of developing diseases associated with neovascularization and / or inflammation or preventing diseases associated with neovascularization and / or inflammation, in particular ophthalmic diseases and / or inflammation associated with neovascularization, while they are metabolically stable for pharmaceutical preparations and administration to subjects in need thereof.

[0144] The compounds described herein are generally described using standard nomenclature. For compounds with asymmetric centers, it is understood that all optical isomers and mixtures thereof are encompassed unless otherwise stated. Compounds with two or more asymmetric elements may also exist as mixtures of diastereomers. In addition, compounds with carbon-carbon double bonds may exist in Z-forms and E-forms, and all isomeric forms of the compounds are included in the present invention unless otherwise stated. When compounds exist in various tautomeric forms, the compounds listed are not limited to any one specific tautomer, but are intended to encompass all tautomeric forms. The compounds are also intended to encompass compounds in which one or more atoms are replaced by isotopes, i.e., atoms having the same atomic number but different mass numbers. As a non-limiting general example, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 11 C. 13 C and 14 C.

[0145] Compounds according to the structural formula provided herein and having one or more than one stereocenter have an enantiomeric excess of at least 50%. For example, these compounds may have an enantiomeric excess of at least 60%, 70%, 80%, 85%, 90%, 95%, or 98%. Some embodiments of the compound have an enantiomeric excess of at least 99%. It is apparent that a single enantiomer (optically active form) can be obtained by asymmetric synthesis, synthesis from optically pure precursors, biosynthesis, for example using modified CYP102 (CYP BM-3) or by resolving racemates, for example enzymatic resolution or by conventional methods, such as crystallization in the presence of a resolving agent or chromatographic separation using, for example, a chiral HPLC column.

[0146] This article uses the term "variable" including variables (e.g., P, E, I, R 1 To R 50 , X to X 81 Certain compounds are described by formulae of R and Y. Unless otherwise indicated, each variable in these formulae is defined independently of any other variable, and any variable that occurs more than once in a formula is defined independently at each occurrence. Thus, for example, if a group is represented by 0 to 2R * substituted, the group may be unsubstituted or substituted with up to two R * group substitution, and each occurrence of R * Independently selected from R * In addition, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds, ie, compounds that can be isolated, characterized, and tested for biological activity.

[0147] "Pharmaceutically acceptable salts" of the compounds disclosed herein are acid or base salts that are generally considered in the art to be suitable for use in contact with human or animal tissues without excessive toxicity or carcinogenicity, and preferably without irritation, allergic reactions, or other problems or complications. These salts include inorganic and organic acid salts of basic residues such as amines, and alkali metal or organic salts of acidic residues such as carboxylic acids.

[0148] Suitable pharmaceutically acceptable salts include, but are not limited to, acid salts such as hydrochloride, phosphate, hydrobromide, malate, glycolate, fumarate, sulfate, sulfamate, sulfanilate, format, toluenesulfonate, methanesulfonate, benzenesulfonate, ethanedisulfonate, 2-hydroxyethylsulfonate, nitrate, benzoate, 2-acetoxybenzoate, citrate, tartrate, lactate, stearate, salicylate, glutamate, ascorbate, pamoic acid, succinate, fumarate, maleate, propionate, hydroxymaleate, hydroiodide, phenylacetate, alkanoic acid salts (e.g., acetate, HOOC-(CH2) n -COOH, wherein n is any integer from 0 to 6, i.e., 0, 1, 2, 3, 4, 5 or 6, etc.). Similarly, pharmaceutically acceptable cations include, but are not limited to, sodium ions, potassium ions, calcium ions, aluminum ions, lithium ions and ammonium ions. One of ordinary skill in the art will recognize other pharmaceutically acceptable salts of the compounds provided herein. Typically, pharmaceutically acceptable acid salts or base salts can be synthesized from a parent compound containing a basic or acidic moiety by any conventional chemical method. In short, these salts can be prepared by reacting the free acid or free base form of these compounds in water or in an organic solvent or in a mixture of the two with a stoichiometric amount of an appropriate base or acid. Typically, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferably used.

[0149] It is obvious that each compound of formula (I) may, but need not, exist in the form of a hydrate, solvate or non-covalent complex. In addition, various crystalline forms and polymorphs are also within the scope of the present invention, as are prodrugs of the compounds of formula (I) provided herein.

[0150] "Prodrugs" are compounds that may not fully meet the structural requirements of the compounds provided herein, but are changed in vivo after administration to a subject or patient to produce 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 hydroxyl, carboxyl, amine or sulfhydryl group is bonded to any group that is cleaved to form a free hydroxyl, carboxyl, amino or sulfhydryl group when administered to a mammalian subject. Examples of prodrugs include, but are not limited to, acetic acid derivatives, formic acid derivatives, phosphoric acid derivatives and benzoic acid derivatives of alcohol and amine functional groups in the compounds provided herein. Prodrugs of compounds provided herein can be prepared by modifying the functional groups present in the compound so that the modified substance is cleaved in vivo to produce the parent compound.

[0151] As used herein, "substituent" refers to a molecular part that is covalently bonded to an atom in a target molecule. For example, a "ring substituent" can be a part such as a halogen, an alkyl, a haloalkyl, or other substituents described herein, which are covalently bonded to an atom as a ring member, preferably to a carbon atom or a nitrogen atom. As used herein, the term "substituted" refers to any one or more than one hydrogen on a specified atom being replaced by a substituent selected from the enumerated substituents, provided that the normal valence of the specified atom is not exceeded and the substitution obtains a stable compound, i.e., a compound that can be isolated, characterized, and tested for its biological activity. When the substituent is an oxo, i.e., =O, then 2 hydrogens on the atom are replaced. An oxo group as a substituent of an aromatic carbon atom causes -CH- to be converted to -C(=O)- and loses aromaticity. For example, a pyridyl group substituted by an oxo group is a pyridone.

[0152] The expression "optionally substituted" means that one, two, three or more than three hydrogen atoms in the group can be replaced independently of one another by corresponding substituents.

[0153] As used herein, the term "amino acid" refers to any organic acid containing one or more than one amino substituent, for example, α-amino, β-amino or γ-amino, derivatives of aliphatic carboxylic acids. In the polypeptide symbols used herein, for example, Xaa5, i.e., Xaa1Xaa2Xaa3Xaa4Xaa5, wherein Xaa1 to Xaa5 are each independently selected from the defined amino acids, according to standard usage and convention, the left-hand direction is the amino terminal direction, and the right-hand direction is the carboxyl terminal direction.

[0154] The term "conventional amino acid" refers to 20 naturally occurring amino acids, and includes all stereoisomers, i.e., its D, L-amino acid, D-amino acid and L-amino acid. These conventional amino acids may also be represented by their conventional three-letter abbreviations or single-letter abbreviations herein, and their abbreviations follow conventional usage (see, e.g., Immunology—A Synthesis, Second Edition, ES Golub and DR Gren, eds., Sinauer Associates, Sunderland Mass. (1991)).

[0155] The term "unconventional amino acid" refers to non-natural amino acids or chemical amino acid analogs, such as α, α-disubstituted amino acids, N-alkyl amino acids, homoamino acids, dehydrogenated amino acids, aromatic amino acids (except phenylalanine, tyrosine and tryptophan) and anthranilic acid, m-aminobenzoic acid or p-aminobenzoic acid. Unconventional amino acids also include compounds with amine and carboxyl functional groups separated in a 1,3 or greater substitution pattern, such as β-alanine, γ-aminobutyric acid, Freidinger lactam, bicyclic dipeptide (BTD), amino-methylbenzoic acid and other substances well known in the art. Pepstatin-like isosteres, hydroxyethylene isosteres, reduced amide bond isosteres, thioamide isosteres, urea isosteres, carbamate isosteres, thioether isosteres, vinyl isosteres and other amide bond isosteres known in the art can also be used. The use of analogs or unconventional amino acids can improve the stability and biological half-life of the added peptide because they are more resistant to decomposition under physiological conditions. Those skilled in the art will recognize that similar substitutions can be made. A non-limiting list of unconventional amino acids and their standard abbreviations (in parentheses) that can be used as suitable building blocks for peptides is as follows: α-aminobutyric acid (Abu), LN-methylalanine (Nmala), α-amino-α-methylbutyric acid (Mgabu), LN-methylarginine (Nmarg), aminocyclopropane (Cpro), LN-methylasparagine (Nmasn), carboxylate LN-methylaspartic acid (Nmasp), aminoisobutyric acid (Aib), LN-methylcysteine ​​(Nmcys), aminonorbornyl (Norb), LN-methylglutamine (NmgL-N), carboxylate LN-methylglutamic acid (Nmglu), cyclohexylalanine (Chexa), LN-methylhistidine (Nmhis), cyclopentylalanine (Cpen), LN-methylisoleucine (Nmile), LN-methylleucine acid (Nmleu), LN-methyllysine (Nmlys), LN-methylmethionine (Nmmet), LN-methylnorleucine (Nmnle), LN-methylvaline (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-tert-butylglycine (Nmtbug), L-norleucine (NIe), L-norvaline (Nva), α-methyl-aminoisobutyrate (Maib),α-Methyl-γ-aminobutyrate (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 (DmgL-N), N-(2-aminoethyl)glycine (Naeg), D-α-methyl alanine (Dmhis), N-(3-aminopropyl)glycine (Norn), D-α-methylisoleucine (Dmile), N-amino-α-methylbutyrate (Nmaabu), D-α-methylleucine (Dmleu), α-naphthylalanine (Anap), D-α-methyllysine (Dmlys), N-benzylglycine (Nphe), D-α-methylmethionine (Dmmet), N-(2-carbamoylethyl)glycine (NgIn), D-α-methylornithine (Dmorn), N-(carbamoylmethyl)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 (DnmgL-N), N-(3-guanidinopropyl)glycine (Narg), DN-methylglutamic acid (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-aminobutyrate (Nmgabu), N-methylcyclohexylalanine (Nmchexa), DN-methylmethionine (Dnmmet), DN-methylornithine (Dnmorn), N-methylcyclopentylalanine (Nmcpen), N-methylglycine (NaIa), DN-methylphenylalanine (Dnmphe), N-methylaminoisobutyrate (Nmaib), DN-methyl Proline (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-methylnaphthylalanine (Nmanap), DN-methylvaline (Dnmval), N-methylpenicillamine (Nmpen), γ-aminobutyric acid (Gabu), N-(p-hydroxyphenyl)glycine (Nhtyr), L- / -butylglycine (Tbug), N-(thio) methyl)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-tert-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-methyl Isoleucine (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),LN-methylhomophenylalanine (Nmhphe), N-(N-(2,2-diphenylethyl)carbamoylmethyl)glycine (Nnbhm), N-(N-(3,3-diphenylpropyl)carbamoylmethyl)glycine (Nnbhe), 1-carboxy-1-(2,2)-diphenyl-ethylamino)cyclopropane (Nmbc), LO-methylserine (Omser), LO-methylhomoserine (Omhser).

[0156] The expression alkyl is understood to mean a saturated, straight-chain or branched hydrocarbon radical having 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, for example n-octyl and in particular 1 to 6 carbon atoms, 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.

[0157] The expression alkenyl is understood to mean an at least partially unsaturated, straight-chain or branched hydrocarbon radical having 2 to 21 carbon atoms, preferably 2 to 6 carbon atoms, i.e. 2, 3, 4, 5 or 6 carbon atoms, for example ethenyl (vinyl), propenyl (allyl), isopropenyl, butenyl, isopentenyl or hex-2-enyl, or 11 to 21 carbon atoms, i.e. 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21 carbon atoms, for example a hydrocarbon radical comprising a methylene chain interrupted by a double bond, as for example found in monounsaturated fatty acids or in the hydrocarbon radicals of polyenes comprising methylene interruptions, for example a hydrocarbon radical comprising two or more than two of the following structural units -[CH=CH-CH2]-, as for example found in polyunsaturated fatty acids. Alkenyl has one or more than one, preferably 1, 2, 3, 4, 5 or 6 double bonds.

[0158] The expression alkynyl is intended to mean an at least partially unsaturated, straight-chain or branched hydrocarbon radical having 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms, in particular 2 to 6 carbon atoms, i.e. 2, 3, 4, 5 or 6 carbon atoms, for example ethinyl, propynyl, butynyl, acetylenyl or propargyl. Preferably, the alkynyl radical has one or two, particularly preferably one, triple bonds.

[0159] Furthermore, the terms alkyl, alkenyl and alkynyl refer to groups in which one or more than one hydrogen atom has been replaced, for example by a halogen atom, preferably F or Cl, such as 2,2,2-trichloroethyl or trifluoromethyl.

[0160] The expression heteroalkyl refers to alkyl, alkenyl or alkynyl radicals, in which one or more than one, preferably 1, 2 or 3 carbon atoms are substituted independently of one another by oxygen, nitrogen, phosphorus, boron, selenium, silicon or sulfur atoms, preferably by oxygen atoms, sulfur atoms or nitrogen atoms. The expression heteroalkyl may also refer to carboxylic acids or to radicals derived from carboxylic acids, for example acyl, acylalkyl, alkoxycarbonyl, acyloxy, acyloxyalkyl, carboxyalkylamide or alkoxycarbonyloxy.

[0161] Preferably, the heteroalkyl group contains 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen atoms, nitrogen atoms and sulfur atoms, especially oxygen atoms and nitrogen atoms. 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 atoms, nitrogen atoms and sulfur atoms, especially oxygen atoms and nitrogen atoms.

[0162] 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 -、R a -O-CO-N(R b )-Y a -、R a -N(R b )-CO-OY a -、R a -N(R b )-CO-N(R c )-Y a -、R a -O-CO-OY a -、R a -N(R b )-C(=NR d )-N(R c )-Y a -、R a -CS-Ya -1. R a -O-CS-Y a -1. R a -CS-O-Y a -1. R a -CS-N(R b )-Y a -1. R a -N(R b )-CS-Y a -1. R a -O-CS-N(R b )-Y a -1. R a -N(R b )-CS-O-Y a -1. R a -N(R b )-CS-N(R c )-Y a -1. R a -O-CS-O-Y a -1. R a -S-CO-Y a -1. R a -CO-S-Y a -1. R a -S-CO-N(R b )-Y a -1. R a -N(R b )-CO-S-Y a -1. R a -S-CO-O-Y a -1. R a -O-CO-S-Y a -1. R a -S-CO-S-Y a -1. R a -S-CS-Y a -1. R a -CS-S-Y a -1. R a -S-CS-N(R b )-Y a -1. R a -N(R b )-CS-S-Y a -1. R a -S-CS-O-Y a -1. R a -O-CS-S-Y a -wherein R a is a hydrogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group or a C2-C6 alkynyl group; Rb is a hydrogen atom, a C1 to C6 alkyl group, a C2 to C6 alkenyl group or a C2 to C6 alkynyl group; R c is a hydrogen atom, a C1 to C6 alkyl group, a C2 to C6 alkenyl group or a C2 to C6 alkynyl group; R d is a hydrogen atom, a C1 to C6 alkyl group, a C2 to C6 alkenyl group or a C2 to C6 alkynyl group, and Y a is a direct bond, a C1 to C6 alkylene, a C2 to C6 alkenylene or a C2 to C6 alkynylene, wherein each heteroalkyl group contains at least one carbon atom and one or more than one hydrogen atom may be substituted by a fluorine or chlorine atom.

[0163] Specific examples of heteroalkyl are methoxy, trifluoromethoxy, ethoxy, n-propoxy, isopropoxy, butoxy, tert-butoxy, methoxymethyl, ethoxymethyl, -CHCHOH, -CHOH, 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, acetoxy, methoxycarbonyl, ethoxycarbonyl, propionyloxy, acetylamino or propionylamino, carboxymethyl, carboxyethyl or carboxypropyl, N-ethyl-N-methylcarbamoyl or N-methylcarbamoyl. Other examples of heteroalkyl are nitrile, isonitrile, cyanate, thiocyanate, isocyanate, isothiocyanate and alkylnitrile groups.

[0164] The expression alkoxy refers to an alkyl group which is singly bonded to oxygen.

[0165] The expression alkylthio refers to an alkyl group which is singly bonded to sulfur.

[0166] The expressions cycloalkyl and carbocycle are understood to mean saturated cyclic hydrocarbon radicals containing one or more than one ring, preferably one or two rings, and containing 3 to 14 ring carbon atoms, preferably 3 to 10 ring carbon atoms, in particular 3, 4, 5, 6 or 7 ring carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, spiro[4,5]decyl, norbornyl, cyclohexyl, decahydronaphthyl, bicyclo[4.3.0]nonyl, tetrahydronaphthalene or cyclopentylcyclohexyl. The expression cycloalkyl also means radicals in which one or more than one hydrogen atom has been replaced by a fluorine, chlorine, bromine or iodine atom or by an OH, =O, SH, NH2, =NH, N3 or NO2 group, thus, for example, cyclic ketones, such as cyclohexanone, 2-cyclohexenone or cyclopentanone. Other specific examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, spiro[4,5]decyl, norbornyl, cyclohexyl, cyclopentenyl, cyclohexadienyl, decahydronaphthyl, bicyclo[4.3.0]nonyl, tetralin, cyclopentylcyclohexyl, fluorocyclohexyl or cyclohex-2-enyl.

[0167] The expression aryl refers to aromatic groups which contain one or more than one ring having 6 to 14 ring carbon atoms, preferably 6 to 10 ring carbon atoms, in particular 6 ring carbon atoms.

[0168] The expression heteroaryl is understood to mean an aromatic radical which contains one or more than one ring having 5 to 14 ring atoms, preferably 5 to 10 ring atoms, in particular 5 or 6 ring atoms, which contains one or more than one, 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, Azolyl, iso Azolyl, triazolyl, tetrazolyl, iso oxazolyl, indazolyl, indolyl, benzimidazolyl, benzo Azolyl, benzyl The term heterocycloalkyl refers to a cycloalkyl group as defined above, wherein one or more than one (preferably one, two or three) ring carbon atoms are each independently substituted by an oxygen atom, a nitrogen atom, a silicon atom, a selenium atom, a phosphorus atom or a sulfur atom (preferably by an oxygen atom, a sulfur atom or a nitrogen atom). The heterocycloalkyl group preferably has one or two rings containing 3 to 10 (especially 3, 4, 5, 6 or 7) ring atoms (preferably selected from C, O, N and S). The expression heterocycloalkyl also refers to groups in which one or more than one hydrogen atom has been replaced by a fluorine, chlorine, bromine or iodine atom or by an OH, =O, SH, =S, NH2, =NH, N3 or NO2 group. Examples are piperidinyl, prolyl, imidazolidinyl, piperazinyl, morpholinyl, urotropinyl, pyrrolidinyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrofuranyl or 2-pyrazolinyl as well as lactams, lactones, cyclic imides and cyclic anhydrides.

[0169] The expression alkylcycloalkyl refers to a group containing a cycloalkyl group according to the above definition as well as an alkyl, alkenyl or alkynyl group, for example alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkenyl, alkenylcycloalkyl and alkynylcycloalkyl. Alkylcycloalkyl preferably contains a cycloalkyl group containing 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 a group containing an aryl group according to the above definition as well as an alkyl, alkenyl, alkynyl and / or cycloalkyl group, for example arylalkyl, arylalkenyl, arylalkynyl, arylcycloalkyl, arylcycloalkenyl, alkarylcycloalkyl and alkylarylcycloalkenyl. Specific examples of aralkyl groups are toluene, xylene, mesitylene, styrene, benzyl chloride, o-fluorotoluene, 1H-indene, tetralin, dihydronaphthalene, indanone, phenylcyclopentyl, cumene, cyclohexylphenyl, fluorene and indane. Aralkyl groups preferably contain one or two aromatic ring systems (1 or 2 rings) containing 6 to 10 carbon atoms and one or two alkyl, alkenyl and / or alkynyl groups and / or cycloalkyl groups containing 1 or 2 to 6 carbon atoms, the cycloalkyl group containing 5 or 6 ring carbon atoms.

[0170] The statement heteroalkylcycloalkyl refers to an alkylcycloalkyl as defined above, wherein one or more than one carbon atom, preferably 1, 2 or 3 carbon atoms are independently replaced by oxygen atoms, nitrogen atoms, silicon atoms, selenium atoms, phosphorus atoms or sulphur atoms (preferably replaced by oxygen atoms, sulphur atoms or nitrogen atoms). Heteroalkylcycloalkyl preferably contains 1 or 2 ring systems with 3 to 10 (particularly 3, 4, 5, 6 or 7) ring atoms, and 1 or 2 alkyl, alkenyl, alkynyl or heteroalkyl with 1 or 2 to 6 carbon atoms. Examples of these groups are alkylheterocycloalkyl, alkylheterocycloalkenyl, alkenylheterocycloalkyl, alkynylheterocycloalkyl, heteroalkylcycloalkyl, heteroalkylheterocycloalkyl and heteroalkylheterocycloalkenyl, and the cyclic group is saturated or monounsaturated, diunsaturated or triunsaturated.

[0171] The expression heterocycle refers to heteroaryl as defined above and cycloalkyl or carbocycle as defined above, in which one or more than one (preferably 1, 2 or 3) ring carbon atoms are each independently substituted by oxygen atoms, nitrogen atoms, silicon atoms, selenium atoms, phosphorus atoms or sulfur atoms, preferably by oxygen atoms, sulfur atoms or nitrogen atoms. The heterocycle preferably has 1 or 2 rings containing 3 to 10 ring atoms, in particular 3, 4, 5, 6 or 7 ring atoms, preferably selected from C, O, N and S. Examples are aziridinyl, oxiranyl, thiiranyl, oxaziridinyl, dioxirane, azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiolanyl, phospholyl, silolanyl, oxazolyl, thiazolyl, isothiazolyl, imidazolidinyl, pyrazolidinyl, Oxazolidinyl, isocyanate oxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperazinyl, morpholinyl, thiomorpholinyl, trioxanyl, azepanyl, oxepanyl, thiepanyl, homopiperazinyl or hexamethylenetetramine.

[0172] The expression heteroaralkyl refers to an aralkyl group as defined above, in which one or more than one (preferably 1, 2, 3 or 4) carbon atoms are each independently replaced by an oxygen atom, a nitrogen atom, a silicon atom, a selenium atom, a phosphorus atom, a boron atom or a sulfur atom (preferably an oxygen atom, a sulfur atom or a nitrogen atom), i.e. a group containing an aryl or heteroaryl group and an alkyl, alkenyl, alkynyl and / or heteroalkyl and / or cycloalkyl and / or heterocycloalkyl group, respectively, according to the above definitions. Heteroaralkyl preferably contains one or two aromatic ring systems (1 or 2 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, wherein 1, 2, 3 or 4 of these carbon atoms have been replaced by oxygen atoms, sulfur atoms or nitrogen atoms.

[0173] Examples are arylheteroalkyl, arylheterocycloalkyl, arylheterocycloalkenyl, arylalkylheterocycloalkyl, arylalkenylheterocycloalkyl, arylalkynylheterocycloalkyl, arylalkylheterocycloalkenyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylcycloalkyl, heteroarylcycloalkenyl, heteroarylheterocycloalkyl, heteroarylheterocycloalkenyl, heteroarylalkylcycloalkyl, heteroarylalkylheterocycloalkenyl, heteroarylheteroalkylcycloalkyl, heteroarylheteroalkylcycloalkenyl and heteroarylheteroalkylheterocycloalkyl, the cyclic radical being saturated or mono-, di- or tri-unsaturated. Specific examples are tetrahydroisoquinolyl, benzoyl, 2- or 3-ethylindolyl, 4-methylpyrido, 2-, 3- or 4-methoxyphenyl, 4-ethoxyphenyl, 2-, 3- or 4-carboxyphenylalkyl.

[0174] As already stated above, the expressions cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl also refer to groups in which one or more than one hydrogen atom has been replaced, independently of one another, by a fluorine, chlorine, bromine or iodine atom or by an OH, =O, SH, =S, NH2, =NH, N3 or NO2 group.

[0175] Unless otherwise defined, the generic term ring as used herein includes cycloalkyl or carbocyclic, heterocyclic, aryl and heteroaryl.

[0176] The expressions halo, halogen or halogen atom as used herein refer to fluorine, chlorine, bromine or iodine, preferably fluorine and / or chlorine.

[0177] The expression monosaccharide or disaccharide and derivatives thereof as used herein refers to carbohydrates or sugars that are or are derived from monosaccharides or disaccharides.

[0178] Examples of monosaccharides, disaccharides and derivatives include glucose, 3-O-methyl-glucose, 1-deoxy-glucose, 6-deoxy-glucose, galactose, mannose, fructose, xylose, ribose, cellobiose, maltose, lactose, gentiobiose, sucrose, trehalose and mannitol, sorbitol and ribitol. Preferably, the saccharide is a D-type saccharide, such as D-glucose, 3-O-methyl-D-glucose, 1-deoxy-D-glucose, or 6-deoxy-D-glucose, D-galactose, D-mannose.

[0179] As used herein, phrases defining the limits of a length range, 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 explicitly mentioned integers is intended to include and disclose any integers defining the limits and any integer included in the range.

[0180] The expression "-C(=O)O- moiety" is used herein to clearly define a group comprising sp bonded to (i) any carbon atom or heteroatom and to (ii) an oxygen atom. 2 -hybridized carbonyl carbon, the oxygen atom may in turn be attached to a hydrogen atom or any other chemical atom. For the description of "-C(=O)O- moiety", the term "carboxy" is avoided as it may be mistakenly regarded as describing only carboxylic acids.

[0181] The term "in the alpha position" is used to describe a directly adjacent position, whereas the term "in the beta position" denotes an adjacent position of an atom or group A and an atom or group B, characterized in that another atom or group is located between A and B.

[0182] As used herein, the term oxalamide refers to an optionally substituted organic compound containing two carbonyl carbons and two nitrogens, which compound is an optionally substituted diamide derived from any oxalic acid.

[0183] Those skilled in the art will readily recognize that some of the n-3 PUFA analogs of formula (I) of the present invention represent "bioisosteres" of naturally occurring epoxy metabolites produced by cytochrome P450 (CYP) enzymes catalyzing ω-3 (n-3) polyunsaturated fatty acids (PUFAs). Bioisosteres are compounds produced by the exchange of atoms or groups of atoms with other broadly similar atoms or groups of atoms, thereby producing new compounds with similar biological properties to the parent compound. For example, the bioisosteric principle has been used by medicinal chemists to improve the desired biological or physical properties of a compound, for example, to reduce toxicity, change activity, change the pharmacokinetics of a compound and / or the metabolism of a compound. For example, replacing a hydrogen atom with a fluorine atom at a site of metabolic oxidation in a compound can prevent such metabolism from occurring. Because the size of the fluorine atom is similar to that of a hydrogen atom, the overall topological structure of the molecule is not significantly affected, thereby leaving the desired biological activity unaffected. However, due to the blocking of the metabolic pathway, the compound may have a longer half-life. Another example is the bioisosteric substitution of the carboxylic acid group, which results in analogs showing improved bioavailability, enhanced blood-brain barrier penetration, increased activity, better chemical stability and / or selectivity for the target (see, e.g., the textbook "The practice of medicinal chemistry", edited by Camille Georges Wermuth, 3rd edition, Academic Press, 2008, e.g., pages 303 to 310; Ballatore C. et al., "Carboxylic Acid (Bio) Isosteres in Drug Design", ChemMedChem 8, 385-395 (2013)). In addition, the bioisosteric principle can also be used to provide a "prodrug" of a compound, i.e., a compound that is initially administered to a subject or patient in an inactive (or less active) form, and then undergoes the body's normal metabolic process to change it in vivo to its active form. For example, conjugation of compounds to lipids and / or sugar units results in analogs (prodrugs) that exhibit increased 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)).

[0184] The n-3PUFA analogs of the general formula (I) of the present invention can be prepared by many 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 field of synthetic organic chemistry or method variations understood by those skilled in the art. Unless otherwise indicated, all variables, such as n, k, R 2 (also called R2), R 6 , R 7 , R 8 , R 41 , R 42 , R 44 and R 45 The term "compound" refers to any of the following compounds: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 6

[0185] The compounds of the present invention are effective in treating, reducing the risk of, or preventing diseases associated with neovascularization and / or inflammation. In one embodiment, the disease is a disease associated with neovascularization. In another embodiment, the disease is a disease associated with inflammation.

[0186] Examples of diseases associated with inflammation include inflammatory diseases, inflammation caused by other diseases of whatever type, etiology or pathogenesis, inflammation caused by the inflammatory diseases exemplified below, and immune diseases.

[0187] In one embodiment, the disease associated with inflammation is an inflammatory disease. Examples of inflammatory diseases are acute phase reactions, local and systemic inflammation.

[0188] In one embodiment, the disease associated with inflammation is an immune disease. Examples of immune diseases are hyperesthesia, autoimmune diseases, transplant rejection, transplant toxicity, granulomatous inflammation / tissue remodeling, myasthenia gravis, immunosuppression, immune complex diseases, antibody excess and antibody deficiency, and vasculitis.

[0189] In one embodiment, a disease associated with inflammation is inflammation caused by another disease of whatever type, etiology or pathogenesis, or inflammation caused by an inflammatory disease. Examples of these conditions and diseases include inflammatory bowel disease, including Crohn's disease and ulcerative colitis, irritable bowel syndrome, enteritis, liver disease, pancreatitis, nephritis, cystitis (interstitial cystitis), otitis media, periodontitis, inflammatory skin diseases such as psoriasis, eczema, atopic diseases, dermatitis, juvenile or adult-onset rheumatoid arthritis and gouty arthritis, ankylosing spondylitis, adult-onset or pediatric (systemic onset juvenile idiopathic arthritis) Still's disease, psoriatic arthritis, osteoarthritis, and burns, sprains or fractures with edema , cerebral edema, angioedema, vasculitis, diabetic vasculopathy, type I diabetes, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, postcapillary resistance or diabetic syndrome associated with insulitis (e.g., hyperglycemia, polyuria, proteinuria, and increased urinary excretion of nitrites and kallikrein), gallbladder disease, multiple sclerosis, epilepsy, amyotrophic lateral sclerosis, systemic inflammatory response syndrome (SIRS), ischemia-reperfusion injury and atherosclerosis, septic shock, anti-volemic and / or antihypertensive drugs Inflammation caused by the lungs, migraines, gingivitis, osteoporosis, benign prostatic hyperplasia, overactive bladder, fibrotic diseases such as pulmonary fibrosis in Crohn's disease, renal fibrosis, progressive sclerosis and recurrent stricture formation, respiratory diseases such as asthma, atopic or non-atopic asthma, occupational asthma, exercise-induced bronchoconstriction, bronchitis, pneumoconiosis including alum deposition, anthracis, asbestosis, lithosis, camel feather deposition, siderosis, silicosis, tobacco dust and byssinusitis, chronic obstructive pulmonary disease Lung diseases including emphysema, adult respiratory distress syndrome, pneumonia, allergic rhinitis, vasomotor rhinitis and pleurisy, autoinflammatory diseases such as familial Mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), neonatal-onset multisystem inflammatory disease (NOMID), familial cold autoinflammatory syndromes (FCAS), including familial cold urticaria (FCU), suppurative arthritis pustular gangrenosum (PAPA) syndrome, and Muckle-Wells disease.

[0190] In preferred embodiments, the disease associated with neovascularization and / or inflammation is an ophthalmic disease associated with neovascularization, such as an ophthalmic disease associated with corneal, retinal, choroidal, uveal or iris neovascularization and / or associated with inflammation. Preferred ophthalmic diseases associated with neovascularization are age-related macular degeneration, such as neovascular (wet) AMD or atrophic (dry) AMD. In this embodiment, treatment results in vascular degeneration. In some embodiments, the ophthalmic disease associated with neovascularization is a retinopathy, preferably retinopathy of prematurity (ROP); diabetic retinopathy; diabetic proliferative retinopathy; retinal vein occlusion, such as branch retinal vein occlusion, central retinal vein occlusion; sickle cell retinopathy; and radiation retinopathy; Best (Best) disease; or Stargardt disease. Preferred ophthalmic diseases associated with inflammation are age-related macular degeneration.

[0191] In one embodiment, the disease associated with neovascularization and / or inflammation is not a cardiovascular disease.

[0192] In preferred embodiments, the compound or composition used according to the present invention is administered orally, topically, subcutaneously, intravitreal, intramuscularly, intraperitoneally, intravenously or intranasally, preferably orally or intravenously, more preferably orally or intraperitoneally. The preferred delivery route of ophthalmic drugs for treating ophthalmic diseases is local, local to the eye (e.g., subconjunctival, intravitreal, behind the eyeball, in the anterior chamber) and systemic. The latter is preferably achieved by oral, intramuscular or intravenous administration.

[0193] It is further preferred that the dosage form of the compound or composition used according to the present invention is 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, liposome compositions and injections.

[0194] The compound or composition used according to the present invention may further include at least one compound of formula (I) and optionally one or more than one carrier material, such as cyclodextrin (e.g., hydroxypropyl β-cyclodextrin), micelle or liposome, excipient and / or adjuvant. It may additionally include, for example, water, buffer (e.g., neutral buffered saline or phosphate buffered saline), ethanol, mineral oil, vegetable oil, dimethyl sulfoxide, carbohydrate (e.g., glucose, mannose, sucrose or dextran), mannitol, protein, adjuvant, polypeptide or amino acid (e.g., glycine), antioxidant, chelating agent (e.g., EDTA) or glutathione and / or preservative one or more than one. In addition, one or more than one other active ingredients may be but not necessarily included in the composition provided herein. For example, the compounds of the present invention may advantageously be used in combination with antibiotics, antifungal agents or antiviral agents, antihistamines, nonsteroidal anti-inflammatory drugs, antirheumatic drugs that improve disease, anti-inflammatory drugs for treating autoimmune diseases, cytostatic drugs, anti-angiogenic drugs or the above-mentioned mixtures. Preferably, the drug is an anti-angiogenic drug, more preferably an inhibitor of vascular endothelial growth factor (VEGF) or vascular endothelial growth factor receptor (VEGFR).

[0195] The composition used can be formulated for any suitable route of administration, including, for example, topical administration, such as transdermal or ocular, oral, oral, nasal, vaginal, rectal or parenteral administration. The term parenteral as used herein includes subcutaneous, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intracranial, intrathecal, intraocular, periocular, intraorbital, intrasynovial, intraperitoneal and ocular local (e.g., subconjunctival, intravitreal, behind the eyeball, anterior chamber) injection and any similar injection or infusion technique. In certain embodiments, the composition of the suitable form for oral use is preferred. These forms include, for example, tablets, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard capsules or soft capsules, or syrups or elixirs. In other embodiments, provided herein is a composition that can be formulated into a lyophilized product.

[0196] Compositions for oral administration may further comprise one or more than one component, such as sweeteners, flavoring agents, coloring agents and / or preservatives, to provide an attractive and palatable formulation. Tablets contain active ingredients and incorporate physiologically acceptable excipients suitable for preparing tablets. These excipients include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period of time. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used. Methods for preparing such compositions are known (see, for example, HC Ansel and NG Popovish, Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th ed., Lea and Febiger (1990)).

[0197] Formulations for oral administration may also be provided as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oily medium such as peanut oil, liquid paraffin or olive oil.

[0198] Aqueous suspensions contain the active ingredient in admixture with excipients suitable for the preparation of aqueous suspensions. These excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic; dispersants or wetting agents such as naturally occurring phosphatides such as lecithin, condensation products of olefin oxides and fatty acids such as polyoxyethylene stearate, condensation products of ethylene oxide with long chain fatty alcohols such as heptadecanyloxyethanol, condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides such as polyethylene sorbitan monooleate. The aqueous suspension 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, for example sucrose or saccharin.

[0199] Oily suspensions can be prepared by suspending the active ingredient in a vegetable oil (e.g., peanut oil, olive oil, sesame oil, or coconut oil) or a mineral oil (e.g., liquid paraffin). Oily suspensions may contain thickeners, such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners and / or flavorings as described above may be added to provide a palatable oral preparation. Such suspensions may be preserved by adding an antioxidant such as ascorbic acid.

[0200] Dispersible powders and granules suitable for preparing an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersant or wetting agent, a suspending agent and one or more preservatives. Examples of suitable dispersants or wetting agents and suspending agents are provided as described above. Additional excipients, such as sweeteners, flavoring agents and coloring agents, may also be present.

[0201] The composition used may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, such as olive oil or peanut oil; a mineral oil, such as liquid paraffin; or a mixture thereof. Suitable emulsifiers include naturally occurring gums, such as gum arabic or tragacanth; naturally occurring phospholipids, such as soy lecithin; and esters or partial esters derived from fatty acids and hexitol; anhydrides, such as sorbitan monooleate; and condensation products of partial esters derived from fatty acids and hexitol with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain one or more than one sweetener and / or flavoring agent.

[0202] Syrups and elixirs may be formulated with sweeteners, for example glycerol, propylene glycol, sorbitol or sucrose. Such preparations may also contain one or more demulcents, preservatives, flavorings and / or coloring agents.

[0203] The compound used according to the present invention can be formulated for external or local application, such as topical application to the skin or mucous membrane, such as the eye. The preparation for topical application generally comprises a local solvent in combination with an active agent, which may or may not have additional optional components. Suitable local solvents and additional components are well known in the art, and it is apparent that the choice of the solvent depends on a specific physical form and mode of delivery. The local solvent includes water; organic solvents, such as alcohols, such as ethanol or isopropanol or glycerol; glycols, such as butylene, isoprene or propylene glycol; aliphatic alcohols, such as lanolin; mixtures of water and organic solvents and mixtures of organic solvents (such as alcohol and glycerol); lipid-based materials, such as fatty acids, acylglycerols including oils (such as mineral oils, fats of natural or synthetic origin), phosphoglycerides, sphingolipids and waxes; protein-based materials, such as collagen and gelatin; non-volatile and volatile silicone-based materials; and hydrocarbon-based materials, such as microsponges and polymer matrices. The composition may further include one or more than one component suitable for improving the stability or effectiveness of the administered formulation, such as stabilizers, suspending agents, emulsifiers, viscosity modifiers, gelling agents, preservatives, antioxidants, skin penetration enhancers, humectants and sustained release materials. Examples of these components are described in Martindale-The Extra Pharmacopoeia (Pharmaceutical Press, London 1993) and Martin (ed.), Remington's Pharmaceutical Sciences. The formulation may include microcapsules, such as hydroxymethylcellulose or gelatin-microcapsules, liposomes, albumin microspheres, microemulsions, nanoparticles or nanocapsules.

[0204] The topical preparations used can be prepared in various physical forms, including, for example, solids, pastes, creams, foams, lotions, gels, powders, aqueous liquids, emulsions, sprays, eye drops and skin patches. The physical appearance and viscosity of these forms can be controlled by the presence and amount of emulsifiers and viscosity modifiers present in the preparation. Solids are usually firm and non-infusible, usually formulated into strips or sticks, or granular forms; solids can be opaque or transparent, and optionally can 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 usually similar to each other, with the main difference being their viscosity; lotions and creams can be opaque, translucent or transparent and usually contain emulsifiers, solvents and viscosity modifiers as well as moisturizers, emollients, fragrances, dyes / colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product. Gels can be prepared with a range of viscosities, from thick or high viscosity to thin or low viscosity. These preparations, such as lotions and creams, may also contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes / colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product. Liquids are thinner than creams, lotions or gels and usually do not contain emulsifiers. Liquid topical products usually contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes / colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product.

[0205] Emulsifiers suitable for topical preparations include, but are not limited to, ionic emulsifiers, cetearyl alcohol, nonionic emulsifiers such as polyoxyethylene oleyl ether, PEG-40 stearate, ceteareth-12, ceteareth-20, ceteareth-30, cetearethhalcohol, PEG-100 stearate, and glyceryl stearate. Suitable viscosity modifiers include, but are not limited to, protective colloids or nonionic gums, such as hydroxyethylcellulose, xanthan gum, aluminum magnesium silicate, silicon dioxide, microcrystalline wax, beeswax, paraffin, and cetyl palmitate. Gel compositions can be formed by adding gelling agents such as chitosan, methylcellulose, ethylcellulose, polyvinyl alcohol, polyquaternium salts, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carbomer, or ammoniated glycyrrhizinate. Suitable surfactants include, but are not limited to, nonionic surfactants, amphoteric surfactants, ionic surfactants, and anionic surfactants. For example, one or more than one 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 topical formulations.

[0206] Suitable preservatives include, but are not limited to, antimicrobial agents such as methylparaben, propylparaben, sorbic acid, benzoic acid, and formaldehyde; and 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, neopentanoic acid isostearate, 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 topical formulations include, but are not limited to, abrasives; absorbents; anti-caking agents; defoamers; antistatic agents; astringents such as witch hazel, alcohol, and herbal extracts (e.g., chamomile extract); binders / excipients, buffers; chelating agents; film formers; conditioning agents; propellants; sunscreens; pH adjusters and protective agents.

[0207] Examples of suitable topical vehicles for formulating gels are: hydroxypropylcellulose (2.1%); 70 / 30 isopropyl alcohol / water (90.9%); propylene glycol (5.1%); and polysorbate 80 (1.9%). Examples of suitable topical vehicles for formulating foams are: cetyl alcohol (1.1%); stearyl alcohol (0.5%); Quaternium 52 (1.0%); propylene glycol (2.0%); ethanol 95PGF3 (61.05%); deionized water (30.05%); P75 hydrocarbon propellant (4.30%). All percentages are by weight.

[0208] Typical delivery methods for 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; dropper application; sprinkling; soaking; and rinsing. Controlled release vehicles may also be used, and the composition may be formulated as a transdermal patch for transdermal administration.

[0209] The composition for use can be formulated into an inhalation preparation, including sprays, mists or aerosols. These preparations are particularly suitable for treating asthma or other respiratory diseases. For inhalation preparations, the compounds provided herein can 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 with propellants (e.g., CFC or HFA) or physiologically and environmentally acceptable propellants. Other suitable devices are breath-operated inhalers, multi-dose dry powder inhalers and aerosol nebulizers. Aerosol preparations for the inventive method typically include propellants, surfactants and cosolvents, and can be filled into conventional aerosol containers closed by suitable metering valves.

[0210] Inhalant compositions can comprise liquid or powder compositions containing active ingredients suitable for atomization and intrabronchial use or aerosol compositions used by an aerosol unit that releases a metered dose. Suitable liquid compositions include active ingredients in a pharmaceutically acceptable aqueous solvent for suction, such as isotonic saline or antibacterial water. Solutions are applied by a pump or extrusion-actuated atomizer or by any other conventional means so that the liquid composition of the desired dose is inhaled into the patient's lungs. Suitable preparations for use, such as nasal sprays or nasal drops, wherein the carrier is a liquid, including aqueous or oily solutions of active ingredients.

[0211] Formulations or compositions suitable for nasal administration, wherein the carrier is a solid, include coarse powders having a particle size in the range of, for example, 20 microns to 500 microns, which are administered in the manner of snuff, i.e., by rapid inhalation through the nasal passages from a powder container close to the nose. Suitable powder compositions, by way of illustration, include a powder formulation of the active ingredient thoroughly mixed with lactose or other inert powders useful for intrabronchial administration. The powder composition may be administered via an aerosol dispenser or contained in a rupturable capsule which may be inserted by the patient into the device which pierces the capsule and blows the powder out in a steady stream suitable for inhalation.

[0212] The composition for use can also be prepared in the form of a suppository, for example for rectal administration. Such a composition can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols.

[0213] The composition used can be formulated into a sustained-release preparation, for example, a preparation, such as a capsule, that produces a slowly released modulator after administration. Such preparations can generally be prepared using well-known techniques and administered by, for example, oral, rectal or subcutaneous implantation or by implantation at a desired target site. The carriers used in these preparations are biocompatible and may also be biodegradable; preferably, the preparation provides a relatively constant level of modulator release. The amount of modulator included in the sustained-release preparation depends on, for example, the site of implantation, the rate of release, and the expected duration of release, as well as the nature of the disease to be treated or prevented.

[0214] However, it should be understood that the specific dosage level for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combinations (i.e., other drugs used to treat the patient), and the severity of the specific disease being treated.

[0215] Preferred compounds of the invention possess certain pharmacological properties. These properties include, but are not limited to, oral bioavailability, such that the preferred oral dosage forms discussed above can provide therapeutically effective levels of the compounds in vivo.

[0216] The n-3 PUFA derivatives provided herein are preferably administered orally or parenterally to a patient (eg, a human) and are present in at least one body fluid or tissue of the patient.

[0217] As used herein, the term "treatment" encompasses any type of condition-modifying treatment and includes symptomatic treatment (i.e., treatment after the onset of symptoms), any of which may be prophylactic. However, condition-modifying treatment may involve administration prior to the onset of symptoms to prevent, at least delay, or reduce the severity of symptoms after onset. Condition-modifying treatment may also be therapeutic, i.e., after the onset of symptoms, to reduce the severity and / or duration of symptoms. Treatment after the onset of symptoms may also simply involve stopping the progression of the disease (disease stabilization). In certain embodiments, the n-3 PUFA derivatives provided herein are administered prophylactically, i.e., to actually prevent the disease and / or symptoms, ideally but not necessarily, before the onset of the disease and / or symptoms. It should be understood that in the context of the present invention, the terms "prevention" and "prophylactic" simply describe the administration of the compounds of the present invention prior to the onset of symptoms. Prophylactic administration may be administration prior to the onset of symptoms that are clearly associated with the disease discussed herein: for example, when a subject exhibits certain symptoms, the n-3 PUFA derivatives provided herein may be administered to him or her prophylactically. The certain symptoms may indicate a tendency to develop one of the conditions and diseases that can be treated with the n-3 PUFA derivatives of the present invention. These indicative symptoms are, for example, high blood pressure or diabetes. This preventive treatment is called primary prevention. In another embodiment, when the subject previously suffered from a condition or disease that can be treated with the n-3 PUFA derivatives of the present invention, but is not currently showing any symptoms, the n-3 PUFA derivatives provided herein can be administered prophylactically. This preventive treatment is called secondary prevention. Patients who receive n-3 PUFA derivatives for primary or secondary prevention are considered to be in need of such treatment. Patients can include, but are not limited to, mammals, especially humans; domesticated companion animals, such as dogs, cats, horses, and livestock (e.g., cattle, pigs, sheep), and use the dosages described herein.

[0218] The activity of the n-3 PUFA analogs according to the invention can be determined, for example, in appropriate in vitro and / or in vivo assays. For example, the biological activity of the n-3 PUFA analogs according to the invention can be determined using the established Kang and Leaf cell models known to those skilled in the art (Proc Natl Acad Sci USA, 1994. 91 (21): p. 9886-90).

[0219] The following figures and examples are intended to illustrate the present invention rather than to limit the scope of the present invention described in the accompanying claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0220] Figure 1 : Efficacy of a compound designated "Compound 1" having a structure according to Formula (VI) in a rat laser-induced choroidal neovascularization model as assessed by measuring vascular leakage using fluorescent angiography:

[0221] Fluorescein angiography grading data (mean ± SD) on days 14 and 21 after induction of choroidal neovascularization (laser burn), score range: arbitrary units from 0 to 3. Fluorescein leakage was assessed in the fluorescein angiograms by two independent investigators in a blinded study group, and the scores were as follows: score 0: no leakage; score 1: slight staining; score 2: moderate staining; score 3: significant staining, n = 10 animals / group, 6 lesions per animal, statistical methods: Kruskal-Wallis test and Dunn's multiple comparison test, * p<0.05, po: oral administration, ip: intraperitoneal administration, IVT: intravitreal administration, FA: fluorescein angiography.

[0222] Figure 2 : Figure 2 The metabolically stable analogs of 17,18-EEQ (Compound 2) showed anti-inflammatory effects on HL-1 cardiomyocytes. Cardiomyocyte cell lines (immortalized cardiomyocytes from mice, HL-1 cells) were used. The cells were treated with vehicle (0.01% ethanol) or different concentrations of test compounds (Compound 2: c E =10 nM, 100 nM or 1 μM). At the same time, cells were challenged with 1 μg / mL lipopolysaccharide (LPS). After 24 hours of incubation, cells were processed to measure viability.

[0223] Figure 3 : Figure 3 The metabolically stable analogs of 17,18-EEQ (Compound 2) showed anti-inflammatory effects on HL-1 cardiomyocytes. Cardiomyocyte cell lines (immortalized cardiomyocytes from mice, HL-1 cells) were used. The cells were treated with vehicle (0.01% ethanol) or different concentrations of test compounds (Compound 2: c E =10 nM, 100 nM or 1 μM). At the same time, cells were challenged with 1 μg / mL lipopolysaccharide (LPS). After 24 hours of incubation, cells were processed to measure the release of the proinflammatory cytokine TNFα.

[0224] Figure 4 : Figure 4The inhibitory effect of a metabolically stable analog of 17,18-EEQ (Compound 2) on cardiac inflammation in a rat model of severe hypertension and end-organ damage was shown. The regulation of inflammation was measured by macrophage infiltration stained with ED1 as an inflammatory marker. The values ​​shown are expressed as median values ​​with interquartile ranges. The count values ​​were pooled in 20 visual field intervals. The results showed that dTGR animals had significantly higher amounts of infiltrated macrophages in cardiac tissue compared to untreated SD animals. However, compared to vehicle-treated dTGR, Compound 2 treatment resulted in a significant reduction in macrophage infiltration (ED1-positive cells) in dTGR animals.

[0225] Figure 5 : Figure 5 The inhibitory effect of a metabolically stable analog of 17,18-EEQ (Compound 2) on renal inflammation in a rat model of severe hypertension and end-organ damage was shown. The regulation of inflammation was measured by macrophage infiltration stained with ED1 as an inflammatory marker. The values ​​shown are expressed as median values ​​with interquartile ranges. The count values ​​were pooled in 20 visual field intervals. The results showed that dTGR animals had significantly higher amounts of infiltrated macrophages in renal tissue compared to untreated SD animals. However, compared to vehicle-treated dTGR, Compound 2 treatment resulted in a significant reduction in macrophage infiltration (ED1-positive cells) in dTGR animals. DETAILED DESCRIPTION

[0226] Example 1 Synthesis of Compounds

[0227] The syntheses of selected compounds of the present invention are described below.

[0228] Compound 1

[0229] The synthesis of compound 1 (Comp-01) was similar to that of compound 3, whereas the urea group was introduced following the synthetic route described in patent application WO2010 / 081683 (Example 13).

[0230] Compound 2 Synthesis Summary

[0231]

[0232] General approach

[0233] NMR spectra were recorded on a Bruker Avance 400 MHz 1 HNMR and recorded at 100 MHz 13CNMR. LCMS was performed on a Shimadzu LCMS2010 (column: sepax ODS 50×2.0 mm, 5 um) quadrupole mass spectrometer or on an Agilent 1200HPLC, 1956MSD (column: Shim-pack XR-ODS 30×3.0 mm, 2.2 um) quadrupole mass spectrometer operating in ES (+) ionization mode. Chromatographic purification was performed by flash chromatography using 100 to 200 mesh silica gel. Anhydrous solvents were pretreated with a 3A MS column before use. Unless otherwise specified, all commercially available reagents were used as received.

[0234] General procedure for preparing compound 2

[0235]

[0236]

[0237] Methylamine (64.29 g, 952.17 mmol, 1.30 equiv) in 500 mL of THF was added with Et3N (75 g, 732.44 mmol), and the solution was added to compound 1 (100.00 g, 732.44 mmol, 1.00 equiv) and Et3N (111 g, 1.1 mol) in THF (1.5 L) at -10 ° C. The mixture was 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 by silica gel (PE:EA=3:1 to 1:1) to give compound 2 (70.00 g, 533.82 mmol, yield 72.88%) as a yellow oil.

[0238] TLC information (PE: EtOAc = 2: 1); R f (Compound 2) = 0.39; LCMS:

[0239] ET2662-1-P1A(M+H + ):131.7; 1 H NMR (CDCl3, 400 MHz) 4.36 to 4.24 (q, J = 8 Hz,

[0240] 2H), 2.93 to 2.85 (d, J = 4 Hz, 3H), 1.38 to 1.30 (t, J = 8 Hz, 3H)

[0241] General procedure for preparing compound 4

[0242]

[0243] Reagent nt Mw. Dosage mmol Proportion Additional Information Compound 3 98.14 47.5g 484 1 Compound 4 147.13- 78.33g 532.4 1.1 <![CDATA[PPh3]]> 262.29 133.3g 508.2 1.05 DIAD 202.21 107.66g 532.4 1.1 THF 1.8L Product (Compound 5) 227.26 42.5g 374.02 Yield: 77.3%

[0244] A solution of compound 3 (47.50 g, 484.00 mmol, 1.00 equiv) and DIAD (107.66 g, 532.40 mmol, 1.10 equiv) in anhydrous THF (50 mL) was slowly added to a solution of compound 4 (78.33 g, 532.40 mmol, 1.10 equiv) and PPh3 (133.30 g, 508.20 mmol, 1.05 equiv) in anhydrous THF (100 mL) at 0°C via cannula. The flask and cannula were washed with an additional portion of dry THF (30 mL) to ensure complete addition. The reaction was gradually warmed to 25°C and stirred for 18 h. Then H2O (1000 mL) was added, extracted with EA (500 mL x 2), concentrated and purified by silica gel (PE:EA = 0 to 10:1) to give compound 5 (42.5 g, 374.02 mmol, yield 77.28%) as a white solid.

[0245] TLC information (PE: EtOAc = 5: 1); R f (Compound 3) = 0.2; R f (Compound 5) = 0.5; 1 H NMR (CDCl3, 400 MHz) 7.86 to 7.79 (m, 2H), 7.72 to 7.67 (m, 2H), 3.73 to 3.66 (t, J = 8 Hz, 2H), 2.27 to 2.20 (m, 2H), 1.95 to 1.91 (t, J = 4 Hz, 1H), 1.85 to 1.75 (m, 2H), 1.61 to 1.52 (m, 2H)

[0246] General procedure for the preparation of compound 6

[0247]

[0248] Reagents Mw. Dosage mmol Proportion Additional Information Compound 5 227.26 88g 387.22 1 NIS 224.98 130.68g 580.83 1.5 <![CDATA[AgNO3]]> 169.87 16.44g 96.81 0.25 THF 1.6L Product (Compound 6) 353.15 118.6g 335.8 Yield: 86%

[0249] NIS (130.68 g, 580.83 mmol, 1.50 equiv) was added to a solution of compound 5 (88.00 g, 387.22 mmol, 1.00 equiv) and AgNO3 (16.44 g, 96.81 mmol, 0.25 equiv) in anhydrous THF (1600 mL) at 25°C. The reaction headspace was purged with N2, and the reaction mixture was protected from light with an aluminum foil wrap and stirred for 16 h. The mixture was poured into water (1000 mL), extracted with EA (600 mL×3), concentrated and purified by silica (PE:EA=10:1 to 2:1) to give compound 6 (118.6 g, 1.01 mol, yield 86.78%) as a white solid.

[0250] TLC information (PE: EtOAc = 20: 1); R f (Compound 5) = 0.22; R f (Cpd 6) = 0.21; 1 H NMR (CDCl3, 400 MHz) 7.87 to 7.82 (m, 2H), 7.74 to 7.69 (m, 2H), 3.74 to 3.67 (t, J = 8 Hz, 2H), 2.45 to 2.39 (t, J = 8 Hz, 2H), 1.84 to 1.74 (m, 2H), 1.61 to 1.52 (m, 2H)

[0251] General procedure for the preparation of compound 7

[0252]

[0253] Reagents Mw. Dosage mmol Proportion Additional Information Compound 6 353.15 157g 444.57 1 <![CDATA[BH3.DMS]]> 58mL 577.94 1.3 2-Methyl-2-butene 70.13 87.3g 1240 2.8 AcOH 260mL THF 1.2L Product (Compound 5) 355.17 135g 380.1 Yield: 85%

[0254] 2-Methylbut-2-ene (87.30 g, 1.24 mol, 2.80 equiv) was added to a 0°C solution of BH3·Me2S (43.91 g, 577.94 mmol, 1.30 equiv) in THF (300 mL) over 30 min. After 1 h, the reaction mixture was warmed to 25°C and stirred for 90 min. After cooling to 0°C again, a solution of compound 6 (157.00 g, 444.57 mmol, 1.00 equiv) in THF (900 mL) was added slowly over 1 h. After the addition was complete, the cold bath was removed and the reaction mixture was stirred at 25°C. After 2 h, the reaction was cooled to 0°C again, glacial AcOH (260 mL) was added slowly over 30 min (caution: gas release) and stirred at 25°C for 16 h. TLC (PE:EA=10:1) showed the reaction was completed, the mixture was poured into water (1 L), extracted with EA (300 mL×2), concentrated and purified by silica gel (PE:EA=0-10:1) to give compound 7 (135 g, 380.1 mmol, yield 85.50%) as a yellow oil.

[0255] TLC information (PE: EtOAc = 10: 1); R f (Cpd 6) = 0.5; R f (Cpd 7) = 0.55; 1 H

[0256] NMR (CDCl3, 400MHz) 7.88 to 7.80 (m, 2H), 7.75 to 7.67 (m, 2H), 6.24 to 6.11 (m, 2H), 3.74 to 3.66 (t, J = 8 Hz, 2H), 2.24 to 2.15 (q, J = 8 Hz, 2H), 1.78 to 1.67 (m, 2H), 1.55 to 1.44 (m, 2H)

[0257] General procedure for the preparation of compound 8

[0258]

[0259] Reagents Mw. Dosage mmol Proportion Additional Information Compound 7 355.17 138g 388.55 1 <![CDATA[N2H4.H2O]]> 50.06 97.25g 1940 5 MeOH 2L Product (Compound 8) 225.07 81g 683.79 Yield: 92%

[0260] At 0°C, N2H4·H2O (97.25 g, 1.94 mol, 5.00 equivalents) was added to a solution of compound 7 (138.00 g, 388.55 mmol, 1.00 equivalents) in anhydrous MeOH (2.00 L) and stirred at 25°C for 18 h, TLC (PE: EA = 10: 1) showed that the reaction was complete, the reaction mixture was concentrated, the residue was poured into DCM (5000 mL) and stirred for 30 minutes. Filter and wash the filter cake with DCM (1 L × 2), and the filtrate was concentrated to give compound 8 (162.00 g, crude product) as a yellow oil.

[0261] TLC information (PE: EtOAc = 10: 1); R f (Cpd 7) = 0.5; R f (Cpd 8) = 0; TLC information (DCM: MeOH = 10: 1); R f (Cpd 7) = 1; R f (Cpd 8) = 0.2; 1 H NMR: (CDCl3, 400 MHz) 6.19 to 6.07 (m, 2H), 2.73 to 2.59 (m, 2H), 2.20 to 2.05 (m, 2H), 1.75 to 1.55 (m, 2H), 1.51 to 1.36 (m, 4H)

[0262] General procedure for preparing compound 9

[0263]

[0264] Reagents Mw. Dosage mmol Proportion Additional Information Compound 8 225.07 92g 408.76 1 Compound 2 131.13 53.6g 408.76 1 E3 101.19 49.64g 590.51 1.2 EtOH 1.5L Product (Compound 9) 310.13 90g 232.16 Yield: 57%

[0265] Compound 8 (92.00 g, 408.76 mmol, 1.00 equiv), compound 2 (53.60 g, 408.76 mmol, 1.00 equiv) and Et3N (49.64 g, 490.51 mmol, 1.20 equiv) in anhydrous ethanol (1.5 L) were heated at 60°C for 20 h. TLC (DCM: MeOH = 10: 1) showed that the reaction was complete, and the mixture was concentrated to about 300 mL. Filtered and concentrated to give compound 9 (90 g, 232.16 mmol, yield 57%) as a white solid.

[0266] TLC information (DCM:MeOH=10:1); R f (Cpd 8) = 0.2; R f (Cpd 9) = 0.5; 1 H NMR: (CDCl3, 400 MHz) 7.57 to 7.37 (s, 2H), 6.25 to 6.20 (d, J = 8 Hz, 1H), 6.18 to 6.11 (q, J = 8 Hz, 1H), 3.37 to 3.30 (q, J = 8 Hz, 2H), 2.93 to 2.88 (q, J = 4 Hz, 3H), 2.21 to 2.13 (m, 2H), 1.66 to 1.56 (m, 2H), 1.53 to 1.43 (m, 2H)

[0267] General procedure for preparing compound 12

[0268]

[0269] Reagents Mw. Dosage mmol Proportion Additional Information Compound 10 114.1 25g 197.2 1 90％ Compound 11 114.18 27.02g 236.63 1.2 <![CDATA[In(OTf)3]]> 560 22.09g 39.44 0.2 Toluene 350mL Compound 12 200.27 35g 139.81 Yield: 71%

[0270] Compound 10 (25.00 g, 197.20 mmol, 1.00 equiv) in toluene (75 mL) was added to a solution of compound 11 (27.02 g, 236.63 mmol, 1.20 equiv) and In(OTf)3 (22.09 g, 39.44 mmol, 0.20 equiv) in toluene (275 mL) over 20 minutes. The mixture was then stirred at 25°C for 48 h. The mixture was concentrated and purified by silica gel (PE: EA = 20: 1) to give ethyl compound 12 (35.00 g, 139.81 mmol, 70.90% yield, purity 80%) as a yellow oil.

[0271] TLC information (PE: EtOAc = 10: 1); R f (Cpd 11) = 0.21; R f (Cpd 12) = 0.55; 1HNMR (CDCl3, 400MHz) 5.86 to 5.72 (m, 1H), 5.03 to 5.86 (m, 2H), 4.24 to 4.17 (q, J = 8 Hz, 2H), 4.07 to 4.01 (s, 2H), 3.54 to 3.47 (t, J = 8 Hz, 2H), 2.09 to 1.98 (m, 2H), 1.68 to 1.55 (m, 2H), 1.45 to 1.32 (m, 4H), 1.30 to 1.25 (t, J = 8 Hz, 3H) General procedure for the preparation of compound 13

[0272]

[0273] Reagents Mw. Dosage mmol Proportion Additional Information Compound 12 200.27 10.07g 50.3 1.2 90％ Compound 9 310.13 13g 41.92 1 9-BBN 100.6mL 100.6 2.4 <![CDATA[Na2CO3]]> 200mL 2M <![CDATA[Pd(PPh3)C 12 ]]> 701.9 1.47g 2.1 0.05 THF 800mL Compound 13 384.51 6.5g 16.06 Yield: 38%

[0274] To an oven-dried flask containing 9-BBN (17.53 g, 100.60 mmol, 2.40 equiv) in THF (540 mL) was added a solution of compound 12 (10.07 g, 50.30 mmol, 1.20 equiv) in THF (60 mL) at 0°C. After stirring at 25°C for 16 h, an aqueous solution of Na2CO3 (200 mL of a 2M solution prepared from H2O sparged with argon) was added. After 2 h, Pd(PPh3)2Cl2 (1.47 g, 2.10 mmol, 0.05 equiv) was added, followed by compound 9 (13.00 g, 41.92 mmol, 1.00 equiv) dissolved in THF (200 mL). The resulting red solution was protected from light. The reaction was stirred at 50°C for 5 h. LCMS showed the reaction was complete. After cooling to 25°C, the reaction mixture was concentrated under vacuum, and the residue was purified with silica gel (PE:EA=10:1 to 3:1) to give compound 13 (6.5 g, 16.06 mmol, yield 38.31%, purity 95%) as a yellow solid.

[0275] TLC information (PE: EtOAc = 2: 1); R f (Cpd 12) = 0.3; R f (Cpd 13) = 0.3; LCMS:

[0276] ET2662-38-P1D(M+H + ): 385.1; 1 H NMR: (CDCl3, 400MHz) to 7.38 (s, 1H), 5.41 to 5.25 (m, 2H), 4.25 to 4.17 (q, J = 8 Hz, 1H), 4.07 to 4.02 (s, 2H), 3.54 to 3.47 (t, J = 8 Hz, 2H), 3.34 to 3.26 (q, J = 8 Hz, 2H), 2.92 to 2.87 (d, J = 8 Hz, 3H), 2.08 to 1.94 (m, 4H), 1.65 to 1.51 (m, 4H), 1.43 to 1.23 (m, 13H)

[0277] General procedure for preparing compound 02 (Comp-02)

[0278]

[0279] Reagents Mw. Dosage mmol Proportion Additional Information Compound 13 384.51 7.5g 19.51 1 90％ LiOH 23.95 0.9341g 39.02 2 <![CDATA[H2O]]> 40mL THF 70mL Compound 13 356.46 4g 10.72 Yield: 55%

[0280] To a solution of compound 13 (7.50 g, 19.51 mmol, 1.00 equiv) in THF (70.00 mL) was added LiOH (934.31 mg, 39.02 mmol, 2.00 equiv) in H2O (40.00 mL) at 0°C, and the reaction mixture was stirred at 0°C to 25°C for 1 h. LCMS showed that the reaction was complete. H2O (60 mL) was then added to the reaction mixture, the aqueous phase was treated with 3N HCl (10 mL) to pH = 3 to 4, extracted with EA (100 mL×3), dried, and the organic phase was concentrated to give a crude product. The residue was purified by a gel column (PE: EA = 5: 1 to EA) to give compound 02 (4.00 g, 10.72 mmol, yield 54.95%, purity 95.51%)

[0281] TLC information (DCM:MeOH=10:1); R f (Cpd 13) = 0.9; R f ( Compound 2 )=0.4; MS:ET2662-43-P1C(M+Na + ): 379.2; 1 H NMR (CDCl3, 400 MHz) 7.84 (s, 1H), 7.74 (s, 1H), 5.40 to 5.32 (m, 2H), 4.11 (s, 2H), 3.59 to 3.55 (t, J = 6.4 Hz, 2H), 3.35 to 3.32 (t, J = 6.8 Hz, 2H), 2.92 to 2.91 (d, J = 5.2 Hz, 3H), 2.07 to 2.00 (m, 4H), 1.64 to 1.59 (m, 4H), 1.42 to 1.32 (m, 10H); 13C NMR (CDCl3, 100MHz) δ173.7, 160.7, 159.8, 130.5, 129.0, 72.0, 67.8, 39.7, 29.4, 29.3, 29.0, 29.0, 28.6, 27.1, 26.8, 26.7, 25.8

[0282] Compound 03 (Comp-03)

[0283] Synthesis Summary

[0284]

[0285] Synthesis of 2-(hex-5-yn-1-yl)isoindoline-1,3-dione (2): According to previous literature 1 , 5-hexyn-1-ol (1) (5 g, 1 eq.) and diisopropyl azodicarboxylate (DIAD, 10.5 g, 1.02 eq.) in anhydrous THF (30 mL) were slowly added via cannula to a 0°C solution of phthalimide (7.5 g, 51 mmol) and triphenylphosphine (TPP, 13.4 g, 1 eq.) in anhydrous THF (50 mL). The flask and cannula were washed with an additional portion of dry THF (20 mL) to ensure complete addition. The reaction was allowed to gradually warm to room temperature overnight. After a total of 18 h, all volatiles were evaporated and purified using a Teledyne Isco The residue was purified by RF chromatography system (80 g SiO2 column, hexanes, 2 min; 0 to 20% EtOAc / hexanes, 12 min; 20% EtOAc / hexanes, 6 min) to give 2 (8.3 g, 72%) as a white solid, whose spectral values ​​were consistent with those reported. 2 The same.

[0286]

[0287] Synthesis of 2-(6-iodohex-5-yn-1-yl)isoindoline-1,3-dione (3): According to previous literature 3 , N-iodosuccinimide (NIS, 7.4 g, 1.5 equiv) was added in one portion to a room temperature solution of alkyne 2 (5.0 g, 22 mmol) and AgNO3 (0.93 mg, 0.25 equiv) in anhydrous THF (120 mL). The reaction headspace was flushed with argon and the reaction mixture was protected from light with an aluminum foil wrap. After 4 h, the reaction mixture was poured into H2O (200 mL) and extracted with Et2O (2×50 mL). The ether extracts were washed with brine (3×60 mL) (note: the biphasic mixture turned brown). The combined aqueous phases were re-extracted with Et2O (2×50 mL). The combined ether extracts were dried over Na2SO4, filtered, and concentrated on a rotary evaporator. The product was purified by chromatography on a Teledyne Isco The residue was purified by RF chromatography system (80 g SiO2 column, hexanes, 2 min; 0 to 40% EtOAc / hexanes, 8 min; 40% EtOAc / hexanes, 10 min; 40% to 100% EtOAc / hexanes, 5 min; 100% EtOAc, 3 min) to give 3 (97%) as a white solid with a melting point of 132.5°C to 132.7°C. 1 H NMR (500 MHz, CDCl3) δ 7.85 (ddd, J = 5.4, 3.0, 1.0 Hz, 2H), 7.72 (ddd, J = 5.5, 3.0, 1.0 Hz, 2H), 3.71 (t, J = 7.1 Hz, 2H), 2.42 (t, J = 7.0 Hz, 2H), 1.83 to 1.73 (m, 2H), 1.61 to 1.51 (m, 2H); 13 C NMR (100MHz, CDCl3) δ168.62, 134.14, 132.30, 123.44, 94.04, 37.60, 27.91, 25.89, 20.60, -6.27.

[0288]

[0289] Synthesis of 2-(6-iodohexyl-5(Z)-en-1-yl)isoindoline-1,3-dione (4): According to previous literature 4 , neat 2-methyl-2-butene (4.2 mL, 2.8 eq.) was added to a 0°C THF solution (3 mL) of BH3·Me2S (2.0 M in THF, 9.2 mL, 1.3 eq.) over 5 min. After 1 h, the reaction mixture was warmed to room temperature and stirred for 90 min. After cooling to 0°C again, a solution of iodine 3 (5 g, 1 eq.) in THF (30 mL) was slowly added over 5 min. After the addition was complete, the cold bath was removed and the reaction mixture was stirred at room temperature. After 2 h, the reaction was cooled to 0°C again, followed by the slow addition of glacial AcOH (8.5 mL) over 5 min (caution: gas release). After stirring overnight (14 h), the reaction mixture was diluted with H2O (20 mL) and then carefully poured into a stirring saturated sodium bicarbonate solution (40 mL). The biphasic mixture was extracted with ether (2 x 40 mL), and the combined ether extracts were washed with water, brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by RF chromatography system (40 g SiO2 column, 0-20% EtOAc / hexane elution, 8 min; 20% EtOAc / hexane elution, 6 min) to give a mixture of 4 and borane byproduct (4.52 g). Further purification was postponed to the next step.

[0290]

[0291] Synthesis of 6-iodohexyl-5(Z)-en-1-amine (5): According to previous literature 5 , 40 wt% MeNH2 in H2O solution (15mL) was added to a room temperature anhydrous EtOH (20mL) solution of crude product 4 (4.52g). After overnight stirring (18h), the reaction mixture was poured into ice water (100mL) and extracted with Et2O (30mL×2). The combined ether extracts were washed with cold 1N HCl solution (20mL×2). The combined aqueous washings were adjusted to pH 8 with a diluted NaOH aqueous solution. The solution was extracted with Et2O (30mL×2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to obtain a crude product 5 (1.12g) in the form of a brown oil, which was used in the next step without further purification. 1H NMR (500 MHz, CDCl 3 ) δ 6.29 to 6.08 (m, 2H), 2.71 (tt, J=7.0, 1.8 Hz, 2H), 2.16 (app q, J=6.5 Hz, 2H), 1.78 to 1.52 (m, 2H).

[0292]

[0293] N 1 -(6-iodohex-5(Z)-en-1-yl)-N 2 -Synthesis of methyloxamide (7): According to previous literature 6 A solution of iodoolefin 5 (1.12 g, 4.98 mmol), ethyl 2-(methylamino)-2-oxoacetate (6) (0.62 g, 1.2 eq.) and triethylamine (0.83 mL, 1.2 eq.) in anhydrous ethanol (10 mL) was heated at 60 °C. After 20 h, the brown solution was cooled to room temperature and concentrated under vacuum. The reaction mixture was prepared using Teledyne Isco The residue was purified by RF chromatography system (25 g SiO2 column, 0 to 50% EtOAc / hexane elution, 10 min; 50% EtOAc / hexane elution, 10 min) to give 7 (0.93 g, 60%) as a white solid, mp 99.7-99.8°C. 1 H NMR (500 MHz, CDCl 3) δ 7.46 (br s, 2H), 6.32 to 6.02 (m, 2H), 3.34 (app q, J = 6.9 Hz, 2H), 2.91 (d, J = 5.3 Hz, 3H), 2.18 (dt, J = 7.5 Hz, 7.0 Hz, 2H), 1.68 to 1.59 (m, 2H), 1.54 to 1.42 (m, 2H); 13 C NMR (100MHz, CDCl3) δ160.47, 159.70, 140.43, 83.07, 39.40, 34.11, 28.61, 26.15, 25.11.

[0294]

[0295] Synthesis of ethyl 2-(oct-7-en-1-yloxy)acetate (10): According to previous literature 7 , pure 8 (1.92 g, 1.2 eq) was added to a suspension of In(OTf)3 (1.57 g, 20 mol%) in anhydrous toluene (20 mL) at room temperature. Ethyl diazoacetate (9) (1.60 g, 14 mmol) was added slowly under argon atmosphere over 5 min (caution: exothermic) to give a yellow solution. After 2 days, the reaction mixture was concentrated under vacuum and purified by Teledyne Isco The residue was purified by RF chromatography system (25 g SiO 2 column, 0-10% EtOAc / hexane elution, 5 min; 10% EtOAc / hexane elution, 8 min) to give 10 (2.72 g, 97%) as a colorless oil. 1 H NMR (500 MHz, CDCl3) δ 5.80 (ddt, J = 16.9 Hz, 10.2 Hz, 6.6 Hz, 1H), 5.08 to 4.84 (m, 2H), 4.22 (q, J = 7.1 Hz, 2H), 4.06 (s, 2H), 3.52 (t, J = 6.7 Hz, 2H), 2.13 to 1.96 (m, 2H), 1.72 to 1.52 (m, 2H), 1.48 to 1.33 (m, 4H), 1.28 (t, J = 7.1 Hz, 3H); 13 CNMR (100MHz, CDCl3) δ170.70, 138.99, 114.48, 71.97, 68.48, 60.86, 33.84, 29.55, 28.84, 25.63, 14.34.

[0296]

[0297] Ethyl 2-((13-(2-(methylamino)-2-oxoacetylamino)trideca-8(Z)-en-1-yl)oxy)acetate Synthesis of (11):To an oven-dried flask containing ethyl 2-(oct-7-en-1-yloxy)acetate (10) (220 mg, 1.2 eq) was added a solution of 9-BBN (0.5 M in THF, 2.4 eq, 4.40 mL). After stirring at room temperature for 3 h, aqueous Na2CO3 (1.5 mL of a 2 M solution prepared from H2O sparged with argon) was added. After 5 min, Pd(PPh3)2Cl2 (33 mg, 5 mol%) was added followed by 7 (284 mg, 0.92 mmol) dissolved in THF (4 mL). The resulting red solution was protected from light while another portion of aqueous Na2CO3 (0.5 mL of a 2 M solution) was added. The reaction was continued at room temperature (14 h) and then at 50 °C for 4 h. After cooling to room temperature, the reaction mixture was concentrated under vacuum and the residue was purified by chromatography using Teledyne Isco RF chromatography system (24g SiO2 column, 0 to 40% EtOAc / hexane elution, 6 minutes; 40% EtOAc / hexane elution, 8 minutes; 40% to 100% EtOAc / hexane elution, 4 minutes) purification to give the ether 11 (330 mg, 90%) as an off-white solid. Analytical samples were purified by preparative TLC to give 11 as a white low melting solid.

[0298] TLC: 50% EtOAc / hexanes, R f ~0.49. 1 H NMR (500 MHz, CDCl3) δ 7.45 (br s, 2H), 5.42 to 5.26 (m, 2H), 4.22 (q, J = 7.2 Hz, 2H), 4.06 (s, 2H), 3.52 (t, J = 6.7 Hz, 2H), 3.31 (dt, J = 7.0 Hz, 6.5 Hz, 2H), 2.91 (d, J = 5.1 Hz, 3H), 2.15 to 1.91 (m, 4H), 1.70 to 1.50 (m, 2H), 1.44 to 1.31 (m, 12H), 1.29 (t, J = 7.1 Hz, 3H); 13 C NMR (100MHz, CDCl3) δ170.62, 160.55, 159.66, 130.58, 128.86, 71.96, 68.64, 39.55, 29.61, 29.51, 29.30, 29.19, 27.20, 26.83, 26.67, 26.15, 25.93, 14.21.

[0299]

[0300] Synthesis of 2-((13-(2-(methylamino)-2-oxoacetamido)trideca-8(Z)-en-1-yl)oxy)acetic acid (12): To a room temperature solution of 11 (720 mg, 1.87 mmol) in THF (44 mL) was added LiOH (9 mL of a 1.0 M aqueous solution). After 48 h, the reaction was cooled to 4 °C and acidified to pH 4 with 2N HCl aqueous solution. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (15 mL x 3). The combined organic extracts were dried over Na2SO4, filtered through a sintered funnel, and concentrated under vacuum. The product was purified by HPLC using Teledyne Isco The crude product was purified by RF chromatography system (12 g SiO2 column, eluting with 0 to 80% EtOAc / hexanes in 15 min; eluting with 80% EtOAc / hexanes in 5 min) to give 12 (232 mg, 33%) as a white solid, mp 94.6-94.7°C.

[0301] 1 H NMR (500 MHz, CDCl3) δ 7.90 (s, 1H), 7.66 (s, 1H), 5.48 to 5.22 (m, 2H), 4.10 (s, 2H), 3.58 (t, J = 6.5 Hz, 2H), 3.32 (dt, J = 7.0, 6.5 Hz, 2H), 2.91 (d, J = 5.2 Hz, 3H), 2.16 to 1.90 (m, 4H), 1.71 to 1.48 (m, 4H), 1.45 to 1.18 (m, 10H); 13 C NMR (75MHz, CD3OD) δ176.96, 160.32, 160.12, 130.65, 129.99, 72.51, 69.84, 3 9.45, 29.82, 29.58, 29.15, 27.71, 27.38, 27.24, 27.08, 26.83, 25.84, 25.03.

[0302]

[0303] Synthesis of compound 3:A mixture of EDCI (275 mg, 1.3 eq.) and triethylene glycol (1.5 mL, 10 eq.) was dried under high vacuum for 90 minutes. The reaction flask was flushed with argon and DMAP (175 mg, 1.3 eq.), acetonitrile (50 mL) and acid 12 (395 mg, 1.1 mmol) dissolved in CH2Cl2 (20 mL) were added. After 3 days, the reaction mixture was concentrated under vacuum, and the crude residue was dissolved in EtOAc (20 mL) and washed with 1N HCl (20 mL) and brine (20 mL). The aqueous washings were re-extracted with EtOAc (20 mL×2). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under vacuum. Using Teledyne Isco The residue was purified by RF chromatography system (12 g SiO2 column, 0 to 80% EtOAc / hexane elution, 8 min; 80% EtOAc / hexane elution, 4 min; 80% to 100% EtOAc / hexane elution, 3 min; 100% EtOAc elution, 15 min; 10% MeOH / CH2Cl2 elution, 5 min) to give analog 13 (174 mg, 32%) as a white solid, mp 65.3°C to 65.8°C.

[0304] 1 H NMR (500 MHz, CDCl3) δ 7.46 (s, 2H), 5.41 to 5.27 (m, 2H), 4.33 (t, J = 4.7 Hz, 2H), 4.11 (s, 2H), 3.77 to 3.70 (m, 4H), 3.70 to 3.64 (m, 4H), 3.61 (app t, J=4.5Hz, 2H), 3.52 (t, J=6.7Hz, 2H), 3.42 (t, J=6.1Hz, OH), 3.31 (dt, J=7.0, 6.5Hz, 2H), 2.91 (d, J=5.2Hz, 3H ), 2.44 (s, 1H), 2.05 (dt, J=7.5, 7.0Hz, 2H), 2.00 (dt, J=7.0, 6.5Hz, 2H), 1.62 to 1.50 (m, 4H), 1.45 to 1.21 (m, 10H); 13 C NMR (125MHz, CDCl3) δ170.86, 160.83, 159.95, 130.76, 129.12, 72.76, 72.21, 70.77, 70.52, 69.19, 68.34, 63.84, 61.92, 39.78, 29.84, 29.73, 29.54, 29.42, 29.02, 27.44, 27.09, 26.92, 26.42, 26.15.

[0305] Compound 4 (Comp-04)

[0306] The synthesis of compound 4 (Comp-04) was similar to that of compound 2 (Comp-02), whereas the urea group was introduced following the synthetic route described in patent application WO2010 / 081683 (Example 6).

[0307] Compound 5 (Comp-05)

[0308] Synthesis Summary

[0309]

[0310] General procedure for preparing compound 4-2

[0311] Reagents Mw. Dosage Moore Proportion Additional Information Compound 4-1 219.02 30.0g 137 mmol 1.0 equivalent Compound 1 98.14 13.4g 137 mmol 1.0 equivalent Cul 190.45 522mg 2.74 mmol 0.02 equivalent <![CDATA[Pd(PPh3)4]]> 1155.56 1.58g 1.37 mmol 0.01 equivalent TEA 480mL Product: (Compound 4-2) 189.25 21.0g 99.9 mmol Yield: 73%

[0312] Compound 1 (13.4 g, 137 mmol, 1.0 equiv.), CuI (522 mg, 2.74 mmol, 0.02 equiv.), Pd(PPh3)4 (1.58 g, 1.37 mmol, 0.01 equiv.) were added to a mixture of compound 4-1 (30.0 g, 137 mmol, 1.0 equiv.) in TEA (480 mL) at 25°C under N2 environment and stirred at 25°C for 16 h. TLC (petroleum ether / ethyl acetate = 1 / 1, R f =0.5) showed that the reaction was complete. The solution was poured into NH4Cl aqueous solution (1.0 L), extracted with DCM (200 mL×5), and the combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluted with petroleum ether: EtOAc (10:1, 1:1)) to give compound 4-2 (21.0 g, yield 73%) as a yellow oil.

[0313] 1 H NMR: ET5008-6-P1b1 400 MHz CDCl3; 7.30 to 7.24 (m, 1H), 7.10 (t, J = 7.6 Hz, 1H), 6.73 to 6.65 (m, 2H), 4.19 (br, 2H), 3.74 (m, 2H), 2.54 (t, J = 6.0 Hz, 2H), 1.87 to 1.68 (m, 4H), 1.50 to 1.45 (m, 1H).

[0314] General procedure for preparing compound 4-3

[0315]

[0316] Reagents Mw. Dosage Moore Proportion Additional Information Compound 4-2 189.25 21.0g 111 mmol 1.0 equivalent Pd / c 500mg MeOH 500mL Product: (Compound 4-3) 193.28 17.0g 83.6 mmol Yield: 75%

[0317] Pd / C (500 mg) was added to a mixture of compound 4-2 (21.0 g, 111 mmol, 1.0 equiv) in MeOH (500 mL) and stirred at 50 psi of H2 and 25 °C for 16 h. LC-MS (ET5008-10-P1A5, product: RT = 1.10 min) showed that the reaction was complete. The solution was then filtered and concentrated to give compound 4-3 (17.0 g, 75% yield) as a yellow oil.

[0318] 1 H NMR: 5008-10-P1b1 400 MHz CDCl3; 7.08 to 7.03 (m, 2H), 6.78 to 6.69 (m, 2H), 3.69 to 3.62 (m, 4H), 2.52 (t, J = 8.0 Hz, 2H), 1.68 to 1.59 (m, 4H), 1.47 to 1.42 (m, 4H), 1.31 to 1.27 (m, 1H).

[0319] General procedure for preparing compound 4-4

[0320]

[0321] Reagents Mw. Dosage Moore Proportion Additional Information Compound 4-3 193.28 17.0g 88.0 mmol 1.0 equivalent <![CDATA[NaNO2]]> 69.00 6.07g 88.0 mmol 1.0 equivalent KI 166.00 43.8g 264 mmol 3.0 equivalent <![CDATA[Concentrated H2SO4]]> 98.08 30.2g 308 mmol 3.5 equivalent <![CDATA[H2O]]> 560mL Product: (Compound 4-4) 304.17 17.0g 50.3 mmol Yield: 57%

[0322] Concentrated H2SO4 (30.2 g, 308 mmol, 3.5 eq) was added to a H2O solution (500 mL) of compound 4-3 (17.0 g, 88.0 mmol, 1.0 eq) at 0°C under N2 environment. A solution of NaNO2 (6.07 g, 88.0 mmol, 1.0 eq) in H2O (30.0 mL) was added to the above solution at 0°C and stirred at 0°C for 15 minutes. A solution of KI (43.8 g, 264 mmol, 3.0 eq) in H2O (30.0 mL) was added at 0°C and the resulting suspension was warmed to 25°C and stirred for 45 minutes. TLC (petroleum ether / ethyl acetate = 1 / 1, R f =0.9) showed that the reaction was complete. H2O (400 mL) was added, extracted with EtOAc (350 mL×3), and the combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluted with petroleum ether: EtOAc (100: 1, 10: 1)) to give compound 4-4 (17.0 g, yield 57%) as a brown oil.

[0323] 1H NMR: ET5008-22-P1b1 400MHz CDCl3; 7.80 (d, J = 7.2 Hz, 1H), 7.28 to 7.23 (m, 1H), 7.21 to 7.18 (m, 1H), 6.89 to 6.85 (m, 1H), 3.65 (t, J = 6.8 Hz, 2H), 2.71 (t, J = 8.0 Hz, 2H), 1.61 to 1.50 (m, 4H), 1.45 to 1.40 (m, 4H), 1.31 to 1.28 (m, 1H).

[0324] General procedures for preparing compounds 4-5'

[0325]

[0326] Reagents Mw. Dosage Moore Proportion Additional Information Compound 4-4 304.17 10.0g 32.9 mmol 1.0 equivalent <![CDATA[BrCH2CO2tBu]]> 195.05 7.70g 39.5 mmol 1.2 equivalent KOH 56.11 33.0g 588 mmol 18 equivalent <![CDATA[Bu4NHSO4]]> 339.53 5.58g 16.4 mmol 0.50 equivalent Toluene 50.0mL <![CDATA[H2O]]> 50.0mL Product: (Compound 4-5') 418.31 5.40g 12.3 mmol Yield: 37%

[0327] To a mixture of BrCH2CO2tBu (7.70 g, 39.5 mmol, 1.2 eq.) and compound 4-4 (10.0 g, 32.9 mmol, 1.0 eq.) in toluene (50.0 mL) at 0°C, Bu4NHSO4 (5.58 g, 16.4 mmol, 0.50 eq.) and KOH (33.0 g, 588 mmol, 17.9 eq.) in H2O (50.0 mL) were added, and the mixture was stirred at 25°C for 16 h. TLC (petroleum ether / ethyl acetate=10 / 1, R f =0.62) showed 40% of SM remaining. H2O (200 mL) was added, extracted with DCM (200 mL×2), and the combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluted with petroleum ether: EtOAc (40:1)) to give compound 4-5' (5.40, yield 37%) as a yellow oil.

[0328] 1 H NMR: ET5008-26-P1b1 400 MHz CDCl3; □ 7.82 (d, J = 7.2 Hz, 1H), 7.30 to 7.26 (m, 1H), 7.23 to 7.20 (m, 1H), 6.91 to 6.88 (m, 1H), 3.97 (s, 2H), 3.53 (t, J = 6.8 Hz, 2H), 2.72 (t, J = 8.0 Hz, 2H), 1.69 to 1.59 (m, 4H), 1.58 to 1.43 (m, 13H).

[0329] General procedures for preparing compounds 4-6

[0330]

[0331] Reagents Mw. Dosage Moore Proportion Additional Information Compound 4-5' 418.31 5.40g 12.9 mmol 1.0 equivalent Compound 2 169.22 2.18g 12.9 mmol 1.0 equivalent Cul 190.45 49.2mg 258 mmol 0.02 equivalent <![CDATA[PdCl2(PPh3)2]]> 701.90 181mg 258 mmol 0.02 equivalent <![CDATA[Et3N]]> 110mL Product: (Compound 4-6) 459.62 3.00g 6.20 mmol Yield: 48%

[0332] To a mixture of compound 4-5' (5.40 g, 12.9 mmol, 1.0 equiv) and compound 2 (2.18 g, 12.9 mmol, 1.0 equiv) in Et3N (110 mL) at 25°C under N2 environment, CuI (49.2 mg, 258 μmol, 0.02 equiv) and PdCl2(PPh3)2 (181 mg, 258 μmol, 0.02 equiv) were added and stirred at 25°C for 16 h. TLC (petroleum ether / ethyl acetate = 1 / 1, R f =0.3) showed that the reaction was complete. Then NH4Cl aqueous solution (200mL) was added, extracted with EtOAc (200mL×3), and the combined organic layer was washed with brine, dried with Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluted with petroleum ether: EtOAc (10:1, 1:1)) to give compound 4-6 (3.00, yield 48%) as a yellow oil.

[0333] 1 H NMR: ET5008-32-P1b1 400MHz CDCl3; □7.41 to 7.34 (m, 1H), 7.23 to 7.06 (m, 3H), 4.97 to 4.87 (m, 1H), 3.97 (s, 2H), 3.53 (t, J = 6.8 Hz, 2H), 3.43 to 3.33 (m, 2H), 2.72 (t, J = 8.0 Hz, 2H), 2.64 (J = 8.0 Hz, 2H), 1.69 to 1.59 (m, 4H), 1.55 to 1.43 (m, 22H).

[0334] General procedures for preparing compounds 4-7

[0335]

[0336] Reagents Mw. Dosage Moore Proportion Additional Information Compound 4-6 459.62 3.00g 6.53 mmol 1.0 equivalent Pd / C 200mg MeOH 20.0mL Product: (Compound 4-7) 463.65 2.50g 4.91 mmol Yield: 75%

[0337] Pd / C (200 mg) was added to a mixture of compound 4-6 (3.00 g, 6.53 mmol, 1.0 equiv) in MeOH (20.0 mL) and stirred at 50 psi of H2 and 25°C for 5 h. LC-MS (ET5008-10-P1A4, product: RT = 1.04 min) showed that the reaction was complete. The solution was then filtered and concentrated to give compound 4-7 (2.50 g, 75% yield) as a yellow oil.

[0338] 1H NMR: ET5008-33-P1b1 400 MHz CDCl3; □7.13 (s, 4H), 4.54 (s, 1H), 3.96 (s, 2H), 3.52 (t, J=6.8 Hz, 2H), 3.18 to 3.14 (m, 2H), 2.65 to 2.57 (m, 4H), 1.75 to 1.54 (m, 10H), 1.53 to 1.37 (m, 20H).

[0339] General procedure for preparing compounds 4-10

[0340]

[0341] Reagents Mw. Dosage Moore Proportion Additional Information Compound 4-7 463.65 1.00g 2.16 mmol 1.0 equivalent HCl / EtOAc 30.0mL 4N Product: (Compound 4-10) 343.89 800mg 2.33 mmol Crude products

[0342] A mixture of compound 4-7 (1.00 g, 2.16 mmol, 1.0 equiv) in HCl / EtOAc (30.0 mL) was heated to 50° C. and stirred at 50° C. for 0.5 h. LC-MS (ET5008-34-P1A4, product: RT=0.698 min) showed that the reaction was complete. The mixture was concentrated to give crude compound 4-10 (800 mg) as a yellow solid.

[0343] General procedure for preparing compound 05 (Comp-05)

[0344]

[0345] Reagents Mw. Dosage Moore Proportion Additional Information Compound 4-10 343.89 800mg 2.33 mmol 1.0 equivalent Compound R1 131.13 611mg 4.66 mmol 2.0 equivalent <![CDATA[Et3N]]> 101.19 2.36g 23.3 mmol 10 equivalent EtOH 40.0mL Product: Compound 05 392.49 370mg 933 micromoles Yield: 40%

[0346] To a mixture of compound 4-10 (800 mg, 2.33 mmol, 1.0 equiv) in EtOH (40.0 mL) was added Et3N (2.36 g, 23.3 mmol, 10.0 equiv) and compound R1 (611 mg, 4.66 mmol, 2.0 equiv) at 25 ° C. The solution was then stirred at 60 ° C for 20 hours. LC-MS (ET5008-35-P1A1, product: RT = 0.81 minutes) showed that the reaction was complete. The solution was concentrated. The residue was purified by preparative HPLC (TFA conditions) to give compound 05 (370 mg, 40% yield) as a white solid.

[0347] HPLC separation method:

[0348]

[0349]

[0350] 1H NMR: ET5008-35-P1b1 400 MHz CDCl3; 10.46 (br, 1H), 8.35 (s, 1H), 7.74 (s, 1H), 7.12 (s, 4H), 4.12 (s, 2H), 3.59 (t, J = 6.0 Hz, 2H 2H), 3.35 (q, J = 7.2 Hz, 2H), 2.92 (d, J = 5.2 Hz, 3H), 2.65 to 2.57 (m, 4H), 1.68 to 1.44 (m, 14H).

[0351] For the synthesis of compounds 14 to 32, general structural units were pre-synthesized:

[0352] Building block 1 (BB-1)

[0353] N'-[(5Z)-6-Iodohex-5-en-1-yl]-N-methyloxalamide

[0354] Step 1:

[0355] PPh3 (140 g) and phthalimide (82.5 g) were suspended in dry THF (500.0 mL) and cooled to 0°C. A solution of 5-hexyn-1-ol (50.0 g) and diisopropyl azodicarboxylate (110 mL) in anhydrous THF (100 mL) was then added dropwise over 45 minutes. The resulting mixture was stirred at 0°C for 1 h and then stirred at room temperature overnight.

[0356] Remove as much THF as possible in vacuo. Suspend the residue in PE / EtOAc=9:1 (700 mL) and stir vigorously. Decant the solvent from the precipitated OPPh3. During this process, white needles (product) are formed in the decanted solvent, which are filtered off and set aside (F1).

[0357] The OPPh3 precipitate was then further washed several times with PE / EtOAc=9:1. All filtrates were then combined and evaporated in vacuo (F2). The needles from F1 were dissolved in EtOAc (200 mL) and washed with 1N NaOH (2×75 mL) and brine (50 mL), dried over Na2SO4 and concentrated under vacuum. The residue was filtered through SiO2 sheets (eluent CH2Cl2). The solvent was removed in vacuo, and the oily residue was placed in a refrigerator over the weekend, and then white needles were formed. The mixture was diluted with PE, and the product was then filtered out, which was washed with PE and dried in vacuo to obtain F1 in the form of white needles. The mother liquor was merged with F2.

[0358] The yellow oil of F2 is dissolved in EtOAc (400mL) and washed with 1N NaOH (3×150mL) and brine (50mL). The organic layer is dried over Na2SO4 and concentrated in vacuo. The residue is purified by SiO2 column chromatography (eluent CH2Cl2). The parts containing the product are combined and evaporated. PE is added to the yellow oily residue, and then a precipitate is formed. The mixture is cooled to 0°C, and then the solid is filtered out and washed with PE to obtain F2 as a white solid. The mother liquor is evaporated. PE is added to the oily residue, and then a precipitate is formed. The mixture is left to stand in a refrigerator for 2h, and then the precipitate is filtered out, washed with PE and dried in vacuo to obtain F3 as a light yellow solid.

[0359] Step 2:

[0360] 2-(Hex-5-yn-1-yl)-2,3-dihydro-1H-isoindole-1,3-dione (46.3 g), AgNO3 (8.65 g) and NIS (68.8 g) were placed in a 1 liter flask. Dry THF (500 mL) was added, the flask was flushed with argon and wrapped with aluminum foil to protect the reaction from light. The mixture was then stirred at room temperature under argon atmosphere for 16 h. Monitoring by LC / MS showed product.

[0361] The reaction mixture was decanted from the formed precipitate, diluted with water (400 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with water (100 mL), saturated Na2SO3 (3 × 100 mL) and brine (100 mL), dried over Na2SO4 and concentrated in vacuo. The residue was recrystallized from EtOH to give F1 as a white solid. The mother liquor was evaporated and recrystallized again from EtOH to give F2 as a yellow solid.

[0362] Step 3:

[0363] 2-Methyl-2-butene (29.4 mL) was added dropwise to a cooled solution of BH3·SMe2 (2.00 M in THF, 64.4 mL) at 0°C and stirred at 0°C for 1 h, then at room temperature for 1 h. The mixture was then added dropwise to a cold suspension of 2-(6-iodohex-5-yn-1-yl)-2,3-dihydro-1H-isoindole-1,3-dione (17.5 g) in 0°C THF (200 mL). After the addition was complete, the resulting mixture was stirred at room temperature for 1 h. Monitoring by LC / MS showed complete consumption of the starting material. The reaction mixture was cooled to 0°C, then HOAc (30.0 mL) was added dropwise, stirred at 0°C for 30 minutes, then stirred at room temperature overnight. Monitoring by LC / MS showed the product.

[0364] THF was removed as much as possible in vacuo. The residue was then slowly poured into a solution of NaOH (15.0 g) in H2O (200 mL) and extracted with CH2Cl2 (3×100 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was used as is for further transformation.

[0365] Step 4:

[0366] 2-[(5Z)-6-iodohex-5-en-1-yl]-2,3-dihydro-1H-isoindole-1,3-dione (17.6 g, crude IK-0353 / 4) was dissolved in MeOH (150 mL). Hydrazine hydrate (6.00 mL) was added and the resulting mixture was stirred at room temperature for 16 h. Monitoring by LC / MS showed product.

[0367] MeOH was removed in vacuo. The residue was suspended in CH2Cl2 (300 mL). The solid was filtered off and washed with CH2Cl2 (2×100 mL). The combined filtrate was then washed with water (2×100 mL), dried over Na2SO4 and concentrated under vacuum to give the crude product as an orange oil, which was used as is for further conversion.

[0368] Step 5:

[0369] Ethyl chloroformate (10.0 g) was dissolved in THF (50 mL) and cooled to 0°C. Pyridine (7.70 mL) was added dropwise and the mixture was stirred at 0°C for 30 minutes. Methylamine (2.0 M in THF, 47.6 mL) was then added dropwise. Stirring was continued at 0°C for 3 h. Monitoring by TLC (PE / EtOAc=1:3) showed the product.

[0370] The precipitated salts were filtered off and the filtrate was evaporated. The residue was dissolved in EtOAc (200 mL), washed with 1N HCl (2 x 50 mL), dried over Na2SO4 and concentrated in vacuo to give the product of sufficient purity as a brown oil.

[0371] Step 6:

[0372] (5Z)-6-iodohexyl-5-ene-1-amine (11.15 g) was dissolved in EtOH (200 mL). (Methylcarbamoyl)ethyl formate (6.50 g) and NEt (8.26 mL) were added and the resulting mixture was stirred at 50 ° C for 24 h. Monitoring by LC / MS showed incomplete conversion. Additional (methylcarbamoyl)ethyl formate (1.00 g) and NEt (4.00 mL) were added and stirring continued at 50 ° C for 24 h. Monitoring by LC / MS showed the product.

[0373] EtOH was removed in vacuo. The residue was purified by SiO2 column chromatography (CH2Cl2→CH2Cl2 / MeOH=50:1→CH2Cl2 / MeOH=20:1). The product-containing portions were combined and evaporated. EtOAc (30 mL) was added to the partially solid residue, treated with ultrasound and placed in a refrigerator over the weekend. The precipitate was then filtered out, washed with a small amount of ice-cold EtOAc and dried in vacuo.

[0374] Yield: 10.3 g (67%) of light yellow solid.

[0375] Building block 2 (BB-2)

[0376] N'-[4-(2-Iodophenyl)butyl]-N-methyloxalamide

[0377] Step 1:

[0378] PPh3 (95.5 g), phthalimide (56.1 g) and 3-butene-1-ol (25.0 g) were suspended in dry THF (250 mL) and cooled to 0°C. Diisopropyl azodicarboxylate (75.1 mL) was then added dropwise over 20 minutes. The resulting mixture was stirred at 0°C for 30 minutes and then at room temperature overnight. The product was monitored by LC / MS.

[0379] Remove THF as much as possible in vacuum. The oily residue is diluted with PE / EtOAc=9:1 (400mL) and stirred vigorously until precipitation occurs. Filter out the precipitated OPPh3 and wash thoroughly with PE / EtOAc=9:1. The combined filtrate is filtered through SiO2 sheets and then evaporated. The residue is diluted with PE (200mL), mixed vigorously and placed in an ice bath. Then filter out the precipitated product and wash with PE to obtain a product of sufficient purity as a light yellow solid.

[0380] Step 2:

[0381] 2-(But-3-ene-1-yl)-2,3-dihydro-1H-isoindole-1,3-dione (22.1 g) was placed in a 1 L flask under an argon atmosphere. 9-BBN (0.5 M in THF, 273 mL) was then added dropwise at 0°C and the resulting mixture was stirred at 0°C for 30 minutes and then at room temperature overnight. A solution of Na2CO3 (48.4 g) in water (250 mL) was then added and stirring continued at room temperature for 30 minutes. 2-iodo-aniline (20.0 g) and PdCl2(PPh3)2 (2.80 g) were then added and the mixture was heated to 50°C for 4 h. Monitoring by LC / MS showed the product.

[0382] The reaction mixture was diluted with EtOAc (200 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (300 mL), and the combined organic layers were washed with brine (200 mL) and dried over Na2SO4. The residue was purified by SiO2 (PE / EtOAc=6:4) column chromatography.

[0383] Step 3:

[0384] 2-[4-(2-Aminophenyl)butyl]-2,3-dihydro-1H-isoindole-1,3-dione (22.0 g) was dissolved in acetone (100 mL). Water (200 mL) and concentrated H2SO4 (13.9 mL) were then added and the resulting suspension was cooled to 0°C. A solution of NaNO2 (5.23 g) in water (50 mL) was added dropwise and the mixture was stirred at 0°C for 30 minutes. A solution of KI (37.2 g) in water (50 mL) was then added dropwise and the reaction mixture was warmed to room temperature and stirred for 20 h. Monitoring by LC / MS showed the product.

[0385] The reaction mixture was diluted with saturated Na2SO3 (200 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (150 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by SiO2 (PE / EtOAc=8:2) column chromatography.

[0386] Step 4:

[0387] 2-[4-(2-iodophenyl)butyl]-2,3-dihydro-1H-isoindole-1,3-dione (21.2 g) was suspended in MeOH (300 mL). Hydrazine hydrate (5.10 mL) was added and the resulting mixture was stirred at room temperature for 3 days. Monitoring by LC / MS showed product.

[0388] MeOH was removed in vacuo. The residue was suspended in CH2Cl2 (200 mL). The solid was filtered off and washed with CH2Cl2 (100 mL). The combined filtrate was then washed with water (2×100 mL). The combined aqueous layer was re-extracted with CH2Cl2 (50 mL), and the combined organic layer was then dried over Na2SO4 and concentrated in vacuo to obtain a product of sufficient purity as a yellow oil.

[0389] Step 5:

[0390] Ethyl chloroformate (10.0 g) was dissolved in THF (50 mL) and cooled to 0°C. Pyridine (7.70 mL) was added dropwise and the mixture was stirred at 0°C for 30 minutes. Methylamine (2.0 M in THF, 47.6 mL) was then added dropwise. Stirring was continued at 0°C for 3 h. The product was shown by TLC monitoring (PE / EtOAc=1:3).

[0391] The precipitated salts were filtered off and the filtrate was evaporated. The residue was dissolved in EtOAc (200 mL), washed with 1N HCl (2 x 50 mL), dried over Na2SO4 and concentrated in vacuo to give the product of sufficient purity as a brown oil.

[0392] Step 6:

[0393] 4-(2-iodophenyl)butan-1-amine (11.0 g, crude IK-0355710) was dissolved in EtOH (100 mL). Ethyl (methylcarbamoyl)formate (5.76 g) and NEt3 (6.67 mL) were added and the resulting mixture was stirred at 50° C. for 18 h. Monitoring by LC / MS showed product.

[0394] The reaction mixture was cooled to room temperature. EtOH was removed in vacuo. The residue was filtered through a SiO2 pad (CH2Cl2 / MeOH=98:2). Further purification was performed by recrystallization from EtOAc.

[0395] Yield: 7.76 g (54%) beige solid.

[0396] Building Block 4 (BB-4)

[0397] 2-{[(8Z)-13-[(methylcarbamoyl)formamido]tridec-8-en-1-yl]oxy}acetic acid

[0398] Step 1:

[0399] NaH (60% in mineral oil, 771 mg) was suspended in dry THF (20.0 mL). The mixture was cooled to 0 ° C, and then 6-heptene-1-ol (1.18 mL) was added. Stirring was continued at 0 ° C for 30 minutes, and then a solution of bromoacetic acid (1.34 g) in THF (10.0 mL) was added dropwise. After the addition was complete, the ice bath was removed and stirred for 15 minutes, and then the mixture was heated to 70 ° C for 1.5 h. The product was displayed by TLC monitoring (PE / EtOAc=1:1).

[0400] The reaction mixture was poured into 1N NaOH (50 mL) and extracted with EtOAc (2×30 mL). The combined organic layer contained no product and was discarded. The aqueous layer was carefully acidified with concentrated HCl and extracted again with EtOAc (3×30 mL). The combined organic layer was dried over Na2SO4 and concentrated in vacuo to give the product of sufficient purity as a colorless oil.

[0401] Step 2:

[0402] 1,1'-Carbonyldiimidazole (15.6 g) was suspended in THF (200 mL). A solution of 2-(hept-6-ene-1-yloxy)acetic acid (15.1 g) in THF (20 mL) was then added dropwise and the resulting mixture was stirred at room temperature for 6 h. THF was then removed in vacuo and MeOH (200 mL) was added to the residue. The mixture was stirred at room temperature for 3 days. The product was displayed by TLC monitoring (PE / EtOAc=9:1).

[0403] MeOH was removed in vacuo. PE (200 mL) was added to the residue and stirred vigorously for 5 minutes. The solvent was then decanted from the thick oily residue, which was further washed with PE (2 × 100 mL) and then discarded. The combined PE portion was washed with 1N HCl (100 mL) and 1N NaOH (100 mL), dried with Na2SO4 and concentrated under vacuum to obtain a product of sufficient purity as a colorless liquid.

[0404] Step 3:

[0405] Methyl 2-(hept-6-en-1-yloxy)acetate (2.88 g) was placed in a 100 mL flask under argon atmosphere and cooled to 0°C. 9-BBN (0.5 M in THF, 38.7 mL) was then added dropwise and the resulting mixture was stirred at 0°C for 30 minutes and then at room temperature for 2 hours. A solution of Na2CO3 (6.84 g) in water (30.0 mL) was then added and stirring continued at room temperature for 30 minutes. N'-[(5Z)-6-iodohexyl-5-en-1-yl]-N-methyloxalamide (BB-1, 4.00 g) and PdCl2(PPh3)2 (453 mg) were then added and the mixture was heated to 50°C for 1.5 hours. Monitoring by LC / MS showed product.

[0406] The reaction mixture was cooled to room temperature and separated. The aqueous layer was extracted with EtOAc (100 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4 and concentrated under vacuum. The residue was purified by SiO2 column chromatography (PE / EtOAc 1:1).

[0407] Step 4:

[0408] Methyl 2-{[(8Z)-13-[(methylcarbamoyl)formamido]tridec-8-en-1-yl]oxy}acetate (400 mg) was suspended in MeOH (20.0 mL). NaOH (3N, 5.00 mL) was added and the resulting mixture was stirred at room temperature for 15 minutes. Monitoring by LC / MS showed product.

[0409] The reaction mixture was poured into 1N HCl (30 mL).The precipitated product was filtered off, washed with water and dried in vacuo.

[0410] Yield: 869 mg (86%) beige solid.

[0411] Building Block 6 (BB-6)

[0412] 2-[3-(2-{4-[(methylcarbamoyl)formamido]butyl}phenyl)propoxy]acetic acid

[0413] Step 1:

[0414] NaH (60% in mineral oil, 15.2 g) was suspended in dry THF (250 mL). The mixture was cooled to 0°C and then allyl alcohol (11.8 mL) was added. Stirring was continued at 0°C for 30 minutes and then a solution of bromoacetic acid (26.3 g) in THF (50.0 mL) was added dropwise. After the addition was complete, the ice bath was removed and stirred for 15 minutes, then the mixture was heated to 70°C for 3 hours and stirred at room temperature overnight.

[0415] The reaction mixture was poured into water (250 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layer did not contain product and was discarded. The aqueous layer was carefully acidified with concentrated HCl and extracted again with EtOAc (3 × 100 mL). The combined organic layer was dried over Na2SO4 and concentrated under vacuum to obtain a sufficiently pure product as a light brown liquid.

[0416] Step 2:

[0417] 1,1'-Carbonyldiimidazole (30.7 g) was suspended in THF (200 mL). 2-(Propan-2-en-1-yloxy)acetic acid (crude product IK-0352 / 9) was then added dropwise and the resulting mixture was stirred at room temperature for 7 h. THF was then removed in vacuo and MeOH (200 mL) was added to the residue. The mixture was stirred at room temperature overnight. The product was shown by TLC monitoring (PE / EtOAc=8:2).

[0418] MeOH is removed in vacuo. PE (200mL) is added to the residue and stirred vigorously for 5 minutes. Then the solvent is decanted from the thick oily residue, which is further washed with PE (2 × 100mL). Monitoring by TLC shows that most of the product is retained in the oily residue, so it is washed with MTBE (4 × 100mL). PE and MTBE layers are combined, washed with 1N HCl (3 × 100mL) and saline (50mL), and Na is used SO4 is dried and concentrated under vacuum to obtain a product of sufficient purity as a light yellow liquid.

[0419] Step 3:

[0420] Methyl 2-(prop-2-en-1-yloxy)acetate (1.30 g) was placed in a 100 mL flask under argon and cooled to 0°C. 9-BBN (0.5 M in THF, 25.0 mL) was then added dropwise and the resulting mixture was stirred at 0°C for 30 minutes and then at room temperature for 2 hours. A solution of Na2CO3 (4.41 g) in water (25.0 mL) was then added and stirring continued for 30 minutes at room temperature. N'-[4-(2-iodophenyl)butyl]-N-methyloxalamide (BB-2, 3.00 g) and PdCl2(PPh3)2 (292 mg) were then added and the mixture was heated to 50°C for 4 hours and then stirred at room temperature overnight. Monitoring by LC / MS showed incomplete conversion. Additional methyl 2-(prop-2-en-1-yloxy)acetate (650 mg) was placed in a separate flask under argon. 9-BBN (0.5M in THF, 12.5 mL) was added at room temperature and the mixture was stirred at room temperature for 2 h. A saturated solution of Na2CO3 (10 mL) was added and stirring was continued at room temperature for 30 minutes. The mixture was then added to the above reaction mixture. After adding fresh PdCl2(PPh3)2 (200 mg), the mixture was stirred at 50°C for 2 h. Monitoring by LC / MS showed the product.

[0421] The reaction mixture was cooled to room temperature and separated. The aqueous layer was extracted with EtOAc (100 mL). The combined organic layer was washed with salt water (50 mL), dried over Na2SO4 and concentrated under vacuum. The residue was purified by SiO2 column chromatography (PE / EtOAc 3:7).

[0422] Step 4:

[0423] Methyl 2-[3-(2-{4-[(methylcarbamoyl)formamido]butyl}phenyl)propoxy]acetate (2.04 g) was dissolved in THF (30 mL). NaOH (3N, 30 mL) and MeOH (20 mL) were added and the resulting mixture was stirred at room temperature for 5 minutes. Monitoring by LC / MS showed product.

[0424] The reaction mixture was acidified with 6N HCl and extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 and concentrated under vacuum. The residue was purified by SiO 2 short column (CH 2 Cl 2 / MeOH=9:1).

[0425] Yield: 1.56 g (80%) beige solid.

[0426] Building Block 8 (BB-8)

[0427] N'-[(5Z)-13-Hydroxytridec-5-en-1-yl]-N-methyloxalamide

[0428] Step 1:

[0429] 6-Hepten-1-ol (3.00 g) and imidazole (3.57 g) were dissolved in DMF (20.0 mL). TIPSCl (6.18 mL) was added and the resulting mixture was stirred at 60° C. for 6 h. Monitoring by TLC (PE / EtOAc=8:2) showed almost complete conversion.

[0430] The reaction mixture was diluted with water (100 mL) and extracted with MTBE (3×40 mL). The combined organic layers were washed with 1N HCl (2×50 mL) and brine (20 mL), dried over Na2SO4 and concentrated under vacuum. The residue was purified by SiO2 column chromatography (PE / EtOAc=95:5).

[0431] Step 2:

[0432] (Hept-6-en-1-yloxy)tri(propyl-2-yl)silane (1.57 g) was placed in a 100 mL flask under an argon atmosphere and cooled to 0°C. 9-BBN (0.5 M in THF, 14.5 mL) was then added dropwise and the resulting mixture was stirred at 0°C for 30 minutes and then at room temperature for 2 hours. A solution of Na2CO3 (2.56 g) in water (15.00 mL) was then added and stirring continued at room temperature for 30 minutes. N'-[(5Z)-6-iodohexyl-5-en-1-yl]-N-methyloxalamide (BB-1, 1.50 g) and PdCl2(PPh3)2 (170 mg) were then added and the mixture was heated to 50°C for 2 hours. Monitoring by LC / MS showed the product.

[0433] The reaction mixture was cooled to room temperature and separated. The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated under vacuum. The residue was filtered through SiO2 sheet (PE / EtOAc=4:6). The crude product thus obtained was used as is for further conversion.

[0434] Step 3:

[0435] (Hept-6-en-1-yloxy)tri(propyl-2-yl)silane (2.20 g, crude IK-0357 / 16) was dissolved in THF (50 mL) and cooled to 0° C. TBAF·3H2O (2.29 g) was added and the resulting mixture was stirred at 0° C. for 30 minutes and then at room temperature for 6 hours. Monitoring by TLC (PE / EtOAc=1:1) and LC / MS showed complete conversion.

[0436] The reaction mixture was poured into water (100 mL) and extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 and concentrated under vacuum. The residue was passed through a SiO 2 short column (PE / EtOAc=1:1→EtOAc).

[0437] Yield: 1.11 g (77%) beige solid.

[0438] Building Block 9 (BB-9)

[0439] N'-{4-[2-(3-hydroxypropyl)phenyl]butyl}-N-methyloxalamide

[0440] Step 1:

[0441] 2-Propene-1-ol (3.00 g) and imidazole (7.03 g) were dissolved in DMF (20.0 mL). TIPSCl (14.4 mL) was added and the resulting mixture was stirred at 60 ° C for 6 h. TLC monitoring (PE / EtOAc=8:2) showed almost complete conversion. The reaction mixture was diluted with water (100 mL) and extracted with MTBE (3×40 mL). The combined organic layer was washed with 1N HCl (2×50 mL) and brine (20 mL), dried over Na2SO4 and concentrated under vacuum. The residue was purified by SiO2 column chromatography (PE / EtOAc=95:5).

[0442] Step 2:

[0443] (Prop-2-en-1-yloxy)tri(prop-2-yl)silane (1.33 g) was placed in a 100 mL flask under argon atmosphere and cooled to 0° C. 9-BBN (0.5 M in THF, 14.2 mL) was then added dropwise and the resulting mixture was stirred at 0° C. for 30 minutes and then at room temperature for 2 h.

[0444] Then add a solution of Na2CO3 (2.21g) in water (15.0mL) and continue stirring at room temperature for 30 minutes. Then add N'-[4-(2-iodophenyl)butyl]-N-methyloxalamide (1.50g) and PdCl2(PPh3)2 (146mg) and heat the mixture to 50°C for 3h. Monitor the product by LC / MS. The reaction mixture is cooled to room temperature and separated. The aqueous layer is extracted with EtOAc (100mL). The combined organic layers are washed with brine (50mL), dried with Na2SO4 and concentrated under vacuum. The residue is passed through a SiO2 short column (PE / EtOAc=1:1). The crude product is then used as is for further conversion.

[0445] Step 3:

[0446] N-Methyl-N'-{4-[2-(3-{[tri(propane-2-yl)silyl]oxy}propyl)phenyl]butyl}ethanediamide (1.87 g, crude product IK-0357 / 17) was dissolved in THF (50 mL) and cooled to 0°C. TBAF·3H2O (1.97 g) was added and the resulting mixture was stirred at 0°C for 30 minutes and then at room temperature for 16 h. Monitoring by LC / MS showed complete conversion. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated under vacuum. The residue was passed through a SiO2 short column (PE / EtOAc=1:1→EtOAc).

[0447] Yield: 911 mg (75%) beige solid.

[0448] Building Block 11 (BB-11)

[0449] N'-[(5Z)-13-(2-aminoethoxy)tridec-5-en-1-yl]-N-methyloxalamide

[0450] Step 1:

[0451] NaH (60% in mineral oil, 7.71 g) was suspended in dry THF (200 mL). The mixture was cooled to 0 ° C, and then 6-heptene-1-ol (11.8 mL) was added. Stirring was continued at 0 ° C for 30 minutes, and then a solution of bromoacetic acid (13.4 g) in THF (100 mL) was added dropwise. After the addition was complete, the ice bath was removed and stirred for 15 minutes, and then the mixture was heated to 70 ° C for 3 h. The product was displayed by TLC monitoring (PE / EtOAc=1:1).

[0452] The reaction mixture was poured into 1N NaOH (300 mL) and extracted with EtOAc (2×100 mL). The combined organic layer contained no product and was discarded. The aqueous layer was carefully acidified with concentrated HCl and extracted again with EtOAc (3×100 mL). The combined organic layer was dried over Na2SO4 and concentrated under vacuum to obtain a sufficiently pure product as a light brown oil.

[0453] Step 2:

[0454] 1,1'-Carbonyldiimidazole (15.6 g) was suspended in THF (200 mL). A solution of 2-(hept-6-en-1-yloxy)acetic acid (15.1 g) in THF (20 mL) was then added dropwise and the resulting mixture was stirred at room temperature for 6 h. THF was then removed in vacuo and MeOH (200 mL) was added to the residue. The mixture was stirred at room temperature for 3 days. Monitoring by TLC (PE / EtOAc=9:1) showed the product.

[0455] MeOH was removed in vacuo. PE (200 mL) was added to the residue and stirred vigorously for 5 minutes. The solvent was then decanted from the thick oily residue, which was further washed with PE (2 × 100 mL) and then discarded. The combined PE portion was washed with 1N HCl (100 mL) and 1N NaOH (100 mL), dried with Na2SO4 and concentrated under vacuum to obtain a product of sufficient purity as a colorless liquid.

[0456] Step 3:

[0457] Methyl 2-(hept-6-en-1-yloxy)acetate (5.00 g) was dissolved in CH2Cl2 (100 mL) and cooled to 0°C. DIBALH (1.00 M in CH2Cl2, 61.7 mL) was added dropwise, and the resulting mixture was stirred at 0°C for 30 minutes and then at room temperature overnight. Monitoring by TLC (PE / EtOAc=8:2) showed complete conversion.

[0458] The reaction mixture was cooled to 0 ° C and carefully quenched with saturated Na2SO4 aqueous solution. The mixture was then diluted with CH2Cl2 (100 mL), stirred vigorously for 20 minutes, and then filtered through celite. The filter cake was washed several times with CH2Cl2. The combined filtrate was concentrated under vacuum to obtain a product of sufficient purity as a colorless liquid.

[0459] Step 4:

[0460] PPh3 (7.17 g), phthalimide (4.21 g) and 2-(hept-6-en-1-yloxy)ethan-1-ol (4.12 g) were suspended in dry THF (100 mL) and cooled to 0°C. Diisopropyl azodicarboxylate (5.79 mL) was then added dropwise over 20 minutes. The resulting mixture was stirred at 0°C for 30 minutes and then at room temperature overnight.

[0461] Remove as much THF as possible in vacuo. Dilute the oily residue with PE / EtOAc=9:1 (200 mL) and stir vigorously until precipitation occurs. Filter out the precipitated OPPh3 and wash thoroughly with PE / EtOAc=9:1. Filter the combined filtrate through a SiO2 sheet (eluent PE / EtOAc=9:1) and evaporate. Purify the residue by SiO2 column chromatography (PE / EtOAc=8:2).

[0462] Step 5:

[0463] 2-[2-(Hept-6-en-1-yloxy)ethyl]-2,3-dihydro-1H-isoindole-1,3-dione (2.22 g) was placed in a 100 mL flask under argon atmosphere and cooled to 0°C. 9-BBN (0.5 M in THF, 19.3 mL) was then added dropwise and the resulting mixture was stirred at 0°C for 30 minutes and then at room temperature for 2 hours. A solution of Na2CO3 (3.42 g) in water (20.0 mL) was then added and stirring was continued at room temperature for 30 minutes. N'-[(5Z)-6-iodohex-5-en-1-yl]-N-methyloxalamide (BB-1, 2.00 g) and PdCl2(PPh3)2 (226 mg) were then added and the mixture was heated to 50°C for 1.5 hours. Monitoring by LC / MS showed product.

[0464] The reaction mixture was cooled to room temperature and separated. The aqueous layer was extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated under vacuum. The residue was purified by SiO2 column chromatography (PE / EtOAc=4:6).

[0465] Step 6:

[0466] N'-[(5Z)-13-[2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)ethoxy]tridec-5-en-1-yl]-N-methyloxalamide (2.36 g) was suspended in MeOH (100 mL). Hydrazine hydrate (486 μL) was added and the resulting mixture was stirred at room temperature for 16 h. Monitoring by LC / MS showed product.

[0467] MeOH was removed in vacuo. The residue was suspended in 7N NH3 in CH2Cl2 / MeOH = 9:1 (100 mL), filtered through a SiO2 sheet, and further eluted with 7N NH3 in CH2Cl2 / MeOH = 9:1 (300 mL) solution. The filtrate was concentrated under vacuum to give 1.68 g of crude product. 60 mg was purified by preparative TLC (7N NH3 in CH2Cl2 / MeOH = 9:1). The remaining crude product was used as is for further conversion.

[0468] Yield: 41 mg (2%) light yellow solid (purified).

[0469] Compound 14 (Comp-14)

[0470] N-Methyl N'-[(5Z)-13-[(1H-1,2,3,4-tetrazolyl-5-yl)methoxy]tridec-5-en-1-yl]ethanediamide

[0471] Step 1:

[0472] NaH (60% in mineral oil, 7.71 g) was suspended in dry THF (200 mL). The mixture was cooled to 0°C and 6-heptene-1-ol (11.8 mL) was then added. Stirring was continued at 0°C for 30 minutes and then a solution of bromoacetic acid (13.4 g) in THF (100 mL) was added dropwise. After the addition was complete, the ice bath was removed and stirred for 15 minutes, and then the mixture was heated to 70°C for 3 h. The product was shown by TLC operation (PE / EtOAc=1:1). The reaction mixture was poured into 1N NaOH (300 mL) and extracted with EtOAc (2×100 mL). The combined organic layers did not contain the product and were discarded. The aqueous layer was carefully acidified with concentrated HCl and extracted again with EtOAc (3×100 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to obtain a product of sufficient purity as a light brown oil.

[0473] Yield: 14.1 g (93%) of light brown oil.

[0474] Step 2:

[0475] A mixture of 2-(hept-6-en-1-yloxy)acetic acid (3.00 g) and SOCl2 (15.00 mL) was heated to 70 ° C for 1 h. Excess SOCl2 was then removed under vacuum and the residue was dissolved in dichloroethane (15.0 ml). Ammonia was then slowly bubbled through the solution for 5 minutes. The reaction mixture was diluted with water (50 mL) and extracted with CH2Cl2 (3×30 mL). The combined organic layers were washed with saturated NaHCO3 (30 mL) and brine (10 mL), dried over Na2SO4 and concentrated under vacuum to obtain a product of sufficient purity as a white solid. m=2.16 g (y=62%). Similar to IK-0367 / 1 in TLC.

[0476] Step 3:

[0477] 2-(Hept-6-en-1-yloxy)acetamide (2.61 g) was dissolved in CH2Cl2 (50 mL). NEt3 (6.35 mL) was added and the mixture was cooled to 0°C. A solution of POCl3 (1.54 mL) in CH2Cl2 (4 mL) was slowly added. Stirring was then continued at 0°C for 15 minutes. Monitoring by TLC (PE / EtOAc=8:2) showed the product.

[0478] Saturated NaHCO (5.00 mL) was added at 0°C and stirred at this temperature for 30 minutes. The mixture was allowed to reach room temperature, diluted with water (15.0 mL) and extracted with CHCl (3×20 mL). The combined organic layers were washed with saturated NaHCO (10.0 mL) and brine (10.0 mL), dried over NaSO, and then filtered through a SiO sheet (eluent CHCl). The product was obtained in sufficient purity as a colorless oil after evaporation. m=2.08 g, y=89%.

[0479] Step 4:

[0480] 2-(Hept-6-ene-1-yloxy)acetonitrile was placed in a 10 mL flask under an argon atmosphere and cooled to 0°C. 9-BBN (0.5M THF solution, 1.63 mL) was then added dropwise and the resulting mixture was stirred at 0°C for 30 minutes and then at room temperature for 2 h. A solution of Na2CO3 (288 mg) in degassed water (1 mL) was then added and stirring continued for 30 minutes at room temperature. N'-[(5Z)-6-iodohexyl-5-ene-1-yl]-N-methyloxalamide (168 mg) and PdCl2(PPh3)2 (19 mg) were then added and the mixture was heated to 50°C overnight. Water was added and the mixture was extracted with DCM. The organic layer was dried over MgSO4, filtered, and the solvent was evaporated. The mixture was purified by preparative TLC (DCM / MeOH 95 / 5). m=70 mg, y=38%.

[0481] Step 5:

[0482] N'-[(5Z)-13-(Cyanomethoxy)tridec-5-en-1-yl]-N-methyloxalamide, sodium azide and triethylamine hydrochloride were dissolved in THF, and the reaction mixture was stirred at 70°C overnight.

[0483] Water and ethyl acetate were added. The mixture was acidified with 3N HCl. The aqueous layer was then extracted with ethyl acetate (×3) (acidic pH), and the combined organic layers were washed with brine. The organic layer was dried over MgSO4, filtered and the solvent was removed under vacuum. m=82 mg. The product was purified by preparative TLC (DCM / MeOH 95 / 5).

[0484] Yield: 8 mg (10%) white powder.

[0485] Compound 15 (Comp-15)

[0486] N'-(4-{2-[3-(Carbamoylmethoxy)propyl]phenyl}butyl)-N-methyloxalamide

[0487] 250 mg (0.72 mmol) of 2-[3-(2-{4-[(methylcarbamoyl)formamido]butyl}phenyl)propoxy]acetic acid (BB-6) and 164.1 mg (0.86 mmol) of EDCI were dissolved in 20 ml of DCM. 36.5 mg (2.14 mmol, 5.35 ml) of aqueous ammonia (0.4 M in THF) were added and the mixture was stirred at room temperature over the weekend.

[0488] The mixture was poured into 50 ml of water and extracted with DCM (3 x 50 ml). The combined organic layers were dried over Na2SO4 and concentrated.

[0489] Yield: 50 mg (20%), white solid.

[0490] Compound 16 (Comp-16)

[0491] N-Methyl N'-[(5Z)-13-[(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methoxy]tridec-5-en-1-yl]ethanediamide

[0492] Step 1:

[0493] NaH (60% in mineral oil, 7.71 g) was suspended in dry THF (200 mL). The mixture was cooled to 0 ° C, and 6-heptene-1-ol (11.8 mL) was added. Stirring was continued at 0 ° C for 30 minutes, and then a solution of bromoacetic acid (13.4 g) in THF (100 mL) was added dropwise. After the addition was complete, the ice bath was removed and stirred for 15 minutes, and then the mixture was heated to 70 ° C for 3 h. The product was displayed by monitoring by TLC (PE / EtOAc=1:1). The reaction mixture was poured into 1N NaOH (300 mL) and extracted with EtOAc (2×100 mL). The combined organic layer did not contain the product and was discarded. The aqueous layer was carefully acidified with concentrated HCl and extracted again with EtOAc (3×100 mL). The combined organic layer was dried with Na2SO4 and concentrated under vacuum to obtain a product of sufficient purity as a light brown oil.

[0494] Step 2:

[0495] 1,1'-Carbonyldiimidazole (15.6g) was suspended in THF (200mL). Then a solution of 2-(hept-6-ene-1-yloxy)acetic acid (15.1g) in THF (20mL) was added dropwise and the resulting mixture was stirred at room temperature for 6h. THF was then removed in vacuo and MeOH (200mL) was added to the residue. The mixture was stirred at room temperature for 3 days. The product was displayed by TLC monitoring (PE / EtOAc=9:1). MeOH was removed in vacuo. PE (200mL) was added to the residue and stirred vigorously for 5 minutes. The solvent was then decanted from the thick oily residue, which was further washed with PE (2×100mL) and then discarded. The combined PE portion was washed with 1NHCl (100mL) and 1N NaOH (100mL), dried with Na2SO4 and concentrated under vacuum to obtain a product of sufficient purity as a colorless liquid.

[0496] Step 3:

[0497] 500 mg (2.68 mmol) and 1.34 g (26.9 mmol, 1.30 ml) of hydrazine hydrate were dissolved in 5 ml of EtOH and stirred at 70° C. for 4.5 h (→ clear solution).

[0498] →LC / MS: GH-0513 / 1-1

[0499] →TLC (EA / PE 1:1): starting material completely consumed

[0500] The mixture was evaporated to dryness.

[0501] Step 4:

[0502] 500 mg (2.68 mmol) of 2-(hept-6-en-1-yloxy)acetohydrazide (GH-0513 / 1) were dissolved in 3 ml of AcOH. 653.3 mg (8.05 mmol) of potassium cyanate dissolved in 3 ml of water were added and the mixture was stirred at room temperature for 1.5 h (yellow solution). The mixture was evaporated to dryness.

[0503] Step 5:

[0504] The oily residue was dissolved in 10 ml of 2M NaOH and heated to reflux for 2 h. LC / MS: GH-0515 / 1-2: Complete consumption of intermediate 1. The mixture was acidified with concentrated hydrochloric acid and extracted with EA (3×20 ml). The combined organic layers were dried over Na2SO4 and concentrated to dryness. The crude solid was recrystallized from ACN.

[0505] Step 6:

[0506] 92.0 mg (0.44 mmol) of 3-[(hept-6-en-1-yloxy)methyl]-4,5-dihydro-1H-1,2,4-triazol-5-one (GH-0515 / 1) dissolved in 2 ml of anhydrous THF was added to a solution of 88.5 mg (0.73 mmol, 1.45 ml) of 9BBN (0.5 M in THF) under an argon atmosphere and the mixture was stirred overnight at room temperature. 153.8 mg (1.45 mmol) of Na2CO3 in 1 ml of water was added and stirring was continued at room temperature for 15 minutes. Then 90.0 mg (0.29 mmol) N'-[(5Z)-6-iodohexyl-5-en-1-yl]-methyloxalamide (IK-0356 / 2) and 10.2 mg (14.5 μmol) PdCl2(PPh3)2 dissolved in 2 ml THF were added and the mixture was heated to 50°C for 4 h (yellow biphasic mixture).

[0507] →LC / MS: GH-0516 / 1-1: Product detected

[0508] The organic layer was separated by pipette and evaporated to dryness. The R of the possible product was determined by silica gel flash column chromatography (DCM / MeOH 20:1→9:1, f : 0.62) to purify the crude product and recrystallize from CAN.

[0509] Yield: 51 mg (0.13 mmol, 45%).

[0510] Compound 17 (Comp-17)

[0511] N-Methyl N'-[(5Z)-13-[(phenylcarbamoyl)methoxy]tridec-5-en-1-yl]ethanediamide

[0512] 2-{[(8Z)-13-[(methylcarbamoyl)formamido]tridec-8-en-1-yl]oxy}acetic acid (BB-4, 50.0 mg, 140.3 μmol), aniline (26 μl, 280.5 μmol), HBTU (53.4 mg, 140.3 μmol) and DMAP (1.7 mg, 14.0 μmol) were placed in a G16 vial. DMF (2.00 ml) and NEt3 (78.0 μl, 561.1 μmol) were added and the resulting mixture was stirred at room temperature for 16 h. The product was displayed by LC / MS monitoring.

[0513] The reaction mixture was diluted with water (20 ml) and extracted with Et2O (3 x 20 ml). The combined organic layers were washed with saturated NaHCO3 (20 ml) and brine (10 ml), dried over Na2SO4 and concentrated under vacuum. The product was lyophilized.

[0514] Yield: 52 mg (87%), white solid.

[0515] Compound 18 (Comp-18)

[0516] N-methyl N'-[(5Z)-13-{[( alkyl-4-yl)carbamoyl]methoxy}tridec-5-en-1-yl]ethanediamide

[0517] 2-{[(8Z)-13-[(methylcarbamoyl)formamido]tridec-8-en-1-yl]oxy}acetic acid (BB-4, 50.0 mg, 140.3 μmol), 4-aminotetrahydropyran (29 μl, 280.5 μmol), HBTU (53.4 mg, 140.3 μmol) and DMAP (1.7 mg, 14.0 μmol) were placed in a G16 vial. DMF (2.00 ml) and NEt (78.0 μl, 561.1 μmol) were added and the resulting mixture was stirred at room temperature for 16 h. The product was monitored by LC / MS. The reaction mixture was diluted with water (20 ml) and extracted with Et O (3×20 ml). The combined organic layers were washed with saturated NaHCO (20 ml) and brine (10 ml), dried over Na SO and concentrated under vacuum. The product was lyophilized.

[0518] Yield: m=58 mg (94%), white solid.

[0519] Compound 19 (Comp-19)

[0520] N-methyl N'-[(5Z)-13-{[(1,3- oxazol-2-yl)carbamoyl]methoxy}tridec-5-en-1-yl]ethanediamide

[0521] 2-{[(8Z)-13-[(methylcarbamoyl)formamido]tridec-8-en-1-yl]oxy}acetic acid (BB-4, 50.0 mg, 140.3 μmol), 1,3- Oxazol-2-amine (24 mg, 280.5 μmol), HBTU (53.4 mg, 140.3 μmol) and DMAP (1.7 mg, 14.0 μmol) were placed in a G16 vial. DMF (2.00 ml) and NEt3 (78.0 μl, 561.1 μmol) were added and the resulting mixture was stirred at room temperature for 16 h. Monitoring by LC / MS showed product.

[0522] The reaction mixture was diluted with water (20 ml) and extracted with Et2O (3×20 ml). The combined organic layers were washed with saturated NaHCO3 (20 ml) and brine (10 ml), dried over Na2SO4 and concentrated under vacuum. The residue was purified by preparative TLC (DCM / MeOH=95:5).

[0523] Yield: 11 mg (19%), white solid.

[0524] Compound 20 (Comp-20)

[0525] N'-[(5Z)-13-{[(4-methoxyphenyl)carbamoyl]methoxy}tridec-5-en-1-yl]-N-methyloxalamide

[0526] 2-{[(8Z)-13-[(methylcarbamoyl)formamido]tridec-8-en-1-yl]oxy}acetic acid (BB-4, 50.0 mg, 140.3 μmol), p-anisidine (35 mg, 280.5 μmol), HBTU (53.4 mg, 140.3 μmol) and DMAP (1.7 mg, 14.0 μmol) were placed in a G16 vial. DMF (2.00 ml) and NEt3 (78.0 μl, 561.1 μmol) were added and the resulting mixture was stirred at room temperature for 16 h. Monitoring by LC / MS showed product.

[0527] The reaction mixture was diluted with water (20 ml) and extracted with Et2O (3×20 ml). The combined organic layers were washed with saturated NaHCO3 (20 ml) and brine (10 ml), dried over Na2SO4 and concentrated under vacuum. The residue was purified by preparative TLC (DCM / MeOH=98:2).

[0528] Yield: 18 mg (28%), beige solid.

[0529] Compound 21 (Comp-21)

[0530] N-Methyl N'-[4-(2-{3-[(phenylcarbamoyl)methoxy]propyl}phenyl)butyl]ethanediamide

[0531] 40 mg (0.11 mmol) of 2-[3-(2-{4-[(methylcarbamoyl)formamido]butyl}phenyl)propoxy]acetic acid (BB-6), 26.3 mg (0.14 mmol) of EDCI and 11.7 mg (0.13 mmol, 11.5 μl) of aniline were dissolved in 3 ml of DCM and stirred at room temperature over the weekend (clear solution).

[0532] The mixture was evaporated to dryness and the product was observed by preparative TLC (1 mm, DCM / MeOH 20:1, R f :0.54) Purification:

[0533] Yield: 24 mg (51%), white solid.

[0534] Compound 22 (Comp-22)

[0535] N-Methyl N'-[4-(2-{3-[2-oxo-2-(pyrrolidin-1-yl)ethoxy]propyl}phenyl)butyl]ethanediamide

[0536] 50 mg (0.14 mmol) of 2-[3-(2-{4-[(methylcarbamoyl)formamido]butyl}phenyl)propoxy]acetic acid (BB-6), 32.8 mg (0.17 mmol) of EDCI and 20.3 mg (0.29 mmol, 23.4 μl) of pyrrolidine were dissolved in 3 ml of DCM and stirred at room temperature for 1.5 h (clear solution).

[0537] The mixture was evaporated to dryness and the product was identified by preparative TLC (1 mm, DCM / MeOH 10:1, R f :0.46) purification.

[0538] Yield: 20 mg (35%), white solid.

[0539] Compound 23 (Comp-23)

[0540] N-Methyl N'-[4-(2-{3-[2-(morpholin-4-yl)-2-oxoethoxy]propyl}phenyl)butyl]ethanediamide

[0541] 50 mg (0.14 mmol) of 2-[3-(2-{4-[(methylcarbamoyl)formamido]butyl}phenyl)propoxy]acetic acid (BB-6, IK-0358 / 6), 32.8 mg (0.17 mmol) of EDCI and 24.9 mg (0.29 mmol, 24.9 μl) of morpholine were dissolved in 3 ml of DCM and stirred at room temperature over the weekend (clear solution).

[0542] The mixture was evaporated to dryness and the product was identified by preparative TLC (1 mm, DCM / MeOH 10:1, R f :0.48) purification.

[0543] Yield: 34 mg (58%), white solid.

[0544] Compound 24 (Comp-24)

[0545] 4-{2-[3-(2-{4-[(methylcarbamoyl)formamido]butyl}phenyl)propoxy]acetamido}benzoic acid

[0546] Step 1:

[0547] 50 mg (0.14 mmol) of 2-[3-(2-{4-[(methylcarbamoyl)formamido]butyl}phenyl)propoxy]acetic acid (BB-6, IK-0358 / 6), 32.8 mg (0.17 mmol) of EDCI and 43.1 mg (0.29 mmol) of methyl 4-aminobenzoate were dissolved in 3 ml of DCM and stirred at room temperature for 1.5 h (clear solution).

[0548] The mixture was evaporated to dryness and the product was isolated by preparative TLC (1 mm, EA / PE 4:1, R f :0.31) purification.

[0549] Step 2:

[0550] To a solution of 48 mg (0.10 mmol) of N-methyl-N'-{4-[2-(3-{[(pyridin-2-yl)carbamoyl]methoxy}propyl)phenyl]butyl}ethanediamide (GH-0498 / 1) in 2 ml of THF were added 16.7 mg (0.40 mmol) of LiOH monohydrate dissolved in 0.5 ml of water, and the mixture was stirred at room temperature overnight (two-phase mixture).

[0551] The mixture was poured into 1N HCl solution (10 mL) and extracted with DCM (3×20 ml). The combined organic layers were dried over Na 2 SO 4 and concentrated to dryness. The R of the possible product was determined by preparative TLC (DCM / MeOH / FA 100:10:1).f : 0.43) to purify the crude product.

[0552] Yield: 10 mg (21%), white solid.

[0553] Compound 25 (Comp-25)

[0554] N'-[(5Z)-13-[2-(4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl)-2-oxoethoxy]tridec-5-en-1-yl]-N-methyloxalamide

[0555] 2-{[(8Z)-13-[(methylcarbamoyl)formamido]tridec-8-en-1-yl]oxy}acetic acid (BB-4, 50 mg), DCC (34.7 mg), DMAP (22.3 mg) and 2,4(3H,5H)-furandione (15.4 mg) were placed in a G16 vial. CH2Cl2 (3.00 mL) was added and the resulting mixture was stirred at room temperature for 18 h. Monitoring by LC / MS showed product.

[0556] The reaction mixture was diluted with water (30 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4 and concentrated under vacuum. The residue was purified by preparative TLC (CH2Cl2 / MeOH=9:1).

[0557] Yield: 20 mg (33%), beige solid.

[0558] Compound 26 (Comp-26)

[0559] N'-[4-(2-(3-[2-(hydroxymethyl)phenoxy]propyl)phenyl)butyl]-N-methyloxalamide

[0560] Step 1:

[0561] Salicylaldehyde (2.00 g) and imidazole (2.79 g) were dissolved in DMF (20.0 mL). TIPSCl (5.96 mL) was added and the resulting mixture was stirred at 60° C. for 2 days. Monitoring by TLC (PE / EtOAc=95:5) and LC / MS showed incomplete conversion. Additional TIPSCl (2.00 mL) was added and stirring was continued at 60° C. for 3 days. Monitoring by TLC (PE / EtOAc=95:5) and LC / MS showed almost complete conversion. The reaction mixture was diluted with water (100 mL) and extracted with MTBE (3×40 mL). The combined organic layers were washed with 1N NaOH (30 mL) and brine (20 mL), dried over Na2SO4 and concentrated under vacuum. The residue was purified by SiO2 column chromatography (PE / EtOAc=95:5).

[0562] Yield: 3.54 g (78%), light yellow liquid

[0563] Step 2:

[0564] 2-{[tri(propane-2-yl)silyl]oxy}benzaldehyde (3.54 g) was dissolved in EtOH (30.0 mL) and cooled to 0 ° C. NaBH4 (481 mg) was added and the resulting mixture was stirred at 0 ° C for 30 minutes and then at room temperature for 18 h. The product was displayed by TLC (PE / EtOAc=8:2) and LC / MS monitoring. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated under vacuum. The residue was purified by SiO2 column chromatography (PE / EtOAc=8:2).

[0565] Yield: 2.73 g (77%), yellow oil

[0566] Step 3:

[0567] (2-{[tri(propane-2-yl)silyl]oxy}phenyl)methanol (400 mg) was dissolved in dry THF (15 mL). NaH (60% in mineral oil, 85.6 mg) was added and the mixture was stirred at room temperature for 15 minutes. Allyl bromide (309 μL) was then added and the resulting mixture was stirred at room temperature overnight. The product was displayed by LC / MS monitoring. The reaction mixture was diluted with water (50 mL) and extracted with CH2Cl2 (3×30 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated under vacuum. The crude product thus obtained was used as is for further conversion.

[0568] Yield: 480 mg (crude product), yellow oil

[0569] Step 4:

[0570] {2-[(prop-2-en-1-yloxy)methyl]phenoxy}tri(prop-2-yl)silane (178 mg) was placed in a 10 mL flask under an argon atmosphere and cooled to 0°C. Then 9-BBN (0.5M in THF, 1.38 mL) was added dropwise and the resulting mixture was stirred at 0°C for 30 minutes and then at room temperature for 2 hours. Then a solution of Na2CO3 (147 mg) in water (1.50 mL) was added and stirring continued at room temperature for 30 minutes. Then N'-[4-(2-iodophenyl)butyl]-N-methyloxalamide (BB-2, 100 mg) and PdCl2(PPh3)2 (9.7 mg) were added and the mixture was heated to 50°C for 3 hours. The product was displayed by LC / MS monitoring. The reaction mixture was cooled to room temperature, diluted with water (20 mL) and separated into layers. The aqueous layer was extracted with EtOAc (15 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4 and concentrated under vacuum. The residue was passed through a short column of SiO2 (PE / EtOAc=1:1). The crude product was then used as is for further transformation.

[0571] Yield: 235 mg (crude product) yellow oil

[0572] Step 5:

[0573] N-Methyl-N'-[4-(2-[3-[(2-{[tri(propane-2-yl)silyl]oxy}phenyl)methoxy]propyl}phenyl)butyl]ethanediamide (154 mg, crude product IK-0357 / 19) was dissolved in THF (5.00 mL). TBAF·3H2O (87.0 mg) was added and the resulting mixture was stirred at room temperature for 30 minutes. LC / MS operation showed complete conversion. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4 and concentrated under vacuum. The residue was purified by preparative TLC (CH2Cl2 / MeOH=95:5).

[0574] Yield: 75 mg (66%), white solid.

[0575] Compound 27 (Comp-27)

[0576] N'-[(5Z)-13-(2-Hydroxyphenoxy)tridec-5-en-1-yl]-N-methyloxalamide

[0577] Step 1:

[0578] N'-[(5Z)-13-Hydroxytriazine-5-en-1-yl]-N-methyloxalamide (BB-8, 400 mg) was suspended in CH2Cl2 (20 mL). PPh3 (598 mg) and CBr4 (756 mg) were added and the resulting mixture was stirred at room temperature for 1.5 h. Monitoring by TLC (PE / EtOAc=1:1) and LC / MS showed complete conversion.

[0579] The reaction mixture was concentrated in vacuo and the residue was purified by preparative TLC (PE / EtOAc=1:1).

[0580] Step 2:

[0581] N'-[(5Z)-13-Bromotride-5-en-1-yl]-N-methyloxalamide (50 mg), catechol (76.2 mg) and K2CO3 (57.4 mg) were placed in a G16 vial. DMF (3.00 mL) was added and the resulting mixture was stirred at 60° C. for 2.5 h. Monitoring by LC / MS showed product.

[0582] The reaction mixture was diluted with water (40 mL) and extracted with MTBE (3×20 mL). The combined organic layers were washed with water (20 mL) and brine (10 mL), dried over Na 2 SO 4 and concentrated under vacuum. The residue was purified by preparative TLC (CH 2 Cl 2 / MeOH=95:5).

[0583] Yield: 43 mg (80%), white solid.

[0584] Compound 28 (Comp-28)

[0585] N-Methyl N'-[4-(2-{3-[2-(morpholin-4-yl)-2-oxoethoxy]propyl}phenyl)butyl]ethanediamide

[0586] 50 mg (0.14 mmol) of 2-[3-(2-{4-[(methylcarbamoyl)formamido]butyl}phenyl)propoxy]acetic acid (BB-8, IK-0358 / 6), 32.8 mg (0.17 mmol) of EDCI and 24.9 mg (0.29 mmol, 24.9 μl) of morpholine were dissolved in 3 ml of DCM and stirred at room temperature over the weekend (clear solution).

[0587] The mixture was evaporated to dryness and the product was identified by preparative TLC (1 mm, DCM / MeOH 10:1, R f :0.48) purification.

[0588] Yield: 34 mg (58%), white solid.

[0589] Compound 29 (Comp-29)

[0590] N'-(4-{2-[3-(3-hydroxyphenoxy)propyl]phenyl}butyl)-N-methyloxalamide

[0591] Step 1:

[0592] N'-{4-[2-(3-hydroxypropyl)phenyl]butyl}-N-methyloxalamide (BB-9, 400 mg) was suspended in CH2Cl2 (20 mL). PPh3 (610 mg) and CBr4 (771 mg) were added and the resulting mixture was stirred at room temperature for 30 minutes. TLC (PE / EtOAc=1:1) and LC / MS monitoring showed complete conversion. The reaction mixture was concentrated in vacuo and the residue was purified by preparative TLC (PE / EtOAc=1:1).

[0593] Step 2:

[0594] N'-{4-[2-(3-bromopropyl)phenyl]butyl}-N-methyloxalamide (50 mg), 1,3-benzenediol (77.5 mg) and K2CO3 (58.4 mg) were placed in a G16 vial. DMF (3.00 mL) was added and the resulting mixture was stirred at 60° C. for 1 h. Monitoring by LC / MS showed product.

[0595] The reaction mixture was diluted with water (40 mL) and extracted with MTBE (3×20 mL). The combined organic layers were washed with water (20 mL) and brine (10 mL), dried over Na 2 SO 4 and concentrated under vacuum. The residue was purified by preparative TLC (CH 2 Cl 2 / MeOH=95:5).

[0596] Yield: 40 mg (74%), white solid.

[0597] Compound 30 (Comp-30)

[0598] N'-[(5Z)-13-(4-Hydroxyphenoxy)tridec-5-en-1-yl]-N-methyloxalamide

[0599] Step 1:

[0600] N'-[(5Z)-13-Hydroxytridec-5-en-1-yl]-N-methyloxalamide (BB-8, 400 mg) was suspended in CH2Cl2 (20 mL). PPh3 (598 mg) and CBr4 (756 mg) were added and the resulting mixture was stirred at room temperature for 1.5 h. TLC (PE / EtOAc=1:1) and LC / MS control showed complete conversion.

[0601] The reaction mixture was concentrated in vacuo and the residue was purified by preparative TLC (PE / EtOAc=1:1).

[0602] Step 2:

[0603] N'-[(5Z)-13-bromotride-5-en-1-yl]-N-methyloxalamide (50 mg), hydroquinone (76.2 mg) and K2CO3 (57.4 mg) were placed in a G16 vial. DMF (3.00 mL) was added and the resulting mixture was stirred at 60° C. for 2.5 h. Monitoring by LC / MS showed product.

[0604] The reaction mixture was diluted with water (40 mL) and extracted with MTBE (3×20 mL). The combined organic layers were washed with water (20 mL) and brine (10 mL), dried over Na 2 SO 4 and concentrated under vacuum. The residue was purified by preparative TLC (CH 2 Cl 2 / MeOH=95:5).

[0605] Yield: 43 mg (80%), white solid.

[0606] Compound 31 (Comp-31)

[0607] N'-(4-{2-[3-(4-hydroxyphenoxy)propyl]phenyl}butyl)-N-methyloxalamide

[0608] Step 1:

[0609] N'-{4-[2-(3-hydroxypropyl)phenyl]butyl}-N-methyloxalamide (BB-9, 400 mg) was suspended in CH2Cl2 (20 mL). PPh3 (610 mg) and CBr4 (771 mg) were added and the resulting mixture was stirred at room temperature for 30 minutes. Monitoring by TLC (PE / EtOAc=1:1) and LC / MS showed complete conversion.

[0610] The reaction mixture was concentrated in vacuo and the residue was purified by preparative TLC (PE / EtOAc=1:1).

[0611] Step 2:

[0612] N'-{4-[2-(3-bromopropyl)phenyl]butyl}-N-methyloxalamide (50 mg), hydroquinone (77.5 mg) and K2CO3 (58.4 mg) were placed in a G16 vial. DMF (3.00 mL) was added and the resulting mixture was stirred at 60°C for 1 h. Monitoring by LC / MS showed product.

[0613] The reaction mixture was diluted with water (40 mL) and extracted with MTBE (3×20 mL). The combined organic layers were washed with water (20 mL) and brine (10 mL), dried over Na 2 SO 4 and concentrated under vacuum. The residue was purified by preparative TLC (CH 2 Cl 2 / MeOH=95:5).

[0614] Yield: 39 mg (72%), white solid.

[0615] Compound 3" (Comp-3")

[0616] N'-[4-(2-{3-[(4-hydroxyphenyl)methoxy]propyl}phenyl)butyl]-N-methyloxalamide

[0617] Step 1:

[0618] 4-Hydroxybenzaldehyde (2.00 g) and imidazole (2.79 g) were dissolved in DMF (20.0 mL). TIPSCl (5.96 mL) was added and the resulting mixture was stirred at 60 °C for 2 d.

[0619] Monitoring by TLC (PE / EtOAc=95:5) and LC / MS showed complete conversion.

[0620] The reaction mixture was diluted with water (100 mL) and extracted with MTBE (3×40 mL). The combined organic layers were washed with 1N NaOH (30 mL) and brine (20 mL), dried over Na2SO4 and concentrated under vacuum. The residue was purified by SiO2 column chromatography (PE / EtOAc=95:5).

[0621] Yield: 3.94 g (86%), light yellow oil

[0622] Step 2:

[0623] 4-{[Tri(propan-2-yl)silyl]oxy}benzaldehyde (3.94 g) was dissolved in EtOH (30.0 mL) and cooled to 0° C. NaBH4 (535 mg) was added and the resulting mixture was stirred at 0° C. for 30 min and then at room temperature for 18 h.

[0624] Monitoring by TLC (PE / EtOAc=8:2) and LC / MS showed the product.

[0625] The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 and concentrated under vacuum. The residue was purified by SiO 2 column chromatography (PE / EtOAc=8:2).

[0626] Step 3:

[0627] (4-{[tri(propane-2-yl)silyl]oxy}phenyl)methanol (300 mg) was dissolved in dry THF (5.00 mL). NaH (60% in mineral oil, 64.2 mg) was added and the mixture was stirred at room temperature for 15 minutes. Allyl bromide (231 μL) was then added and the resulting mixture was stirred at room temperature for 2.5 h. Complete conversion was shown by LC / MS operation.

[0628] The reaction mixture was poured into water (30 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated under vacuum. The residue was used as such for further transformations.

[0629] Yield: 372 mg (crude product), yellow oil

[0630] Step 4:

[0631] {4-[(prop-2-en-1-yloxy)methyl]phenoxy}tri(prop-2-yl)silane (356 mg) was placed in a 10 mL flask under argon atmosphere and cooled to 0° C. 9-BBN (0.5 M in THF, 3.33 mL) was then added dropwise and the resulting mixture was stirred at 0° C. for 30 minutes and then at room temperature for 2 h.

[0632] Then add a solution of Na2CO3 (147 mg) in water (3.00 mL) and continue stirring at room temperature for 30 minutes. Then add N'-[4-(2-iodophenyl)butyl]-N-methylethylenediamine (BB-2, 100 mg) and PdCl2(PPh3)2 (9.7 mg), and heat the mixture to 50°C for 2 h. The product is shown by LC / MS operation. The reaction mixture is cooled to room temperature, diluted with water (20 mL) and separated. The aqueous layer is extracted with EtOAc (15 mL). The combined organic layers are washed with brine (10 mL), dried with Na2SO4 and concentrated under vacuum. The residue is passed through a SiO2 short column (PE / EtOAc=1:1). The crude product is then still used as is for further conversion.

[0633] Yield: 248 mg (crude product), yellow oil

[0634] Step 5:

[0635] N-methyl-N'-[4-(2-[3-[(4-{[tri(propan-2-yl)silyl]oxy}phenyl)methoxy]propyl}phenyl)butyl]ethanediamide (154 mg, crude IK-0357 / 20) was dissolved in THF (5.00 mL). TBAF.3H2O (131 mg) was added and the resulting mixture was stirred at room temperature for 30 minutes. Monitoring by LC / MS showed complete conversion.

[0636] The reaction mixture was poured into water (40 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 and concentrated under vacuum. The residue was purified by preparative TLC (CH 2 Cl 2 / MeOH=95:5).

[0637] Yield: 76 mg (68%) white solid.

[0638] Table 1: Calculated accurate masses of compounds 14 to 32

[0639]

[0640] Example 2: Efficacy of Compound 1 in the Laser-Induced Rat Choroidal Neovascularization Model Assessed by Measuring Vascular Leakage Using Fluorescent Angiography

[0641] The laser-induced rat CNV model is a widely used model to demonstrate the therapeutic efficacy of drugs for the treatment of several ocular diseases characterized by angiogenesis and eye inflammation, such as wet age-related macular degeneration (AMD). In this model, focused laser burns in the Bruch's membrane layer lead to destruction and local damage to the membrane, as well as subsequent inflammation and new blood vessel growth. These newly formed blood vessels are usually leaky. This leakage is measured by extravasation of a fluorescent dye (fluorescein) at the back of the eye and is a recognized marker of vascular leakage, which is proportional to the amount of newly grown blood vessels. This method is also a prior art method in human clinical practice.

[0642] All standard operating procedures and protocols described in this study plan have been reviewed by the Ethics Committee. All animals were treated in accordance with Directive 2010 / 63 / UE of the European Convention for the protection of vertebrate animals used for experimental and other scientific purposes and in accordance with the Association for Research in Vision and Ophthalmology (ARVO) statement for the use of animals in ophthalmic vision research.

[0643] Animals: Brown Norway rats were 8 to 10 weeks old on the day of induction.

[0644] Induction of neovascularization: Animals were anesthetized by intramuscular injection of a mixture of xylazine and ketamine. Prior to treatment, the pupil of the right eye was dilated by instillation of one drop of 0.5% tropicamide. Six burns were produced in the right eye of the anesthetized animals by applying 170 mW to 180 mW of 532 nm laser (Viridis laser, Quantel, France) for 0.1 sec at a 75 μm spot around the optic nerve between the major retinal vascular branches. The generation of bubbles during laser application confirmed the rupture of Bruch's membrane.

[0645] Treatment: For the vehicle control group on day 0, just after induction of neovascularization, the vehicle (5 μL) was injected into the vitreous of the right eye using a 30-G needle mounted on a 100 μL Hamilton syringe under an operating microscope. Administration has been performed on anesthetized animals (same anesthesia as for neovascularization induction). In the first treatment group, compound 1 (100 μL / 100 g) having a structure shown in formula (VI) was administered intraperitoneally once a day from day 0 (3 hours ± 15 minutes before induction) to day 23. In another treatment group, compound 1 was orally administered twice a day by gavage (1 mL / 100 g) from day 0 (3 h ± 15 minutes before induction) to day 22 (q7h ± 30 minutes).

[0646] Fluorescein angiography: Fluorescein angiography was performed in the laser-irradiated right eye on days 14 and 21 using the Heidelberg retinal angiography (HRA). After anesthesia (see above), 250 μL / 100 g body weight of 10% sodium fluorescein was injected subcutaneously, and fluorescent images were recorded 10 minutes after the injection of the dye. For the evaluation of fluorescein angiography, leakage of fluorescein was assessed in the angiograms by two independent investigators masked to the study group and scored as follows: score 0: no leakage; score 1: slight staining; score 2: moderate staining; score 3: marked staining.

[0647] Termination of life: At the end of the study on day 23, all animals were anesthetized (see above) and then euthanized using an intracardiac overdose of pentobarbital. This method is one of the recommended methods by European authorities.

[0648] Statistical analysis: Statistical analysis was performed using Prism software. Kruskal-Wallis analysis has been performed and Dunett's multiple comparison test was used to evaluate drug effects; each treatment group was compared with the vehicle group at each time point. p values ​​below 0.05 were considered significant.

[0649] The results are as follows Figure 1 shown.

[0650] Example 3 Distribution of Compound 2 in different compartments of the rabbit eye after oral, topical or intravitreal administration

[0651] This example shows that the highest ocular exposure of Compound 02 is achieved in the posterior eye following intravitreal injection.

[0652] Materials and methods

[0653] Study design: In order to gain a deeper understanding of the distribution behavior of synthetic 17,18-EEQ agonists, ocular pharmacokinetic studies were performed in dyed HY79b rabbits. Briefly, Tables 2 to 4 show that 15 male rabbits of each administration route were anesthetized by intramuscular injection of a mixed solution of xylazine and ketamine at the sampling time point. Blood was collected by cardiac puncture in a K3EDTA tube and centrifuged at 2000g for 10 minutes at 4°C. About 3mL of plasma was sampled, placed in a plastic tube, quickly frozen in liquid nitrogen and stored at -80°C until assayed. The animals were then euthanized by intracardiac injection of an overdose of pentobarbital. This method is one of the euthanasia methods recommended by European authorities (French Decree No. 2013-118, dated February 1, 2013, issuing the European Directive 2010 / 63 / UE. J.Offic.Rp.Fr.2013; Chapter 24 of Chapter 130). Immediately after euthanasia, samples were taken from both eyes quickly and carefully, placed in plastic tubes, weighed, quickly frozen in liquid nitrogen and stored at -80°C until assayed. The content of compound 02 was determined in eye samples and plasma according to the established RRLCMS / MS method. The results are listed in Tables 5 to 7 and are expressed as the average values ​​of different pharmacokinetic parameters. Chromatogram integration was performed using MassHunter software. The software calculates apparent Cmax and Tmax, T1 / 2, AUC1-48h. Concentrations are expressed in ng / g or ng / mL for tissue compartments / eye compartments.

[0654] result

[0655] After oral administration, Compound 02 was below the detection limit (0.1 ng / 10 μl injection) in aqueous humor samples (except one of 15 animals) and retina (except two of 15 animals) samples. However, oral administration of Compound 2 reached effective dose levels (246 ng / g) and considerable plasma levels (1213 ng / mL, 1 h after administration) 1 h after administration of 2 mg / kg (0.2 mg / mL) in choroidal tissue. Corresponding to the maximum level, considerable exposure (AUC 1-48小时 (ng×h / mL): 1387 and 6331).

[0656] For topical administration, the formulation of Compound 02 was found to be very well tolerated macroscopically as examined by ophthalmoscopy. Table 6 shows that, in addition to generally very low levels, the highest dose levels were observed in the aqueous humor (88 ng / mL 1 h after administration), followed by the choroid (79 ng / g 1 h after administration). Only low levels were reached in both the retina and plasma (24 ng / g 1 h after administration and 31 ng / mL 0.5 h after administration). After topical administration, the highest dose levels were observed in all tested ocular tissues (AUC 1-48小时 (ng×h / mL): 324 in aqueous humor, 117 in choroid, and 21 in retina) and AUC in plasma (262 ng×h / mL) 1-48小时 The value is low.

[0657] Also for intravitreal injections, the formulation of Compound 02 was found to be very well tolerated macroscopically as checked by eye examination with a slit lamp. Table 7 shows that considerable levels of Compound 02 were found in all tissues of the eye and plasma. The highest levels were found in the choroid (14957 ng / g at 1 h after injection), followed by the retina and vitreous (10052 ng / g and 6647 ng / mL at 1 h after injection). With the exception of plasma (287 ng×h / mL), exposures >55000 (AUC 1-48小时 (ng×h / mL): vitreous: 55401, choroid: 63283, retina: 79866).

[0658] In conclusion, the highest ocular exposure of Compound 02 in the posterior eye was achieved after intravitreal injection compared to oral and topical administration.

[0659] Table 2 Study design for oral administration

[0660]

[0661] Table 3 Study design for topical administration

[0662]

[0663] Table 4 Study design for intravitreal administration

[0664]

[0665] Table 5 Pharmacokinetic parameters in ocular tissues and plasma after oral administration

[0666]

[0667] Cmax = the highest mean value measured (ng / g or mL tissue)

[0668] Tmax = time point when the highest average value is measured (hours)

[0669] AUC time 1 to time 2 = area under the curve (ng / g or mL tissue) t1 / 2 = ln(2) / (-a), where a = ln(concentration) slope = f(t)

[0670] t1 / 2=calculated based on Tmax value

[0671] NA = Not applicable, insufficient data available

[0672] Table 6 Pharmacokinetic parameters in ocular tissues and plasma after topical administration

[0673]

[0674] Cmax = the highest mean value measured (ng / g or mL tissue)

[0675] Tmax = time point when the highest average value is measured (hours)

[0676] AUC Time 1 to Time 2 = Area under the curve (ng / g or mL tissue)

[0677] t1 / 2 = ln(2) / (-a), where a = slope of ln(concentration) = f(t)

[0678] t1 / 2=calculated based on Tmax value

[0679] NA = Not applicable, insufficient data available

[0680] Table 7 Pharmacokinetic parameters in ocular tissues and plasma after intravitreal injection

[0681]

[0682] Cmax = the highest mean value measured (ng / g or mL tissue)

[0683] Tmax = time point when the highest average value is measured (hours)

[0684] AUC Time 1 to Time 2 = Area under the curve (ng / g or mL tissue)

[0685] t1 / 2 = ln(2) / (-a), where a = slope of ln(concentration) = f(t)

[0686] t1 / 2 = calculated based on Tmax value

[0687] NA = Not applicable, insufficient data available

[0688] Example 4: Anti-inflammatory effects of metabolically stable analogs of 17, 18-EEQ (Compound 02) on HL-1 cardiomyocytes

[0689] Materials and methods

[0690] In order to study the anti-inflammatory potential of the compounds as part of the present invention in vitro, a cardiomyocyte cell line (mouse-derived immortalized cardiomyocytes, HL-1 cells) was used. The cells were treated with vehicle (0.01% ethanol) or different concentrations of the test compounds (compound 02: c E =10 nM, 100 nM or 1 μM). At the same time, cells were challenged with 1 μg / mL lipopolysaccharide (LPS). After 24 h of incubation, cells were processed to measure viability ( Figure 2 ) and the release of the pro-inflammatory cytokine TNFα ( Figure 3 ).

[0691] result

[0692] The results are as follows Figure 2 and Figure 3 As shown. Inflammatory stimulation LPS leads to a significant decrease in cell viability. This cytotoxic effect is reversed by compound 02 in a dose-dependent manner, as shown Figure 2 In addition, LPS incubation significantly induced the production of the pro-inflammatory cytokine TNFα ( Figure 3 Compound 2 alone had no effect on TNFα production. LPS-induced TNFα release from HL-1 cells was significantly and dose-dependently reduced by compound 2 ( Figure 3 ).

[0693] Example 5: Inhibitory effects of metabolically stable analogs of 17,18-EEQ (Compound 02) on renal and cardiac inflammation in a rat model of severe hypertension and end-organ damage

[0694] Materials and methods

[0695] The purpose of this study will be to evaluate and compare the effects of continuous oral treatment of a metabolically stable analog of 17,18-EEQ (Compound 02) or vehicle (isotonic saline) in male double transgenic rats (dTGR) on physiological parameters, clinical chemistry and end-organ damage. Untreated Sprague-Dawley rats (SD) with the same genetic background were used as controls. Double transgenic rats overexpressing human renin and angiotensinogen genes develop severe hypertension and are a model of Ang-II-induced end-organ damage with cardiac hypertrophy and renal failure. In addition, the dTGR model is characterized by severe atrial hypertension, cardiac hypertrophy and renal failure with significant fibrosis and inflammation.

[0696] Before starting the experiment, animals were randomly assigned to compound treatment groups or vehicle treatment groups. Before the experiment, for all treatment groups and SD control animals, the food was changed to ω-6-rich food. Animals treated with dTGR compounds were administered 1.33 mg / kg twice a day by gavage for 21 days. Compound 02 was prepared in 61.6ppm Na2CO3 and 0.9% NaCl ready-to-use solutions for administration, while dTGR animals were administered twice a day with 0.9% NaCl ready-to-use solutions as vehicle controls. The dosage was 5.0 mL / kg body weight. After 21 days of treatment, at 7 weeks of age, animals were killed by heart removal under pentobarbital anesthesia (20 mg / kg body weight, heparin 500 I. / E.mL) and blood and organs were harvested. The heart and kidneys were removed and weighed. The heart and kidneys were separated and quickly frozen in liquid nitrogen for molecular biological analysis, frozen in -40°C isopentane and stored at -80°C for cryosectioning. Frozen kidneys and hearts embedded in TissueTek were cryosectioned to 5 μm thickness. The cryosections were fixed with ice-cold acetone, washed with PBS and blocked with normal donkey serum at room temperature. The sections were then incubated overnight with the primary monoclonal antibody mouse anti-ED1 (cD68) (AbD serotec) in a dark and humid chamber at 4 ° C. After washing with PSB, the slides were incubated with the secondary antibody donkey anti-mouse (Cy3) in a dark and humid chamber at room temperature for 90 minutes, and then the slides were mounted using Vectashield. The samples were analyzed using a Zeiss Axioplan-2 imaging microscope with a digital image processing program AxioVision 4.8. All evaluations were performed by a single-blind investigator. Analysis of infiltrating macrophages was performed by counting ED1-positive cells in sections of heart (ventricle) and kidney tissue (outer medulla and cortex). The data are expressed as the sum of 20 randomly selected visual field intervals, with no overlapping fields of view for each section.

[0697] Statistical analysis was performed using software R for immunohistochemistry. Since the data were nonparametric (counts), the Kruskall-Wallis test was used for overall group differences, while paired U tests with FDR correction were used to analyze differences between groups. P values ​​below 0.05 were considered significant.

[0698] result

[0699] Figure 4 and Figure 5 The stable analogs of 17,18-EEQ (Compound 02) showed the potential to modulate inflammation in dTGR animals. Figure 4 ) and kidneys( Figure 5) was measured, with macrophage infiltration by ED1 staining as an inflammatory marker. The values ​​shown are median values ​​with interquartile ranges. Count values ​​were pooled in 20 visual field intervals. The results showed that dTGR animals had significantly higher amounts of infiltrated macrophages ( Figure 4 and Figure 5 ). However, Compound 02 treatment resulted in a significant reduction in macrophage infiltration (ED1 positive cells) in dTGR animals compared to vehicle treated dTGR.

Claims

1. Compounds of formula (VI): or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for treating a condition associated with neovascularization and / or inflammation, reducing the risk of developing a condition associated with neovascularization and / or inflammation, or preventing a condition associated with neovascularization and / or inflammation, The disorder is selected from age-related macular degeneration (AMD), vasculitis, nephritis, diabetic angiopathy, diabetic nephropathy, diabetic retinopathy, ischemia-reperfusion injury, renal fibrosis, tumor necrosis factor receptor-associated periodic syndrome (TRAPS) and atherosclerosis.

2. The method according to claim 1, wherein the compound is administered orally, topically, subcutaneously, intramuscularly, intravenously, intranasally or intraocularly.

3. The use according to claim 1, wherein the dosage form of the compound is selected from sprays, aerosols, foams, inhalants, powders, tablets, capsules, teas, syrups, granules, ointments, creams, gels, suppositories, lozenges, liposome compositions and injections.

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